MEMORANDUM
DATE:
September
28,
2005
SUBJECT:
Azadioxabicyclooctane:
AD
Revised
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
(
RED)
Document.
Case
No.
3023.
PC
Codes
107001,
107002,
107003.

FROM:
Tim
McMahon,
Ph.
D.
Senior
Toxicologist
Najm
Shamim,
Ph.
D.
Chemist
Kathryn
Montague,
Biologist
Talia
Milano,
Chemist
Cassi
Walls,
Ph.
D.,
Chemist
Jonathan
Chen,
PhD.,
Toxicologist
Antimicrobials
Division
(
7510C)

TO:
Tom
Luminello,
Chemical
Review
Manager
Team
32,
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

Attached
is
the
Preliminary
Risk
Assessment
for
Azadioxabicyclooctane
for
the
purpose
of
issuing
a
Reregistration
Eligibility
Decision
(
RED).
The
disciplinary
science
chapters
and
other
supporting
documents
for
the
azadioxabicyclooctane
RED
are
also
included
as
attachments
as
follows:
2
Azadioxabicyclooctane:
Report
of
the
Antimicrobials
Divisions's
Toxicology
Endpoint
Selection
Committee
(
ADTC),
May
2005
Toxicology
Science
Chapter
for
the
Reregistration
Eligibility
Decision
Document,
From
M.
Ottley
to
T.
McMahon,
May
2005
Occupational
and
Residential
Exposure
Assessment
for
Azadioxabicyclooctane
.
From
T.
Milano,
Chemist,
to
T.
Luminello,
Chemical
Review
Manager.
July
2005.
Azadioxabicyclooctane­
Dietary
Exposures
and
Risks
from
Antimicrobial
Indirect
Food
Contact
Uses.
Memorandum
from
Cassi
L.
Walls,
Ph.
D.
to
Timothy
F.
McMahon,
Ph.
D.
,
September
2005
Product
Chemistry
of
Azadioxabicyclooctane.
From
Najm
Shamim,
Ph.
D.
to
T.
McMahon,
Ph.
D.
,
April
2005
Environmental
Fate
Assessment
of
Azadioxabicyclooctane
for
the
Reregistration
Eligibility
Decision
(
RED)
Document.
From
Najm
Shamim,
Ph.
D.
Chemist,
to
­­­­­­.
May
2005,
Ecological
Hazard
and
Environmental
Risk
Assessment
for
Azadioxabicyclooctane
to
be
included
in
the
RED.
From
K.
Montague
to
­­­­­­­­
May
2005,
Epidemiology
Assessment
based
on
Incident
Reports.
From
J.
Chen,
Ph.
D.
Toxicologist,
to
Tim
McMahon,
Ph.
D.
Toxicologist
,
May
2005.
3
TABLE
OF
CONTENTS
1.0
EXECUTIVE
SUMMARY
.............................................................................................
5
2.0.
PHYSICAL
AND
CHEMICAL
PROPERTIES
.............................................................
14
2.1
Chemical
Identification.......................................................................................
14
2.2
Physical/
Chemical
Properties..............................................................................
14
3.0
HAZARD
CHARACTERIZATION
..............................................................................
15
3.1
Hazard
Profile....................................................................................................
15
3.2
FQPA
Considerations.........................................................................................
23
3.3
Dose­
Response
Assessment................................................................................
23
3.4
Endocrine
Disruption                       .
25
4.0
EXPOSURE
ASSESSMENT
AND
CHARACTERIZATION
.......................................
25
4.1
Summary
of
Registered
Uses..............................................................................
25
4.2
Dietary
Exposure/
Risk
Pathway
.........................................................................
27
4.2.3
Acute
and
Chronic
Dietary
Exposure
Characterization............................
28
4.3
Water
Exposure/
Risk
Pathway
...........................................................................
29
4.4
Residential
Exposure/
Risk
Pathway....................................................................
29
4.4.1
Handler
..................................................................................................
29
4.4.2.
Post­
application
.....................................................................................
32
5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
..............
32
5.1
Acute
Dietary
Risk.............................................................................................
32
5.2
Chronic
Dietary
Risk..........................................................................................
32
5.3
Short
­
term
Aggregate
Risk................................................................................
32
6.0
CUMULATIVE
EXPOSURE
AND
RISK.....................................................................
33
7.0
OCCUPATIONAL
EXPOSURE
AND
RISK................................................................
34
7.1
Handler                            
..
34
7.2
Post­
application
.................................................................................................
39
8.0
ENVIRONMENTAL
RISK...........................................................................................
40
8.1
Ecological
Hazard
.............................................................................................
40
8.2
Environmental
Fate
and
Transport......................................................................
43
8.3
Environmental
Exposure
and
Risk......................................................................
45
8.4
Endangered
Species
Considerations....................................................................
45
9.0
INCIDENTS
.................................................................................................................
46
a.
OPP=
s
Incident
Data
System
(
IDS)..........................................................
46
b.
Poison
Control
Center
............................................................................
46
4
c.
California
Data
­
1982
­
1986
.................................................................
46
d.
National
Pesticide
Telecommication
Network
(
NPTN)
...........................
46
e.
Published
Scientific
Literature.................................................................
46
10.0
Data
Gaps                              ...
47
11.0
REFERENCES..............................................................................................................
49
1.0
EXECUTIVE
SUMMARY
Azadioxabicyclooctane
(
AZA)
consists
of
an
equilibrium
mixture
of
three
oligomers
(
I:
5­
hydroxymethoxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3,3,0)
octane;
II:
5­
hydroxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3,3,0)
octane;
III:
5­
hydroxypoly(
methylene­
oxy)
[
74%
C2,
21%
C3,
4%
C4,
1%
C5)]
­
methyl­
1­
aza­
3,7­
dioxabicyclo(
3,3,0)
octane).
AZA
is
the
reaction
product
of
the
powder,
2­
Amino­
2­(
hydroxymethyl)­
1,3
propanediol
(
common
synonym:
tris(
hydroxymethyl)
aminomethane)
and
formalin(
50%
aqueous
formaldehyde
solution).
The
resulting
product
is
a
50%
active
aqueous
solution
of
the
three
oligomers
listed
above.
The
most
recent
label
lists
the
ratio
of
these
three
oligomers
as
16%
(
I),
28.8%
(
II),
and
5.2%
(
III)
These
cannot
be
divided
into
components
for
individual
testing.

The
AZA
mixture
is
registered
for
use
as
a
preservative
in
lated
paints,
latex
emulsions,
slurries
and
pigment
dispersions,
inks,
adhesives,
construction
materials
such
as
caulks
and
sealants,
metalworking
fluids,
testile
fiber­
finish
solutions,
paper
coatings
(
limited
to
contact
with
dry
food
only),
general
use
in
petroleum
production
recovery,
and
wax
emulsions.
The
use
of
AZA
in
paper
coatings
will
result
in
indirect
contact
with
food
and
thus
dietary
risks
from
food
residues
must
be
assessed.
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
Hazard
Azadioxabicyclooctane
has
a
moderate
order
of
acute
toxicity
via
the
oral
and
dermal
routes
of
exposure
(
Toxicity
Category
III)
and
a
moderate
to
severe
acute
toxicity
via
the
inhalation
route
(
Toxicity
Category
II).
Azadioxabicyclooctane
produces
severe
irritation
to
the
eyes
(
Toxicity
Category
I)
and
moderate
irritation
to
the
skin
(
Toxicity
Category
III).

Repeated
dose
toxicity
data
for
azadioxabicyclooctane
are
limited
to
a
90­
day
oral
toxicity
study
in
the
rat,
a
21­
day
dermal
toxicity
study
in
the
rabbit,
and
a
dermal
developmental
toxicity
study
in
the
rat.

In
a
90­
day
oral
toxicity
study
(
MRIDs
41641606,
00109245,
410801010),
Nuosept
®
95
(
Lot
No.
005­
267)
was
administered
to
20
CD1
Sprague­
Dawley
derived
rats/
sex/
dose
in
drinking
water
at
dose
levels
of
0,
125,
625,
or
3125
ppm
(
daily
estimated
doses
of
10.6,
56.5,
and
228.9
mg/
kg/
day
in
males
and
12.2,
64.3,
and
255.9
mg/
kg/
day
for
females).
Four
rats/
sex/
group
were
kept
for
a
4­
week
recovery
period
to
determine
reversibility
of
effects.
The
LOAEL
for
this
study
was
determined
to
be
56.5
and
64.3
mg/
kg/
day
in
males
and
females,
respectively,
based
on
reduced
water
consumption.
The
NOAEL
was
determined
to
be
10.6
and
12.2
mg/
kg/
day
for
males
and
females,
respectively.
The
90­
day
study
is
classified
unacceptable/
guideline
but
is
upgradable.

In
a
21­
day
dermal
toxicity
study
(
MRID
41641605),
Nuosept
®
95/
Nuosept
®
C
(
Lot
number
84­
11;
purity
not
reported)
was
administered
directly
to
the
skin
of
New
Zealand
White
rabbits
(
5/
sex/
group)
at
doses
of
0,
100,
300,
and
1000
mg/
kg/
day,
6
hours/
day
for
5
days/
week
during
a
21­
day
period.
No
treatment­
related
effects
were
observed
on
clinical
observations,
mean
6
absolute
or
relative
organ
weights,
food
consumption,
body
weight,
hematology,
or
clinical
chemistry
parameters.
The
systemic
NOAEL
was
determined
to
be
greater
than
or
equal
to
1000
mg/
kg/
day
and
the
LOAEL
greater
than
1000
mg/
kg/
day.
The
dermal
LOAEL
was
determined
to
be
100
mg/
kg/
day
(
based
on
dermal
effects).
A
dermal
NOAEL
for
Nuosept
95/
Nuosept
C
could
not
be
determined
based
on
skin
effects
at
the
low
dose.
This
21­
day
dermal
toxicity
study
in
the
rabbit
is
classified
as
acceptable
(
non­
guideline).

In
a
dermal
developmental
toxicity
study
(
MRID
41537501,
reformat
of
41699001),
Nuosept
®
95
(
Batch
No.
006­
097­
597,
50.38%;)
in
distilled
water
was
applied
dermally
to
mated
female
Crl:
COBS
CD
(
SD)
BR
VAF+
rats
(
25/
dose)
at
dose
levels
of
0,
100,
300,
or
1000
mg/
kg/
day
from
days
6
through
15
of
gestation
(
gd
6­
15).
An
additional
25
mated
female
rats
were
administered
distilled
water
from
gd
6­
15.
There
were
no
treatment
related
effects
in
mortality,
clinical
signs,
weight
gain,
food
consumption,
gross
necropsy
parameters
and
cesarean
parameters.
There
was
clear
evidence
of
maternal
dermal
effects
(
edema,
erythema,
scabbing)
in
all
treatment
groups.
The
LOAEL
for
maternal
dermal
toxicity
was
determined
to
be
100
mg/
kg/
day
(
based
on
dermal
edema,
erythema,
and
scabbing);
a
NOAEL
could
not
be
established.
The
systemic
maternal
toxicity
NOAEL
was
determined
to
be
greater
than
or
equal
to
1000
mg/
kg/
day;
the
systemic
maternal
toxicity
LOAEL
greater
than
1000
mg/
kg/
day.
There
were
no
embryotoxic
or
fetotoxic
effects
observed
in
this
study.
The
developmental
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day;
the
developmental
LOAEL
is
greater
than
1000
mg/
kg/
day.
This
developmental
toxicity
study
in
the
rat
is
classified
as
unacceptable/
guideline
and
is
upgradable.

There
are
no
data
on
the
reproductive
toxicity
of
azadioxabicyclooctane.
There
are
also
no
carcinogenicity
nor
chronic
toxicity
data
for
azadioxabicyclooctane.

Azadioxabicyclooctane
has
been
tested
for
mutagenic
activity
in
several
assays,
including
a
bacterial
DNA
damage/
repair
assay
(
MRID
93050019;
93050020),
dominant
lethal
assay
(
MRID
00088953),
unscheduled
DNA
synthesis
assay
(
MRID
93050021;
42711001;
41642401),
micronucleus
assay
(
41728601),
in
vitro
cell
transformation
assay
(
MRID
93050022),
and
the
Ames
assay
(
MRID
93050017;
93050018).
In
the
Ames
Salmonella
test
,
azadioxabicyclooctane
was
negative
in
all
strains
tested,
but
deficiencies
in
the
studies
were
identified
and
these
deficiencies
must
be
addressed
to
upgrade
the
studies.
Azadioxabicyclooctane
was
also
negative
in
the
micronucleus
assay,
but
was
positive
in
one
unscheduled
DNA
synthesis
assay
(
93050021)
and
the
bacterial
DNA
damage/
repair
assay.
Several
tests
(
MRID
numbers
93050022
through
93050025)
were
conducted
with
C3H/
10T1/
2
cell
cultures
examining
cell
transformation
in
vitro.
Although
results
were
largely
negative,
these
studies
collectively
did
not
properly
identify
the
test
material
being
examined.
In
fact,
only
one
study
(
MRID
93050018)
properly
characterized
the
test
material.
Thus,
although
the
data
suggest
largely
negative
responses,
the
lack
of
test
article
characterization
(
especially
in
light
of
positive
responses
observed
in
two
studies)
points
to
the
need
for
proper
test
article
characterization
before
an
adequate
conclusion
can
be
made
about
the
mutagenicity
of
azadioxabicyclooctane.

