Document ID: EPA-HQ-OPP-2005-0200-0017
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-22T05:00Z

1
August
31,
2005
MEMORANDUM
Subject:
Response
to
Public
Comments
on
the
Draft
Risk
Assessment
for
1,2­
Benzisothiazolin­
3­
one
(
BIT).

From:
Rebecca
Miller,
Chemical
Review
Manager
Antimicrobials
Division
Office
of
Pesticide
Programs
To:
OPP
Public
Docket
for
1,2­
Benzisothiazolin­
3­
one
(
BIT)
Docket
#
OPP­
2005­
0200
Introduction
This
document
addresses
the
public
comments.
The
public
comments
were
based
solely
on
those
submitted
on
behalf
of
Acti­
Chem
Specialties,
Inc.;
Arch
Chemicals,
Inc.,
Clariant
Corporation;
International
Specialty
Products,
Rohm
&
Haas
Company,
and
Troy
Corporation
in
response
to
EPA's
draft
risk
assessment
(
RA)
for
BIT.
The
comments
submitted
by
these
registrants
include
areas
of
toxicology,
exposure,
and
risks.
EPA
has
responded
to
the
specific
comments,
and
where
appropriate,
has
made
modifications
to
the
RA
as
noted
below.

RA
Incorporated
Comments
The
following
captures
the
changes
the
Agency
has
made
to
the
draft
risk
assessment
based
on
the
public
comments
received
in
Phase
3
of
the
Tolerance
Reassessment
Advisory
Committee
(
TRAC)
process.

°
Additional
risk
characterization
language
will
be
added
to
account
for
the
100%
bioavailability
factor
assumed
for
the
occupational
airless
sprayer
handler
MOE.
The
characterization
is
qualitative
indicating
that
EPA
believes
that
the
paint
matrix
will
most
likely
reduce
the
dermal
absorption
of
BIT,
and
therefore,
the
dermal
MOE
of
90
may
be
an
overestimate
of
risk.

°
The
need
for
additional
carcinogenicity
data
for
the
metal
working
fluid
(
MWF)
use
of
BIT
will
only
be
held
in
reserve
if
the
use
is
restricted
to
"
enclosed
metal
working
systems".
Otherwise,
the
carcinogenicity
data
are
still
required.

°
A
second
application
rate
will
be
added
to
the
PRA
for
the
pet
product
use
(
i.
e.,
0.032
percent
ai).

°
The
textile
use
will
be
properly
characterized
to
reflect
the
low
adsorption
of
BIT
to
clothing
and
the
fact
that
the
estimate
does
not
include
the
reduction
in
the
2
amount
of
BIT
within
the
washer
after
the
spin
cycle.
This
new
information
will
preclude
the
need
for
confirmatory
data.

°
Additional
risk
characterization
language
will
be
added
to
the
handler
risk
assessment
for
oil
recovery
fluids
to
better
characterize
the
potential
extrapolation
error
for
large
volumes.
The
inhalation
MOEs
presented
for
all
of
the
other
scenarios
are
greater
then
1000,
and
therefore,
a
confirmatory
inhalation
toxicity
study
is
not
warranted.

General
Comments
and
Responses
The
comments
are
summarized
as
presented
by
the
registrants.

