Document ID: EPA-HQ-OPP-2004-0305-0033
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-22T05:00Z

Agency
Response
to
Arch
Chemical's
Phase
I
Comments
Regarding
PHMB
Preliminary
Risk
Assessment
November
22,
2005
Case
3122
PC
Code
111801
Office
of
Pesticide
Programs
Antimicrobials
Division
U.
S.
Environmental
Protection
Agency
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
Page
2
of
33
On
July
15,
2004,
the
PHMB
technical
registrants
received
the
preliminary
risk
assessment
(
PRA)
for
poly(
hexamethylenebiguanide)
hydrochloride
(
PHMB)
from
the
Antimicrobials
Division
for
Phase
I
of
the
reregistration
process.
On
August
13,
2004,
Arch
Chemicals,
Inc.
made
comments
on
the
PHMB
PRA.
The
Antimicrobials
Division
has
prepared
this
document
to
respond
to
all
the
comments
from
Arch
Chemicals.

The
comments
and
responses
to
the
comments
are
listed
below:

Arch's
Comments:
PHMB
is
regulated
by
the
EPA
only
under
FIFRA,
as
all
registered
uses
are
classified
as
nonfood
uses.
We
believe
that
the
extension
of
dietary
assessments
to
be
inappropriate
by
FDA
under
FFDCA
Section
409
when
there
are
no
food
uses
regulated
by
EPA
under
FFDCA
Section
408.
The
use
of
dietary
risk
assessments
and
the
associated
standards
under
Section
408,
as
required
for
food
uses
regulated
by
EPA
under
the
1996
Food
Quality
Protection
Act
amendments
to
FFDCA,
are
an
unreasonable
extension
of
the
Agency's
authority
under
FIFRA
and
are
an
ad
hoc
imposition
of
additional
requirements.
We
believe
that
the
extent
of
the
Agency's
authority
under
FIFRA
2(
bb)
is
limited
to
the
type
of
indirect
incidental
oral
ingestion
which
is
pertinent
to
product
regulated
by
EPA
as
nonfood
pesticides
under
FIFRA.

EPA
Response:
Based
on
a
review
of
product
labels
containing
PHMB,
four
uses,
2
disinfectants,
latex
adhesives,
and
tunnel
pasteurization,
have
been
identified
as
having
the
potential
to
cause
indirect
dietary
exposure
due
to
indirect
food
contact.
The
Agency's
reasoning
and
authority
for
conducting
the
dietary
risk
assessment
is
further
explained
later
in
this
document.

Arch's
Comments:
1.0
Executive
summary
Paragraph
1
refers
to
PHMB
use
as
a
"
preservative
for
flowers".
As
we
understand
this
use,
the
purpose
of
the
PHMB
in
this
case
is
to
prevent
microbial
growth
in
the
cut
flower
water,
hence
keep
the
water
clean
and
odor
free.
To
call
this
a
preservative
for
flowers
(
hence
associated
uses
considered
for
outdoor
use)
is
false
and
should
be
corrected.

EPA
Response:
"
Preservative
for
flowers"
has
been
changed
to
"
preservative
for
cut
flowers"
throughout
the
document.

Arch's
Comments:
2.1
Chemical
Identification
Vantocil
IB
is
registered
as
a
material
preservative
only
and
Vantocil
P
is
registered
as
a
manufacturing
use
product
only.
Also,
the
RED
document
says
in
multiple
places,
that
the
use
of
PHMB
in
swimming
pools
is
as
a
fungicide
and/
or
algicide,
and
not
that
it
is
a
sanitizer
against
bacteria.

EPA
Response:
This
has
been
corrected
to
list
PHMB
as
a
sanitizer
in
swimming
pools
in
the
document.
Page
3
of
33
Arch's
Comments:
3.0
Hazard
Arch's
predecessor
company,
Avecia,
responded
to
EPA's
first
and
second
HIARC
report
on
PHMB
via
letters
dated
October
21,
2002
and
March
18,
2004
(
copies
attached).
Both
of
these
letters
point
out
EPA's
erroneous
use
of
old,
outdated
and
unacceptable
studies
in
quoting
acute
toxicity
values
for
PHMB.
There
are
several
acceptable
or
tentatively
acceptable
valid
acute
toxicity
studies
on
PHMB
that
should
be
correctly
referred
to
regarding
PHMB's
acute
toxicity
effects,
particularly
with
regard
to
skin
and
eye
irritation.
These
are
outlined
in
the
acute
toxicity
data
table
attached
to
this
letter.

EPA
Response:
Document
currently
reflects
only
acceptable
studies.

Arch's
Comments:
The
rabbit
developmental
toxicity
study
summary
(
MRID
42865901)
refers
to
"
increased
mortality"
at
40mg/
kg.
In
fact,
only
one
death
actually
occurred
at
40mg/
kg/
day,
and
this
was
most
likely
as
a
consequence
of
mal­
dosing.
One
other
animal
was
sacrificed
for
humane
reasons
because
of
poor
condition;
the
remaining
four
were
killed
because
they
aborted
and,
without
fetuses
for
evaluation,
no
longer
served
a
purpose
on
the
study.
The
statement
regarding
"
increased
mortality"
needs
to
be
revised
to
include
those
comments
or
removed.

Summarizing
the
rat
developmental
toxicity
study
MRID
65131),
comment
is
made
to
effects
seen
at
a
dose
of
100mg/
kg/
day.
Whilst
the
actual
dose
given
was
2000ppm,
this
equates
to
172.4mg/
kg/
day,
and
not
100mg/
kg/
day
as
quoted.
In
addition,
extra
ribs
in
the
fetus
are
also
mentioned.
These
have
been
shown
to
be
transitory
and
associated
with
non­
specific
maternal
toxicity
and
reference
to
such
should
be
made.

EPA
Response:
The
document
has
further
characterized
the
effects
observed
and
explained
that
there
were
no
increased
susceptibility
of
offspring
to
the
developmental
or
reproductive
effects
of
PHMB.

Arch's
Comments:
Reference
is
made
to
a
developmental
toxicity
study
in
mice
(
MRID
93191029).
This
was
considered
unacceptable
by
the
agency
at
early
stages
of
re­
registration
(
US
EPA
3/
9/
95
Reregistration
Status
Report
Card
for
PHMB),
but
no
repeat
study
was
required
because
both
the
rat
and
rabbit
developmental
toxicity
studies
were
considered
acceptable.
Consequently,
any
reference
to
the
mouse
developmental
study
should
be
deleted.

EPA
Response:
Study
is
no
longer
in
the
document.

Arch's
Comments:
The
high
dose
for
the
dog
study
is
given
as
75mg/
kg/
day.
The
actual
dose
given
in
the
diet
to
the
animals
was
3000ppm.
However,
the
test
facility
calculates
the
mean
dose
value
for
this
3000ppm
dose
to
be
91mg/
kg,
and
not
the
75mg/
kg
as
given.
Page
4
of
33
EPA
Response:
Dose
was
corrected
in
document.

Arch's
Comments:
Comments
on
the
carcinogenicity
studies
in
rats
and
mice
refer
to
significant
trends
seen
in
the
incidence
of
vascular
tumors.
Although
a
significant
increase
in
vascular
tumors
was
seen
at
the
high
dose
of
4000ppm
,
that
dose
was
in
exceedance
of
the
MTD
for
studies
of
this
type
and,
hence,
is
not
relevant
for
an
assessment
of
the
likely
carcinogenic
risk,
as
confirmed
by
EPA
in
the
7/
16/
2003
CARC
Report.
Any
increase
in
vascular
tumors
observed
at
the
low­
and
middose
were
well
within
the
historical
control
range
for
the
C57
mouse
used
in
the
study.

EPA
Response:
The
Committee
found
that
the
dose
was
adequate
not
excessive.

Arch's
Comments:
Regarding
the
comments
on
the
dermal
carcinogenicity
study,
it
should
be
noted
that
the
mid
dose
was
6.0mg
(
2%
PHMB
in
ethanol)
and
not
the
20%
in
ethanol
as
indicated.
Reference
is
also
made
on
"
increasing
trends
for
liver
angiosarcomas".
Contention
of
this
evaluation
is
given
in
more
detail
in
comments
made
on
the
Toxicology
Disciplinary
Chapter.
Furthermore,
the
CARC
itself
concluded
that
these
tumors
should
be
considered
equivocal,
hence
we
would
contest
that
it
is
inappropriate
to
mention
them
in
this
summary.

EPA
Response:
This
error
has
been
corrected,
and
the
document
now
shows
6.0
mg
is
equivalent
to
2%
PHMB
in
ethanol.

Arch's
Comments:
Avecia's
two
responses
to
the
HIARC
reports,
mentioned
above,
thoroughly
reviews
the
PHMB
toxicology
endpoint
selection
for
PHMB
risk
assessment.
We
wish
to
reiterate
here
that
the
PHMB
dermal
absorption
factor
is
estimated
to
be
less
than
1%
(
MRID
45710806)
and
that
it
is
incorrect
to
assume
a
100%
dermal
absorption
factor.
Further
discussion
on
the
HIARC
is
provided
below.

EPA
Response:
The
current
document
uses
dermal
studies,
and,
therefore,
no
dermal
absorption
factor
is
necessary.
This
issue
was
also
previously
addressed
in
the
response
to
comment
document
for
the
HIARC
Report
(
ISSUE
1,
page
2
of
6,
September
24,
2004).

Arch's
Comments:
Water
Exposure
and
risk
It
is
our
understanding
that
PHMB
is
used
to
preserve
water
for
cut
flowers
and
not
as
part
of
liquid
plant
food.
Consequently,
this
is
an
indoor
and
not
an
outdoor
use,
and
the
appropriate
corrections
should
be
made.

EPA
Response:
This
use
was
always
considered
as
such,
and
the
document
does
indicate
this.
Page
5
of
33
Arch's
Comments:
Aggregate
exposures
and
risk
Please
refer
to
comments
on
the
dietary
risk
assessment.
In
summary,
a
dietary
risk
assessment
is
not
required
and
it
is,
therefore,
incorrect
to
include
dietary
assessment
in
the
aggregate
risk
assessment.

EPA
Response:
Addressed
below.

Arch's
Comments:
Incidence
Report
Assessments
Comment
is
made
that
most
of
the
incidences
were
related
to
irritation
and/
or
allergic
type
reactions.
Whilst
there
is
a
possibility
of
PHMB
to
cause
irritation
type
reactions,
without
following
up
on
all
the
reported
cases
it
is
supposition
to
assume
that
the
cases
of
allergic
type
reactions
are
a
true
finding,
and
not
just
further
cases
of
irritancy.
As
such,
we
would
contest
that
the
summary
review
should
refer
to
factual
information,
and
not
supposition.
Relevant
data
show
that
PHMB
is
not
a
dermal
sensitizer
in
humans
(
Avecia's
letter
of
March
18,
2004).

EPA
Response:
As
was
written
in
the
Response
to
Comments
document
concerning
the
HIARC
Report:
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.
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.
Page
6
of
33
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)
were
applied
to
each
subject.
No
adverse
effects
occurred
in
any
of
the
subjects.
Therefore,
the
induction
phase
indicates
that
these
individuals
have
not
been
induced
by
the
1.0
%
v/
v
of
PHMB
solution.
After
a
10­
day
resting
period,
in
the
induction
phase,
the
researcher
continued
to
challenge
these
subjects
at
1.0%
and
0.2%
applied
to
new
skin
on
the
opposite
arm
for
48
hours.
No
adverse
effects
or
unanticipated
reactions
were
observed
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
had
any
signs
of
irritation
in
the
induction
phase
of
the
study.
Therefore,
given
the
limited
number
of
individuals
involved
in
the
study
and
inadequate
dosing
in
the
induction
phase,
the
Agency
considers
the
Kaidbey
(
1995)
study
inadequate
to
assess
the
dermal
sensitization
potential
of
PHMB.

Arch's
Comments:
3.1
Hazard
Profile
Acute
toxicity
Please
refer
to
the
above
comments
on
the
relevant
acute
toxicity
studies
for
PHMB.
Further,
the
Agency
has
determined
that
none
of
the
20%
PHMB
products
is
Toxicity
Category
I,
as
evidenced
by
the
label
wording
on
registered
products.