From
the
available
repeat
dose
toxicity
studies,
there
was
no
evidence
of
neurotoxicity
of
azadioxabicyclooctane.
7
On
December
5,
2002,
the
Antimicrobials
Division
Toxicology
Endpoint
Selection
Committee
(
ADTC)
reviewed
the
available
Toxicology
data
for
Azadioxacyclooctane
and
discussed
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Azadioxacyclooctane
was
also
evaluated
by
the
committee
in
order
to
meet
the
statutory
requirements
of
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
A
summary
of
the
results
of
this
meeting
is
shown
below.

Dietary
Endpoints:
The
acute
and
chronic
dietary
endpoint
(
reference
dose,
or
RfD)
was
selected
from
a
90­
day
oral
toxicity
study
in
rats
(
MRID
41641606
and
00109245).
The
NOAEL
of
10.6
mg/
kg/
day
was
used
for
both
the
general
population
as
well
as
females
ages
13­
50
based
on
decreased
water
consumption
at
a
dose
of
56.5
mg/
kg/
day
in
the
study.
Although
the
available
data
did
not
show
any
apparent
effect
on
offspring,
the
endpoint
of
10.6
mg/
kg
from
the
90­
day
toxicity
study
was
used
due
to
the
uncertainty
in
the
existing
database
for
possible
effects
that
would
be
relevant
to
the
female
13+
subpopulation.
Using
an
uncertainty
factor
of
1000
for
the
acute
RfD
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
FQPA
hazard
based
safety
factor)
and
an
uncertainty
factor
of
3000
for
the
chronic
RfD
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
3x
for
lack
of
a
long­
term
study
and/
or
endpoint,
10x
FQPA
safety
factor)
the
Acute
and
Chronic
Population
Adjusted
Dose
(
PAD)
values
were
determined
to
be
0.01
and
0.003
mg/
kg/
day
respectively.

Incidental
Oral
Endpoints:
Incidental
oral
endpoints
were
determined
not
to
be
needed
for
azadioxabicyclooctane.
At
this
time,
there
were
no
incidental
oral
exposure
scenarios
identified
from
the
uses
of
azadioxabicyclooctane,
and
therefore
incidental
oral
toxicity
endpoints
were
not
necessary
at
this
time.

Dermal
Endpoints:
Short­,
intermediate­,
and
long­
term
dermal
endpoints
were
based
on
the
results
of
two
studies:
the
21­
day
dermal
toxicity
study
in
rabbits
and
the
dermal
developmental
toxicity
study
in
rats
(
MRIDs
41641605
and
41699001).
Both
of
these
studies
showed
the
presence
of
dermal
effects
at
a
dose
of
100
mg/
kg/
day
but
no
significant
systemic
effects
up
to
and
including
a
limit
dose
of
1000
mg/
kg/
day.
Although
no
systemic
effects
were
noted
from
dermal
application,
the
dermal
irritation
observed
at
100
mg/
kg/
day
in
both
studies
was
selected
for
dermal
risk
assessments.
As
labeling
language
is
not
a
viable
option
for
addressing
the
dermal
irritation
concern
from
some
of
the
registered
uses
of
AZA
(
the
active
ingredient
is
used
as
a
materials
preservative
in
paint,
caulks,
and
sealants)
and
as
metalworking
fluid
use
risk
can
not
be
mitigated
through
use
of
personal
protective
equipment,
the
dermal
irritation
endpoint
was
selected
in
this
case.
An
extra
uncertainty
factor
of
3x
is
applied
to
the
dermal
endpoint,
to
account
for
lack
of
a
NOAEL.
In
addition,
for
the
long­
term
dermal
endpoint,
an
additional
uncertainty
factor
of
3x
is
used
for
lack
of
a
chronic
endpoint.
The
target
MOE
is
therefore
300
for
short­
and
intermediateterm
exposure,
and
1000
for
chronic
exposure.
8
Inhalation
Endpoints:
The
inhalation
endpoint
for
all
durations
of
exposure
was
also
based
on
the
90­
day
oral
toxicity
study
in
rats,
summarized
above
for
the
dietary
endpoint.
In
the
case
of
inhalation,
a
maximum
uncertainty
factor
of
3000
was
applied
to
the
oral
endpoint
selected
for
inhalation
risk
determination.
The
uncertainty
factors
are:
10x
interspecies
extrapolation,
10x
intraspecies
variation;
an
additional
10x
uncertainty
factor
for
extrapolation
from
an
oral
endpoint;
and
a
3x
for
lack
of
adequate
histopathology
reporting
in
the
90­
day
study
that
may
bear
upon
the
conclusions
of
the
study.

There
are
no
carcinogenicity
data
for
azadioxabicyclooctane.
A
determination
of
carcinogenic
potential
cannot
be
made
based
on
the
available
data.
Metalworking
cutting
fluid
use
triggers
the
requirement
for
carcinogenicity
studies
and
chronic
toxicity
studies
as
described
in
the
1987
Antimicrobial
Data
Call
In
Notice.
Based
on
estimated
residues
in
food
from
the
paper
coating
use,
carcinogenicity
and
chronic
toxicity
data
could
also
be
triggered.

FQPA
Safety
Factor:
The
ADTC
recommended
that
the
special
10x
hazard­
based
safety
factor
under
the
FQPA
be
retained
(
10x)
for
azadioxabicyclooctane.
There
is
only
one
prenatal
dermal
developmental
toxicity
study
available
for
azadioxabicyclooctane
and
there
is
no
reproductive
toxicity
information
or
studies.
While
the
developmental
study
showed
no
evidence
of
susceptibility
of
offspring
to
this
chemical,
the
dermal
route
of
administration
is
not
a
good
indicator
of
potential
effects
from
oral
exposures
and
the
available
data
do
not
examine
potential
reproductive
effects
of
the
chemical.
In
addition,
information
on
the
test
article
characterization
is
not
resolved
at
this
time.

Dietary
Exposure
and
Risk:
AD
considered
potential
dietary
exposure
to
azadioxabicyclooctane
from
use
in
paper
coatings.
When
assessing
acute
and
chronic
(
non­
cancer)
dietary
risk,
AD
considered
potential
dietary
exposure
to
the
U.
S.
population
including
infants
and
children
as
well
as
to
females
13­
50
years
Dietary
risk
estimates
are
presented
as
a
percentage
of
the
aPAD
or
chronic
PAD
(
i.
e.
reference
dose
value
divided
by
the
FQPA
safety
factor).
Dietary
exposures
that
are
less
than
100%
of
the
aPAD
or
cPAD
are
below
the
Agency=
s
level
of
concern.

Acute
dietary
risks
were
calculated
from
use
of
azadioxabicyclooctane
in
paper
coating
and
paper
adhesive
preservatives.
Utilizing
the
acute
PAD
of
0.01
mg/
kg/
day
and
chronic
PAD
of
0.003
mg/
kg/
day,
the
dietary
risks
were
estimated.
Cumulative
exposure
from
use
as
a
preservative
in
paper
coatings
and
adhesives
exceeded
100%
of
the
acute
PAD
for
adults
and
children
(
110%
and
386%
respectively).

The
chronic
non­
cancer
dietary
analysis
indicates
risks
of
concern
for
both
children
and
adults
exposed
to
azadioxabicyclooctane
in
paper
coating
and
paper
adhesive
preservatives
(
367%
and
1285%
of
the
chronic
PAD
for
adults
and
children,
respectively
Drinking
Water
Exposure
and
Risk:
None
of
the
uses
associated
with
azadioxabicyclooctane
are
expected
to
impact
either
surface
or
ground
water
resources.
Therefore,
no
drinking
water
9
assessment
was
performed.

Residential
Exposure:
Azadioxabicyclooctane
is
used
as
a
materials
preservative
in
paints.
Dermal
and
inhalation
exposures
and
risks
from
residential
use
of
azadioxabicyclooctane
in
paint
by
brush,
roller
application,
and
airless
sprayer
were
calculated
at
the
maximum
application
rate
of
0.25%
a.
i.
by
weight
and
the
minimum
application
rate
of
0.05%
a.
i.
by
weight.
Only
short­
term
exposures
and
risks
were
assessed,
because
of
the
frequency
that
a
residential
painter
is
assumed
to
come
into
contact
with
azadioxabicyclooctane
treated
paint.
In
addition,
postapplication
residential
dermal
exposures
were
not
assessed
for
contact
with
wet
paint
because
the
paint
is
expected
to
dry
within
a
day,
so
any
potential
exposure
is
expected
to
be
negligible.
The
potential
postapplication
inhalation
exposure
is
also
expected
to
be
minimal
because
azadioxabicyclooctane
has
a
low
vapor
pressure
(
i.
e.
<
2.1x10­
5
mmHg
@
20oC)
and
is,
therefore
not
likely
to
generate
sufficient
vapor
to
cause
an
inhalation
concern
to
the
residential
populations
performing
post
application
tasks,
or
occupying
treated
areas.
At
the
maximum
application
rate,
the
calculated
dermal
MOE
of
780
exceeds
the
acceptable
MOE
of
300
and
is
therefore
not
of
concern.
At
the
minimum
application
rate,
the
calculated
dermal
MOE
of
3900
is
greater
than
both
target
MOEs
of
300
and
1000
and
is
therefore
not
of
concern.
The
inhalation
MOE
from
brush/
roller
application
is
53,000
which
is
not
of
concern
(
target
MOE
=
3000).
From
use
of
paint
treated
with
azadioxabicyclooctane
by
airless
sprayer
application,
dermal
and
inhalation
MOEs
were
also
calculated
at
the
maximum
and
minimum
application
rates.
The
dermal
MOE
of
490
at
the
maximum
application
rate
presents
no
risk
of
short­
term
or
intermediate­
term
risk
(
i.
e.
is
>
300).
At
the
minimum
application
rate,
the
calculated
dermal
MOE
of
2500
presents
no
risk
of
concern.
Inhalation
MOE
for
airless
sprayer
application
at
the
maximum
rate
was
2400,
below
the
target
of
3000,
which
presents
a
risk
of
concern.
However,
at
the
minimum
application
rate,
the
inhalation
MOE
is
calculated
as
12,000,
which
is
not
of
concern.

Aggregate
Exposure
and
Risk:
For
aggregate
exposure
and
risk,
oral
and
inhalation
exposures
to
azadioxabicyclooctane
can
be
aggregated
based
on
the
use
of
the
same
study
and
endpoint
characterizing
exposures
by
these
routes.
Dermal
exposures
are
not
aggregated,
based
on
the
use
of
different
studies
and
endpoint
selected.
Therefore,
aggregate
risk
assessments
would
be
performed
for
short­
term
oral
and
inhalation
and
intermediate­
term
oral
and
inhalation
exposures.
Average
dietary
exposure
is
used
for
estimation
of
oral
exposure
in
the
aggregate
calculation,
consistent
with
the
policy
of
the
Office
of
Pesticide
Programs.
Drinking
water
risk
would
not
be
included
in
aggregate
risk
assessments
as
none
of
the
uses
associated
with
azadioxabicyclooctane
are
expected
to
impact
either
surface
or
ground
water
resources.

A
formal
estimation
of
aggregate
risk
was
not
performed
for
azadioxabicyclooctane,
as
the
dietary
risk
alone
exceeds
the
target
limit
determined
through
the
hazard
identification
by
the
ADTC.
Dietary
exposures
must
be
reduced
to
an
acceptable
level
in
order
for
an
estimation
of
aggregate
risk
to
be
performed.
It
is
assumed
under
the
present
circumstances
that
there
are
risks
of
concern
from
aggregate
exposures,
based
on
the
risk
10
from
dietary
use
alone.

Occupational
Exposure:
The
following
exposed
occupational
populations
have
been
identified:
(
1)
handlers
(
mixers,
loaders,
applicators)
of
azadioxabicyclooctane
treated
products
using
liquid
pour
and
liquid
pump
methods;
and
(
2)
occupational
painter
scenarios;
(
3)
machinist
exposure
to
metalworking
fluids;
(
4)
occupational
post­
application
scenarios.
Exposures
and
risks
were
assessed
for
short­
term
and
intermediate­
term
scenarios.

