1
MEMORANDUM
DATE:
September
27,
2005
SUBJECT:
Azadioxabicyclooctane­
Dietary
Exposures
and
Risks
from
Antimicrobial
Indirect
Food
Contact
Uses
FROM:
Cassi
L.
Walls,
Ph.
D.,
Chemist
Risk
Assessment
and
Science
Support
Branch
(
RASSB)
Antimicrobials
Division
(
7510C)

THROUGH:
Norm
Cook,
Branch
Chief
Risk
Assessment
and
Science
Support
Branch
(
RASSB)
Antimicrobials
Division
(
7510C)

TO:
Timothy
F.
McMahon,
Ph.
D.,
Risk
Assessor
Antimicrobials
Division
(
7510C)

Tom
Luminello,
Chemical
Review
Manager
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

PC
Codes:
107001;
107002;
107003
Attached
is
a
review
of
the
dietary
exposures
and
risks
for
the
antimicrobial
uses
of
azadioxabicyclooctane
to
support
the
reregistration
eligibility
decision
(
RED)
document.

Azadioxabicyclooctane
Dietary
Exposure
The
Antimicrobials
Division
(
AD)
assessed
the
potential
dietary
exposure
to
the
active
ingredient,
azadioxabicyclooctane,
from
its
use
as
paper
coating
and
paper
adhesive
preservatives.
Azadioxabicyclooctane
has
been
cleared
by
the
US
Food
and
Drug
Administration
(
US
FDA)
for
use
as
an
antibacterial
preservative
in
paper
and
paperboard
products
contacting
dry
food
only
in
21CFR176.180
as
well
as,
a
component
in
paper
adhesives
in
21CFR175.105.

The
intended
uses
for
azadioxabicyclooctane
have
been
clarified
in
the
Steptoe
and
Johnson
letter
dated
September
19,
2005.
There
is
no
use
intended
for
this
chemical
as
a
pulp
and
paper
preservative(
slimicide
use).
The
current
label
needs
to
be
revised
to
clarify
and
reflect
the
actual
use
patterns
in
the
pulp
and
paper
industry.
As
written,
the
label
permits
use
in
slurries.
This
could
be
interpreted
to
mean
slurries
in
the
paper
pulping
industry.

US
FDA
has
estimated
a
Cumulative
Dietary
Concentration
of
12
ppb
and
a
Cumulative
Dietary
Exposure
Intake
(
CEDI)
of
0.006
mg/
kg/
day
for
azadioxabicyclooctane
(
http://
www.
cfsan.
fda.
gov/~
dms/
opa­
tedi.
html)
however,
AD
does
not
have
the
specific
details
(
i.
e.,
application
rates
or
residue
migration
potential)
used
by
US
FDA
in
their
review
of
this
2
petition.
No
residue
data
have
been
submitted
to
AD
in
support
of
the
azadioxabicyclooctane
indirect
food
contact
uses.
A
screening­
level
assessment
has
been
conducted
using
the
US
FDA's
Center
for
Food
Safety
&
Applied
Nutrition's
(
CFSAN)
approach
as
presented
in
"
Preparation
of
Food
Contact
Notifications
and
Food
Additive
Petitions
for
Food
Contact
Substances:
Chemistry
Recommendations"
dated
April
2002.

AD
calculated
"
worst­
case"
dietary
concentration
values,
as
summarized
in
Table
1,
using
the
labeled
maximum
application
rate
for
the
paper
coating
preservative
use.
The
Steptoe
and
Johnson
letter
clarifies
the
paper
coating
use
that
it
is
intended
for
paper
coatings
in
contact
with
dry
food.
The
label
has
also
been
clarified
for
the
coating
use.
EPA
has
also
used
the
default
US
FDA
assumptions
for
preservation
of
paper
adhesives,
and
have
used
the
EPA
standard
values
for
body
weight.

TABLE
1
Dietary
Exposure
to
Azadioxabicyclooctane
from
Paper
Coating
and
Paper
Adhesive
Preservative
Uses
Use
Dietary
Conc.
(
ppb)
Estimated
Daily
Intake
(
µ
g/
person/
day)
Daily
Dietary
Dose
(
mg/
kg
bw/
day)
Paper
coating
Preservative
5.0
15.
(
adult)
7.5
(
child)
0.00021
(
adult)
0.00050
(
child)
Paper
adhesive
Preservative
7.0
21.0
(
adult)
10.5
(
child)
0.00030
(
adult)
0.00070
(
child)

Paper
Coating
Preservative
Use
Azadioxabicyclooctane
can
be
used
to
preserve
paper­
coating
formulations.
Dietary
exposures
to
azadioxabicyclooctane
from
this
type
of
use
were
estimated
using
the
following
assumptions:

The
FDA
considers
that
the
migration
of
residue
components
in
coated
paper
intended
for
use
with
dry
foods
will
not
exceed
50
ppb
in
the
packaged
food.

 
The
consumption
factor
(
CF)
(
percentage
of
daily
diet
expected
to
contact
paper
coatings)
is
10%.

 
Adult
food
consumption
is
3
kg/
day;
child
food
consumption
is
1.5
kg/
day.

 
Adult
body
weight
is
70
kg;
child
body
weight
is
15
kg.