EPA
Response:
Table
3
has
been
updated
to
reflect
the
correct
Toxicity
Categories.

Arch's
Comments:
Developmental
Toxicity
The
dose
level
for
the
rats
are
given
as
50
and
100mg/
kg,
whereas
the
actual
calculated
equivalent
doses
for
the
1000
or
2000ppm
administered
should
be
86.2
or
172.4mg/
kg/
day.
In
addition,
this
refers
to
the
PHMB
a.
i.
itself,
and
not
the
20%
a.
i.
as
indicated
in
the
text.
The
appropriate
corrections
should
be
made.

EPA
Response:
Doses
have
been
corrected
in
the
document.

Arch's
Comments:
Reiterating
earlier
comments
made
on
the
rabbit
developmental
study
 
reference
is
made
to
"
increased
mortality"
at
40mg/
kg.
In
fact,
only
one
death
actually
occurred
at
40mg/
kg/
day,
and
this
was
most
likely
as
a
consequence
of
mal­
dosing.
One
other
animal
was
sacrificed
for
Page
7
of
33
humane
reasons
because
of
poor
condition;
the
remaining
four
were
killed
because
they
aborted
and,
without
fetuses
for
evaluation,
no
longer
served
a
purpose
on
the
study.
The
statements
need
to
be
corrected
or
removed.

EPA
Response:
Although
the
relationship
of
the
effect
to
test
article
has
been
called
into
question,
there
was
an
increased
fetal
and
litter
incidence
of
unossified
and/
or
fused
sternebrae
in
offspring.
There
is
sufficient
uncertainty
with
regard
to
what
caused
this
effect
for
the
Agency
to
stay
with
the
20
mg/
kg/
day
value.

Arch's
Comments:
Reference
is
made
to
a
developmental
toxicity
study
in
mice
(
MRID
93191029).
This
was
considered
unacceptable
by
the
agency
at
early
stages
of
re­
registration,
but
no
repeat
study
was
required
because
both
the
rat
and
rabbit
developmental
toxicity
studies
were
considered
acceptable.
Consequently,
it
would
be
correct
to
delete
all
reference
to
this
study.

EPA
Response:
Study
was
removed
from
the
document.

Arch's
Comments:
Reproductive
Toxicity
Note
that
the
dose
level
of
2000ppm
refers
to
the
PHMB
a.
i.
itself,
and
not
the
20.2%
technical
as
is
inferred.

EPA
Response:
Dose
levels
were
corrected
and
are
currently
stated
as
mg
active
ingredient/
kg/
day.

Arch's
Comments:
Carcinogenicity
Minor
spelling
error
(
paragraph
2,
line
2)
suggest
"
sited"
should
read
"
sites"

EPA
Response:
Current
document
reflects
this
change.

Arch's
Comments:
Table
3
As
commented
previously,
reference
is
made
to
both
the
acute
eye
and
dermal
irritation
as
being
Toxicity
Category
I.
However,
as
the
Acute
Toxicity
Data
Summary
submitted
along
with
this
letter
shows,
a
number
of
other
acute
skin
and
eye
irritation
studies
on
various
grades
of
PHMB
have
been
submitted
to
the
Agency.
What
these
show
is
that
for
PHMB
20%
technical
active,
the
skin
irritation
should
be
toxicity
category
III,
and
the
eye
irritation
toxicity
category
II.
As
such,
we
would
ask
that
these
references
be
amended
in
the
document.
The
Agency
previously
determined
that
the
cited
studies
for
eye
irritation
and
dermal
irritation
were
unacceptable
and
required
that
new
studies
be
conducted.
(
See
EPA,
6/
15/
1978,
Toxicity
Branch
review
of
all
tox
studies
submitted
under
10182­
EUP­
11).
The
studies
accepted
by
EPA
are
MRID
125846
for
eye
irritation
and
71357
for
dermal
irritation.
Based
on
EPA
review
during
FIFRA
88
Page
8
of
33
reregistration,
the
citation
for
acute
dermal
toxicity
was
rejected;
the
correct
study
citation
is
MRID
30330.

EPA
Response:
Table
3
has
been
updated
to
accurately
reflect
the
appropriate
studies.

Arch's
Comments:
Table
4
870.3250
90­
day
dermal
toxicity:
the
table
comments
that
the
study
is
satisfied
by
the
90­
day
oral
and
dermal
absorption
factor.
The
HIARC
recommend
that
the
NOAEL
of
150mg/
kg
from
the
80­
week
skin
painting
study
be
used
as
the
dose
endpoint
for
dermal
toxicity.
Correct
the
table
to
be
consistent
with
the
HIARC
decision.

EPA
Response:
Table
4
has
been
updated
to
accurately
reflect
the
recommendation
of
the
HIARC.

Arch's
Comments:
870.3200a
prenatal
development
in
rodents:
as
indicated
previously,
the
NOAELs
given
are
incorrect.
The
dose
level
for
the
rats
are
given
as
10,
50
and
100mg/
kg,
whereas
the
actual
calculated
equivalent
doses
for
the
200,
1000
or
2000ppm
administered
should
be
17.2,
86.2
or
172.4mg/
kg/
day.
Furthermore,
we
dispute
the
Developmental
NOAEL,
based
on
the
increase
incidence
of
extra
ribs
in
the
fetus.
Although
there
was
an
increased
incidence
of
extra
ribs,
subsequent
to
the
study
being
conducted
these
have
been
shown
to
be
transitory
in
the
Alpk:
APfSD
rat
and
associated
with
non­
specific
maternal
toxicity
(
Wickramaratne,
Jour
Appl
Tox,
8(
2),
1988).
Consequently,
these
should
not
be
considered
as
a
developmental
toxicity
effect,
but
as
a
consequence
of
maternal
toxicity.

EPA
Response:
Doses
corrected
in
the
prenatal
developmental
study
in
rodents
(
870.3700a).
The
Agency
acknowledges
the
comment
regarding
the
significance
of
increased
incidence
of
extra
ribs.
It
is
understood
that
this
effect
is
considered
transitory
and
is
a
non­
specific
effect.
Therefore,
the
Developmental
NOAEL
will
be
re­
stated
as
172.4
mg/
kg/
day
and
the
Developmental
LOAEL
will
be
stated
as
>
172.4
mg/
kg/
day.

Arch's
Comments:
Therefore,
we
suggest
that
the
maternal
NOAEL
is
17.2
mg/
kg/
day,
and
the
LOAEL
86.2mg/
kg/
day,
and
that
the
developmental
NOAEL
is
172.4mg/
kg/
day.
Please
correct
the
table.

EPA
Response:
The
table
reflects
these
maternal
NOAEL
and
LOAEL
and
a
developmental
NOAEL
of
86.2
mg/
kg/
day.

Arch's
Comments:
870.3800
reproduction
and
fertility
effects:
the
offspring
NOAEL
is
given
as
2000mg/
kg/
day,
whereas
it
should
be
2000ppm.
Page
9
of
33
EPA
Response:
This
dose
was
corrected
in
the
document.

Arch's
Comments:
870.4100b
chronic
toxicity
dogs:
the
mean
dose
values
for
the
300,
1500
and
3000ppm
dose
level
as
calculated
by
the
test
facility
are
given
as
9,
46
and
91mg/
kg/
day
for
males
and
9,
45
and
91mg/
kg/
day
for
females,
respectively.
Consequently,
the
LOAEL
should
be
91mg/
kg/
day,
and
the
NOAEL
45­
46mg/
kg/
day.

EPA
Response:
The
LOAEL
and
NOAEL
have
been
corrected
in
the
document.

Arch's
Comments:
870.4200:
the
summary
as
given
is
not
consistent
with
the
text
as
given
in
section
3.1
(
Hazard
Profile).
The
table
needs
to
be
corrected.

EPA
Response:
Table
4
has
been
updated
to
be
consistent
with
the
text.

Arch's
Comments:
870.4300
carcinogenicity
in
mice:
the
mean
dose
levels
given
for
the
dermal
study
(
15,
150
and
750mg/
kg)
refer
to
PHMB
a.
i.
and
not
the
20%
solution
as
indicated.
In
addition,
regarding
the
comments
about
evidence
of
carcinogenicity
observed,
we
suggest
that
this
does
not
reflect
the
summary
as
given
in
section
3.1
(
Hazard
Profile)
or
the
conclusions
of
the
CARC.
In
both
cases,
any
effects
seen
were
only
observed
at
dose
levels
above
the
MTD,
and
in
the
case
of
the
dermal
study
were
only
considered
equivocal.
Consequently,
the
summary
conclusion
of
"
evidence
of
carcinogenicity
observed"
is
not
appropriate
and
is
inconsistent
with
the
CARC
conclusion.

EPA
Response:
The
doses
were
corrected
to
accurately
reflect
mg
of
active
ingredient:
55,
167,
715
mg/
kg/
day
in
males
and
69,
217,
856
mg/
kg/
day
in
females.
The
document
no
longer
states
that
"
evidence
of
carcinogenicity
observed."
It
now
states:
Classification
of
Carcinogenic
Potential.
Based
on
the
weight
of
the
evidence,
the
CARC
concluded,
in
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July
1999),
that
PHMB
is
classified
into
the
category
"
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.
This
classification
is
mainly
due
to
treatment­
related
significant
increase
in
vascular
tumors
in
females
via
the
oral
route
at
an
adequate
dose.

Arch's
Comments:
3.2
FQPA
Considerations
The
provisions
of
FQPA
apply
only
where
there
is
a
food­
use
regulated
by
EPA
under
FFDCA
Section
408.
Since
all
uses
of
PHMB
regulated
by
EPA
are
nonfood,
the
provisions
of
FQPA
do
Page
10
of
33
not
apply.
However,
we
agree
that
there
is
no
evidence
it
would
cause
any
concerns
if
FQPA
were
applicable.

EPA
Response:
As
is
discussed
below,
in
the
section
on
the
Dietary
Assessment,
the
Agency
does
not
believe
that
all
PHMB
uses
are
nonfood
uses.

Arch's
Comments:
3.3
Dose­
response
assessment
Chronic
dietary:
the
study
and
toxicological
effects
makes
reference
to
the
mouse
developmental
study.
As
mentioned
previously,
this
study
was
considered
unacceptable
by
EPA
earlier
in
the
re­
registration
process
and
should
be
removed.
In
addition,
as
also
indicated
previously,
the
LOAEL
for
the
rat
developmental
study
should
be
86.2mg/
kg/
day
and
not
the
50mg/
kg/
day
as
quoted.

EPA
Response:
The
study
has
been
removed
from
the
document.

Arch's
Comments:
The
chronic
and
intermediate
reference
doses
are
based
on
the
NOAEL
for
maternal
toxicity
from
a
rabbit
developmental
toxicity
study.
However,
EPA
guidance
(
Rowlands,
1997)
identifies
that
chronic
reference
doses
are
to
be
set
on
the
basis
of
chronic
studies,
if
available,
and
that
such
chronic
studies
can
be
used
for
the
intermediate
term
reference
dose.
As
such,
the
lowest
NOAEL
for
a
chronic
study
is
36mg/
kg/
day
for
the
dietary
chronic
toxicity
study
in
rats
(
MRID
44059301)
and
should
be
the
basis
for
establishing
an
intermediate
term
and
chronic
oral
reference
dose
for
PHMB.

EPA
Response:
This
comment
was
addressed
in
the
HIARC
response
to
comment
document
of
September
24,
2004
(
ISSUE
2).

Arch's
Comments:
Dermal
exposure:
The
relative
dermal
absorption
rate
is
given
as
100%.
As
submitted
in
MRID
45710806,
we
believe
this
is
not
correct
and
suggest
that
a
factor
of
less
than
1%
is
still
highly
conservative
for
risk
assessment
purposes.
The
reasons
behind
this
(
as
outlined
in
MRID
45710806)
are
given
below:

PHMB
is
a
polymeric
material,
with
an
average
molecular
weight
of
approximately
2650
(
by
size
exclusion
chromatography),
based
on
an
average
of
10­
13
monomer
units
but
containing
up
to
40
monomers.
Polymers
such
as
this
are
not
readily
absorbed
through
the
skin
or
via
the
gastrointestinal
system,
due
to
a
combination
of
high
molecular
weight
and
poor
solubility.
Nor
do
such
polymers
readily
break
down
into
easily
absorbable
fractions.