For
the
handler
scenarios
considered
in
this
assessment,
all
dermal
and
inhalation
calculated
MOEs
were
not
of
concern,
with
the
exception
of
three
scenarios:
(
1)
using
airless
sprayer
application
at
the
maximum
recommended
rate
of
0.25%
a.
i.,
the
calculated
inhalation
MOE
of
720
was
below
the
target
MOE
of
3000.;
(
2)
a
machinist
handling
drilling
muds
treated
at
the
maximum
application
rate
of
0.25%
a.
i.
,
where
the
calculated
inhalation
MOE
of
1800
is
below
the
target
of
3000;
(
3)
machinist
handling
flooding
fluids
treated
with
azadioxabicyclooctane
at
0.25%
a.
i.,
via
liquid
pump,
the
inhalation
MOE
is
1,800,
which
is
less
than
the
target
inhalation
MOE
of
3,000.
However,
at
the
minimum
application
rate,
inhalation
MOEs
are
above
the
target
level
for
these
three
scenarios.

Occupational
post­
application
handler
scenarios
for
metalworking
fluid
exposure
was
assessed
only
for
long­
term
exposure.
The
Dermal
MOE
of
540
at
the
maximum
application
rate
is
below
the
target
of
1000,
but
at
the
minimum
application
rate
of
0.05%
the
dermal
MOE
is
1600,
above
the
target
of
1000
and
is
therefore
not
of
concern.
There
are
no
inhalation
risks
of
concern
for
this
scenario.

Occupational
post­
application
exposure
of
bystanders
with
treated
paint
were
considered
to
be
minimal
and
were
not
assessed.

Environmental
Fate
Assessment:
The
Agency's
database
on
the
environmental
fate
of
azadioxabicyclooctane
is
incomplete;
only
an
abiotic
aqueous
hydrolysis
study
is
available
for
this
mixture.
However,
for
the
present
risk
assessment,
the
Agency's
EPISuite
Program
was
used,
which
is
an
estimation
program
of
physical
and
chemical
characteristics
as
well
as
some
fate
and
transport
parameters
of
chemicals.
This
results
in
a
conservative
fate
assessment
of
azadioxabicyclooctane.
The
three
components
of
azadioxabicyclooctane
identified
are:
5­
hydroxymethoxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3.3.0)
octane
(
16.0%),
(
component
A)
5­
hydroxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3.3.0)
octane
(
28.8%),
(
component
B)
and
5­
hydroxypoly(
methyleneoxy)*
methyl­
1­
aza­
3,7­
dioxabicyclo(
3.3.0)
octane
(
5.2%),
(
component
C)
where
the
polychain
is
extended
as:
74%
C2,
21%
C3,
AND
4%
C4,
AND
1%
C5
(
meaning
from
1
C
to
C5
chain
lengths
of
CH2O
groups
are
added).

Under
abiotic
conditions,
the
azadioxabicyclooctane
mixture
is
hydrolytically
unstable
with
a
half
life
of
0.347
days
at
pH
5,
1.74
days
at
pH
7
,
and
approximately
15
days
at
pH
9.
It
is,
therefore,
not
likely
to
be
persistent
in
water.
11
Components
A
and
B
of
the
mixture
are
likely
to
volatilize
into
the
atmosphere
as
their
vapor
pressures
vary
between
0.0004
to
0.003
mm
Hg.
Component
C
is
likely
to
have
less
volatility
as
the
side
chain
of
CH2O
groups
are
added
into
the
structure.
Estimated
half
lives
in
the
atmosphere
for
components
A
and
B
are
1.2
and
1.4
hours.
Hence
these
two
chemicals
are
not
likely
to
persist
in
the
atmosphere.
Estimated
log
Kow
s
of
components
A
and
B
are
respectively
are
­
2.23
and
­
1.55
(
very
highly
miscible
in
water
and
show
no
tendency
for
dissolving
organic
solvents),
the
mixture
is
not
likely
to
bioaccumulate
in
aquatic
organisms.

MITI
linear
biodegradability
(
modified
linear
biodegradation
method)
for
components
A
and
B
indicates
a
fast
biodegradation
is
highly
probable
in
soils
and
water.
Most
likely
these
pesticides
do
not
pose
a
concern
for
surface
and
ground
water
contamination
Ecological/
Environmental
Risk
Assessment:
The
ecological
hazard
data
for
azadioxabicyclooctane
was
conducted
on
the
formulated
product
Nuosept7
95.
The
percentages
of
the
three
octanes
in
the
formulation
varied
slightly
in
the
submitted
studies;
ratios
are
listed
in
the
tables,
where
information
was
available.
The
EPA=
s
ECOTOX
database
(
EPA,
2002)
was
also
searched
for
avian,
fish,
invertebrate,
mammalian
and
plant
data
on
the
components
of
azadioxabicyclooctane,
but
no
data
were
found
.

Acute
oral
toxicity
testing
required
for
indoor
uses
of
azadioxabicyclooctane
was
conducted
in
the
Mallard
duck.
This
study
indicated
that
Nuosept7
95
is
practically
non­
toxic
to
birds
on
an
acute
oral
basis.
Although
conducted
using
a
formulated
product
and
not
the
TGAI,
these
studies
are
considered
adequate
to
support
the
registered
uses
on
Azadioxabicyclooctane,
as
Nuosept7
95
is
the
only
end­
use
product.
Subacute
dietary
toxicity
testing
using
the
TGAI
is
not
required
for
the
currently
supported
uses
on
Azadioxabicyclooctane;
however,
three
avian
dietary
studies
were
previously
submitted
to
the
Agency.
Results
of
testing
in
the
bobwhite
quail
and
Mallard
duck
indicated
that
Nuosept7
95
is
practically
non­
toxic
to
birds
via
dietary
exposure.
Although
conducted
using
a
formulated
product
and
not
the
TGAI,
these
studies
are
considered
adequate
to
support
the
registered
uses
on
Azadioxabicyclooctane,
as
Nuosept7
95
is
the
only
end­
use
product.

Two
freshwater
fish
toxicity
studies
were
submitted
to
the
Agency
for
azadioxabicyclooctane,
using
the
formulated
product
Nuosept7
95.
These
studies
are
currently
classified
as
supplemental
and
can
potentially
be
upgraded
to
acceptable
if
sufficient
information
on
the
composition
and
purity
of
the
test
substance
used
is
submitted.

Results
of
testing
on
the
aquatic
invertebrate
Daphnia
magna
indicated
that
Nuosept7
95
is
slightly
toxic
to
aquatic
invertebrates
on
an
acute
basis.
Although
conducted
on
the
formulated
product
and
not
the
TGAI,
the
study
is
considered
adequate
to
support
the
currently
registered
uses
of
azadioxabicyclooctane,
since
Nuosept7
95
is
the
only
end­
use
product.
12
Acute
testing
with
estuarine/
marine
organisms
is
required
to
support
the
oil
recovery
uses
of
azadioxabicyclooctane.
This
testing
is
conducted
with
one
fish
species,
a
bivalve,
and
an
additional
invertebrate.
The
results
indicated
that
Nuosept7
95
is
practically
non­
toxic
to
marine/
estuarine
fish
but
slightly
toxic
to
marine/
estuarine
invertebrates.

Overall,
results
of
environmental
testing
of
azadioxabicyclooctane
indicate
that
the
indoor
uses
of
Aza
are
not
likely
to
pose
risk
to
fish,
wildlife
or
plants
due
to
the
low
likelihood
of
exposure
and
the
low
toxicity
of
the
compound.
The
offshore
oil
production
use
of
Aza
was
previously
addressed
(
Environmental
Fate
and
Effects
Division
review,
7/
14/
83),
and
the
application
of
500­
2000
ppm
drilling
fluid
treatment
or
100­
1000
ppm
flooding
fluid
treatment
was
considered
Aunlikely
to
adversely
affect
aquatic
organisms
due
to
the
low
toxicity
and
large
dilution
factor.@
The
Agency
assumes
that
the
waste
streams
occurring
from
terrestrial
oil
production
are
actively
managed
under
local
environmental
regulations
to
prevent
adverse
ecological
effects.

Endangered
Species:
The
Agency
has
developed
the
Endangered
Species
Protection
Program
to
identify
pesticides
whose
use
may
cause
adverse
impacts
on
endangered
and
threatened
species,
and
to
implement
mitigation
measures
that
address
these
impacts.
The
Endangered
Species
Act
requires
federal
agencies
to
ensure
that
their
actions
are
not
likely
to
jeopardize
listed
species
or
adversely
modify
designated
critical
habitat.
To
analyze
the
potential
of
registered
pesticide
uses
to
affect
any
particular
species,
EPA
puts
basic
toxicity
and
exposure
data
developed
for
risk
assessments
into
context
for
individual
listed
species
and
their
locations
by
evaluating
important
ecological
parameters,
pesticide
use
information,
the
geographic
relationship
between
specific
pesticide
uses
and
species
locations,
and
biological
requirements
and
behavioral
aspects
of
the
particular
species.
A
determination
that
there
is
a
likelihood
of
potential
impact
to
a
listed
species
may
result
in
limitations
on
use
of
the
pesticide,
other
measures
to
mitigate
any
potential
impact,
or
consultations
with
the
Fish
and
Wildlife
Service
and/
or
the
National
Marine
Fisheries
Service
as
necessary.

Due
to
the
low
likelihood
of
exposure
and
low
toxicity
of
azadioxabicycloctane,
the
indoor
uses
of
the
compound
are
not
likely
to
adversely
affect
listed
species.
Likewise,
offshore
oil
production
use
of
azadioxabicyclooctane
is
considered
unlikely
to
adversely
affect
listed
species
due
to
the
low
toxicity
of
the
compound
and
the
large
dilution
factor
in
offshore
operations.
The
Agency
assumes
that
the
waste
streams
occurring
from
terrestrial
oil
production
are
actively
managed
under
local
environmental
regulations
to
prevent
adverse
ecological
effects,
and
are
therefore
not
likely
to
adversely
affect
listed
species
or
critical
habitats.
13
Incidence
Report
Assessment:
The
following
databases
were
searched
for
information
on
incidents
involving
exposure
to
azadioxabicyclooctane:

a.
OPP
Incident
Data
System
(
IDS)
b.
Poison
Control
Centers
data
(
1993­
1998)
c.
California
Department
of
Pesticide
Regulation
(
1982­
2002)
d.
National
Pesticide
Telecommunications
Network
(
NPTN)
(
1984­
1991),
and
e.
Published
Incident
Reports
There
were
no
reports
located
of
any
incidents
involving
exposure
to
azadioxabicycloctane.
14
2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
2.1
Chemical
Identification
Chemical
identification
parameters,
including
chemical
and
common/
trade
names,
CAS
Number,
and
molecular
formula
are
provided
in
Table
1.

Table
1.
Chemical
Identification
Chemical
Name
Common/
Trade
Names
Azadioxabicyclooctane
IUPAC
Names
I:
5­
hydroxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3,3,0)
octane;
II:
5­
hydroxymethoxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3,3,0)
octane;
III:
5­
hydroxypoly(
methylene­
oxy)
methyl­
1­
aza­
3,7­
dioxabicyclo(
3,3,0)
octane
Other
Names
Nuosept
95
CAS
Number
56709­
13­
8
Empirical
Formula
50%
aqueous
solution
of
I,
II,
and
III
above
(
ratio
of
28.8%
/
16.0%
/
5.2%).
1
1the
ratio
of
these
isomers
has
been
corrected
on
the
most
recent
Nuosept
®
95
label.
Previous
labels
had
indicated
a
different
ratio
of
the
isomers.

2.2
Physical/
Chemical
Properties
The
physical
and
chemical
properties
of
azadioxabicyclooctane
are
shown
in
Table
2.
15
Table
2.
Physical/
Chemical
Properties
for
Azadioxabicyclooctane
Color
Clear
pale
yellow
Physical
State
Clear
liquid
pH
6.33
at
25oC
Solubility
in
organic
solvents
Hexane
0.2
g/
100
g
at
25oC
Petroleum
ether
0.
2
g/
100
g
at
25oC
Xylene
1.5
g/
100
g
at
25oC
Benzene
2.8
g/
100
g
at
25oC
Ethyl
ether
28.0
g/
100
g
at
25oC
Vapor
Pressure
20­
43
mm
Hg
at
90
oC
<
2.1
x
10­
5
mm
Hg
at
20oC
3.0
HAZARD
CHARACTERIZATION
3.1
Hazard
Profile
A
detailed
hazard
assessment
for
azadioxabicyclooctane
is
presented
in
the
attached
appendix.
Table
3
presents
the
acute
toxicity
data
for
azadioxabicyclooctane.
Table
4
highlights
key
toxicological
studies
for
azadioxabicyclooctane.