Calculations:

Determination
of
dietary
concentration:
3
Consumption
factor
x
50
ppb
azadioxabicyclooctane
residue
in
food
x
.1(
CF)
=
5
ppb
Determination
of
the
Estimated
Daily
Intake
(
EDI):
Dietary
conc.
x
Daily
food
consumption
Adult:
(
0.0050
µ
g
ai/
g
food)
(
3000
g
food
/
day)
=
15
µ
g
ai/
person/
day
Child:
(
0.0050
µ
g
ai/
g
food)
(
1500
g
food
/
day)
=
7.5
µ
g
ai/
person/
day
Determination
of
the
Daily
Dietary
Dose:
EDI
/
Body
Weight
Adult:
(
15.0
µ
g
ai
/
day)
(
mg/
1000
µ
g)
/
(
70
kg)
=
0.00021
mg
ai/
kg
bw/
day
Child:
(
7.5
µ
g
ai/
day)
(
mg/
1000
µ
g)
/
(
15
kg)
=
0.0005
mg
ai/
kg
bw/
day
Paper
Adhesive
Preservative
Use
Azadioxabicyclooctane
can
be
used
to
preserve
paper­
adhesive
formulations.
Dietary
exposures
to
azadioxabicyclooctane
from
this
type
of
use
were
estimated
using
the
following
assumptions:

 
Based
on
FDA's
guidance
document,
it
was
assumed
that
a
chemical
used
as
"
an
adhesive
or
adhesive
component
in
accordance
with
the
limitations
of
21CFR175.105,
migration
levels
for
the
substance
generally
will
be
assumed
to
be
no
greater
that
50
ppb.
Applying
a
CF
(
consumption
factor)
of
0.14
for
adhesives
gives
a
dietary
concentration
of
7
ppb"
(
US
FDA,
2002).
Note:
CF
is
the
percentage
of
daily
diet
expected
to
contact
paper
adhesives.

 
Adult
food
consumption
is
3
kg/
day;
child
food
consumption
is
1.5
kg/
day.

 
Adult
body
weight
is
70
kg;
child
body
weight
is
15
kg.

Calculations:

Determination
of
the
Estimated
Daily
Intake
(
EDI):
Dietary
conc.
x
Daily
food
consumption
Adult:
(
0.007
µ
g
ai/
g
food)
(
3000
g
food
/
day)
=
21.0
µ
g
ai/
person/
day
Child:
(
0.007
µ
g
ai/
g
food)
(
1500
g
food
/
day)
=
10.5
µ
g
ai/
person/
day
Determination
of
the
Daily
Dietary
Dose:
EDI
/
Body
Weight
Adult:
(
21.0
µ
g
ai
/
day)
(
mg/
1000
µ
g)
/
(
70
kg)
=
0.00030
mg
ai/
kg
bw/
day
Child:
(
10.5
µ
g
ai/
day)
(
mg/
1000
µ
g)
/
(
15
kg)
=
0.00070
mg
ai/
kg
bw/
day
Cumulative
Dietary
Exposure
Since
azadioxabicyclooctane
can
be
used
as
a
preservative
in
paper
coatings
and
adhesives,
the
dietary
exposures
resulting
from
both
uses
must
be
added
together
because
both
the
coatings
and
adhesives
could
be
used
together
within
one
paper
product.
The
cumulative
4
estimated
dietary
intakes
(
CEDI)
of
azadioxabicyclooctane
from
its
use
in
the
manufacture
of
food­
contact
paper
and
paperboard
are
presented
in
Table
2.

TABLE
2
Cumulative
Estimated
Dietary
Intake
of
Azadioxabicyclooctane
Use
Dietary
Conc.
(
ppb)
Estimated
Daily
Intake
(
µ
g/
person/
day)
Daily
Dietary
Dose
(
mg/
kg
bw/
day)
Paper
Coating
Preservative
5.0
15
(
adult)
7.5
(
child)
0.00021
(
adult)
0.0005
(
child)
Paper
Adhesive
Preservative
7.0
21.0
(
adult)
10.5
(
child)
0.00030
(
adult)
0.00070
(
child)
Cumulative
12.0
36
(
adult)
18
(
child)
0.00051
(
adult)
0.0012
(
child)

Dietary
Risk
of
Azadioxabicyclooctane
Paper
Uses
Utilizing
the
acute
PAD
of
0.01
mg/
kg/
day
and
chronic
PAD
of
0.003
mg/
kg/
day,
the
dietary
risks
were
estimated
and
summarized
in
Table
3.
The
paper
coating
use
and
adhesive
uses
do
not
exceed
the
Agency's
level
of
concern
for
both
the
acute
and
chronic
exposure
durations.

TABLE
3
Dietary
Risks
of
Azadioxabicyclooctane
Use
Daily
Dietary
Dose
(
mg/
kg
bw/
day)
%
aPAD
%
cPAD
5
Paper
Coating
Preservative
0.00021
(
adult)
0.0005
(
child)
2.1%
(
adult)
5%
(
child)
7.0%
(
adult)
16.6%
(
child)
Paper
Adhesive
Preservative
0.00030
(
adult)
0.00070
(
child)
3%
(
adult)
7%
(
child)
10%
(
adult)
23%
(
child)
Cumulative
0.00051
(
adult)
0.0012
(
child)
5.1%
(
adult)
12%
(
child)
17%
(
adult)
39.6%
(
child)
%
PAD
=
exposure/
PAD
x
100
Note:
due
to
spreadsheet
rounding,
the
values
presented
may
not
be
exact
US
Food
and
Drug
Administration
(
US
FDA)
Center
for
Food
Safety
&
Applied
Nutrition's
(
CFSAN).
2002.
"
Preparation
of
Food
Contact
Notifications
and
Food
Additive
Petitions
for
Food
Contact
Substances:
Chemistry
Recommendations."
http://
www.
cfsan.
fda.
gov/~
dms/
opa2pmnc.
html.
April.