EPA
Response:
The
current
document
uses
dermal
studies,
and,
therefore,
no
dermal
absorption
factor
is
necessary.
Page
11
of
33
Arch's
Comments:
In
studies
designed
to
evaluate
the
absorption,
distribution,
metabolism
and
excretion
of
radiolabeled
PHMB
following
oral
administration
in
rodents
(
MRID
77926,
86363,
43567001,
43599901),
it
has
been
determined
that
there
is
very
little
absorption
of
PHMB,
with
more
than
93%
excreted
in
the
faeces.
Of
the
limited
amount
not
directly
excreted,
there
is
very
little
actually
absorbed
(
2
to
3%).
What
is
absorbed
tends
to
be
the
lower
molecular
weight
fractions
(
i.
e.,
approximately
MW
1230),
although
absorption
of
those
fractions
still
is
extremely
low.
The
poor
absorption
from
the
digestive
system
following
oral
administration
is
not
unexpected
for
a
polymeric
material
such
as
PHMB.

Studies
of
the
in
vitro
dermal
absorption
of
PHMB
clearly
confirm
that
little
to
no
PHMB
is
absorbed
following
dermal
exposure,
which
is
not
unexpected
for
a
material
such
as
PHMB.
There
are
3
separate
studies
(
MRID
44046301,
44119301,
and
44596001),
each
of
which
followed
appropriate,
scientifically
recognized
and
valid
procedures
that
are
consistent
with
current
guidance
(
OECD
1996
and
2000,
EPA
1999
and
EPA
1992).
These
studies
document
that
absorption
of
radio­
labeled
PHMB
through
human
epidermis
is
essentially
nil.
In
a
comparative
in
vitro
study
using
rat
and
human
epidermis,
absorption
by
rat
skin
was
much
higher
than
by
human
skin
(
MRID
44046301).
While
a
percent
absorption
cannot
be
calculated
on
the
basis
of
the
information
contained
within
MRID
44046301,
the
data
from
that
study
support
essentially
no
absorption
across
human
epidermis
(
not
detectable
after
70
hr,
with
level
of
detection
of
0.1
µ
g/
cm2).
Low
but
detectable
levels
were
found
in
this
study
using
rat
skin.
Those
experimental
results
are
consistent
with
data
reported
in
the
literature
(
EPA
1992)
that
rat
skin
is
3
to
5X
more
permeable
than
is
human
skin.
MRID
44119301
identified
that
there
was
greater
relative
absorption
across
human
epidermis
at
lower
initial
dose
levels
over
the
96
hr
study.
The
highest
percent
absorption
reported
in
that
study
was
0.15
%.
MRID
44596001,
which
reported
on
absorption
across
human
epidermis
at
a
higher
temperature
(
40
°
C)
over
a
24
hr
period,
showed
that
0.007%
of
the
applied
dose
was
absorbed.
Both
the
measured
percentages
in
the
two
studies,
along
with
the
lack
of
any
detectable
levels
in
the
third,
support
that
dermal
absorption
of
PHMB
by
human
skin
is
well
below
1%
of
the
applied
dose.

EPA
Response:
The
current
document
uses
dermal
studies,
and,
therefore,
no
dermal
absorption
factor
is
necessary.

Arch's
Comments:
In
order
to
determine
an
appropriate
dermal
absorption
rate
for
PHMB,
the
following
whole
animal
toxicity
studies
can
be
considered:
 
21
day
dermal
toxicity
study
in
rat
(
MRID
43045901),
systemic
NOAEL
greater
than
200
mg/
kg
bw,
LOAEL
greater
than
200
mg/
kg
(
no
adverse
effects
reported
in
study).
It
should
be
noted
that
higher
doses
could
not
be
used
due
to
the
severe
skin
irritant
effects
of
PHMB.
 
developmental
toxicity
study
in
rat
(
MRID
65131,
42992101),
maternal
NOAEL
10
mg/
kg
bw/
day,
LOAEL
50
mg/
kg
bw/
day
(
decreased
body
weight,
food
consumption)
Page
12
of
33
The
ratio
of
the
oral
LOAEL
to
the
dermal
LOAEL
(
50/>
200)
identifies
that
a
factor
of
25%
or
less
could
be
considered
as
a
dermal
absorption
factor
for
PHMB.
Due
to
the
high
skin
irritancy
associated
with
PHMB,
higher
dermal
application
rates
could
not
be
assessed,
and
the
25%
factor
greatly
overestimates
dermal
absorption.
In
this
case,
it
may
be
more
appropriate
to
use
the
NOAELs
from
the
two
studies,
resulting
in
a
factor
of
5%
or
less,
since
no
NOAEL
was
determined
in
the
dermal
toxicity
study.
Taking
into
account
the
results
of
the
in
vitro
studies
and
the
relation
between
rat
and
human
skin
permeability,
a
factor
of
less
than
1%
dermal
absorption
for
humans
is
highly
conservative
for
risk
assessment
purposes.
This
is
consistent
with
the
in
vitro
results
and
with
the
anticipated
lack
of
absorption
based
on
the
polymeric
character
of
the
compound.

EPA
Response:
The
current
document
uses
dermal
studies,
and,
therefore,
no
dermal
absorption
factor
is
necessary.

Arch's
Comments:
4.1
Summary
of
Registered
Uses
As
mentioned
in
comments
on
section
1.0,
Para
1
refers
to
PHMB
use
as
a
"
preservative
for
flowers".
As
we
understand
it,
the
purpose
of
the
PHMB
is
to
prevent
microbial
growth
in
the
cut
flower
water,
hence
keeping
the
water
clean
and
odor
free.
To
call
this
a
preservative
for
flowers
(
hence
associated
uses
considered
for
outdoor
use)
is
not
correct
and
needs
to
be
corrected.
The
use
is
limited
to
wholesalers/
bouquet
makers
and
florists.
Further,
the
extensive
material
preservative
uses
of
PHMB
should
be
added.
Table
5:
the
listed
plant
food
use
is
incorrect.
First
of
all,
the
use
is
not
plant
food.
The
registered
product
contains
no
nutrients.
Also,
the
use
instructions
do
not
identify
any
homeowner
uses.

EPA
Response:
"
Preservative
for
flowers"
was
changed
to
"
preservative
for
cut
flowers"
throughout
document.
Any
reference
to
plant
food
was
removed.

Arch's
Comments:
Table
5:
­
under
"
material
preservatives"
 
it
is
incorrect
to
list
the
disinfectant
uses
under
this
category.
Those
uses
should
appear
under
"
Residential
and
Public
Access
Premises".

EPA
Response:
This
has
been
corrected
in
the
document.

Arch's
Comments:
4.2
Dietary
Exposure/
Risk
Pathway
This
entire
section
needs
to
be
significantly
revised,
based
on
the
comments
specifically
associated
with
the
Dietary
Risk
Assessment
document,
which
appear
elsewhere
in
this
response.
It
should
be
noted
that
tunnel
pasteurization
is
associated
almost
exclusively
with
treatment
of
beer
containers.
Page
13
of
33
EPA
Response:
The
Agency
has
determined
that
a
dietary
assessment
is
necessary
when
the
active
ingredient
comes
into
contact
with
a
surface
that
also
comes
into
contact
with
food.
Such
indirect
foodcontact
surfaces
do
trigger
a
dietary
assessment.
The
tunnel
pasteurization
was
further
explained
in
the
document:
"
Because
the
bottles
or
cans
are
already
sealed,
the
possibility
of
infiltration
of
this
product
from
tunnel
pasteurization
water
into
the
food
appears
to
be
minimal."

Arch's
Comments:
4.3
Water
Exposure/
Risk
Pathway
The
reference
to
"
liquid
plant
food"
needs
to
be
corrected;
there
is
no
registered
product
containing
plant
nutrients,
and
all
uses
are
indoors
by
commercial
cut
flower
handlers
to
help
preserve
previously
cut
flowers.

EPA
Response:
Any
reference
to
liquid
plant
food
has
been
removed.

Arch's
Comments:
5.0
Aggregate
risk
assessment
and
risk
characterization
This
section
needs
to
be
extensively
revised,
based
on
the
corrections
needed
in
the
supporting
sections
and
documents.

EPA
Response:
The
current
aggregate
risk
assessment
accurately
reflects
the
dietary
intake
as
well
as
other
scenarios
that
the
Agency
deemed
reasonable
to
co­
occur.

Arch's
Comments:
General
comments
on
Exposure
Arch
is
participating
in
the
American
Chemistry
Council
Antimicrobial
Exposure
Assessment
Task
Force
II.
EPA
has
indicated
on
many
occasions
that
further
considerations
on
exposure
data
requirements
and
assessment
will
be
held
in
abeyance
until
the
task
force
study
is
completed.
There
is
no
mention
of
exposure
assessment
task
force
participation
in
any
of
the
draft
PHMB
RED
documents
and
we
believe
EPA
is
incorrect
in
not
mentioning
participation
in
the
task
force
data
development
program.

EPA
Response:
While
the
data
being
generated
by
the
ACC
Task
Force
is
likely
to
fulfill
some
of
the
exposure
data
requirements
that
will
be
issued
in
the
RED,
the
Agency
is
under
no
obligation
to
mention
Task
Force
participation
in
the
RED
document
itself.
The
registrant
may
reply
to
the
DCI
with
information
about
its
participation
in
the
Task
Force
and
the
data
that
is
intended
to
be
provided
through
the
Task
Force.
Page
14
of
33
Response
to
PHMB
Dietary
Risk
Assessment
(
RED
Chapter),
dated
June
9,
2003
and
to
the
draft
RED
Document
Arch's
Comments:
Disinfectant
Uses
The
Agency
conducted
a
dietary
risk
assessment
for
PHMB
for
disinfectant
uses.
We
believe
that
the
Agency
has
conducted
that
dietary
risk
assessment
in
error
and
in
an
arbitrary
and
capricious
manner
and
that
it
should
be
eliminated
from
further
consideration,
for
the
reasons
discussed
below.

Even
when
FDA
regulated
food­
contact
sanitizers
under
FFDCA
Section
409,
EPA
always
has
regulated
hard­
surface
disinfectant
uses,
such
as
those
registered
for
PHMB,
as
nonfood
uses.
Even
with
the
transfer
of
regulatory
responsibility
for
the
food­
contact
sanitizers
from
FDA
under
Section
409
to
EPA
under
Section
408,
EPA
has
continued
to
regulate
hard­
surface
disinfectants
as
non­
food
uses.

EPA
(
the
Agency)
has
not,
at
any
time,
published
any
changes
to
its
regulations
or
policies
to
reclassify
such
uses
as
food
use,
with
any
associated
requirements
for
submission
of
data
to
support
food
use
applications.
The
Agency
has
not
previously,
nor
does
it
now,
require
the
establishment
of
tolerances
or
exemptions
from
tolerance
for
registration
of
disinfectants.
EPA
confirms
that
the
disinfectant
uses
are
not
food
uses,
by
its
statements
in
the
Dietary
Risk
Assessment
chapter,
under
Section
II:
"
these
uses
do
not
fall
under
the
guidelines
associated
with
residue
chemistry .
There
are
no
outstanding
residue
chemistry
issues
pertaining
to
this
product."
Therefore,
the
use
of
a
dietary
risk
assessment
model
for
a
nonfood
use
is
inappropriate.