Acute
Toxicity.
The
acute
oral
toxicity
of
azadioxabicyclooctane
is
low,
with
a
calculated
median
lethal
dose
of
1940
mg/
kg
from
a
study
in
the
rat
(
MRID
41641601).
Pale
kidneys,
enlarged
spleen,
and
livers
with
focal
hemosiderosis
were
observed
in
this
study.
The
acute
dermal
toxicity
of
azadioxabicyclooctane
is
also
low,
with
a
dermal
median
lethal
dose
of
greater
than
2000
mg/
kg
(
MRID
41671801).
Dermal
effects
were
noted,
but
no
systemic
toxicity.
The
acute
inhalation
toxicity
study
(
MRID
42650901)
showed
a
median
lethal
dose
range
of
between
0.441
mg/
L
and
0.819
mg/
L
in
males,
and
between
0.819
mg/
L
and
1.397
mg/
L
in
females,
with
epistaxis,
labored
breathing,
rales,
and
rhinorrhea
in
all
dose
groups.
Corneal
opacity
was
observed
in
the
primary
eye
irritation
study
(
MRID
41641602)
resulting
in
a
Toxicity
Category
I
classification.
Moderate
dermal
irritation
effects
were
noted
in
the
primary
dermal
irritation
study
(
MRID
41641603),
leading
to
a
Toxicity
category
III
classification.
16
Subchronic
Toxicity
In
a
90­
day
oral
toxicity
study
(
MRIDs
41641606
,00109245,
410801010),
Nuosept
®
95
(
Lot
No.
005­
267)
was
administered
to
20
CD1
Sprague­
Dawley
derived
rats/
sex/
dose
in
drinking
water
at
dose
levels
of
0,
125,
625,
or
3125
ppm
(
daily
doses
were
estimated
to
be
10.6,
56.5,
and
228.9
mg/
kg/
day
in
males
and
12.2,
64.3,
and
255.9
mg/
kg/
day
for
females).
Four
rats/
sex/
group
were
kept
for
a
4­
week
recovery
period
to
determine
reversibility
of
effects.
No
signs
of
toxicity
due
to
Nuosept
95
treatment
were
noted
in
mortality,
clinical
observations,
hematology,
clinical
chemistry,
ophthalmology,
gross
pathology,
or
histopathology.
Body
weight
and
body
weight
gain
were
lower
in
high­
dose
males
and
females
compared
to
their
respective
controls.
Although
food
consumption
was
reduced
in
the
intermediate
and
high­
dose
groups
in
both
males
and
females,
the
food
efficiency
was
unaffected.
Water
consumption
was
drastically
(
approximately
30­
50%)
reduced
in
high­
dose
males
and
females
throughout
the
entire
study
period.
Due
to
the
reduction
in
water
consumption,
the
intake
of
test
article
did
not
reach
predicted
levels.
The
systemic
LOAEL
was
determined
to
be
56.5
and
64.3
mg/
kg/
day
in
males
and
females,
respectively,
based
on
the
reduction
in
water
consumption.
The
systemic
NOAEL
was
determined
to
be
10.6
and
12.2
mg/
kg/
day
for
males
and
females,
respectively.

In
a
21­
day
dermal
toxicity
study
(
MRID
41641605),
Nuosept
®
95/
Nuosept
®
C
(
Lot
number
and
purity
not
reported)
was
administered
directly
to
the
skin
of
New
Zealand
White
rabbits
(
5/
sex/
group)
at
doses
of
0,
100,
300,
and
1000
mg/
kg/
day,
6
hours/
day
for
5
days/
week
during
a
21­
day
period.
No
treatment­
related
effects
on
clinical
observations
and
mean
absolute
or
relative
organ
weights
were
observed.
Significant
findings
were
presented
for
food
consumption,
body
weight,
hematology,
and
clinical
chemistry
parameters,
however
these
findings
were
not
considered
to
be
treatment­
related.
Extensive
damage
to
the
treated
skin
was
observed
in
all
of
the
rabbits
in
the
high­
dose
group.
Numerous
microscopic
changes
in
the
skin
as
well
as
increases
of
neutrophils
and
platelets
were
observed
and
were
considered
to
be
secondary
to
tissue
repair.
The
dermal
LOAEL
is
100
mg/
kg/
day
(
based
on
dermal
effects).
The
dermal
NOAEL
for
Nuosept
95/
Nuosept
C
could
not
be
determined
because
mild
skin
effects
were
observed
at
the
low
dose.
The
systemic
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day
and
the
LOAEL
is
greater
than
1000
mg/
kg/
day.
17
Developmental
Toxicity:
In
a
dermal
developmental
toxicity
study
(
MRID
41537501,
reformat
of
41699001),
Nuosept
®
95
(
Batch
No.
006­
097­
597,
50.38%;)
in
distilled
water
was
applied
dermally
to
mated
female
Crl:
COBS
CD
(
SD)
BR
VAF+
rats
(
25/
dose)
at
dose
levels
of
0,
100,
300,
or
1000
mg/
kg/
day
from
days
6
through
15
of
gestation
(
gd
6­
15).
An
additional
25
mated
female
rats
were
administered
distilled
water
from
gd
6­
15.
There
were
no
treatment
related
effects
in
mortality,
clinical
signs,
weight
gain,
food
consumption,
gross
necropsy
parameters
and
cesarean
parameters.
There
was
clear
evidence
of
maternal
dermal
effects
in
all
treatment
groups.
The
low­
dose
group
had
well­
defined
erythema,
scabbing
that
obscured
some
of
the
treatment
site,
and
well­
defined
edema
in
most
animals
by
study
termination.
The
intermediate­
dose
group
displayed
moderate/
well­
defined
erythema.
Half
of
the
animals
had
scabbing
that
completely
obscured
the
treatment
site,
and
edema
that
was
well­
defined
by
study
termination.
The
highdose
group
exhibited
well­
defined
erythema,
scabbing
that
obscured
the
treatment
site
in
all
animals
by
gd
10,
and
moderate
to
severe
edema
that
extended
to
the
underlying
musculature.
The
LOAEL
for
maternal
dermal
toxicity
is
100
mg/
kg/
day
(
based
on
severe
dermal
irritation);
a
NOAEL
could
not
be
established.
The
systemic
maternal
toxicity
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day;
the
systemic
maternal
toxicity
LOAEL
is
greater
than
1000
mg/
kg/
day.
There
were
no
other
embryotoxic
or
fetotoxic
effects
observed
in
this
study.
The
developmental
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day;
the
developmental
LOAEL
is
greater
than
1000
mg/
kg/
day.

Reproductive
Toxicity
:
There
are
no
reproductive
toxicity
data
available
for
azadioxabicyclooctane.
A
reproductive
toxicity
study
is
normally
required
for
food­
contact
uses
of
antimicrobials
as
well
as
metalworking
fluid
use,
as
is
the
case
for
azadioxabicyclooctane.

Chronic
Toxicity.
There
are
no
chronic
toxicity
studies
available
for
azadioxabicyclooctane.
Metalworking
fluid
use
normally
requires
chronic
toxicity
studies
for
proper
risk
assessment.

Carcinogenicity.
There
are
no
carcinogenicity
data
for
azadioxabicyclooctane.
Metalworking
fluid
use
normally
requires
carcinogenicity
studies
in
two
species
(
rat
and
mouse).

Mutagenicity.
Azadioxabicyclooctane
has
been
tested
for
mutagenic
activity
in
several
assays,
including
a
bacterial
DNA
damage/
repair
assay
(
MRID
93050019;
93050020),
dominant
lethal
assay
(
MRID
00088953),
unscheduled
DNA
synthesis
assay
(
MRID
93050021;
42711001;
41642401),
micronucleus
assay
(
41728601),
in
vitro
cell
transformation
assay
(
MRID
93050022),
and
the
Ames
assay
(
MRID
93050017;
93050018).
In
the
Ames
Salmonella
test
,
azadioxabicyclooctane
was
negative
in
all
strains
tested,
but
deficiencies
in
the
studies
were
identified
and
these
deficiencies
must
be
addressed
to
upgrade
the
studies.
Azadioxabicyclooctane
was
also
negative
in
the
micronucleus
assay,
but
was
positive
in
one
unscheduled
DNA
synthesis
assay
(
93050021)
and
the
bacterial
DNA
damage/
repair
assay.
Several
tests
(
MRID
numbers
93050022
through
93050025)
were
conducted
with
C3H/
10T1/
2
cell
cultures
examining
cell
transformation
in
vitro.
Although
results
were
largely
negative,
these
studies
collectively
did
not
properly
identify
the
test
material
being
examined.
In
fact,
only
one
study
(
MRID
93050018)
18
properly
characterized
the
test
material.
Thus,
although
the
data
suggest
largely
negative
responses,
the
lack
of
test
article
characterization
(
especially
in
light
of
positive
responses
observed
in
two
studies)
points
to
the
need
for
proper
test
article
characterization
before
an
adequate
conclusion
can
be
made
about
the
mutagenicity
of
azadioxabicyclooctane.

Neurotoxicity.
From
the
available
repeat
dose
toxicity
studies,
there
was
no
evidence
of
neurotoxicity
of
azadioxabicyclooctane
Metabolism.
There
are
no
metabolism
data
for
azadioxabicyclooctane.

Table
3.
Acute
Toxicity
Profile
for
Azadioxabicyclooctane
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.1100
(
§
81­
1)
Acute
Oral­
Rat
Nuosept
®
95
(
50%
a.
i.)
MRID
41641601
LD50
=
1940
mg/
kg/
day
III
870.1200
(
§
81­
2)
Acute
Dermal­
Rabbit
Nuosept
®
95
(
50%
a.
i.)
MRID
41671801
LD50
>
2000
mg
/
kg
III
870.1300
(
§
81­
3)
Acute
Inhalation­
Rat
Nuosept
®
95
(
50%
a.
i.)
MRID
42650901
Combined
LC50
 
>
0.441
mg/
L<
0.819
mg/
L
II
870.2400
(
§
81­
4)
Primary
Eye
Irritation­
Rabbit
Nuosept
®
95
(
50%
a.
i.)
MRID
41641602
Corrosive
I
870.2500
(
§
81­
5)
Primary
Dermal
Irritation­
Rabbit
Nuosept
®
95
(
50%
a.
i.)
MRID
41641603
Moderate
irritant
III
870.2600
(
§
81­
6)
Dermal
Sensitization
NA
Assumed
Sensitizer
no
data
available
19
Table
4.
Non­
Acute
Toxicity
Profile
for
Azadioxabicyclooctane
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3100
(
§
82­
1)
90­
day
Oral
­
Rat
Azadioxabicyclooctane
purity
50%
41641606,
reformat
of
00109245,
supplemental
410801010
unacceptable/
guideline
(
upgradeable)
0,
10.6,
56.5,
or
228.9
mg/
kg/
day
(
males)
0,
12.2,
64.3,
or
255.9
mg/
kg/
day
(
females)
1
Oral
Toxicity
(
males)
NOAEL
=
10.6
mg/
kg/
day
(
males)
=
12.2
mg/
kg/
day
(
females)
LOAEL
=
56.5
mg/
kg/
day
(
males)
=
64.3
mg/
kg/
day
(
females)
based
on
reduced
water
consumption.

870.3200
(
§
82­
2)
21­
day
Dermal
­
Rabbit
Azadioxabicyclooctane
purity
not
reported
41641605
Acceptable/
Non­
guideline
0,
100,
300,
or
1000
mg/
kg/
day
Dermal
Toxicity
NOAEL
not
established
LOAEL
=
100
mg/
kg/
day
(
dermal
effects)
Systemic
Toxicity
NOAEL
 
1000
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
1000
mg/
kg/
day
(
not
established)

870.3700a
(
§
83­
3)
Developmental
­
Rat
Azadioxabicyclooctane
purity
50.38%
41537501,
reformat
of
41699001
unacceptable/
guideline
(
upgradable)
0,
100,
300,
or
1000
mg/
kg/
day
Dermal
Maternal
Toxicity
NOAEL
not
established
LOAEL
=
100
mg/
kg/
day
(
dermal
edema,
erythema,
scabbing)
Systemic
Maternal
Toxicity
NOAEL
=
300
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day
(
decreased
body
weight
gain)
Developmental
Toxicity
NOAEL
 
1000
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
1000
mg/
kg/
day
(
not
established)

870.5265
(
§
84­
2)
Salmonella
typhimurium
reverse
mutation
test
Azadioxabicyclooctane
purity
50%
93050017,
reformat
of
00088956
Unacceptable
­
Guideline
0,
0.01,
0.05,
0.23,
0.45,
or
0.9
µ
L/
plate
Negative
There
was
no
evidence
of
induced
mutant
colonies
over
background.
Positive
and
solvent
controls
induced
the
appropriate
responses
in
the
strains
in
which
they
were
tested;
however,
in
the
absence
of
S9­
mix,
only
strains
TA1535
and
TA1537
were
treated
with
a
positive
control
and
in
the
presence
of
the
S9­
mix,
only
strains
TA98,
TA100,
and
TA1538
were
treated
with
a
positive
control.
20
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.5265
(
§
84­
2)
Salmonella
typhimurium
reverse
mutation
test
Azadioxabicyclooctane
purity
50%
93050018,
reformat
of
00088974
Unacceptable
­
Guideline
0,
5,
10,
50,
100,
or
250
µ
g/
plate
(
initial
assay)
0,
375,
500,
625,
or
750
µ
g/
plate
(
second
assay)
Negative
There
was
no
evidence
of
induced
mutant
colonies
over
background.
The
positive
controls
induced
the
appropriate
responses
in
the
corresponding
strains
in
the
presence
of
S9­
mix;
however,
no
positive
control
was
used
in
the
absence
of
S9­
mix.