(
1)
Comment:
Use
Closure
Memorandum
of
Agreement:
On
June
30,
2003,
EPA
held
a
SMART
meeting
on
BIT.
This
meeting
was
attended
by
representatives
of
several
of
the
above
BIT
registrants.
EPA
issued
SMART
meeting
minutes
via
its
cover
memo
dated
September
12,
2003
(
copy
being
submitted
herewith).
EPA
requested
that
registrants
provide
comments
on
the
minutes
and
indicated
that
a
final
Use
Closure
Memorandum
of
Agreement
would
be
provided
to
the
registrants.
Several
registrants,
in
our
30­
day
comments
on
the
first
draft
BIT
RED,
commented
that
EPA
had
not
issued
the
Use
Closure
Memorandum
of
Agreement.
To
date,
none
of
the
BIT
registrations,
to
our
knowledge,
has
received
a
Use
Closure
Memorandum
of
Agreement
for
BIT.
Nevertheless,
BIT's
use
has
been
reviewed
in
several
draft
versions
of
the
BIT
RED
document
and
we
can
agree
that
BIT's
use
patterns
can
be
categorized
to
include
the
following
generic
use
patterns:
material
preservatives
(
indoor
food
use
[
that
is,
indirect
food
additive
use]
and
indoor/
outdoor
non­
food);
industrial
processes
(
indoor
non­
food),
and
indoor
and
outdoor
residential
uses.

EPA
Response:
A
Use
Closure
Memorandum
was
not
issued
for
BIT,
however,
the
use
patterns
are
in
agreement
between
the
registrants
and
EPA.

(
2)
Comment:
Dermal
Toxicity
Endpoint
Selection:
For
reasons
explained
in
our
letter
dated
July
5,
2005,
we
believe
that
EPA
should
be
using
the
calculated
dermal
NOAEL
of
123
mg/
kg/
day
based
on
the
actual
90­
day
rat
dermal
toxicity
study
and
the
BIT
dermal
absorption
study
rather
than
an
oral
NOAEL
of
5
mg/
kg/
day
from
the
90­
day
oral
dog
study
when
conducting
dermal
exposure
assessments.

EPA
Response:
EPA
considered
the
entire
data
base
that
was
available
for
BIT
in
selecting
endpoints.
When
new
data
were
presented,
the
Antimicrobial's
Division
Toxicology
Endpoint
Selection
Committee
(
ADTC)
re­
evaluated
the
endpoints,
taking
into
consideration
the
impact
that
any
new
data
would
have
on
previous
decisions.
In
carrying
out
the
task
of
endpoint
selection,
the
subchronic
dermal
toxicity
study
in
rats
was
evaluated
for
its
utility
in
the
establishment
of
a
dermal
endpoint.

The
90
day
dermal
toxicity
study
was
determined
by
the
committee
to
have
flaws
that
confounded
its
usefulness
in
the
endpoint
selection
process.
It
appeared
from
the
results
3
of
this
study,
that
the
rats
were
not
only
exposed
dermally
to
BIT
but
that
there
was
a
degree
of
oral
exposure,
possibly
from
ingestion
of
the
test
substance,
that
resulted
in
gastric
irritation
at
all
dose
levels.
Dermal
irritation
was
also
reported
at
all
dose
levels
and
a
NOAEL
could
not
be
determined
with
a
high
level
of
confidence.
It
was
not
clear
to
the
committee,
based
on
these
findings,
what
the
actual
dermal
dose
would
have
been
for
those
treated
animals.

With
regard
to
the
use
of
the
subchronic
dog
study
in
setting
endpoints,
this
study
was
supported
by
findings
in
the
subchronic
rat
study
in
which
the
NOAEL
was
approximately
8
mg/
kg/
day
compared
to
a
NOAEL
of
5
mg/
kg/
day
in
the
dog
study.
Although
the
observations
were
somewhat
different
for
the
two
different
species,
the
NOAELs
are
within
the
same
general
range.

(
3)
Comment:
Carcinogenicity
Data
Requirements
for
the
use
of
BIT
as
a
Preservative
for
Metal
Working
Fluids:
We
wish
to
reiterate
comments
made
in
our
July
5,
2005
letter,
that
is,
in
light
of
favorable
MOE's
and
EPA's
lack
of
concern
regarding
the
use
of
BIT
as
a
MWF
preservative,
the
available
toxicity
data
base
for
the
isothiazolin
class
of
biocides
does
not
warrant
any
additional
carcinogenicity
data
on
BIT,
or
any
other
isothiazolin
biocide.