The
basis
for
the
determination
that
hard­
surface
disinfectants,
which
require
a
potable
water
rinse
on
any
potential
food­
contact
surface,
are
not
food
contact
uses
can
be
found
in
"
Sanitizing
Solutions:
Chemistry
Guidelines
for
Food
Additive
Petitions"
(
US
FDA,
CFSAN,
OPA,
Version
1.1,
January
1993,
hereafter
referred
to
as
FDA
Sanitizing
Guidelines).
In
that
document,
FDA
clearly
distinguishes
food­
contact
sanitizers,
which
may
result
in
their
becoming
components
of
food,
and
disinfectants,
which
do
not:

"
The
use
of
a
solution
as
a
sanitizer
requires
that
application
to
a
food­
contact
surface
be
followed
by
adequate
drainage
prior
to
contact
of
the
surface
with
food
(
21
CFR
178.1010
(
a)).
A
potable
water
rinse
of
the
treated
surface
prior
to
food­
contact
negates
the
intended
effect
of
the
solution
as
a
sanitizer.
Thus,
a
product
intended
for
treating
of
a
food­
contact
surface
and
which
is
to
be
rinsed
from
the
surface
prior
to
food­
contact
is
not
considered
a
sanitizer.
Therefore,
it
is
unnecessary
to
submit
a
petition
for
a
regulation
under
21
CFR
178.1010
for
disinfectants
or
cleaning
solutions
that
are
to
be
rinsed
from
food­
contact
surfaces"
(
emphasis
added)

FDA
clearly
made
a
determination
that
disinfectants
and
cleaning
solutions
are
not
expected
to
become
components
of
food.
Equally,
EPA
has
agreed
and
regulated
disinfectants
in
a
manner
appropriate
to
the
decision
that
such
products
are
not
components
of
food.
Had
that
position
changed,
EPA
would
have
been
required
to
establish
tolerances
or
exemptions
from
tolerance
for
Page
15
of
33
those
uses
following
the
1996
amendments
to
FFDCA
that
transferred
the
jurisdiction
for
regulation
of
hard
surface
sanitizers
and
disinfectants
used
in
contact
with
food
from
FDA
to
EPA.
It
is
noted
that
EPA
has
adopted
the
FDA
Sanitizing
Guidelines
for
regulation
of
food
contact
sanitizers
which
now
are
within
EPA's
authority
for
regulation,
as
evidenced
by
its
multiple
regulatory
tolerance
and
registration
decisions
on
these
types
of
products
since
the
regulatory
responsibility
was
moved
to
EPA.
See
40
CFR
§
180.940.

FDA
further
discusses
their
approach
to
the
determination
of
potential
dietary
intake
of
sanitizers.
Their
approach
and
development
of
a
conservative
"
worst­
case"
assumption
were
based
on
having
reviewed
extensive
amounts
of
data
over
many
years,
and
determining
that
in
most
cases,
there
would
be
no
need
for
petitioners
to
develop
specific
residue
data.
In
fact,
the
vast
majority
of
actual
data
showed
residues
were
in
the
range
of
microgram
or
nanogram
per
cm2
of
treated
area.
Specifically,

"
A
review
of
the
Agency's
accumulation
of
experimental
residue
data
has
led
to
the
conclusion
that
a
"
worst
case"
assumption
for
residual
sanitizer
solution
of
one
milligram
per
square
centimeter
of
treated
surface
(
1
mg/
cm
²
)
is
a
reasonably
conservative
estimate
that
reflects
the
body
of
data.
Therefore,
the
petitioner
may
elect
for
the
Agency
to
use
this
value
for
the
exposure
calculation
or
may
provide
its
own
experimental
data
having
determined
that
the
assumption
of
1
mg
residue/
cm
²
is
excessively
high
as
an
approximation
for
its
formulation.
In
the
absence
of
residue
information,
however,
the
Agency
will
perform
an
exposure
estimate
assuming
this
"
worst
case"
value."

FDA
then
outlines
how
the
estimated
dietary
intake
can
be
calculated,
in
order
to
make
a
safety
determination
for
that
estimated
dietary
intake:

"
The
safety
requirements
depend
on
the
chemical
constituents
of
the
sanitizer
formulation
and
on
the
extent
to
which
these
constituents
or
their
reaction
products
from
food
contact
may
reasonably
be
expected
to
become
a
part
of
food.
The
Agency
will
determine
the
toxicological
studies
needed
to
provide
a
reasonable
assurance
of
no
harm
to
the
public
from
use
of
the
sanitizer
after
establishing
the
probable
daily
intake
of
sanitizer
residue."

"
To
estimate
probable
daily
intakes
three
types
of
information
are
usually
required:
(
1)
sanitizer
residues­­
discussed
above,
(
2)
the
mass
and/
or
volume
of
food
contacting
a
unit
area
of
treated
surface,
and
(
3)
an
estimate
of
an
individual's
daily
intake
of
foods
assumed
to
have
contacted
the
sanitized
surfaces.
The
Agency's
calculations
are
intended
to
reflect
a
reasonable,
yet
conservative,
"
worst
case"
situation."

"
The
broadest
coverage
includes
use
of
the
sanitizer
in
institutional
or
public
eating
facilities.
In
this
case,
the
Agency's
worst­
case
estimate
assumes
that
all
food
consumed
by
an
individual
in
a
single
day
has
contacted
4000
cm
²
of
sanitized
non­
porous
foodcontact
surfaces.
This
contact
area
represents
the
summation
of
the
surface
area
of
silverware,
china,
and
glass
used
by
a
person
who
regularly
eats
three
meals
per
day
in
an
institutional
or
public
facility."
Page
16
of
33
It
is
critical
to
note
that
FDA
guidelines
to
determine
intake
are
based
on
a
contact
area
which
is
defined
as
"
the
summation
of
the
surface
area
of
silverware,
china,
and
glass
used
by
a
person
who
regularly
eats
three
meals
per
day
in
an
institutional
or
public
facility"
(
emphasis
added).

The
label
for
the
EPA­
registered
disinfectant
containing
PHMB
which
could
be
used
by
consumers
in
a
home
environment
specifically
prohibits
the
use
of
the
disinfectant
on
glasses,
dishes,
and
utensils
(
EPA
Reg.
No.
71661­
1;
Surfacine
All­
Purpose
Cleaner).
Further,
the
use
directions
on
the
label
specifically
require
that
all
surfaces
must
be
wiped
dry
of
any
remaining
solution
after
the
specified
contact
time,
with
a
potable
water
rinse
required
after
that
action
on
all
surfaces
that
food
might
contact.

The
other
EPA­
registered
disinfectant
(
EPA
Reg.
No.
50096­
1)
clearly
is
not
intended
for
use
in
the
home
or
food­
contact
uses,
since
its
claims
specifically
identify
it
as
a
"
hospital­
type"
bactericide.
The
registered
uses
of
EPA
Reg.
No.
50091­
1
(
Wipex)
do
not
suggest
it
would
ever
be
sold
to
consumers
or
in
a
residential
environment
in
kitchens,
and
we
believe
it
is
an
unreasonable
interpretation
of
the
label
to
suggest
otherwise.
The
Agency
may
wish
to
consider
requiring
that
registrant
to
include
language
to
better
define
the
permissible
use
areas.

There
is
no
rational,
valid
regulatory
or
scientific
basis
for
the
Agency
to
1)
modify
on
an
ad
hoc
basis
the
FDA
Sanitizing
Guidelines
to
"
fit"
a
home
use
of
a
disinfectant
on
a
kitchen
countertop,
2)
adopt
the
FDA
Sanitizing
Guidelines
for
uses/
products
which
clearly
and
specifically
were
excluded
from
consideration
by
FDA,
3)
attempt
to
adapt
a
regulatory
scheme
intended
for
evaluation
of
the
safety
residues
of
sanitizers
on
silverware,
china
and
glass
in
institutional
settings
to
use
of
entirely
different
types
of
products
on
countertops
in
home
kitchens,
and/
or
4)
attempt
to
regulate
the
disinfectant
on
the
basis
of
such
an
arbitrary
and
capricious
approach.

In
home
use
of
a
product
such
as
Surfacine,
any
contact
of
edible
items
will
be
no
more
than,
at
worst,
incidental
and
intermittent,
with
little
likelihood
any
transfer
of
PHMB.
It
is
more
properly
characterized
as
incidental
oral
ingestion
from
a
post­
application
exposure.
We
believe
that
the
Agency's
assessment
of
the
incidental
oral
ingestion
from
post­
application
residential
exposure
resulting
from
hand­
to
mouth
transfer
from
treated
surfaces
(
floors)
is
more
than
inclusive
of
any
potential
momentary
exposure
of
edible
items
on
countertops,
since
that
assessment
assumes
no
rinsing
of
residues
and
would
qualify
as
a
worst­
case
for
any
incidental
oral
ingestion
regardless
of
the
surface.
As
such,
the
Agency
should
completely
remove
the
erroneous
dietary
risk
assessment
from
further
consideration
in
both
the
Dietary
Risk
Assessment
chapter
and
throughout
the
RED
document.

EPA
Response:
General
Background
Before
1996,
residues
of
products
used
to
clean
food­
contact
surfaces
were
considered
indirect
food
additives,
and
dietary
exposure
to
such
residues
were
therefore
regulated
by
FDA
under
section
409
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
rather
than
by
EPA
under
FFDCA
section
408.
In
order
to
market
such
products
with
pesticidal
claims,
a
producer
would
have
to
obtain
from
FDA
an
FFDCA
section
409
indirect
food
additive
regulation/
clearance
and
Page
17
of
33
apply
to
EPA
for
registration
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA).
Based
on
proof
of
efficacy
and
taking
into
consideration
the
FDA
food
additive
regulation/
clearance,
EPA
would
register
the
product
under
FIFRA.
EPA
would
not
conduct
a
separate
dietary
risk
assessment,
but
would
instead
consider
FDA's
risk
determinations
in
approving
a
section
409
clearance
in
the
FIFRA
risk/
benefit
evaluation.

At
first,
the
only
antimicrobial
pesticides
registered
for
use
on
food
contact
surfaces
were
sanitizers.
Registrants
wanted
to
market
more
potent
antimicrobial
products
with
higher
application
rates,
so
in
the
mid­
1980s,
EPA
recognized
a
new
class
of
antimicrobials,
the
"
hardsurface
disinfectants".
Where
such
products
were
labeled
for
use
on
food­
contact
surfaces,
EPA
considered
them
food­
use
products.
However,
if
a
disinfectant
required
a
potable
water
rinse
after
use,
no
section
409
indirect
food
additive
regulation
or
clearance
was
required.
Data
were
neither
submitted
nor
required
in
support
of
the
presumption
that
there
were
no
residues
after
the
potable
water
rinse.
Based
on
FDA's
lack
of
a
requirement
for
section
409
clearances
and
proof
of
efficacy,
EPA
registered
the
hard­
surface
disinfectants.
1
EPA
continued
to
rely
on
FDA's
evaluations
of
dietary
risk
under
section
409
and
EPA
did
not
perform
separate
dietary
risk
assessments
for
these
products.

In
1996,
the
Food
Quality
Protection
Act
amendments
changed
the
FFDCA
definition
of
"
food
additive"
to
exclude
pesticide
chemicals,
making
them
subject
to
section
408
rather
than
section
409,
and
thus
giving
EPA
sole
jurisdiction
over
dietary
residues
from
sanitizers
and
hard­
surface
disinfectants,
in
addition
to
its
existing
FIFRA
registration
authority.
As
a
result,
FDA
ceased
performing
dietary
risk
assessments
for
these
products.
The
FQPA
amendments
to
section
408
also
included
several
new
provisions
that,
for
the
first
time,
expressly
required
EPA
to
address
certain
factors
in
its
dietary
risk
assessments.
Moreover,
FQPA
amendments
to
FIFRA
section
2(
bb)
require
that
all
dietary
exposures
from
the
use
of
a
pesticide
be
assessed
and
found
to
meet
these
new
section
408
standards.
2
1See
EPA's
efficacy
data
requirements
for
sanitizing
rinses,
DIS/
TSS­
4
(
Jan.
30,
1979):
"
Sanitizers
applied
to
food
contact
surfaces
are
defined
as
incidental
food
additives
under
the
Federal
Food,
Drug,
and
Cosmetic
Act,
as
amended
(
21
U.
S.
C.
201
et
seq.),
and
require
establishment
of
a
food
additive
tolerance.
Recommendation
of
a
potable
water
rinse
after
treatment
does
not
preclude
this
requirement."
Id.
at
1.