870.5395
(
§
84­
2)
Mammalian
erythrocyte
micronucleus
test
­
Mouse
Azadioxabicyclooctane
purity
not
reported
41728601
Unacceptable
­
Guideline
0,
300,
600,
or
1200
mg/
kg
(
males)
0,
600,
1200,
or
2400
mg/
kg
(
females)
Negative
There
was
no
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
PCEs
in
either
sex
at
any
tested
dose
at
either
harvest
time.
No
positive
control
was
used
in
females.
Positive
and
solvent
control
values
were
acceptable.

870.5450
(
§
84­
2)
Dominant
Lethal
­
Rat
Azadioxabicyclooctane
purity
50%
240259303
and
93050026,
reformat
of
00088953
Unacceptable
­
Guideline
0,
125,
625,
or
3125
ppm
Negative
There
was
no
significant
difference
between
the
control
group
and
any
Nuosept
95
treated
group
with
respect
to
fertilization
rate,
dead
implantations,
living
implantations,
preimplantation
loss,
or
total
implantations.
The
only
statistically
and
biologically
significant
effect
observed
in
the
high­
dose
group
was
reduced
water
consumption
and
resultant
reduced
body
weight.
Because
Nuosept
95
was
administered
in
the
drinking
water,
this
effect
may
be
due
to
taste
aversion
of
the
test
substance.

870.5500
(
§
84­
2)
Bacterial
DNA
Damage
or
repair
tests
­
Escherichia
coli
and
Salmonella
typhimurium
Azadioxabicyclooctane
purity
50%
93050019,
reformat
of
00088957
Acceptable
­
Guideline
0,
0.03,
0.3,
0.6,
or
0.9
µ
L/
mL
Positive
There
was
evidence
of
greater
growth
inhibition
or
cell
killing
in
repair­
defective
strains
compared
to
repair
competent
strains.
The
negative
solvent
and
positive
controls
induced
the
appropriate
responses
in
the
corresponding
strains.
21
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.5500
(
§
84­
2)
Bacterial
DNA
Damage
or
repair
tests
­
Escherichia
coli
and
Salmonella
typhimurium
Azadioxabicyclooctane
purity
50%
93050020,
reformat
of
00088958
Unacceptable
­
Guideline
0,
50,
100,
500,
1000,
or
5000
µ
g/
mL
Positive
There
was
evidence
of
greater
growth
inhibition
or
cell
killing
in
repair­
defective
strains
compared
to
repair­
competent
strains.
The
number
of
replicate
plates
and/
or
cultures
was
not
given,
individual
plate
counts
were
not
provided
(
just
summary
data),
the
S9­
mix
composition
was
not
given,
no
information
on
the
test
material
except
the
lot
number
was
provided,
and
the
positive
control
for
the
S.
typhimurium
strains
without
S9­
mix
was
not
specified.

870.5550
(
§
84­
2)
Unscheduled
DNA
Synthesis
in
Mammalian
Cells
in
Culture
­
Rat
Azadioxabicyclooctane
purity
not
reported
93050021,
reformat
of
00088959
Unacceptable
­
Guideline
0,
0.0156,
0.0313,
0.0625,
0.125,
0.25,
0.5,
1.0,
or
2.0
µ
L/
mL
Positive
There
was
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[
nuclear
silver
grain
counts].
The
controls
induced
the
appropriate
responses.

870.5550
(
§
84­
2)
Unscheduled
DNA
Synthesis
in
Mammalian
Cells
in
Culture
­
Rat
Azadioxabicyclooctane
purity
not
reported
42711001
Acceptable
­
Guideline
0,
875,
1750,
or
3500
mg/
kg
Negative
There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[
nuclear
silver
grain
counts],
was
induced
by
Nuosept
95
as
tested
in
this
study.
The
positive
and
solvent
controls
induced
the
appropriate
responses.

(
§
84­
4)
Other
Genotoxicity
In
Vitro
Cell
Transformation
Assay
in
CH3/
10T1/
2
Cells
Azadioxabicyclooctane
purity
50%
93050022
reformat
of
00088960
Acceptable
 
Non­
guideline
0,
0.0005,
0.001,
0.002,
or
0.004
µ
L/
mL
Positive
Nuosept
95
was
tested
from
nontoxic
to
toxic
levels
and
both
positive
and
negative
controls
were
appropriate.
Treatment
with
Nuosept
95
induced
transformation
of
the
CH3/
10T1/
2
cells.
The
transformation
frequency
was
low
compared
to
the
positive
control,
there
was
no
dose
response,
and
no
statistical
methods
were
employed
to
demonstrate
significance;
however,
the
spontaneous
transformation
frequency
of
the
test
system
is
virtually
zero,
so
any
induction
of
transformed
foci
in
an
otherwise
adequate
experiment
is
regarded
as
a
positive
result.
22
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
(
§
84­
4)
Other
Genotoxicity
In
Vitro
Cell
Transformation
Assay
in
CH3/
10T1/
2
Cells
Azadioxabicyclooctane
purity
not
reported
93050023
reformat
of
00088961
Unacceptable
 
Non­
guideline
0,
0.0003,
0.001,
or
0.003
µ
L/
mL
Positive
No
Type
II
or
Type
III
foci
of
transformed
cells
were
observed
in
any
treatment
group.
Cytotoxicity
was
evident
at
the
high
dose,
demonstrated
by
reduction
of
relative
cloning
efficiency
below
50%.
Positive
and
solvent
control
values
were
appropriate.

This
study
is
unacceptable/
non­
guideline
because
it
cannot
be
ascertained
whether
T1597
could
have
been
tested
at
a
considerably
higher
dose
and
because
the
duration
of
incubation
of
the
cell
cultures
following
treatment
was
not
precisely
specified.

(
§
84­
4)
Other
Genotoxicity
In
Vitro
Cell
Transformation
Assay
in
CH3/
10T1/
2
Cells
Azadioxabicyclooctane
purity
not
reported
93050024
reformat
of
00088962
Acceptable
 
Non­
guideline
0,
0.0098,
0.0195,
0.039,
or
0.078
µ
L/
mL
Negative
R­
1162
was
tested
from
nontoxic
to
toxic
levels.
Positive
and
solvent
control
values
were
anomalous
when
expressed
as
relative
cloning
efficiency,
probably
due
to
low
survival
in
the
solvent
control
plates.
Since
survival
in
the
test
and
positive
control
cultures
was
not
reduced,
a
toxic
effect
of
the
solvent
is
not
indicated.
No
transformed
foci
were
observed
in
the
solvent
controls,
and
the
positive
controls
produced
the
expected
number
of
transformed
foci,
so
the
assay
remains
valid.
Treatment
with
R­
1162
did
not
induce
morphologic
transformation
of
CH3/
10T1/
2
cells.

(
§
84­
4)
Other
Genotoxicity
In
Vitro
Cell
Transformation
Assay
in
CH3/
10T1/
2
Cells
Azadioxabicyclooctane
purity
not
reported
93050025
reformat
of
00088963
Acceptable
 
Non­
guideline
0,
0.0006,
0.0012,
0.0024,
or
0.0048
µ
L/
mL
Negative
R­
1143
was
tested
from
nontoxic
to
toxic
levels.
Positive
and
solvent
control
values
were
appropriate.
Treatment
with
R­
1143
did
not
induce
morphologic
changes.
23
3.2
FQPA
Considerations
Under
the
Food
Quality
Protection
Act
(
FQPA),
P.
L.
104­
170,
which
was
promulgated
in
1996
as
an
amendment
to
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
and
the
Federal
Food,
Drug
and
Cosmetic
Act
(
FFDCA),
the
Agency
was
directed
to
"
ensure
that
there
is
a
reasonable
certainty
that
no
harm
will
result
to
infants
and
children"
from
aggregate
exposure
to
a
pesticide
chemical
residue.
The
law
further
states
that
in
the
case
of
threshold
effects,
for
purposes
of
providing
this
reasonable
certainty
of
no
harm,
"
an
additional
tenfold
margin
of
safety
for
the
pesticide
chemical
residue
and
other
sources
of
exposure
shall
be
applied
for
infants
and
children
to
take
into
account
potential
pre­
and
post­
natal
toxicity
and
completeness
of
the
data
with
respect
to
exposure
and
toxicity
to
infants
and
children.
Notwithstanding
such
requirement
for
an
additional
margin
of
safety,
the
Administrator
may
use
a
different
margin
of
safety
for
the
pesticide
residue
only
if,
on
the
basis
of
reliable
data,
such
margin
will
be
safe
for
infants
and
children."

The
toxicology
database
for
Azadioxacyclooctane
with
respect
to
assessing
sensitivity
of
infants
and
children
is
not
complete.
With
respect
to
addressing
sensitivity
of
infants
and
children,
there
is
only
one
study,
a
developmental
toxicity
study
in
rats
conducted
by
the
dermal
route,
available
for
this
chemical
.
Further,
this
study
contains
several
deficiencies
that
must
be
addressed
to
satisfy
the
870.3700
guideline.
From
the
available
repeat
dose
toxicity
studies,
there
was
no
evidence
of
neurotoxicity
of
azadioxabicyclooctane.
However,
the
ADTC
concluded
that,
given
the
data
gaps
for
developmental
and
reproductive
toxicity
for
this
chemical,
neurotoxicity
testing
may
be
required
upon
submission
and
review
of
the
missing
data
for
azadioxabicyclooctane.

The
ADTC
recommended
that
the
special
10x
hazard­
based
safety
factor
under
the
FQPA
be
retained
(
10x)
for
azadioxabicyclooctane.
There
is
only
one
prenatal
dermal
developmental
toxicity
study
available
for
azadioxabicyclooctane
and
there
is
no
reproductive
toxicity
information
or
studies.
While
the
developmental
study
showed
no
evidence
of
susceptibility
of
offspring
to
this
chemical,
the
route
of
administration
is
not
a
good
indicator
of
potential
effects
from
oral
exposures.
In
addition,
as
noted
above,
information
on
the
test
article
characterization
is
not
resolved
at
this
time.

3.3
Dose­
Response
Assessment
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
in
Table
5
below.
24
Table
5.
Toxicological
Endpoint
Selection
for
Azadioxabicyclooctane
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
gen.
pop.)
NOAEL
=
10.6
mg/
kg/
day
UF
=
100
FQPA
SF
=
10x
aPAD
=
acute
RfD
FQPA
SF
=
0.01
mg/
kg/
day
90
day
oral
toxicity
in
rats
NOAEL
=
10.6
mg/
kg/
day
based
on
decreased
water
consumption
at
56.5
mg/
kg/
day
in
males.

Acute
Dietary
(
females
13+)
NOAEL
=
10.6
mg/
kg/
day
UF
=
100
FQPA
SF
=
10x
aPAD
=
acute
RfD
FQPA
SF
=
0.01
mg/
kg/
day
90
day
oral
toxicity
in
rats
NOAEL
=
10.6
mg/
kg/
day
based
on
decreased
water
consumption
at
56.5
mg/
kg/
day
in
males.

Chronic
Dietary
(
All
populations)
NOAEL
=
10.6
mg/
kg/
day
UF
=
300
FQPA
SF
=
10x
cPAD
=
chronic
RfD
FQPA
SF
=
0.003
mg/
kg/
day
90
day
oral
toxicity
in
rats
NOAEL
=
10.6
mg/
kg/
day
based
on
decreased
water
consumption
at
56.5
mg/
kg/
day
in
males.