EPA
Response:
The
Agency
has
read
the
registrant's
comment
regarding
the
need
for
carcinogenicity
data
on
BIT
with
respect
to
metalworking
fluid
use,
and
has
the
following
responses:

a)
Carcinogenicity
risk
assessment
is
separate
from
non­
cancer
risk
assessment.
Margins
of
Exposure
are
not
typically
involved
in
a
carcinogenicity
risk
assessment
except
in
cases
where
there
is
clear
demonstration
of
noncarcinogenicity
or
the
mode
of
action
framework
as
presented
in
the
Agency's
Guidelines
for
Carcinogen
Risk
Assessment
is
followed
and
it
is
demonstrated
that
the
chemical
in
question
causes
cancer
through
a
non­
linear
mode
of
action.

b)
In
the
case
of
BIT,
there
is
no
carcinogenicity
data
for
the
chemical.
The
registrant
cites
a
chronic
drinking
water
study
in
rats
that
was
conducted
on
a
mixture
of
two
isothiazolin
chemicals,
5­
chloro­
2­
methyl­
4­
isothiazolin3­
one
(
CMIT)
and
2­
methyl­
4­
isothiazolin­
3­
one
(
MIT)
in
which
no
increase
in
tumors
was
observed.
The
mixture
tested
was
14.2%
a.
i.
The
Health
Effects
Division's
RfD
Peer
Review
Committee
in
1995
assigned
a
Group
"
D"
classification
for
this
chemical
mixture
based
on
the
absence
of
a
study
in
a
second
species
and
the
corrosive
nature
of
the
material
which
limited
doses
that
could
be
administered.

c)
The
CMIT/
MIT
chemical
tested
in
the
chronic
toxicity
study
(
MRID
43140701)
was
a
14.2%
a.
i.
BIT
is
reported
in
submitted
toxicity
studies
as
73­
100%
a.
i.
Further,
the
chemical
structure
of
BIT
is
not
felt
to
be
so
closely
related
to
CMIT/
MIT
that
an
argument
can
be
made
to
bridge
data
for
CMIT/
MIT
to
BIT.
4
d)
The
registrant
may
claim
that
a
carcinogenicity
study
would
not
be
required
for
the
metalworking
fluid
use
if
the
use
is
for
"
enclosed
metalworking
systems".
Under
this
scenario,
it
has
been
determined
that
certain
toxicology
data
requirements
including
carcinogenicity
testing
would
be
held
in
reserve
pending
review
of
worker
exposure
in
such
enclosed
systems
(
July
5,
2005
memorandum
from
Norm
Cook,
Chief,
Risk
Assessment
and
Science
Support
Branch,
Antimicrobials
Division
to
Marshall
Swindell,
PM
33,
Regulatory
Management
Branch
I,
Antimicrobials
Division).

(
4)
Comment:
Commercial
Airless
Sprayer
(
Painting):
Again,
we
wish
to
reiterate
comments
made
in
our
July
5,
2005
letter
regarding
the
use
of
the
calculated
dermal
tox
endpoint
based
on
the
90­
day
dermal
study
and
dermal
absorption
study
rather
than
on
a
oral
tox
endpoint
from
the
oral
dog
study.
Also,
we
reemphasize
the
fact
that
there
is
a
bioavailability
factor
in
this
exposure
scenario
which
was
also
discussed
in
our
July
5,
2005
letter.

EPA
Response:
See
the
response
to
#
2
concerning
the
dermal
toxicity
endpoint.

In
the
July
5,
2005
letter,
an
argument
was
made
to
use
a
10
percent
bioavailability
factor
in
the
commercial
airless
paint
sprayer
exposure
scenario.
Historically,
EPA/
OPP
has
not
used
a
bioavailability
factor
for
paint
without
chemical­
specific
data.
Nonetheless,
EPA
also
believes
that
such
a
factor,
if
data
were
available,
would
indicate
a
reduction
in
the
dermal
absorption.
EPA
will
add
additional
risk
characterization
language
to
the
RA
qualitatively
indicating
the
potential
reduction
in
the
bioavailability
of
BIT
when
used
in
paints.
The
dermal
risk
for
the
exposure
scenario
in
question
(
i.
e.,
occupational
airless
sprayer)
is
a
MOE
of
90
with
a
target
MOE
of
100.