2FIFRA
section
3(
c)(
5)
prohibits
EPA
from
registering
a
pesticide
that
would
cause
unreasonable
adverse
effects
on
the
environment.
As
amended
by
the
FQPA,
FIFRA
section
2(
bb)(
2)
provides
that
the
term
unreasonable
adverse
effects
on
the
environment
includes
"
human
dietary
risk
from
residues
that
result
from
a
use
of
a
pesticide
in
or
on
any
food
inconsistent
with
the
standard
under
section
408
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
..."
Accordingly,
EPA
must
conduct
a
dietary
risk
assessment
for
any
use
of
a
pesticide
product
likely
to
result
in
dietary
exposure
to
the
pesticide
or
its
degradates,
and
must
conclude
that
the
dietary
exposure
meets
the
FFDCA
section
408
safety
standard
in
order
to
conclude
that
the
pesticide
product
does
not
cause
unreasonable
adverse
effects
pursuant
to
FIFRA
section
2(
bb).
Page
18
of
33
Transitional
provisions
included
in
the
FQPA
amendments
(
see
section
408(
j)
&
(
k))
gave
the
previously
issued
FDA
food
additive
regulations
and
clearances
continuing
effect,
so
the
FQPA
amendments
had
little
initial
impact
on
the
registrants
of
hard­
surface
disinfectants.
However,
in
order
for
EPA
to
make
a
new
section
408
safety
finding,
particularly
as
the
safety
standard
was
amended
by
FQPA,
EPA
generally
needs
more
data
than
was
provided
to
FDA
in
support
of
the
section
409
clearances.
Accordingly,
applications
for
new
registrations
of
food­
use
products,
and
tolerance
reassessment
for
existing
products,
today
require
substantially
more
data
than
would
have
been
required
before
1996.

General
Countertop
Use
Requires
a
Dietary
Risk
Assessment
EPA
considers
use
of
a
pesticide
product
on
any
food­
contact
surface
to
be
an
indirect
food
use.
EPA
regards
kitchen
countertops
as
food­
contact
surfaces
because
food
is
often
placed
on
kitchen
countertops
and
such
food
has
the
potential
to
pick
up
residues
from
products
used
to
clean
those
countertops.
Accordingly,
label
claims
for
use
on
kitchen
countertops
are
considered
indirect
food­
use
claims
if
there
is
a
reasonable
likelihood
of
any
residue
in
or
on
food,
and
require
a
section
408
tolerance
or
exemption
from
the
requirement
of
a
tolerance.

Products
that
are
labeled
for
use
on
"
countertops,"
without
clear
restrictions
precluding
use
on
food­
contact
surfaces,
may
be
used
on
kitchen
countertops.
Because
kitchen
countertops
are
food­
contact
surfaces,
products
that
may
be
used
on
kitchen
countertops
are
regulated
as
indirect
food­
use
products.
It
is
possible
that
a
label
claim
might
be
restricted
to
specific
countertops
that
would
not
be
considered
food­
contact
surfaces;
however,
a
label
that
merely
permits
use
on
"
countertops"
would
allow
use
on
kitchen
countertops.
Therefore,
products
that
are
labeled
for
use
on
"
countertops"
require
a
section
408
tolerance
or
exemption
from
the
requirement
of
a
tolerance,
even
if
the
label
does
not
specifically
recommend
use
on
kitchen
countertops.

This
conclusion
applies
to
hard­
surface
disinfectants,
as
well
as
sanitizers.
Although
label
instructions
for
hard­
surface
disinfectant
products
direct
users
to
use
a
potable
water
rinse
following
application
of
the
product,
there
is
still
potential
for
pesticide
residues
to
remain
on
the
food­
contact
surface
and
from
there
transfer
to
food.
Except
where
the
registrant
or
applicant
submits
data
sufficient
to
support
a
determination
that
there
is
no
reasonable
likelihood
of
any
residue
in
food,
the
Agency
considers
hard­
surface
disinfectants
registered
for
use
on
countertops
to
be
an
indirect
food
use.
You
are
mistaken
in
your
assertion
that
"
EPA
always
has
regulated
hard­
surface
disinfectant
uses...
as
nonfood
uses."
The
Agency
clearly
stated
in
the
1979
DIS/
TSS
efficacy
testing
guidelines
that
a
potable
water
rinse
does
not
alter
the
fact
that
application
of
disinfectants
to
food
contact
surfaces
require
a
dietary
assessment:

"
Sanitizers
applied
to
food
contact
surfaces
are
defined
as
incidental
food
additives
under
the
Federal
Food,
Drug,
and
Cosmetic
Act,
as
amended
(
21
U.
S.
C.
201
et
seq.),
and
require
establishment
of
a
food
additive
tolerance.
Recommendation
of
a
potable
water
rinse
after
treatment
does
not
preclude
this
requirement."
DIS/
TSS­
4
(
Jan.
30,
1979).

Your
argument
that
language
from
Section
II
of
the
preliminary
Dietary
Risk
Assessment
chapter
of
the
PHMB
RED
supports
the
contention
that
disinfectant
uses
are
not
food
uses
misconstrues
that
chapter.
The
countertop
use
does
not
fall
under
the
guidelines
because
the
Page
19
of
33
guidelines
only
pertain
to
direct
food
contact,
not
indirect
food­
contact
uses.
The
sentence
you
quote
from
the
preliminary
Dietary
Risk
Assessment
chapter
that
"[
t]
here
are
no
outstanding
residue
chemistry
issues
pertaining
to
this
product"
is
followed
by
the
explanatory
statement
that
"[
t]
he
Agency
has
used
available
methods
to
estimate
PHMB
residues
on
food
due
to
migration
of
these
products."
Thus,
the
Agency's
statements
in
the
preliminary
Dietary
Risk
Assessment,
when
taken
in
full,
clearly
reflect
EPA's
policy
of
conducting
dietary
risk
assessments
for
countertop
use
of
disinfectants.

Finally,
you
noted
in
your
comments
that
"
Had
that
position
[
that
disinfectants
are
not
expected
to
become
components
of
food]
changed,
EPA
would
have
been
required
to
establish
tolerances
or
exemptions
from
tolerance
for
those
uses
[
disinfectants
and
cleaning
solutions
identified
in
21
C.
F.
R.
178.1010]
following
the
1996
amendments
to
FFDCA
that
transferred
the
jurisdiction
for
regulation
of
hard
surface
sanitizers
and
disinfectants
used
in
contact
with
food
from
FDA
to
EPA."
That
view
is
substantially
correct:
As
a
consequence
of
the
pesticide
reregistration
process,
EPA
recognized
an
absence
of
data
supporting
the
assumption
that
disinfectants
would
not
result
in
food
residues.
EPA
is
therefore
currently
in
the
process
of
establishing
tolerances
or
exemptions
from
the
requirement
of
a
tolerance
for
those
hard
surface
sanitizing
and
disinfecting
solutions
that
present
a
reasonable
likelihood
of
any
residue
in
food.
See
Proposed
Rule:
Tolerance
Exemptions
for
Active
and
Inert
Ingredients
for
Use
in
Antimicrobial
Formulations
(
Food­
Contact
Surface
Sanitizing
Solutions),
68
Fed.
Reg.
37,
778
(
June
25,
2003).

For
the
foregoing
reasons,
EPA
maintains
its
position
that
countertop
use
of
hard
surface
disinfectants
is
an
indirect
food
use
for
which
a
dietary
risk
assessment
is
required
pursuant
to
FIFRA
section
2(
bb),
even
if
the
label
requires
a
potable
water
rinse,
unless
the
registrant
or
applicant
submits
data
sufficient
to
support
a
determination
that
there
is
no
reasonable
likelihood
of
any
residue
in
food.
Products
labeled
for
use
only
on
specific
countertops
that
would
not
be
expected
to
be
food
contact
surfaces
(
e.
g.,
bathrooms,
lab
benches)
might
not
be
considered
food­
use
products
and
might
be
eligible
for
registration
without
a
dietary
risk
assessment.

Arch's
Comments:
Additional
Comments:
Section
III
of
the
RED
Chapter,
PHMB
Dietary
Assessment,
should
be
eliminated
in
its
entirety
as
non­
pertinent,
both
for
the
above
stated
reasons
and
because
the
Agency
did
not
DEEMFCID
consumption
information
or
any
other
items
mentioned
within
that
section.

EPA
Response:
This
section
was
removed
from
the
document.

Arch's
Comments:
In
determining
the
Estimated
Daily
Intake
of
PHMB
used
in
Latex
Adhesives,
a
use
regulated
by
FDA
under
Section
409
of
FFDCA,
the
Agency
has
made
a
calculation
error
in
attempting
to
convert
the
potential
dietary
exposure
to
children.
The
FDA
Chemistry
Guidance
for
Industry
for
Food
Contact
Substances
(
April
2002),
assumes
that
the
daily
consumption
is
3
kg/
person/
day,
combining
both
liquids
and
solids.
That
is
an
adult
consumption
factor.
EPA
simply
divided
the
estimated
daily
intake
using
an
adult
consumption
factor
by
the
average
weight
of
adults
(
males
70
kg,
females
60
kg)
or
children
(
15
kg)
to
come
up
with
an
exposure
in
Page
20
of
33
mg/
kg/
day,
but
failed
to
appropriately
take
into
account
the
different
total
consumption
of
children
vs.
adults,
which
needs
to
be
made
within
the
earlier
calculation
and
not
after
the
fact.
It
is
noted
that
FDA
does
not
separately
address
consumption
of
adults
vs.
children.

EPA
Response:
Since
the
risk
from
latex
adhesives
based
on
an
adult
consumption
rate
(
a
worst
case
scenario)
is
significantly
lower
than
that
from
the
disinfectant
use,
the
total
dietary
risk
was
solely
based
on
the
disinfectant
use.
For
this
reason,
we
do
not
believe
it
is
necessary
to
adjust
the
consumption
factors
for
children.

Arch's
Comments:
The
Agency
should
include
that
the
use
of
PHMB
in
latex
adhesives
is
regulated
by
FDA
under
Threshold
of
Regulation
(
21
CFR
172.39).
We
do
not
believe
that
EPA
should
conduct
a
dietary
risk
assessment
under
FFDCA
Section
408
for
uses
which
are
not
regulated
under
that
section.

EPA
Response:
Due
to
the
fact
that
the
latex
exposure
was
significantly
less
than
the
disinfectant
exposure,
the
final
dietary
exposure
is
solely
based
upon
the
disinfectant
use.
Page
21
of
33
PHMB:
COMMENTS
ON
THE
TOXICOLOGY
DISCIPLINARY
CHAPTER
Toxicology
Disciplinary
Chapter
Arch's
Comments:
4.1
Acute
toxicity
Please
refer
to
comments
above,
with
respect
to
reference
to
the
correct
acute
toxicology
studies
for
PHMB.

EPA
Response:
Addressed
above.

4.3
Prenatal
Developmental
Toxicity
Arch's
Comments:
870.3700a
Rat
The
summary
states
that
the
rats
(
note
spelling
error:
"
rats"
not
"
rates")
were
fed
0,
200,
1000
or
2000ppm,
and
equates
this
to
0,
10,
50
or
100mg/
kg/
day
of
20%
aqueous
solution
of
PHMB.
In
fact,
the
animals
were
fed
diets
containing
0,
200,
1000
or
2000ppm
of
PHMB
itself,
and
not
the
20%
solution.
Furthermore,
the
calculated
equivalent
dose
equates
to
0,
17.2,
86.2
and
172.4mg/
kg/
day,
respectively.
Consequently,
the
maternal
toxicity
NOAEL
is
17.2mg/
kg/
day.

EPA
Response:
Spelling
error
and
doses
have
both
been
corrected
in
the
document.

Arch's
Comments:
In
addition,
although
there
was
an
increased
incidence
of
extra
ribs,
subsequent
to
the
study
being
conducted
these
have
been
shown
to
be
transitory
in
the
Alpk:
APfSD
rat
and
associated
with
non­
specific
maternal
toxicity
(
Wickramaratne,
Jour
Appl
Tox,
8(
2),
1988).
Consequently,
as
these
were
the
only
toxic
effects
noted
in
the
study,
the
developmental
NOEL
should
be
considered
to
be
172.4mg/
kg/
day.

EPA
Response:
The
Agency
acknowledges
the
comment
regarding
the
significance
of
increased
incidence
of
extra
ribs.
It
is
understood
that
this
effect
is
considered
transitory
and
is
a
non­
specific
effect.
Therefore,
the
Developmental
NOAEL
will
be
re­
stated
as
172.4
mg/
kg/
day
and
the
Developmental
LOAEL
will
be
stated
as
>
172.4
mg/
kg/
day.

