1
Memorandum
July
11,
2005
Subject:
Dietary
Risk
Assessment
of
1,2­
Benzthioazolin­
3­
one
for
Reregistration
Eligibility
Decision
(
RED)
Document
To:
Melba
Morrow,
Ph.
D.,
Science
Coordinator
for
Benzisothiazolin
RED
Antimicrobials
Division
(
7510C)

From:
A.
Najm
Shamim,
Ph.
D.,
Chemist
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

Thru:
Rebecca
Miller,
CRM,
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

And
Mark
Hartman,
Chief
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)
2
DIETARY
EXPOSURE
ASSESSMENT
FOR
1,2­
BENZIOSTHIAZOLIN­
3­
ONE
EXECUTIVE
SUMMARY:

1,2­
Bemzisothiazolin­
3­
one
as
an
active
antimicrobials
is
used
as:
a
slimicide
in
paper
manufacturing,
as
a
preservative
coating
on
paper,
as
a
preservative
on
paper
adhesives,
and
as
inorganic
mineral
slurries
which
become
part
of
paper
and
paperboard
products.
All
these
uses
my
result
in
the
indirect
food
contacts
due
to
migration
of
the
pesticide
into
food.
For
this
reason
the
Agency
has
conducted
a
dietary
risk
assessment.
Acute
PAD
and
chronic
PAD
from
all
the
uses
listed
are:
15.
57
%
and
37.07
%.
for
adults
and
children
respectively.
The
Agency
does
not
have
dietary
concerns
from
uses
of
BIT
as
an
active
antimicrobial.

AD's
label
search
has
shown
that
1,2­
Benzisothiazolin­
3­
one
has
been
cleared
for
use
by
US
FDA
with
the
conditions
set
forth
under
Title
21
of
the
Code
of
Federal
Regulations
(
21CFR):
1.
21CFR
175.105­
Components
for
adhesives
2.
21CFR
176.170­
Components
of
paper
and
paperboard
in
contact
with
aqueous
fatty
foods
3.
21CFR
176.180­
Components
of
paper
and
paper
board
in
contact
with
dry
food
4.
21CFR
176.300­
Slimicide
(
in
the
manufacture
of
paper
and
paperboard
that
contact
food)

5.
In
addition,
BIT
has
been
exempted
from
tolerance
under
40CFR
180.1001(
d):
Materials
exempted
from
the
requirements
of
a
tolerance
when
used
in
accordance
with
good
manufacturing
practices
(
GMP)
as
inert
(
or
occasionally
active)
ingredients
in
pesticide
formulations
applied
in
growing
crops
only.
At
use
level
of
10,000
ppm
of
Acticide
BW
10
are
allowed.

BIT's
antimicrobials
uses
include:
slimicide
use
in
paper/
pulp,
paper
coatings,
aqueous
mineral
slurries
as
a
filler
in
paper,
and
paper
adhesives.
AD
has,
therefore,
assessed
the
potential
dietary
exposure
to
such
uses
applying
the
FDA
methodologies.

Label
67071­
24
(
Acticide
BW10)
and
other
labels
show
that
1,2­
Benzisothiazolin­
3­
one
(
BIT)
is
used
as
paper
coating
up
to
5
lbs
per
1000
product.
Same
label
shows
that
in
aqueous
mineral
slurries,
the
maximum
amount
of
BIT
is
5
lbs
per
1000
pounds
of
product.
The
concentration
of
BIT
in
the
Acticide
BW10
formulation
is
only
10%
and
is
not
used
as
a
TGAI.
We
have
used
Acticide
BW10
as
a
representative
of
various
labels
submitted
to
the
Agency.
Application
rates
on
other
labels
do
not
appear
to
exceed
the
rates
used
in
our
calculations.
3
Dietary
Exposures
and
Risks
From
BIT
uses
as
Indirect
Food
Additives.

FDA1,2,3
Method
makes
a
number
of
assumptions
for
calculating
migration
of
active
(
in
this
case
BIT)
from
food
contact
surfaces
(
paper):
1.
Food
contact
surface
(
paper)
can
be
a
one
time
use/
day
or
a
repeat
use
material;
2.
Consumption
factor
(
CF)
or
fraction
of
daily
food
which
comes
in
to
contact
with
the
packaging
surface
(
paper).
CF
represents
the
actual
weight
of
food
that
comes
into
contact
with
the
paper
to
the
weight
of
all
food
packaged
with
paper;
3.
The
CF
varies
from
one
type
of
packaging
(
type
of
paper)
to
the
other
(
type
of
paper).
FDA
methodology
of
migration
of
active
assumes
a
100%
migration
to
the
food
commodities
(
This
represents
a
worst
case
scenario).