(
5)
Comment:
Leave
On
Flea
and
Tick
Aerosol
Pet
Products
 
BIT
as
a
Preservative:
We
wish
to
reiterate
comments
made
in
our
letters
of
July
5,
2005
and
July
6,
2005
on
the
use
of
the
calculated
dermal
NOAEL,
and
specifically
on
the
use
of
the
calculated
dermal
NOAEL
when
risk
assessing
the
use
of
BIT
as
a
preservative
in
leave
on
flea
and
tick
aerosol
pet
products.
By
using
the
calculated
dermal
NOAEL
as
the
tox
endpoint,
acceptable
MOE's
can
be
calculated.

Alternatively,
it
is
our
understanding
that
the
leave
on
flea
and
tick
aerosol
pet
product
formulators
do
not
use
more
than
320
ppm
or
0.032%
BIT,
on
an
active
ingredient
basis,
to
preserve
such
products.
In
light
of
this,
we
believe
that
MOE's
based
on
this
maximum
amount
of
BIT
well
be
acceptable.
Further
explanation
follows:

If,
as
a
worst­
case
scenario,
the
aerosol
flea
and
tick
product
exposure
were
included
in
the
aggregate
risk
assessment,
the
other
(
Child
dermal)
exposures
would
need
to
be
included
(
see
table
20
for
short
term
exposures).

Clothing
0.0007
mg/
kg/
day
mop
0.00055
mg/
kg/
day
combined
=
0.00125
mg
BIT/
kg/
day
5
Maximum
amount
(
exposure)
of
BIT
to
give
an
MOE
of
100
=
0.05
mg/
kg/
day.

Therefore,
the
permissible
amount
from
aerosol
flea/
tick
pet
products
=
0.05
 
0.00125
=
0.04875
mg
BIT/
kg/
day.

If
we
simply
pro­
rata
this
from
the
data
in
Table
16
(
1000
ppm
BIT
=
0.15
mg
BIT/
kg/
day),
then
320
ppm
BIT
in
flea/
tick
aerosol
pet
formulations
=
0.048
mg
BIT/
kg/
day.

Therefore
this
should
be
the
maximum
acceptable
for
aggregate
risk
assessment.

EPA
Response:
See
the
response
to
#
2
concerning
the
dermal
toxicity
endpoint.

Although
the
above
comment
refers
to
BIT
as
"
an
active
ingredient
basis,
to
preserve
such
products",
the
use
is
actually
registered
as
an
inert
use.
The
inert
percent
formulation
of
0.1
percent
was
used
in
all
of
the
EPA
model
simulations.
This
value
was
based
on
the
tolerance
exemption
limitation
as
specified
in
40
CFR
180.920
and
a
review
of
several
Confidential
Statement
of
Formula
(
CSFs)
for
various
types
of
products.
The
registrant's
willingness
to
reduce
the
percent
formulation
to
0.032
percent
as
a
risk
mitigation
measure
will
provide
an
adequate
MOE.
The
use
of
this
aerosol
pet
product
is
assumed
by
EPA
to
be
used
on
an
intermittent
basis
and
the
probability
of
this
use
cooccurring
with
the
scenarios
selected
for
aggregation
(
see
Table
19
of
the
PRA
for
aggregate
exposure)
would
be
minimal,
and
therefore,
the
pet
product
is
not
included
in
the
aggregate
assessment.