Arch's
Comments:
870.3700b
Rabbit
As
before,
although
the
test
article
was
in
the
form
of
a
20%
aqueous
solution,
it
should
be
noted
that
the
doses
given
are,
in
fact,
the
PHMB
a.
i.
itself.
The
summary
comments
that
"
6
rabbits
died
in
the
40mg/
kg/
day
dose
group".
However,
this
description
over
emphasises
the
toxicity
of
PHMB,
since
only
one
death
actually
occurred
at
40mg/
kg/
day,
and
this
was
most
likely
as
a
consequence
of
mal­
dosing.
One
other
animal
was
sacrificed
for
humane
reasons
because
of
poor
condition;
the
remaining
four
were
killed
because
they
aborted
and,
without
foetuses
for
evaluation,
no
longer
served
a
purpose
on
the
study.
This
should
be
corrected.
Page
22
of
33
EPA
Response:
The
doses
have
been
corrected
in
the
document.
The
animal
deaths
were
better
clarified
in
the
document:
"
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
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."

Arch's
Comments:
Comment
is
also
made
on
the
evidence
of
possible
developmental
toxicity
of
PHMB
due
to
minor
defects
in
the
sternebrae.
However,
it
should
be
considered
unlikely
that,
in
the
absence
of
any
other
changes
in
foetal
development,
these
anomalies
are
compound
induced.

EPA
Response:
Although
the
relationship
of
the
effect
to
test
article
has
been
called
into
question,
there
was
an
increased
fetal
and
litter
incidence
of
unossified
and/
or
fused
sternebrae
in
offspring.
There
is
sufficient
uncertainty
with
regard
to
what
caused
this
effect
for
the
Agency
to
stay
with
the
20
mg/
kg/
day
value.

Arch's
Comments:
4.4
Reproductive
Toxicity
As
before,
although
the
test
article
was
in
the
form
of
a
20%
aqueous
solution,
it
should
be
noted
that
the
doses
given
are,
in
fact,
the
PHMB
a.
i.
itself.

EPA
Response:
All
doses
have
been
verified
and
corrected/
adjusted
where
necessary.

4.5
Chronic
Toxicity
Arch's
Comments:
870.4100a
Chronic
Toxicity/
Carcinogenicity
Rat
Regarding
the
comments
on
the
carcinogenicity
potential,
reference
is
also
made
to
the
following
documents
submitted
previously:
Evaluation
of
the
weight
of
evidence
for
the
carcinogenic
potential
of
PHMB
(
MRID
45710801)
Historical
control
data
for
the
occurrence
of
haemangiosarcoma
in
Alpk:
ApfSD
Wistar
rats
(
MRID
45710808)
Comment
is
made
that
liver
hemangiosarcomas
are
rare
in
the
Alpk:
ApfSD
Wistar
rat.
However,
as
is
outlined
in
the
above
mentioned
documentation,
whilst
hemangiosarcomas
in
rats
tend
to
be
uncommon
and
not
to
be
present
in
multiple
organs
in
the
same
animal,
such
vascular
tumours
should
be
addressed
on
an
animal
basis,
rather
than
a
specific
organ.
As
was
also
presented
in
the
documentation,
evaluating
all
the
historical
control
data
on
the
Alpk:
ApfSD
Wistar
from
the
test
facility
showed
an
incidence
of
hemangiosarcomas
between
0
and
1.9%
in
both
males
and
females.
Consequently,
the
incidence
of
1/
64
as
reported
with
PHMB
is
within
this
historical
range.
Furthermore,
a
reported
incidence
of
2%
for
hemangiosarcomas
is
given
in
the
literature.
Page
23
of
33
EPA
Response:
The
CARC
considered
the
historical
control
data
but
determined
the
overall
increase
in
tumors
across
tissues
(
17%)
at
the
high
dose
to
be
outside
of
the
historical
control
range.
This
dose
was
considered
to
be
adequate
but
not
excessive.

Arch's
Comments:
870.4100b
Dog
The
dogs
received
dose
levels
of
0,
300,
1500
and
3000ppm
PHMB
in
the
diet.
These
are
quoted
as
0,
7.5,
37.5
and
75mg/
kg/
day
nominal
dose.
However,
the
mean
dose
values
for
the
300,
1500
and
3000ppm
dose
level
as
calculated
by
the
test
facility
are
given
as
9,
46
and
91mg/
kg/
day
for
males
and
9,
45
and
91mg/
kg/
day
for
females,
respectively.
Consequently,
the
systemic
LOAEL
for
male
and
female
dogs
should
be
91mg/
kg/
day,
and
the
systemic
NOAEL
45­
46mg/
kg/
day.

EPA
Response:
The
doses
were
corrected
in
the
document.

4.6
Carcinogenicity
Arch's
Comments:
870.4200b
Mouse
feeding
Additional
reference
should
also
be
made
to
the
following
documents
submitted
previously:
Evaluation
of
the
weight
of
evidence
for
the
carcinogenic
potential
of
PHMB
(
MRID
45710801)
Historical
control
data
for
occurrence
of
haemangiosarcoma
(
angiosarcoma)
in
C57BL/
10J/
CD­
1
Alpk
mice
(
MRID
45710804)
Exceedance
of
the
maximum
tolerated
dose
at
the
highest
tested
does
of
PHMB
in
mice.
Supplementary
information
to
MRID
44074201
(
MRID
45710805)
PHMB
two­
year
oncogenicity
study
in
mice
Pathology
Working
Group
Peer
Review
(
MRID
45710802)

The
summary
as
written
contains
a
number
of
factual
inaccuracies.
It
quotes
the
incidence
of
male
mice
with
hemangiosarcomas
to
be
20/
55
for
the
4000ppm
dose
against
6/
55
for
control,
and
for
females
17/
55
(
4000ppm)
against
7/
55
control.

However,
as
reported
following
the
PWG
review,
the
actual
incidence
of
hemangiosarcomas
in
male
mice
was
12/
55
(
4000ppm)
against
5/
55
(
control)
and
for
female
mice
10/
55
(
4000ppm)
against
6/
55
(
control).

Furthermore,
the
historical
control
incidence
of
hemangiosarcomas
is
given
as
being
2
­
15%
in
males
and
0
 
9%
in
females.
As
the
report
on
the
historical
control
incidence
shows,
the
actual
ranges
for
animals
with
hemangiosarcomas
was
1.8
 
18.3%
(
males)
and
0
 
10.9%
(
females).

The
summary
also
comments
that
haemangiosarcoma
of
the
liver
was
a
significant
contributory
factor
to
death
of
male
and
female
mice
at
4000ppm
(
which
EPA
agreed
was
above
the
MTD
for
such
a
study
based
on
non­
carcinogenic
effects).
As
is
also
outlined
in
the
above
report
on
the
historical
control
incidence
of
hemangiosarcomas,
it
is
inappropriate
to
record
the
incidence
of
these
particular
vascular
tumours
by
specific
organ.
Because
of
the
multicentric
origin
of
such
Page
24
of
33
tumours
(
and
high
spontaneous
incidence
in
the
C57
mouse)
the
most
appropriate
method
of
evaluation
is
by
the
animal
and
not
by
reference
to
a
specific
organ.
Therefore,
if
statistical
evaluation
is
applied
to
the
groups
excluding
the
4000ppm
MTD
exceedance
group,
no
statistically
significant
findings
of
vascular
tumours
being
a
cause
of
death
are
found.

Comment
is
also
made
that
the
4000ppm
dose,
although
excessive,
was
considered
adequate.
This
is
not
correct
based
on
the
PHMB
CARC
report,
and
we
would
refer
you
to
the
paper
on
the
exceedance
of
the
MTD
as
outlined
above.
For
example,
body­
weight
decreases
of
47
and
32%
in
males
and
females,
respectively,
are
clearly
more
than
5
 
10%
as
recommended
by
current
guidelines.
This
serious
effect
on
bodyweight
gain,
associated
with
a
significant
reduction
in
food
utilisation,
suggests
that
the
4000ppm
dose­
group
greatly
exceeds
the
MTD
and,
as
such,
should
not
be
used
for
the
evaluation
of
any
tumorigenic
risk.

EPA
Response:
This
comment
is
not
consistent
with
the
most
recent
version
of
the
CARC
Memo.
Please
refer
to
the
current
version.

Arch's
Comments:
870.4200b
Mouse
dermal
It
should
be
noted
that
this
study
was
considered
deficient
and
unacceptable
and
invalid
for
an
evaluation
of
dermal
carcinogenicity
by
EPA
at
earlier
stages
in
the
re­
registration
process.
However,
we
do
not
object
to
the
Agency's
dose
endpoint
selection
of
150mg
PHMB
a.
i.
/
kg/
day
for
short­
term
and
immediate­
term
dermal
exposure.

EPA
Response:
This
study
is
not
unacceptable.
It
did
not
fulfil
a
guideline
because
it
was
rat­
specific.

Arch's
Comments:
The
summary
reports
the
treatment
doses
as
being
equivalent
to
0,
15,
150
and
750
mg/
kg/
day
of
20%
PHMB
solution.
In
fact,
the
animals
were
exposed
to
0,
0.6,
6
and
30mg
PHMB
a.
i.
/
mouse/
day,
which
equates
to
an
overall
mean
during
the
course
of
the
study
of
0,
15,
150
and
750mg
PHMB/
mouse/
day,
and
not
the
20%
solution
as
indicated.
In
addition,
the
summary
also
reports
the
6.0mg
treatment
dose
to
be
made
up
of
20%
PHMB
in
ethanol,
whereas
it
was
actually
2%
PHMB
in
ethanol.

EPA
Response:
The
doses
have
been
corrected
in
the
document.

Arch's
Comments:
The
summary
report
also
goes
on
to
discuss
possible
increases
in
tumours
in
mice
at
the
top­
dose
(
30mg/
PHMB/
day).
PHMB
has
been
characterized
as
a
severe
dermal
irritant.
Because
of
this
dermal
irritation,
upper
limit
for
dosing
was
restrained.
Although
PHMB
is
sparingly
absorbed
dermally,
it
was
obvious
from
the
study
results
that
irritation
was
severe
for
the
mice
in
the
high
dose
and
this
contributed
to
the
poor
condition
and
thin
appearance
noted
for
these
animals
throughout
the
study.
It
is
expected
that
the
severe
dermal
irritation
also
enhanced
the
absorption
of
PHMB
from
the
compromised
dosing
sites
on
the
animals.
The
enhanced
absorption
would
Page
25
of
33
result
from
the
destruction
of
the
stratum
corneum
and
permit
rapid
systemic
absorption
of
PHMB.
Therefore,
the
dermal
dose
would
be
exaggerated
and
the
dose
level
not
relevant
for
risk
assessment.
Mean
body
weight
gain
was
also
reduced
in
the
30.0
mg
group.
Overall
mortality
for
the
high
dose
animals
was
75%
compared
to
approximately
30%
in
the
other
groups.
Collectively,
these
results
show
that
the
30.0
mg
dose
was
an
MTD
exceedance
dose.
Microscopic
evaluation
revealed
no
evidence
of
carcinogenicity.
Potential
treatment­
related
tumors
were
limited
to
angiosarcomas
in
the
liver
of
females
from
the
30
mg
group
only.
The
incidence
of
liver
angiosarcomas
was
1/
50
and
1/
50
for
control
males
and
high
dose
males,
respectively,
and
0/
49
and
2/
49
for
control
females
and
high
dose
females,
respectively.
Furthermore,
there
were
also
signs
of
hepatic
inflammation
within
this
high
dose
group.
The
generally
poor
condition
of
the
mice
in
this
group
following
the
prolonged
dermal
administration
to
a
high
irritant
dose
of
PHMB
more
likely
led
to
the
debilitation
in
their
health
status,
making
them
mores
susceptible
to
infection.
Furthermore,
the
results
at
this
high
dose
exceeding
the
MTD
are
still
within
the
historical
range
for
liver
angiosarcomas
(
0
 
8%).

EPA
Response:
The
document
does
acknowledge
that
the
dose
is
excessive.