Short­
Term/
Intermediate­
term
Incidental
Oral
(
1­
30
days;
30
days­
6
months)
No
endpoint
required
Dermal
(
all
durations)
Dermal
LOAEL
=
100
mg/
kg/
day
Occupational
MOE
=
300
(
ST
and
IT)

=
1000
(
LT)
Co­
critical
studies:

21­
day
dermal
toxicity
in
rabbits
LOAEL
=
100
mg/
kg/
day
(
severe
dermal
effects)

developmental
toxicity
in
rats
LOAEL
=
100
mg/
kg/
day
(
severe
dermal
effects)

Inhalation
(
all
durations
)
NOAEL=
10.6
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
MOE
=
3000
(
occupational
and
residential)
90
day
oral
toxicity
in
rats
NOAEL
=
10.6
mg/
kg/
day
based
on
decreased
water
consumption
at
56.5
mg/
kg/
day
in
males.
25
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Cancer
(
oral,
dermal,
inhalation)
No
cancer
data
available
Notes:

UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
3.4
Endocrine
Disruption
EPA
is
required
under
the
Federal
Food
Drug
and
Cosmetic
Act
(
FFDCA),
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC=
s
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
has
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency=
s
EDSP
have
been
developed,
azadioxabicyclooctane
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

4.0
EXPOSURE
ASSESSMENT
AND
CHARACTERIZATION
4.1
Summary
of
Registered
Uses
Azadioxabicyclooctane,
a
microbiocide/
microbiostat
that
controls
slime
forming
bacteria
and
fungi,
is
registered
for
use,
per
label
number
1529­
28,
in
latex
paints,
latex
emulsions,
pigment
dispersions,
inks,
adhesives,
construction
materials,
metalworking
fluids,
textile
fiber
finish
(
only
for
use
on
fibers
that
don't
come
into
direct
contact
with
skin),
paper
coatings
and
paper
adhesives,
general
use
in
petroleum
production
and
recovery,
and
wax
emulsions.
It
26
should
be
noted
that
the
current
label
(
EPA
Reg.
No.
1529­
28)
states
that
azadioxabicyclooctane
can
be
used
as
a
"
pulp
and
paper"
preservative
which
could
imply
the
slimicide
use.
However,
the
slimicide
use
for
azadioxabicyclooctane
has
not
been
cleared
by
US
FDA
and
was
therefore
not
assessed
in
this
document.
If
the
registrant
decides
to
support
the
slimicide
use,
this
information
needs
to
be
provided.
Currently,
there
is
only
one
formulation
of
azadioxabicyclooctane
that
is
registered
for
use
in
the
United
States.
This
formulation
is
a
soluble
concentrate/
liquid
that
contains
approximately
50
percent
active
ingredient.
The
active
ingredient
is
an
equilibrium
mixture
of
three
azadioaxabicyclootanes:
5­
Hydroxymethl­
1­
aza­
3,
7­
dioxabicyclo(
3.3.0)
octane
(
16.0%
of
the
product
formulation),
5­
Hydroxymethoxymethyl­
1­
aza­
3,
7­
dioxabicyclo(
3.3.0)
octane
(
28.8%
of
the
product
formulation),
and
5­(
Hydroxypoly[
methyleneoxy
(
74%
C2,
21%
C3,
4%
C4,
1%
C5)])­
1­
aza­
3,
7­
dioxabicyclo(
3.3.0)
octane
(
5.2%
of
the
product).
Removal
of
any
one
of
these
components
will
shift
the
equilibrium
to
replace
the
missing
component,
which
results
in
a
different
chemical
with
different
properties
Occupational
and
residential
handler
scenarios
considered
in
this
assessment
are
summarized
in
Table
6.
These
scenarios
were
selected
based
on
examination
of
product
labels
describing
uses
for
the
product.

Table
6.

AD
Use
Category
Exposure
Scenario
Occupational
Exposures
Worker
pouring
or
pumping
azadioxabicyclooctane
as
a
preservative
into
adhesives
(
natural­
based
or
synthetic),
caulks,
latex
emulsions,
wax
emulsions,
latex
paint,
inks,
pigment
dispersion,
pigment
slurry,
sealants,
and
textile
fiber
finishes.

Worker
pouring
or
pumping
azadioxabicyclooctane
as
a
preservative
into
metalworking
fluids.

Worker
pouring
or
pumping
azadioxabicyclooctane
as
a
preservative
into
paper
coatings.
a
Professional
application
of
paint
treated
with
azadioxabicyclooctane
using
an
airless
spraying
application
method.

Professional
application
of
paint
treated
with
azadioxabicyclooctane
using
a
paint
brush.
Material
Preservatives
Worker
pouring
or
pumping
azadioxabicyclooctane
as
a
preservative
into
drilling
muds
and
flooding
fluids
for
gas/
oil
recovery
systems.
27
AD
Use
Category
Exposure
Scenario
Residential
Exposures
Applying
paint
treated
with
azadioxabicyclooctane
using
an
airless
sprayer
application
method.
Material
Preservatives
Applying
paint
treated
with
azadioxabicyclooctane
using
a
paint
brush.

a:
The
discrepancy
on
label
1529­
28
needs
to
be
clarified
as
to
whether
or
not
azadioxabicyclooctane
is
used
for
pulp
and
paper
or
for
paper
coatings
because
both
of
these
uses
are
on
the
label,
but
a
rate
is
only
provided
for
the
paper
coating
use.

4.2
Dietary
Exposure/
Risk
Pathway
Potential
dietary
exposures
to
the
active
ingredient,
azadioxabicyclooctane,
from
its
uses
as
paper
coating
and
paper
adhesive
preservative
were
assessed.
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.
It
should
be
noted
that
the
current
label
(
EPA
Reg.
No.
1529­
28)
states
that
azadioxabicyclooctane
can
be
used
as
a
"
pulp
and
paper"
preservative
which
could
imply
the
slimicide
use.
However,
the
slimicide
use
for
azadioxabicyclooctane
has
not
been
cleared
by
US
FDA
and
was
therefore
not
assessed
in
this
document.

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
petition.
Furthermore,
no
residue
data
have
been
submitted
to
AD
in
support
of
the
azadioxabicyclooctane
indirect
food
contact
uses.
Therefore,
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
(
0.25%
or
2500
ppm
of
the
paper
coating)
(
EPA
Reg.
No.
1529­
28),
US
FDA's
default
assumptions
for
preservation
of
paper
adhesives,
and
EPA's
standard
values
for
body
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
estimated
dietary
intakes
(
CEDI)
of
azadioxabicyclooctane
from
its
use
in
the
manufacture
of
food­
contact
paper
28
and
paperboard
are
presented
in
the
following
Tables:

Table
7
Use
Dietary
Conc.
(
ppb)
Estimated
Daily
Intake
(
µ
g/
person/
day)
Daily
Dietary
Dose
(
mg/
kg
bw/
day)
Paper
Coating
Preservative
125.0
375.0
(
adult)
187.5
(
child)
0.0054
(
adult)
0.013
(
child)
Paper
Adhesive
Preservative
7.0
21.0
(
adult)
10.5
(
child)
0.00030
(
adult)
0.00070
(
child)
Cumulative
132.0
396.0
(
adult)
198.0
(
child)
0.0057
(
adult)
0.013
(
child)

a
Adult
Male
Dose
=
EDI/
70
kg
body
weight
b
Adult
Female
Dose
=
EDI/
60
kg
body
weight
c
Child
Dose
=
EDI/
15
kg
body
weight
4.2.3
Acute
and
Chronic
Dietary
Exposure
Characterization
Utilizing
the
acute
PAD
of
0.01
mg/
kg/
day
and
chronic
PAD
of
0.003
mg/
kg/
day,
dietary
risks
were
estimated
and
summarized
in
Table
3.
None
of
the
estimated
exposures
exceeds
the
level
of
concern
for
either
acute
or
chronic
dietary
exposure
in
adults
and
children
as
noted
in
the
table
below.

Table
8:
Estimated
Dietary
Risk
of
Azadioxabicyclooctance
Use
Daily
Dietary
Dose
(
mg/
kg
bw/
day)
%
aPAD
%
cPAD
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)
29
4.3
Water
Exposure/
Risk
Pathway
None
of
the
uses
associated
with
azadioxabicyclooctane
are
expected
to
impact
either
surface
or
ground
water
resources.
Therefore,
no
drinking
water
assessment
was
performed.

4.4
Residential
Exposure/
Risk
Pathway
4.4.1
Handler
Short­
term
exposure
scenarios
identified
for
residential
handlers
are
airless
spraying
and
brush
painting,
both
of
which
arise
as
a
result
of
the
chemical
being
incorporated
as
a
material
preservative
into
paints.
Based
on
end­
use
product
application
methods
and
use
amounts,
it
is
assumed
that
exposures
while
applying
paints
will
be
equal
to
or
greater
than
exposures
that
may
occur
when
an
individual
uses
any
of
the
other
end
use
products
on
label
1529­
28
(
i.
e:
caulks,
inks,
sealants).
Therefore,
residential
handler
exposures
were
assessed
for
the
application
of
paint,
as
this
scenario
represents
maximum
possible
exposure
to
the
chemical.
Also,
it
is
important
to
note
that
label
1529­
28
restricts
the
textile
fiber
finish
use
of
azadioxabicyclooctane
to
fibers
that
are
not
in
direct
contact
with
the
skin,
and
for
this
reason,
the
textile
exposure
was
not
assessed
for
the
residential
setting.

The
daily
dose
(
dermal
and
inhalation),
and
MOEs
for
residential
exposures
are
shown
below:
30
Table
9.0
Short­
Term
Exposures
and
MOEs
for
Residential
Uses
of
Azadioxabicyclooctane
Unit
Exposure
Daily
Dose
(
mg
a.
i./
kg
per
day)
g
MOE
h
Exposure
Scenario
Method
of
Application
Dermal
Unit
Exposure
(
mg/
lb
a.
i.)
Inhalation
Unit
Exposure
(
mg/
lb
a.
i.)
Application
rate
(%
a.
i.
by
weight
of
material
being
treated
=
%
product
by
weight
of
material
treated
x
50%
a.
i.)
Quantity
of
treated
material
handled
per
day
(
lbs)
Dermal
Dose
Inhalation
Dose
Dermal
(
target
=
300)
Inhalation
(
target
=
3000)

Brush/
Roller
230a
0.280c
0.25%
(
max)
20e
(
2
gallons)
0.1643
0.0002
609
53,000
Airless
Sprayer
79b
0.83d
0.25%
(
max)
150
f
(
15
gallons)
0.4232
0.004446
236
2.400
Paints
Airless
Sprayer
79b
0.83d
0.05%
(
min)
i
150
f
(
15
gallons)
0.0846
0.000889
1,181
12,000
a,
c:
The
Unit
Exposures
for
the
brush/
roller
scenario
are
from
the
Residential
SOP's
for
paintbrush
application.

b,
d:
The
Unit
Exposures
for
the
airless
sprayer
scenario
are
from
the
Residential
SOP's
for
the
airless
spraying
application.

e:
This
value
is
from
the
AD
SOP
section
titled
Residential
Handlers
in
which
the
quantity
used
for
the
paintbrush/
roller
application
is
assumed
to
be
2
gallons
(
90th
percentile
value
of
8
gallons
of
latex
paint
used
per
year
divided
by
the
mean
frequency
of
4
painting
events/
year).
As
a
result,
2
gallons
paint
preserved/
day
x
10
lb/
gal
paint
(
density
of
paint)
=
20
lbs
of
treated
paint
handled.

f:
This
value
is
from
the
AD
SOP
section
titled
Residential
Handlers
in
which
the
quantity
used
for
the
airless
painting
application
is
assumed
to
be
15
gallons
(
based
on
coverage
of
200ft2/
gal
and
house
size
of
40
x
30
x
20
ft
(
surface
area
of
2,800ft2)).
The
density
of
paint
is
assumed
to
be
10
lb/
gal,
so
that
15
gallons
x
10
lb/
gal
=
150
lbs
of
treated
paint
handled.

g:
Daily
Dose
(
mg
a.
i./
kg
per
day)
=
Unit
Exposure
(
mg/
lb
a.
i.)
x
rate
x
amount
handled
x
(
1/
body
weight
(
kg))

h:.
MOE
=
Toxicity
Endpoint
(
mg/
kg/
day)
/
Daily
Dose
(
mg/
kg/
day);
where
dermal
NOAEL
=
100
mg/
kg/
day
and
the
inhalation
LOAEL
=
10.6
mg/
kg/
day
i:
The
minimum
application
rate
of
0.1
%
product
by
weight
of
the
latex
paint
treated
was
assessed
because
the
inhalation
MOE
for
the
airless
sprayer
application
was
of
concern
for
a
painter
using
the
paint
that
has
been
treated
at
the
maximum
allowable
rate.
31
Dermal
risks
from
exposure
to
azadioxabicyclooctane
in
paint
by
brush
or
roller
application
were
calculated
at
the
maximum
application
rate
of
0.25%
a.
i.
by
weight.
At
the
maximum
application
rate,
the
calculated
dermal
MOE
of
609
exceeds
the
target
MOE
of
300
for
short­
term
exposure
and
is
therefore
not
of
concern.

Dermal
risk
from
use
of
paint
treated
with
azadioxabicyclooctane
by
airless
sprayer
application
were
calculated
at
the
maximum
and
minimum
application
rates.
The
dermal
MOE
of
236
at
the
maximum
application
rate
presents
a
risk
of
concern
in
that
it
is
less
than
the
target
MOE
of
300.
At
the
minimum
application
rate,
however,
the
calculated
dermal
MOE
of
1181
exceeds
the
target
value
of
300
and
therefore
presents
no
risk
of
concern.