(
6)
Comment:
Fabric
Product
Preservative
(
BIT
Used
to
Preserve
Detergents,
Fabric
Softeners,
Stain
Removers):
The
element
that
EPA
has
omitted
is
the
fact
that
the
total
active
ingredient
is
diluted
in
the
volume
of
wash
water.
Only
the
residual
volume
of
water
on
the
fabric
(
after
draining/
spinning
or
rinsing)
will
then
deposit
BIT
onto
the
textile.
It
is
only
1%
of
this
deposited
amount
which
is
then
transferred
from
cloth
to
skin.

In
the
equations
published
by
HERA,
EPA
seems
to
have
confused
the
term
F1
with
F'.
See
page
18,
Human
Exposure
Assessment.

EPA
version
=
Dermal
Exposure
(
mg/
kg/
day)
=
[((
M
x
F1
x
FD)/
WI)
x
Sder
x
F2
x
F3
x
F4]/
BW
Correct
version
(
see
HERA
web
document
p
70
&
71)
Dermal
Exposure
(
mg/
kg/
day)
=
(
F1
x
C'
x
Sder
x
n
x
F2
x
F3
x
F4)/
BW
Where
C'
=
(
M
x
F'
x
FD)/
Wl
F'
=
percentage
weight
fraction
of
substance
deposited
F'
=
Sw/
Tw
Where
Sw
=
water
mass
left
after
spin
cycle
or
rinse,
in
kg
Tw
=
total
water
mass
initially
present,
in
kg.
6
Equivalent
equation
in
EPA
approach
should
be:­
Dermal
Exposure
(
mg/
kg/
day)
=
[(
F1
x
(
M
x
F'
x
FD)/
WI)
x
Sder
x
F2
x
F3
x
F4]/
BW
This
will
significantly
increase
the
MOE
for
the
potential
exposure
based
on
the
factor:­
Existing
EPA
MOE
x
Tw/
Sw
BIT
substantivity
BIT
will
not
adsorb
onto
textiles/
fabric.
Washing
is
normally
carried
out
at
high
pH,
around
10,
rinsing
is
usually
pH
7
and
softening
at
the
end
of
the
wash
may
be
slightly
acidic,
pH
6
 
7.
Under
all
these
pH
conditions,
BIT
will
not
have
a
positive
charge.
All
of
the
common
fibers
used
for
clothing
have
either
a
negative
charge,
or
are
not
charged.

Cotton,
viscose,
linen,
acrylic
 
all
have
negative
charges
Nylon,
polyester
 
no
charge
These
fibers
will
have
no
ionic
attraction
for
BIT.
There
will
not
be
any
significant
hydrogen
bonding
and
BIT
does
not
have
the
extended
planar
aromatic
structure
required
by
dyestuffs
for
substantivity
to
cotton
(
usually
3
or
more
aromatic
rings)
thus
BIT
will
not
be
able
to
"
dye"
the
anionic
or
neutral
fibers.
Under
laundry
conditions,
BIT
will
not
adsorb
onto
any
of
these
fibres.
The
same
concept
applies
to
dyed
fibers,
even
softened
fibers
 
the
softener
is
cationic,
but
they
do
not
give
the
fiber
a
positive
charge,
just
less
of
a
negative
charge.

From
the
above,
BIT
remains
in
the
wash
water
and
the
vast
majority
is
discharged
to
drain
after
draining/
spinning.
Only
a
small
amount
of
BIT
will
be
present
in
the
residual
entrained
wash
water
and
this
will
be
readily
removed
in
any
rinse
cycle
which
is
omitted
from
the
above
scenario.
Since
all
textile
washing
incorporates
some
element
of
rinsing,
it
is
likely
that
the
potential
for
deposited
residues
of
BIT
on
textiles
is
very
low.
Consequently
the
fraction
of
this
residue
subsequently
transferred
to
the
actual
skin
surface
will
be
very
low.