I
Data
Input
Parameters
for
BIT
Used
as
Paper
Slimicide
1.
Rate
of
Application
of
Active:
Maximum
of
1
lbs
BIT/
ton
of
paper
(
=
0.5
kg/
1000
kg
of
paper)
2.
Paper
slurry:
Prior
to
entering
paper
manufacturing
machine:
1%
(
99%
water
and
1%
pulp).
This
is
an
FDA
assumption
3.
Concentration
of
Slurries
Entering
Driers:
33%
pulp
and
67%
water
(
FDA
Assumption)
4.
Standard
Paper
Weight:
50
mg/
in2
(
FDA
Assumption)
5.
Finished
Paper:
8%
water
and
92%
pulp
(
RASSB
Memo
by
Bob
Quick,
based
on
FDA
Assumption)
4
6.
Mass
of
Food
in
Contact
with
Surface
Area
of
Treated
Paper:
10
g/
in2
(
FDA
Assumption)
7.
Consumption
Factor
(
CF)
for
Treated
Paper
).
10
(
FDA
Assumption)
8.
Daily
Average
Food
Intake
(
Adult)
=
3000
g
9.
Daily
Average
Food
Intake
(
Child)
=
1500
g
Calculations:

a.
As
the
active
is
only
10%,
from
parameters
1
&
2
above,
1
lb/
ton
paper
=
200,000
lb
slurry
x
1%
paper
slurry
=
1
lb/
2000
lbs
of
finished
paper
=
5
ppm
of
active
in
the
paper
slurry.
(
This
is
derived
from
FDA
assumption).
b.
From
in
put
parameter
3,
the
concentration
of
the
active
(
BIT)
present
in
the
pulp
prior
to
entering
the
driers:
Application
Rate
x
%
water/
%
pulp
=
5
ppm
active
=
5
:
g
active/
g
pulp
slurry
x
0.67
water/
0.33
g
pulp
=
10
µ
g
active/
g
pulp.

OUTPUT:
4
Based
on
input
parameters
1
through
7
and
calculations
a
and
b,
the
outputs
are:

1a:
Concentration
of
BIT
in
Food:
µ
g
of
BIT/
mass
of
pulp
x
mass
of
pulp/
mass
of
paper
x
standard
mass
of
paper
x
mass
of
food/
surface
area
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
i
10
µ
g
BIT/
mass
of
pulp
x
0.92
g
pulp/
g
of
paper
x
0.05
g/
in2
x
1
in2
/
10
g
food
=
0.046
µ
g
of
BIT/
g
food
Taking
into
account
of
CF
0f
0.10,
the
actual
dietary
concentration
of
BIT
in
daily
diet
would
be:
0.046
µ
g
BIT/
g
food
x
0.10
=
0.0046
µ
g
of
active/
g
food
­­­­­
ii
1b.
Estimated
Daily
Intake
(
EDI)
for
an
Adult
=
0.0046
µ
g
of
BIT/
g
food
x
3000
g
food
=
13.8
µ
g
BIT/
person/
day
­­­­­­­­­­­­­­­­­­­­­­­
iii
1c.
Estimated
Daily
Intake
(
EDI)
for
a
Child
=
0.0046
µ
g
of
BIT/
g
food
x
1500
g
food
=
6.9
µ
g
BIT/
person/
day
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
iv
Estimated
Daily
Dietary
Dose:
EDI/
Body
Weight:
Adult:
13.8
µ
g
x
mg/
1000
µ
g
/
70
kg/
day
=
1.97
x
10­
4
mg/
kg
BW/
day
Child:
6.9
µ
g
x
mg/
1000
µ
g
/
15
kg
/
day
=
4.6
x
10
µ
mg/
kg
BW/
day
II.
BIT
Use
in
Aqueous
Mineral
Slurries
As
a
Filler
in
Paper
Rate
of
Application:
maximum
level
of
the
active
is
the
same
as
in
I
above,
which
approximates
to
about
600
ppm
of
the
active
BIT.