The
calculated
inhalation
MOE
for
the
paint
use
of
azadioxabicyclooctane
from
brush/
roller
application
was
not
of
concern
(
MOE
of
53,000,
in
excess
of
the
3000
target).
However,
application
by
airless
sprayer
presented
risks
of
concern
for
inhalation
exposure
when
used
at
the
maximum
application
rate,
where
the
inhalation
MOE
of
2400
falls
below
the
acceptable
MOE
of
3000.
At
the
minimum
application
rate,
the
inhalation
MOE
for
this
scenario
was
acceptable
(
MOE
of
12,000).
32
4.4.2
Post­
application
Residential
post
application
exposures
occur
when
bystanders
contact
areas
in
which
the
antimicrobial
end
use
product
has
recently
been
applied.
For
azadioxabicyclooctane
there
are
no
potential
dermal
post
application
exposures
to
assess.
As
for
inhalation
post
application
exposures,
these
are
expected
to
be
minimal
because
the
paint
is
dry
and
the
vapor
pressure
of
azadioxabicyclooctane
is
negligible.

5.0
AGGREGATE
RISK
ASSESSMENTS
AND
RISK
CHARACTERIZATION
As
concluded
by
the
ADTC,
oral
and
inhalation
exposures
to
azadioxabicyclooctane
can
be
aggregated
based
on
the
use
of
the
same
study
and
endpoint
characterizing
exposures
by
these
routes.
Dermal
exposures
are
not
aggregated,
based
on
the
use
of
different
studies
and
endpoint
selected.
Average
dietary
exposure
is
used
for
estimation
of
oral
exposure
in
the
aggregate
calculation,
consistent
with
the
policy
of
the
Office
of
Pesticide
Programs.
Drinking
water
risk
was
not
included
in
aggregate
risk
assessments
as
none
of
the
uses
associated
with
azadioxabicyclooctane
are
expected
to
impact
either
surface
or
ground
water
resources.

Using
this
approach,
aggregate
risks
were
calculated
for
adults
from
oral
exposure
and
residential
painting
exposure
scenarios.
No
aggregate
scenarios
were
identified
for
children.

5.1
Acute
and
Chronic
Aggregate
Dietary
Risk
There
is
only
one
source
of
dietary
exposure
to
azadioxabicyclooctane,
that
from
use
in
paper
making
in
coatings
and
adhesives.
As
noted
in
this
risk
assessment,
cumulative
dietary
risk
from
use
in
paper
coatings
and
paper
adhesives
was
not
of
concern
for
acute
dietary
exposures
in
adults
or
children
(
5.1
and
12%
of
the
aPaD,
respectively),
or
for
chronic
dietary
exposure
in
adults
and
children
(
17%
and
39.6%
of
the
cPaD
respectively).

5.2
Short­
Term
Aggregate
Risk
Short­
term
aggregate
risk
was
only
quantified
for
adults
,
combining
the
dietary
exposure
and
the
painting
inhalation
exposure
scenarios.
Using
the
Aggregate
Risk
Index
approach
as
published
in
the
Agency's
guidance
(
based
on
the
differing
magnitude
of
the
uncertainty
factors
assigned
to
oral
and
inhalation
risk),
ARIs
for
short­
term
aggregate
exposure
in
adults
were
calculated
as
10
and
3.3
for
the
brush/
roller
painting
application
and
airless
sprayer
application
respectively.
As
these
ratios
are
greater
than
1,
there
is
no
risk
of
concern
from
aggregate
exposure
in
adults.
33
6.0
CUMULATIVE
RISK
FQPA
(
1996)
stipulates
that
when
determining
the
safety
of
a
pesticide
chemical,
EPA
shall
base
its
assessment
of
the
risk
posed
by
the
chemical
on,
among
other
things,
available
information
concerning
the
cumulative
effects
to
human
health
that
may
result
from
dietary,
residential,
or
other
non­
occupational
exposure
to
other
substances
that
have
a
common
mechanism
of
toxicity.
The
reason
for
consideration
of
other
substances
is
due
to
the
possibility
that
low­
level
exposures
to
multiple
chemical
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
could
lead
to
the
same
adverse
health
effect
as
would
a
higher
level
of
exposure
to
any
of
the
other
substances
individually.
A
person
exposed
to
a
pesticide
at
a
level
that
is
considered
safe
may
in
fact
experience
harm
if
that
person
is
also
exposed
to
other
substances
that
cause
a
common
toxic
effect
by
a
mechanism
common
with
that
of
the
subject
pesticide,
even
if
the
individual
exposure
levels
to
the
other
substances
are
also
considered
safe.

AD
did
not
perform
a
cumulative
risk
assessment
as
part
of
this
RED
for
azadioxabicyclooctane
because
AD
has
not
yet
initiated
a
review
to
determine
if
there
are
any
other
chemical
substances
that
have
a
mechanism
of
toxicity
common
with
that
of
azadioxabicyclooctane.
For
purposes
of
this
RED,
EPA
has
assumed
that
azadioxabicyclooctane
does
not
have
a
common
mechanism
of
toxicity
with
other
substances.

On
this
basis,
the
Registrant
must
submit,
upon
EPA
=

s
request
and
according
to
a
schedule
determined
by
the
Agency,
such
information
as
the
Agency
directs
to
be
submitted
in
order
to
evaluate
issues
related
to
whether
azadioxabicyclooctane
shares
a
common
mechanism
of
toxicity
with
any
other
substance
and,
if
so,
whether
any
tolerances
for
azadioxabicyclooctane
need
to
be
modified
or
revoked.
If
AD
identifies
other
substances
that
share
a
common
mechanism
of
toxicity
with
azadioxabicyclooctane,
AD
will
perform
aggregate
exposure
assessments
on
each
chemical,
and
will
begin
to
conduct
a
cumulative
risk
assessment.

The
Health
Effects
Division,
Office
of
Pesticide
Programs,
has
recently
developed
a
framework
proposed
for
conducting
cumulative
risk
assessments
on
substances
that
have
a
common
mechanism
of
toxicity.
This
guidance
was
issued
for
public
comment
on
January
16,
2002
(
67
FR
2210­
2214)
and
is
available
from
the
OPP
Website
at:
http://
www.
epa.
gov/
pesticides/
trac/
science/
cumulative_
guidance.
pdf.
In
the
guidance,
it
is
stated
that
a
cumulative
risk
assessment
of
substances
that
cause
a
common
toxic
effect
by
a
common
mechanism
will
not
be
conducted
until
an
aggregate
exposure
assessment
of
each
substance
has
been
completed.

Before
undertaking
a
cumulative
risk
assessment,
AD
will
follow
procedures
for
identifying
chemicals
that
have
a
common
mechanism
of
toxicity
as
set
forth
in
the
A
Guidance
for
Identifying
Pesticide
Chemicals
and
Other
Substances
that
Have
a
Common
Mechanism
of
Toxicity
@

(
64
FR
5795­
5796,
February
5,
1999).
34
7.0
OCCUPATIONAL
EXPOSURE
AND
RISK
7.1
Occupational
Handler
The
exposure
scenarios
identified
for
occupational
workers
are
the
liquid
pour
and
liquid
pump
applications
of
this
chemical
when
it
is
used
as
a
preservative
for
the
label­
specified
materials.
There
are
also
occupational
painter
scenarios
(
which
result
from
the
chemical
being
incorporated
as
a
preservative
into
paints)
that
involve
the
methods
of
applications
of
airless
spraying
and
brush
painting.
The
use
rates
(
maximum
and
minimum)
for
all
potential
uses
of
azadioaxabicyclooctane,
and
the
assumptions
used
to
calculate
them,
are
presented
in
Table
6.1.
The
rates
that
are
provided
in
the
table
are
the
%
product
by
weight
of
material
treated,

along
with
the
%
a.
i.
by
weight
of
material
treated
in
parentheses.
35
Table
10.0:
Short
and
Intermediate
Term
Azadioxabicyclooctane
Exposures
and
MOEs
Associated
with
Occupational
Handlers
a
Unit
Exposure
Daily
Dose
(
mg
a.
i./
kg
per
day)
q
MOEr
Substrate
Treated/
Handled
through
Exposure
Scenario
Method
of
Application
Application
rate
(%
a.
i.

by
weight
of
material
being
treated)
Dermal
Unit
Exposure
(
mg/
lb
a.
i.)
Inhalation
Unit
Exposure
(
mg/
lb
a.
i.)
Quantity
Handled/
Treat
ed
per
day
(
unit
as
indicated)
p
Dermal
Dose
Inhalation
Dose
Dermal
(
target
ST/
IT
MOE
=

300)
Inhalation
(
target
MOE
=

3,000)

Liquid
Pour
(
preservation)
0.25
(
max)
0.135b
0.00346c
19,100
lbs
(
2,000
gallons)
0.0921
0.00236
1,100
4,500
Liquid
Pump
(
preservation)
0.25
(
max)
0.00629d
0.000403e
191,000
lbs
(
20,000
gallons)
0.0429
0.00275
2,300
3,800
Airless
spraying
(
end
user)
0.25
(
max)
14f
0.83g
500
lbs
(
50
gallons)
0.25
0.0148
400
720
Airless
spraying
(
end
user)
0.05
(
min)
14f
0.83g
500
lbs
(
50
gallons)
0.05
0.00296
2,000
3,600
Latex
Paint
(
Latex
Emulsions)
s
Brush
Painting
(
end
user)
0.25
(
max)
24h
0.28i
50
lbs
(
5
gallons)
0.0429
0.0005
2,300
21,000
36
Unit
Exposure
Daily
Dose
(
mg
a.
i./
kg
per
day)
q
MOEr
Substrate
Treated/
Handled
through
Exposure
Scenario
Method
of
Application
Application
rate
(%
a.
i.

by
weight
of
material
being
treated)
Dermal
Unit
Exposure
(
mg/
lb
a.
i.)
Inhalation
Unit
Exposure
(
mg/
lb
a.
i.)
Quantity
Handled/
Treat
ed
per
day
(
unit
as
indicated)
p
Dermal
Dose
Inhalation
Dose
Dermal
(
target
ST/
IT
MOE
=

300)
Inhalation
(
target
MOE
=

3,000)

Liquid
Pour
0.15
(
max)
0.184j
0.00854k
2,865
lbs
(
300
gallons)
0.0113
0.000524
8,900
20,000
Metalworking
cutting
fluids
(
preservation)
Liquid
Pump
0.15
(
max)
0.312l
0.00348m
2,865
lbs
(
300
gallons)
0.0192
0.000214
5,200
50,000
Paper
Coating
(
preservation)
Liquid
Pump
0.25
(
max)
0.00454n
0.000265o
9,550
lbs
(
1000
gallons)
0.0015
0.000090
65,000
120,000
46.7
lbs
(
5.6
gal
(
ST))
0.0002
0.000006
440,000
1.8
x
106
Drilling
Muds
(
end
user)

Flooding
fluids
(
end­
user)
Liquid
Pour
0.25
(
max)
0.135b
0.00346c
23.3
lbs
(
2.8
gal
(
IT))
0.0001
0.000003
890,000
3.7
x
106
a:
The
maximum
application
rate
of
0.5%
product
(
0.25%
a.
i).
by
weight
of
material
treated
generates
an
MOE
of
concern,
whereas
using
materials
treated
at
the
minimum
application
rates
specified
in
the
table,
an
MOE
that
is
not
of
concern
is
generated.
All
of
these
uses
in
Table
6.2
were
assessed
at
this
rate,
except
for
metalworking
fluids.
This
treatment
was
label
specified
to
be
0.3
%
product
(
0.15%
a.
i.)
by
weight
of
the
fluid
treated.

b,
c
:
CMA
preservative
liquid
pour,
gloved
values
for
dermal
and
inhalation
are
0.135
mg/
lb
a.
i.
and
0.00346
mg/
lb
a.
i.,
respectively.

d,
e
:
CMA
preservative
liquid
pump,
gloved
values
for
dermal
and
inhalation
are
0.00629
mg/
lb
a.
i.
and
0.000403
mg/
lb
a.
i.,
respectively.

f,
g
:
PHED
unit
exposure
values
for
a
handler
wearing
gloves
and
applying
paint
using
an
airless
sprayer
were
used,
so
that
the
dermal
and
inhalation
values
were
14
mg/
lb
a.
i.
and
0.830
mg/
lb
a.
i.,
respectively.

h,
i
:
PHED
paintbrush
application
scenario,
gloved
values
for
dermal
and
inhalation
are
24
mg/
lb
a.
i.
and
0.28
mg/
lb
a.
i.,
respectively.

j,
k
:
CMA
MWF
liquid
pour,
gloved
values
for
dermal
and
inhalation
are
0.184
mg/
lb
a.
i.
and
0.00854
mg/
lb
a.
i.,
respectively
l,
m
:
CMA
MWF
liquid
pump,
gloved
values
for
dermal
and
inhalation
are
0.312
mg/
lb
a.
i.
and
0.00348
mg/
lb
a.
i.,
respectively
n,
o
:
CMA
liquid
pump
for
pulp
and
paper,
gloved
values
for
dermal
and
inhalation
are
0.0045
mg/
lb
a.
i.
and
0.00027
mg/
lb
a.
i.,
respectively.

p:
For
the
quantity
handled,
it
is
explained
in
the
MOE
discussion
following,
which
addresses
each
scenario
individually
q:
Daily
Dose
(
mg
a.
i./
kg
per
day)
=
Daily
Dose
(
mg
a.
i./
kg
per
day)
=
Unit
Exposure
(
mg/
lb
a.
i.)
x
rate
x
amount
handled
x
(
1/
body
weight
(
kg))

r:
MOE
=
Toxicity
Endpoint
(
mg/
kg/
day)
/
Daily
Dose
(
mg/
kg/
day);
where
dermal
NOAEL
=
100
mg/
kg/
day
and
the
inhalation
LOAEL
=
10.6
mg/
kg/
day
s:
Latex
paints
are
representative
for
adhesives,
caulks,
ink
dispersions,
pigment
dispersions,
pigment
slurries,
wax
emulsions,
textiles,
and
sealants.

t:
There
is
a
chemical
metering
application
(
i.
e.
liquid
pump)
for
drilling
muds
and
flooding
fluid
uses.
However,
this
was
not
assessed
because
appropriate
unit
exposure
values
are
not
available.
This
is
further
discussed
in
the
End
User
discussion
later
in
the
document.