Arch's
Comments:
Consequently,
as
the
tumour
profile
in
the
other
two
dose
groups
were
normal,
it
cannot
be
concluded
that
PHMB
"
appears
to
be
a
hepatic
carcinogen",
as
was
indicated
in
the
summary
EPA
Response:
The
document
no
longer
claims
that
PHMB
"
appears
to
be
a
hepatic
carcinogen."
Page
26
of
33
PHMB:
COMMENTS
ON
THE
2nd
REPORT
OF
THE
HIARC
EPA
Response:
All
of
the
comments
have
been
addressed
in
the
revised
risk
assessment
and/
or
Toxicology
Disciplinary
Chapter.
However,
we
cannot
change
the
HIARC
Report
itself
without
a
new
meeting
of
the
Committee.

Arch's
Comments:
Introduction
Paragraph
2
of
the
introduction
reads
as:
"
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
"[
]"."

However,
the
fundamental,
yet
flawed,
assumption
made
here
is
that
in
the
individual
animal
reports
the
dose
levels
were
given
as
the
20%
technical
material
test­
formulation.
Although
in
all
cases
the
test
material
would
have
been
a
20%
aqueous
formulation,
with
the
exception
of
the
acute
studies
and
in
vitro
and
in
vivo
genotoxicity
studies,
dose
levels
as
administered
to
the
animals
were
all
reported
as
the
PHMB
a.
i.
itself,
and
not
as
the
20%
formulation.

Consequently,
where
in
the
HIARC
a
NOAEL
is
given
as,
for
example,
20mg/
kg,
it
is
incorrect
to
give
the
pure
PHMB
equivalent
as
[
4].
In
reality,
the
NOAEL
for
the
pure
PHMB
a.
i.
would
be
20mg/
kg.,
whereas
for
the
20%
technical
it
would
be
100mg/
kg.
Comments
to
this
are
made
throughout
this
document.
Corrections
need
to
be
made
to
all
such
erroneous
references.

Developmental
Toxicity
MRID
42865901
As
commented
earlier,
although
the
test
article
was
in
the
form
of
a
20%
aqueous
solution,
it
should
be
noted
that
the
doses
given
are,
in
fact,
the
PHMB
a.
i.
itself.
The
summary
also
comments
that
"
6
rabbits
died
in
the
40mg/
kg/
day
dose
group".
However,
this
description
over
emphasises
the
toxicity
of
PHMB,
since
only
one
death
actually
occurred
at
40mg/
kg/
day,
and
this
was
most
likely
as
a
consequence
of
mal­
dosing.
One
other
animal
was
sacrificed
for
humane
reasons
because
of
poor
condition;
the
remaining
four
were
killed
because
they
aborted
(
due
to
maternal
toxicity)
and,
without
foetuses
for
evaluation,
no
longer
served
a
purpose
on
the
study.

Comment
is
also
made
on
the
evidence
of
possible
developmental
toxicity
of
PHMB
due
to
minor
defects
in
the
sternebrae.
However,
it
should
be
considered
unlikely
that,
in
the
absence
of
any
other
changes
in
fetal
development,
these
anomalies
are
compound
induced.

Report
CTL/
P/
335
The
mouse
developmental
study
was
considered
to
be
unacceptable
in
the
earlier
stages
of
reregistration
As
such,
it
should
not
be
included
in
the
HIARC
assessment.

CTL/
P/
1262
The
summary
states
that
the
rats
were
fed
0,
200,
1000
or
2000ppm,
and
equates
this
to
0,
10,
50
or
100mg/
kg/
day
of
20%
aqueous
solution
of
PHMB.
In
fact,
the
animals
were
fed
diets
Page
27
of
33
containing
0,
200,
1000
or
2000ppm
of
PHMB
itself,
and
not
the
20%
solution.
Furthermore,
the
calculated
equivalent
dose
equates
to
0,
17.2,
86.2
and
172.4mg/
kg/
day,
respectively.
Consequently,
the
maternal
toxicity
NOAEL
is
17.2mg/
kg/
day
and
the
maternal
LOAEL
86.2mg/
kg/
day.

In
addition,
although
there
was
an
increased
incidence
of
extra
ribs,
subsequent
to
the
study
being
conducted
these
have
been
shown
to
be
transitory
in
the
Alpk:
APfSD
rat
and
associated
with
non­
specific
maternal
toxicity
(
Wickramaratne,
Jour
Appl
Tox,
8(
2),
1988).
Consequently,
as
these
were
the
only
toxic
effects
noted
in
the
study,
the
developmental
NOEL
should
be
considered
to
be
172.4mg/
kg/
day.

Reproductive
Toxicity
Study
Conclusions
As
commented
earlier,
the
dose
levels
indicated
of
200,
600
or
2000ppm
refer
to
concentrations
of
PHMB
a.
i.
itself
and
not
the
20%
aqueous
formulation.

HAZARD
IDENTIFICATION
1.
Acute
reference
dose
Refer
to
comments
made
above
on
the
increased
mortality
and
incidence
of
skeletal
abnormalities.

The
dose
and
endpoint
for
establishing
RfD,
as
based
on
the
developmental
toxicity
NOAEL
is
20mg/
kg/
day
(
based
on
effects
seen
at
40mg/
kg/
day).
The
respective
concentrations
given
of
[
4]
and
[
8]
for
the
20mg/
kg
and
40mg/
kg,
respectively,
is
incorrect
for
reasons
given
in
comments
on
the
introduction.

3.
Chronic
Reference
Dose
Comments
made
earlier
on
MRID
42865901
are
reiterated
again:
As
commented
earlier,
although
the
test
article
was
in
the
form
of
a
20%
aqueous
solution,
it
should
be
noted
that
the
doses
given
are,
in
fact,
the
PHMB
a.
i.
itself.
The
summary
also
comments
that
"
6
rabbits
died
in
the
40mg/
kg/
day
dose
group".
However,
this
description
over
emphasises
the
toxicity
of
PHMB,
since
only
one
death
actually
occurred
at
40mg/
kg/
day,
and
this
was
most
likely
as
a
consequence
of
mal­
dosing.
One
other
animal
was
sacrificed
for
humane
reasons
because
of
poor
condition;
the
remaining
four
were
killed
because
they
aborted
(
due
to
maternal
toxicity)
and,
without
foetuses
for
evaluation,
no
longer
served
a
purpose
on
the
study.

Comment
is
also
made
on
the
evidence
of
possible
developmental
toxicity
of
PHMB
due
to
minor
defects
in
the
sternebrae.
However,
it
should
be
considered
unlikely
that,
in
the
absence
of
any
other
changes
in
fetal
development,
these
anomalies
are
compound
induced.

Report
CTL/
P/
335
As
also
commented
earlier,
the
mouse
developmental
study
was
considered
to
be
unacceptable
at
earlier
stages
of
the
re­
registration
process.
As
such,
it
should
not
be
included
in
the
HIARC
assessment.
Page
28
of
33
CTL/
P/
1262
Reiterating
once
again
the
earlier
comments:

The
summary
states
that
the
rats
were
fed
0,
200,
1000
or
2000ppm,
and
equates
this
to
0,
10,
50
or
100mg/
kg/
day
of
20%
aqueous
solution
of
PHMB.
In
fact,
the
animals
were
fed
diets
containing
0,
200,
1000
or
2000ppm
of
PHMB
itself,
and
not
the
20%
solution.
Furthermore,
the
calculated
equivalent
dose
equates
to
0,
17.2,
86.2
and
172.4mg/
kg/
day,
respectively.
Consequently,
the
maternal
toxicity
NOAEL
is
17.2mg/
kg/
day
and
the
maternal
LOAEL
86.2mg/
kg/
day..

In
addition,
although
there
was
an
increased
incidence
of
extra
ribs,
subsequent
to
the
study
being
conducted
these
have
been
shown
to
be
transitory
in
the
Alpk:
APfSD
rat
and
associated
with
non­
specific
maternal
toxicity
(
Wickramaratne,
Jour
Appl
Tox,
8(
2),
1988).
Consequently,
as
these
were
the
only
toxic
effects
noted
in
the
study,
the
developmental
NOEL
should
be
considered
to
be
172.4mg/
kg/
day.

Dose
and
endpoint
for
establishing
RfD
The
chronic
reference
dose
as
given
is
based
on
the
NOAEL
for
maternal
toxicity
from
the
rabbit
developmental
toxicity
study.
However,
EPA
guidance
identifies
that
chronic
reference
doses
are
to
be
set
on
the
basis
of
chronic
studies,
if
available,
and
that
such
chronic
studies
can
be
used
for
the
intermediate
term
reference
dose.
As
such,
the
lowest
NOAEL
for
a
chronic
study
is
36mg/
kg/
day
for
the
dietary
chronic
toxicity
study
in
rats
(
MRID
44059301)
and
should
be
the
basis
for
establishing
an
intermediate
term
and
chronic
oral
reference
dose
for
PHMB.

5.
Intermediate
term
incidental
oral
ingestion
exposure
We
reiterate
the
earlier
comments
made
about
the
mouse
developmental
toxicity
study:
The
mouse
developmental
study
was
considered
to
be
unacceptable
at
re­
registration.
As
such,
it
should
not
be
included
in
the
HIARC
assessment.

Dose
endpoint
for
risk
assessment
The
intermediate
term
oral
ingestion
reference
dose
as
given
is
based
on
the
NOAEL
for
maternal
toxicity
from
the
rabbit
developmental
toxicity
study.
However,
EPA
guidance
identifies
that
chronic
reference
doses
are
to
be
set
on
the
basis
of
chronic
studies,
if
available,
and
that
such
chronic
studies
can
be
used
for
the
intermediate
term
reference
dose.
As
such,
the
lowest
NOAEL
for
a
chronic
study
is
36mg/
kg/
day
for
the
dietary
chronic
toxicity
study
in
rats
(
MRID
44059301)
and
should
also
be
considered
as
the
basis
for
establishing
an
intermediate
term
reference
dose
for
PHMB.

6.
Dermal
Absorption
Factor
The
relative
dermal
absorption
rate
is
given
as
100%.
As
submitted
in
MRID
45710806,
we
contest
this
and
suggest
that
a
factor
of
less
than
1%
is
still
highly
conservative
for
risk
assessment
purposes.
The
reasons
behind
this
(
as
outlined
in
MRID
45710806
and
in
comments
on
the
draft
RED
itself)
are
given
below:

PHMB
is
a
polymeric
material,
with
an
average
molecular
weight
of
approximately
2650
(
by
size
exclusion
chromatography),
based
on
an
average
of
10­
13
monomer
units
but
containing
up
Page
29
of
33
to
40
monomers.
Polymers
such
as
this
are
not
readily
absorbed
through
the
skin
or
via
the
gastrointestinal
system,
due
to
a
combination
of
high
molecular
weight
and
poor
solubility.
Nor
do
such
polymers
readily
break
down
into
easily
absorbable
fractions.

In
studies
designed
to
evaluate
the
absorption,
distribution,
metabolism
and
excretion
of
radiolabeled
PHMB
following
oral
administration
in
rodents
(
MRID
77926,
86363,
43567001,
43599901),
it
has
been
determined
that
there
is
very
little
absorption
of
PHMB,
with
more
than
93%
excreted
in
the
faeces.
Of
the
limited
amount
not
directly
excreted,
there
is
very
little
actually
absorbed
(
2
to
3%).
What
is
absorbed
tends
to
be
the
lower
molecular
weight
fractions
(
i.
e.,
approximately
MW
1230),
although
absorption
of
those
fractions
still
is
extremely
low.
The
poor
absorption
from
the
digestive
system
following
oral
administration
is
not
unexpected
for
a
polymeric
material
such
as
PHMB.