5
lbs
of
BIT
=
2500
ppm;
however,
BIT
as
active
is
used
only
10%
in
the
formulation;
Thus:
0.5
lbs
BIT
=
250
ppm
Data
Input
Paramaters
for
BIT
as
a
Preservative
in
Paper,
with
Clay
Slurries
as
Fillers
1.
Rate
of
Application
of
the
Active
:
250
ppm
2.
Standard
Paper
Weight:
50
mg/
in2
(
FDA
Assumption)
3.
Mass
of
Food
in
Contact
With
Surface
Area
of
Paper
Treated
with
Preservative
(
BIT)
=
10
g
Food/
in2
4.
Consumption
Factor
(
CF)
for
Paper
Treated
With
Preservative
(
BIT)
=
0.10
5.
Finished
Preservative
(
BIT)
Treated
Paper
=
8%
Water
and
92%
Pulp
(
FDA
Assumption)
4
5
6.
Daily
Average
Food
Intake
(
Adult)
=
3,000
g
7.
Daily
Average
Food
Intake
(
Child)
=
1,500
g
2a.
Concentration
of
BIT
in
Paper/
Pulp
FDA
assumes
that
0.1lbs
of
clay
slurries
=
1
lb
of
paper,
that
is
clay
slurry
represents
10%
as
fillers
Rate
of
Application
x
10%
filler
250
ppm
x
0.10
=
25
ppm
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
i
If
the
pulp
is
5%
in
the
slurry
water
(
FDA
assumption)
Amount
of
BIT
is:
0.05
x
25
=
1.25
ppm
of
BIT
in
slurry
water
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
ii
If
mass
of
water
to
mass
of
pulp
is
67%/
33%
(
2:
1)
Amount
of
BIT/
g
pulp
is:
1.25
ppm
x
2
=
2.50
ppm
=
2.5
µ
g
BIT/
g
pulp
­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
iii
2b.
Concentration
of
BIT
in
Food:

Mass
of
BIT/
g
paper
x
mass
of
Pulp/
g
paper
x
standard
mass
of
paper/
in2
paper
x
mass
of
food/
in2
paper:

2.5
µ
g
BIT/
g
paper
x
0.92
g
pulp/
g
paper
x
0.05
g
paper/
in2
paper
x
in2
paper/
10
g
food
=
0.00115
µ
g
BIT/
g
food
=
0.00115
ppm
of
BIT­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­
iv
If
CF
factor
=
0.10:
Amount
of
BIT
in
food
=
0.10
x
0.00115
µ
g
BIT/
g
food
=
0.000115
µ
g
/
food
­­­­­
v
Estimated
Daily
Intake
(
EDI)
for
an
Adult:

0.000115
µ
g/
g
food
x
3000
g
food
=
3.45
µ
g
food/
person/
day
­­­­­­­­­­­­­­­­­­­­­­
vi
Estimated
Daily
Intake
(
EDI)
for
a
Child:

0.000115
µ
g/
g
food
x
1500
g
of
food
=
1.725
µ
g/
person/
day
­­­­­­­­­­­­­­­­­­­­­­­­­­
vii
Estimated
Daily
Dietary
dose:
EDI/
Body
Weight
Adult:
3.45
µ
g
x
mg/
1000
µ
g
/
70
kg
BW/
day
=
4.9
x
10­
5
mg/
kg
BW/
day
Child:
1.75
µ
x
mg/
1000
µ
g/
70
kgBW/
day
=
1.16
x
10­
4
mg/
kg
BW/
day
6
III
BIT
as
Paper
Adhesive
Preservative
Use
Some
AD
Labels
claim
US
FDA
clearance
for
use
as
preservative
use
in
paper
adhesives
in
accordance
with
the
limitations
of
21CFR
175.105,
which
states:
"
migration
levels
for
the
substance
generally
will
be
assumed
to
be
no
greater
than
50
ppb".
Applying
a
consumption
factor
(
CF)
of
0.14
for
adhesives
gives
a
dietary
concentration
of
7
ppb.
It
should
be
noted
that
FDA
derives
the
consumption
factor
(
CF)
from
the
possible
percentage
of
daily
diet
expected
to
contact
the
paper
adhesives.

Calculations:

Estimated
Daily
Intake
(
EDI):
(
Dietary
conc.
X
Daily
food
consumption)
Adult:
(
0.007
µ
g
ai/
g
food)
x
(
300
f
food/
day)
=
21
µ
g
ai
/
person/
day
Child:
((
0.007
µ
g
ai/
g
food)
x
(
1500
g
food/
day)
=
10.
5
µ
g
ai/
person/
day
Estimated
Daily
Dietary
Dose:
EDI/
Body
Weight
Adult:
(
21
µ
g
ai/
day)
x
(
mg/
1000
µ
g)/(
70
kg)
=
0.00030
mg
ai/
kg
bw/
day
Child:
(
10.5
µ
g
ai/
day)
x
(
mg/
1000
µ
g)/(
15
kg)
=
0.0007
mg
ai/
kg
bw/
day
IV.
BIT
as
a
Paper
Coating
Preservative
Use:

As
indicated
by
various
labels
on
BIT
the
active
(
BIT)
is
added
as
preservative
to
paper
coating
formulations
at
a
maximum
application
rate
of
5000
ppm
and
as
the
active
is
10%,
the
actual
application
rate
is
500
ppm.
The
resulting
paper
coating
is
approximately
10%
by
weight
of
the
paper
The
standard
basis
weight
of
paper
is
50
mg/
in2
The
amount
of
food
contacting
the
coated
paper
packaging
is
10
g
of
food/
in2
The
standard
consumption
factor
(
CF)
for
coated
paper
is
0.20
(
fraction
of
daily
diet
expected
to
contact
paper
coatings)
A
100%
migration
of
BIT
is
assumed
from
the
coated
paper
to
the
food
Standard
adult
food
consumption
is
3
kg/
day
and
for
a
child
it
is
1.5
kg/
day
Adult
body
weight
is
70
kg
and
child
body
weight
is
15
kg
Out
Put:

Using
the
equation:

Appl.
Rate
x
%
of
paper
coated
x
basis
paper
wt.
x
surface
area
in
contact
with
food
x
CF
x
%
migration
7
500
µ
g
ai/
g
coating
x
0.10
g
coating/
g
paper
x
0.05
g
paper/
in2
x
in2
paper
/
10
g
food
x
0.2
x
100%
0.050
µ
g
ai/
g
food
or
50
ppb
Determination
of
Estimated
Daily
Intake
(
EDI)
Dietary
Conc.
X
Daily
food
consumption
Adult:
0.050
µ
g/
g
food
x
3000
g
food/
day
=
150
µ
g
ai/
person/
day
Child:
0.050
µ
g/
g
food
x
1500
g
food/
day
=
75
µ
g
ai/
person/
day
Estimation
of
Daily
Dietary
Dose:
EDI/
Body
Weight
Adult:
(
150
µ
g
ai/
day)
x
mg/
1000)
/
70
kg
=
0.0021
mg
ai/
kgbw/
day
Child:
(
75
µ
ai/
day)
x
mg/
1000
µ
g
/
15
kg
=
0.005
mg
ai/
kg
bw/
day
From
toxicological
date,
AD
has
determined
that
acute
PAD
and
chronic
PAD
from
antimicrobials
uses
for
BIT
is
the
same:
0.017
mg/
kg/
day.
%
PAD
=
exposure
/
A
or
c
PAD
x
100.
From
data
in
tables
1
and
2,
%
PAD
are
calculated.
None
of
the
PAD,
acute
or
chronic
dietary
exceed
the
Agency
concerns.

Table
1
Cumulative
Estimated
Dietary
Intake
of
BIT
Use
EDI
(
µ
g/
person/
day)
Daily
Dietary
Dose(
mg/
kg
BW/
day)
Paper
Slimicide
13.8
Adult
6.9
Child
1.97
x
10­
4
Adult
4.6
x
10­
4
Child
Aqueous
Mineral
Slurries
3.45
Adult
1.75
Child
4.9
x
10
­
5
Adult
1.2
x
10­
4
Child
Paper
Adhesive
Preservative
21.0
Adult
10.5
Child
3
x
10­
4
Adult
7
x
10­
4
Child
Paper
Coating
Preservative
150
Adult
75
Child
2.1
x
10­
3
Adult
5
x
10­
3
Child
Cumulative
188.25
Adult
94.5
Child
2.5
x
10­
3
Adult
1.63
x
10­
3
Child
Table
2
Dietary
Risks
of
BIT
Use
Daily
Dietary
Dose
(
mg/
kg
BW
/
day
%
PAD
Pulp/
Paper
Slimicide
1.97
x
10­
4
Adult
4.6
x
10­
4
Child
1.17
Adult
2.7
Child
Aqueous
Mineral
/
Slurries
4.9
x
10­
5
Adult
0.29
Adult
8
1.2
x
10­
4
Child
0.70
Child
Paper
Adhesive
Preservative
3
x
10­
4
Adult
7
x
10­
4
Child
1.76
Adult
4.1
Child
Paper
Coating
Preservative
2.1
x
10­
3
Adult
5.0
x
10­
3
Child
12.35
Adult
29.0
Child
Cumulative
2.5
x
10­
3
Adult
1.63
x
10­
3
Child
15.57
Adult
37.07
Child
BIBLIOGRAPHY
MRID#
CITATIONS
1.
A.
Najm
Shamim:
AD
Document
on:
Dietary
Risk
Assessment
for
Dihalogen
Dialkyl
and
MethylolHydantoins
(
2003).
This
document
lists
the
FDA
assumptions
of
pesticide
migration
form
paper
to
food
through
indirect
food
contact.

2.
Bob
Quick:
AD
Memo
on
Review
of
Lonza
Registration
Request
for
5,5­
Dimethylhydantoins
as
Slimicide
and
Preservative
in
Paper
Manufacture.
Additional
FDA
assumptions
on
pesticide
migration
into
food
from
treated
paper.
(
RASSB
Memo
,
February
2001)

3.
RASSB
Memo
by
Bob
Quick,
with
additional
comments
on
February
2001
Document
4.
Lonza
Document
op
cit
reference
3.