EPA
Response:
The
amount
of
BIT
remaining
on
the
clothing
after
draining/
spinning/
rinsing
during
a
wash
cycle
was
not
included
in
EPA's
calculations.
It
is
appropriate
to
include
a
fraction
to
account
for
the
water
mass
left
after
the
spin
cycle
divided
by
the
total
water
mass
initially
present
in
washer.
However,
this
fraction
is
not
available
at
this
time.
As
a
screening­
level
assessment,
assuming
a
fraction
of
"
1"
for
this
input
still
provides
the
regulatory
managers
with
sufficiently
high
MOEs
(
i.
e.,
MOEs
are
in
the
1000s)
to
make
a
regulatory
decision.
Additional
characterization
language
will
be
added
to
the
RA
to
capture
this
overestimation.
In
addition,
the
chemistry
discussion
concerning
the
lack
of
BIT
adsorbing
to
fabric
will
be
added
to
the
RA.
Initially,
the
RA
indicated
the
need
for
the
registrant
to
provide
data
to
confirm
the
1
percent
transfer
from
clothing
to
skin
cited
from
the
HERC
document.
In
light
of
the
chemistry,
the
default
of
no
reduction
factor
for
draining/
spinning,
and
high
MOEs
in
the
screening­
level
assessment,
data
to
confirm
the
percent
transfer
are
no
longer
needed.
7
(
7)
Comment:
28­
Day
Inhalation
Study:
Regarding
the
occupational
inhalation
exposure
for
liquid
pour
(
Oil
recovery
fluids,
etc.),
the
MOE
given
in
Table
5
Human
Exposure
Assessment
is
850.
An
MOE
>
1000
is
required
to
obviate
the
need
for
inhalation
tox
studies.

The
calculated
MOE
of
850
is
artificially
low
due
to
non­
viable
extrapolation
on
usage
figures.
The
inhalation
exposure
is
the
lowest
listed
at
0.000403
mg
/
lb
active
ingredient.
This
reflects
low
probability
of
inhalation
during
normal
scale
pump
addition
activities.
This
has
been
directly
multiplied
by
the
usage
figure
of
420,000
gallon
/
day
water.
This
is
an
abnormally
large
volume
and
is
unique
to
the
oil
recovery
application.
At
the
dosage
level
of
300
ppm
active
ingredient
=
1050
lb
active
ingredient
or
5,250
lb
formulated
product.

At
this
level
of
usage
the
system
has
to
be
automated
or
enclosed.
The
only
potential
source
of
exposure
would
be
during
coupling
and
uncoupling
of
large
scale
dosing
vessels,
e.
g.,
intermediate
bulk
containers,
or
bulk
tote
containers.
It
is
unrealistic
to
extrapolate
directly
from
such
large
volume
usage
to
an
inhalation
exposure.
A
more
realistic
figure
would
be
generated
from
an
assessment
of
the
number
of
coupling
operations
per
shift
rather
than
the
total
volume
of
processed
liquid.
Alternatively
the
time
spent
per
day
in
(
un)
coupling
could
be
assessed.

In
light
of
the
above
and
the
fact
that
all
inhalation
MOE's
are
acceptable,
we
believe
that
a
28­
day
inhalation
study
with
BIT
is
not
necessary.

EPA
Response:
The
limitation
in
extrapolating
the
CMA
exposure
data
for
closed
loading
to
large
volumes
handled
is
also
a
concern
of
EPA
in
overestimating
potential
exposure.
The
limitation
in
the
existing
CMA
data
for
closed
loading
are
being
rectified
by
the
ACC
Biocides
Exposure
Task
Force
(
i.
e.,
Task
Force
is
collecting
new
exposure
data).
Based
on
the
fact
that
all
of
the
other
BIT
inhalation
exposure
scenarios
indicate
MOEs
greater
than
1000,
and
the
estimated
inhalation
MOE
of
830
for
the
liquid
pump
oil
recovery
fluids
is
believed
to
be
an
overestimate
of
exposure,
a
confirmatory
28­
day
inhalation
study
is
not
warranted
at
this
time.