Studies
of
the
in
vitro
dermal
absorption
of
PHMB
clearly
confirm
that
little
to
no
PHMB
is
absorbed
following
dermal
exposure,
which
is
not
unexpected
for
a
material
such
as
PHMB.
There
are
3
separate
studies
(
MRID
44046301,
44119301,
and
44596001),
each
of
which
followed
appropriate,
scientifically
recognized
and
valid
procedures
that
are
consistent
with
current
guidance
(
OECD
1996
and
2000,
EPA
1999
and
EPA
1992).
These
studies
document
that
absorption
of
radio­
labeled
PHMB
through
human
epidermis
is
essentially
nil.
In
a
comparative
in
vitro
study
using
rat
and
human
epidermis,
absorption
by
rat
skin
was
much
higher
than
by
human
skin
(
MRID
44046301).
While
a
percent
absorption
cannot
be
calculated
on
the
basis
of
the
information
contained
within
MRID
44046301,
the
data
from
that
study
support
essentially
no
absorption
across
human
epidermis
(
not
detectable
after
70
hr,
with
level
of
detection
of
0.1
µ
g/
cm2).
Low
but
detectable
levels
were
found
in
this
study
using
rat
skin.
Those
experimental
results
are
consistent
with
data
reported
in
the
literature
(
EPA
1992)
that
rat
skin
is
3
to
5X
more
permeable
than
is
human
skin.
MRID
44119301
identified
that
there
was
greater
relative
absorption
across
human
epidermis
at
lower
initial
dose
levels
over
the
96
hr
study.
The
highest
percent
absorption
reported
in
that
study
was
0.15
%.
MRID
44596001,
which
reported
on
absorption
across
human
epidermis
at
a
higher
temperature
(
40
°
C)
over
a
24
hr
period,
showed
that
0.007%
of
the
applied
dose
was
absorbed.
Both
the
measured
percentages
in
the
two
studies,
along
with
the
lack
of
any
detectable
levels
in
the
third,
support
that
dermal
absorption
of
PHMB
by
human
skin
is
well
below
1%
of
the
applied
dose.

In
order
to
determine
an
appropriate
dermal
absorption
rate
for
PHMB,
the
following
whole
animal
toxicity
studies
can
be
considered:
 
21
day
dermal
toxicity
study
in
rat
(
MRID
43045901),
systemic
NOAEL
greater
than
200
mg/
kg
bw,
LOAEL
greater
than
200
mg/
kg
(
no
adverse
effects
reported
in
study).
It
should
be
noted
that
higher
doses
could
not
be
used
due
to
the
severe
skin
irritant
effects
of
PHMB.
 
developmental
toxicity
study
in
rat
(
MRID
65131,
42992101),
maternal
NOAEL
10
mg/
kg
bw/
day,
LOAEL
50
mg/
kg
bw/
day
(
decreased
body
weight,
food
consumption)

The
ratio
of
the
oral
LOAEL
to
the
dermal
LOAEL
(
50/>
200)
identifies
that
a
factor
of
25%
or
less
could
be
considered
as
a
dermal
absorption
factor
for
PHMB.
Due
to
the
high
skin
irritancy
associated
with
PHMB,
higher
dermal
application
rates
could
not
be
assessed,
and
the
25%
Page
30
of
33
factor
greatly
overestimates
dermal
absorption.
In
this
case,
it
may
be
more
appropriate
to
use
the
NOAELs
from
the
two
studies,
resulting
in
a
factor
of
5%
or
less,
since
no
NOAEL
was
determined
in
the
dermal
toxicity
study.
Taking
into
account
the
results
of
the
in
vitro
studies
and
the
relation
between
rat
and
human
skin
permeability,
a
factor
of
less
than
1%
dermal
absorption
for
humans
is
highly
conservative
for
risk
assessment
purposes.
This
is
consistent
with
the
in
vitro
results
and
with
the
anticipated
lack
of
absorption
based
on
the
polymeric
character
of
the
compound.

7.
Dermal
Exposure:
Short
term
The
summary
reports
the
6.0mg
treatment
dose
to
be
made
up
of
20%
PHMB
in
ethanol,
whereas
it
was
actually
2%
PHMB
in
ethanol.

The
report
also
concludes
that
"
for
20%
PHMB
solution,
the
NOAEL
=
150mg/
kg/
day".
The
dosing
solutions
were
actually
administered
as
0.6,
6
and
30mg
PHMB
a.
i./
mouse/
day.
Consequently,
as
was
stated
in
the
comments
to
the
introduction,
the
NOAEL
(
as
calculated
in
mg/
kg/
day)
is,
therefore,
for
the
PHMB
a.
i.
and
not
the
20%
solution.

Therefore,
the
dose/
endpoint
for
risk
assessment
is
also
150mg/
kg/
day
of
PHMB
a.
i.

Comment
is
also
made
as
to
the
dermal
sensitization
potential
for
PHMB,
mentioning
that
"
PHMB
is
demonstrated
to
be
a
human
skin
sensitizer
in
the
1981
dermal
sensitization
study".

This
assessment
of
PHMB
as
a
potential
human
sensitizer
is
contested,
and
evidence
supporting
such
was
submitted
in
MRID
45789602.
In
fact,
there
is
no
evidence
that
PHMB
is
a
sensitizer
in
either
humans
or
animals.

In
summary,
PHMB
has
been
shown
to
be
a
dermal
irritant
in
studies
with
humans
and
animals
and
the
degree
of
dermal
irritation
is
concentration
dependent.
Concentrations
of
2%
PHMB
and
above
have
induced
moderate
to
severe
dermal
irritation
in
both
animals
and
humans.
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.
Overall,
the
results
of
relevant
dermal
sensitization
studies
with
humans
show
that
PHMB
is
not
a
dermal
sensitizer
and
PHMB
should
not
be
considered
a
human
sensitizer
under
conditions
of
use
Page
31
of
33
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
Reference
should
also
be
made
to
the
findings
and
report
of
the
CARC.
This
section
should
be
revised
to
reflect
the
conclusions
of
the
CARC.

The
comments
below
are
also
made
in
response
to
the
Toxicology
Disciplinary
Chapter:

EPA
Response:
All
of
the
comments
have
been
addressed
in
the
revised
risk
assessment
and/
or
Toxicology
Disciplinary
Chapter.
However,
we
cannot
change
the
CARC
Memo
itself
without
a
new
meeting
of
the
Committee.

Arch's
Comments:
Chronic
Toxicity/
Carcinogenicity
Rat
(
MRID
44059301
and
44042801)

Regarding
the
comments
on
the
carcinogenicity
potential,
reference
is
also
made
to
the
following
documents
submitted
previously:
Evaluation
of
the
weight
of
evidence
for
the
carcinogenic
potential
of
PHMB
(
MRID
45710801)
Historical
control
data
for
the
occurrence
of
haemangiosarcoma
in
Alpk:
ApfSD
Wistar
rats
(
MRID
45710808)
Comment
is
made
that
liver
hemangiosarcomas
are
rare
in
the
Alpk:
ApfSD
Wistar
rat.
However,
as
is
outlined
in
the
above
mentioned
documentation,
whilst
hemangiosarcomas
in
rats
tend
to
be
uncommon
and
not
to
be
present
in
multiple
organs
in
the
same
animal,
such
vascular
tumors
should
be
addressed
on
an
animal
basis,
rather
than
a
specific
organ.
As
was
also
presented
in
the
documentation,
evaluating
all
the
historical
control
data
on
the
Alpk:
ApfSD
Wistar
from
the
test
facility
showed
an
incidence
of
hemangiosarcomas
between
0
and
1.9%
in
both
males
and
females.
Consequently,
the
incidence
of
1/
64
as
reported
with
PHMB
is
within
this
historical
range.
Furthermore,
a
reported
incidence
of
2%
for
hemangiosarcomas
is
given
in
the
literature
Carcinogenicity
Study
in
mice
(
MRID
44074201)
Additional
reference
should
also
be
made
to
the
following
documents
submitted
previously:
Evaluation
of
the
weight
of
evidence
for
the
carcinogenic
potential
of
PHMB
(
MRID
45710801)
Historical
control
data
for
occurrence
of
haemangiosarcoma
(
angiosarcoma)
in
C57BL/
10J/
CD­
1
Alpk
mice
(
MRID
45710804)
Exceedance
of
the
maximum
tolerated
dose
at
the
highest
tested
does
of
PHMB
in
mice.
Supplementary
information
to
MRID
44074201
(
MRID
45710805)
PHMB
two­
year
oncogenicity
study
in
mice
Pathology
Working
Group
Peer
Review
(
MRID
45710802)

The
summary
as
written
contains
a
number
of
factual
inaccuracies.
It
quotes
the
incidence
of
male
mice
with
hemangiosarcomas
to
be
20/
55
for
the
4000ppm
dose
against
6/
55
for
control,
and
for
females
17/
55
(
4000ppm)
against
7/
55
control.
Page
32
of
33
However,
as
reported
following
the
PWG
review,
the
actual
incidence
of
hemangiosarcomas
in
male
mice
was
12/
55
(
4000ppm)
against
5/
55
(
control)
and
for
female
mice
10/
55
(
4000ppm)
against
6/
55
(
control).

Furthermore,
the
historical
control
incidence
of
hemangiosarcomas
is
given
as
being
2
­
15%
in
males
and
0
 
9%
in
females.
As
the
report
on
the
historical
control
incidence
shows,
the
actual
ranges
for
animals
with
hemangiosarcomas
was
1.8
 
18.3%
(
males)
and
0
 
10.9%
(
females).

The
summary
also
comments
that
haemangiosarcoma
of
the
liver
was
a
significant
contributory
factor
to
death
of
male
and
female
mice
at
4000ppm
(
which
is
also
contested
as
being
above
the
MTD
for
such
a
study).
As
is
also
outlined
in
the
above
report
on
the
historical
control
incidence
of
hemangiosarcomas,
it
is
inappropriate
to
record
the
incidence
of
these
particular
vascular
tumours
by
specific
organ.
Because
of
the
multicentric
origin
of
such
tumours
(
and
high
spontaneous
incidence
in
the
C57
mouse)
the
most
appropriate
method
of
evaluation
is
by
the
animal
and
not
by
reference
to
a
specific
organ.
Therefore,
if
statistical
evaluation
is
applied
to
the
groups
excluding
the
4000ppm
MTD
exceedance
group,
no
statistically
significant
findings
of
vascular
tumours
being
a
cause
of
death
are
found.

Comment
is
also
made
that
the
4000ppm
dose,
although
excessive,
was
considered
adequate.
This
is
not
correct
based
on
the
PHMB
CARC
report,
and
we
would
refer
you
to
the
paper
on
the
exceedance
of
the
MTD
as
outlined
above.
For
example,
body­
weight
decreases
of
47
and
32%
in
males
and
females,
respectively,
are
clearly
more
than
5
 
10%
as
recommended
by
current
guidelines.
This
serious
effect
on
bodyweight
gain,
associated
with
a
significant
reduction
in
food
utilisation,
suggests
that
the
4000ppm
dose­
group
greatly
exceeds
the
MTD
and,
as
such,
should
not
be
used
for
the
evaluation
of
any
tumorigenic
risk.

Mouse
dermal
carcinogenicity
(
MRID
00066475
and
00104796)
It
should
be
noted
that
this
study
was
considered
deficient
and
unacceptable
and
invalid
for
an
evaluation
of
dermal
carcinogenicity
in
the
earlier
stages
of
re­
registration
However,
we
do
not
object
to
the
Agency's
dose
endpoint
selection
of
150mg
PHMB
a.
i.
/
kg/
day
for
short­
term
and
immediate­
term
dermal
exposure.

The
summary
reports
the
treatment
doses
as
being
equivalent
to
0,
15,
150
and
750
mg/
kg/
day
of
20%
PHMB
solution.
In
fact,
the
animals
were
exposed
to
0,
0.6,
6
and
30mg
PHMB
a.
i.
/
mouse/
day,
which
equates
to
an
overall
mean
during
the
course
of
the
study
of
0,
15,
150
and
750mg
PHMB/
mouse/
day,
and
not
the
20%
solution
as
indicated.
In
addition,
the
summary
also
reports
the
6.0mg
treatment
dose
to
be
made
up
of
20%
PHMB
in
ethanol,
whereas
it
was
actually
2%
PHMB
in
ethanol.

IV
Hazard
Characterization
Minor
spelling
error
in
that
"
chronicrat"
should
read
"
chronic
rat".

Please
refer
to
previous
comments
on
the
PHMB
acute
toxicity
studies
for
reference
to
the
correct
toxicity
studies.
Page
33
of
33
VII
Summary
of
Toxicological
endpoints
Reference
is
made
to
the
individual
comments
made
earlier
within
this
document,
many
of
which
have
a
direct
impact
upon
the
summary
table.
These
need
to
be
revised
to
be
consistent
with
the
other
corrections.