As
noted
in
the
above
table,
most
dermal
and
inhalation
MOEs
were
not
of
concern
for
occupational
handlers,
with
the
exception
of
the
following:

1)
airless
spraying
of
latex
paint
containing
0.25%
a.
i.
(
inhalation
MOE
of
720).

As
noted
in
the
occupational/
residential
exposure
chapter,
however,
"
drilling
muds
have
a
recommended
application
rate
of
0.05%

product
(
0.025%
a.
i.)
by
weight
of
material
being
treated
and
when
this
value
is
used
in
the
assessment,
the
inhalation
MOE
is
21,000.

Likewise,
flooding
fluids
have
a
recommended
application
rate
of
0.01%
product
(
0.005%
a.
i.)
by
weight
of
material
being
treated,
and
when
this
value
is
used,
the
inhalation
MOE
becomes
110,000.
As
a
result,
if
the
worker
is
in
the
presence
of
materials
treated
at
the
recommended
minimum
application
rate,
this
will
remove
the
inhalation
concern
that
arises
for
the
liquid
pump
application
of
this
chemical."
39
7.2
Occupational
Post­
Application
Occupational
painter
post­
application
exposures
result
when
bystanders
contact
areas
in
which
the
antimicrobial
end­
use
product
has
been
recently
applied.
For
azadioaxabicyclootane,
exposures
are
expected
to
be
minimal.

Metalworking
Fluids:

There
is
a
potential
for
dermal
and
inhalation
exposure
when
a
worker
handles
treated
metalworking
fluids.
This
route
of
exposure
occurs
after
the
chemical
has
been
incorporated
into
the
metal
working
fluid
and
a
machinist
is
using/
handling
this
treated
end­
product.
The
exposure
is
assessed
and
the
MOEs
are
in
Table
11.0,
with
explanations
and
the
appropriate
equations.
A
screening­
level
long­
term
dermal
exposure
estimate
was
derived
through
using
the
2­
hand
imersion
model
from
ChemSTEER.
The
model
is
available
at
www.
epa.
gov/
opptintr/
exposure/
docs/
chemsteer.
htm
Table
11.0
Daily
Dose
Long
Term
MOE
Substrate
Treated/
Handled
through
Exposure
Scenario
Method
of
Application
Application
Rate
(%
a.
i.
by
weight
of
material
being
treated)
Dermal
Dose
Inhalation
Dose
Dermal
Inhalation
Liquid
Pour
Liquid
Pump
0.15
0.1854
0.00107
540
9900
Metalworking
cutting
fluids
Liquid
Pour
Liquid
Pump
0.05
0.0618
0.000357
1,600
30,000
At
the
maximum
application
rate
(
0.3%
product
by
weight
of
material
to
be
treated,
0.15%
a.
i.)
on
the
label
permitted
for
MWF,
there
is
concern
with
the
dermal
exposure
to
the
worker.
The
target
MOE
for
LT
exposure
is
1,000,
and
at
the
maximum
rate,
the
MOE
is
540
which
is
a
concern.
However,
when
the
worker
comes
into
contact
with
fluid
that
has
been
treated
at
the
minimum
application
rate
(
0.1%
product
by
weight
of
material
to
be
treated,
0.05%
a.
i.),
the
MOE
is
1,600
which
is
not
of
concern
since
it
is
greater
than
1,000.
Post
application
exposure
to
MWF
will
not
present
any
dermal
concern
if
the
fluid
the
worker
is
exposed
to
has
been
treated
at
the
rate
of
0.1%
product
by
weight
of
MWF
treated.
40
8.0
ENVIRONMENTAL
RISK
ASSESSMENT
8.1
Ecological
Hazard
Azadioxabicyclooctane
demonstrates
low
toxicity
to
birds
and
mammals
and
slight
toxicity
to
freshwater
aquatic
organisms.
All
submitted
ecological
toxicity
studies
were
conducted
with
the
formulated
product
Nuosept7
95.
Although
conducted
using
a
formulated
product
and
not
the
TGAI,
the
submitted
studies
for
avian
acute,
avian
subacute,
freshwater
invertebrate,
and
estuarine/
marine
organisms
are
considered
adequate
to
support
the
registered
uses
on
Aza,
as
Nuosept7
95
is
the
only
end­
use
product
Submitted
data
on
acute
toxicity
to
freshwater
fish
was
considered
supplemental
but
could
be
updgraded
upon
submission
of
information
on
the
composition
and
purity
of
the
test
substance
used.
Submission
of
data
regarding
toxicity
to
wild
mammals,
chronic
toxicity
for
freshwater
organisms,
chronic
toxicity
testing
for
marine/
estuarine
organisms,
and
plants
was
not
required
for
the
uses
of
azadioxabicyclooctane.
A
summary
of
submitted
data
is
provided
below.

Table
12.0
Acute
Oral
Toxicity
of
Nuosept7
95
to
Birds
Species
%
Active
Ingredient
(
ai)
Endpoint
(
mg
/
kg
product)
Toxicity
Category
Satisfies
Guidelines/
Comments
Reference
Mallard
duck
(
Anas
platyrhynchos)
107001
24.5%
107002
17.7%
107003
7.8%
LD50
>
2,510
NOEL
=
2510
(
mortality)
Practically
non­
toxic
Yes
­
acceptable
for
formulated
product
­
14­
day
test
duration
Beavers,
1983
(
ACC
#
250533)

Table
13.0
Subacute
Dietary
Toxicity
of
Nuosept7
95
to
Birds
41
Species
%
Active
Ingredient
(
ai)
Endpoint
(
ppm)
Toxicity
Category
Satisfies
Guidelines/
Comments
Reference
Bobwhite
quail
(
Colinus
virginianus)
50%
LC50
>
5,200
a.
i.
(>
10,400
product)
NOEC
1541
ppm
a.
i.
(
3082
ppm
product)
Practically
non­
toxic
No
­
supplemental
study
­
administered
in
drinking
water
rather
than
food
Hakin
et
al.,
1990
(
MRID
416848­
01)

Bobwhite
quail
(
Colinus
virginianus)
not
reported
LC50
>
10,000
ppm
product
NOEC
10,000
ppm
Practically
non­
toxic
Yes
­
acceptable
for
formulated
product
­
single
mortality
at
10,000
ppm;
no
other
mortality
reported
Truslow
Farms,
1974.
(
ACC#
24878)

Mallard
duck
(
Anas
platyrhynchos)
not
reported
LC50
>
10,000
ppm
product
NOEC
10,000
ppm
Practically
non­
toxic
Yes
­
acceptable
for
formulated
product
­
no
mortality
reported
at
any
test
concentration
Truslow
Farms,
1974.
(
ACC#
24878)

NOAEC=
No­
observable
adverse
effect
concentration
Table
14.0Acute
Toxicity
of
Nuosept7
95
to
Freshwater
Fish
Species
%
Active
Ingredient
(
ai)
Endpoints
(
ppm
product)
Toxicity
Category
Satisfies
Guidelines/
Comments
Reference
Rainbow
trout
(
Oncorhynchus
mykiss)
not
reported
LC50
=
240
NOEC
=
87
practically
non­
toxic
No
­
supplemental
­
96h
test
duration;

­
static
system
Bentley
and
Sleight,
1974
(
ACC
#
247878;
MRID
930500­
15)

Bluegill
(
Lepomis
macrochirus)
not
reported
LC50
=
163
NOEC
=
87
practically
non­
toxic
No
­
supplemental
­
96h
test
duration;

­
flow­
through
system
Bently
and
Bevier,
1974
(
ACC#
247878;
MRID
930500­
15)

Table
15.0
Acute
Toxicity
of
Nuosept7
95
to
Marine/
Estuarine
Fish
Species
%
Active
Ingredient
(
ai)
Endpoints
(
ppm
product)
Toxicity
Category
Satisfies
Guidelines/
Comments
Reference
42
Sheepshead
minnow
(
Cyprinodon
variegatus)
PC
code
%
107001
24.5%
107002
17.7%
107003
7.8%
LC50
=
440
ppm
NOEC
=
250
ppm
practically
non­
toxic
Yes
­
acceptable
for
formulated
product
­
96h
test
duration;
­
static
system
Ward,
1983.
(
ACC#
250533)

Table
16.0
Acute
Toxicity
of
Nuosept7
95
to
Freshwater
Invertebrates
Table
17.0
Acute
Toxicity
of
Nuosept
95
to
Marine/
Estuarine
Invertebrates
Species
%
Active
Ingredient
(
ai)
Endpoints
(
ppm
product)
Toxicity
Category
Satisfies
Guidelines/
Comments
Reference
Eastern
oyster
(
Crassostrea
virginica)
PCCode
%
107001
24.5%
107002
17.7%
107003
7.8%
EC50
=
42
NOEC
=
25
slightly
toxic
Yes
­
core
study
on
formulated
product
­
embryo­
larvae
test
­
48h
test
duration;
­
static
system
­
endpoint
immobilization
Ward,
1983.
(
ACC#
250533)

Mysid
(
Americamysi
s
bahia)
107001
24.5%
107002
17.7%
107003
7.8%
LC50
=
88
ppm
NOEC
<
50
ppm\
slightly
toxic
Yes
­
core
for
formulated
product
­
96h
test
duration
­
static
system
Ward,
1983.
ACC#
250533
Water
flea
(
Daphnia
magna)
107001
24.5%
107002
17.7%
10700
3
7.8%
EC50
=
77
NOEC
=
7.7
slightly
toxic
Yes
­
acceptable
for
formulated
product
­
48h
test
duration;
­
static
system
Suprenant,
1983
(
ACC#
250533/
MROD
#
930500­
16)
43
8.2
Environmental
Fate
and
Transport
Azadioxabicyclooctane
(
is
a
mixture
of
three
acetals:
5­
hydroxymethoxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3.3.0)
octane
(
28.8%),
(
component
A,
PC
code
107002)
5­
hydroxymethyl­
1­
aza­
3,7­
dioxabicyclo(
3.3.0)
octane
(
16.0%),
(
component
B,
PC
code
107001)
5­
hydroxypoly(
methyleneoxy)*
methyl­
1­
aza­
3,7­
dioxabicyclo(
3.3.0)
octane
(
5.2%),
(
component
C,
PC
code
107003)
where
the
polychain
is
extended
as:
74%
C2,
21%
C3,
AND
4%
C4,
AND
1%
C5
(
meaning
from
1
C
to
C5
chain
lengths
of
CH2O
groups
are
added).
EPI
Suite
lacks
estimation
of
the
third
of
the
three
isomers
(
CAS#
56709­
13­
8).

Under
abiotic
conditions,
the
mixture
of
these
acetals
is
hydrolytically
unstable
with
half­
lives
of
0.347
days
at
pH
5,
1.74
days
at
pH
7
and
approximately
15
days
at
pH
9.
It
is,
therefore,
not
likely
to
be
persistent
in
water.

Components
A
and
B
of
the
mixture
are
likely
to
volatilize
into
the
atmosphere
as
their
vapor
pressures
vary
between
0.0004
to
0.003
mm
Hg.
Component
C
is
likely
to
have
less
volatility
as
the
side
chain
of
CH2O
groups
are
added
into
the
structure.
Estimated
half
lives
in
the
atmosphere
for
components
A
and
B
are
1.2
and
1.4
hours.
Hence,
these
two
chemicals
are
not
likely
to
persist
in
the
atmosphere.

Estimated
log
Kow
s
of
components
A
and
B
are
respectively
are
­
2.23
and
­
1.55
(
very
highly
miscible
in
water
and
show
no
tendency
for
dissolving
organic
solvents);
therefore,
the
mixture
is
not
likely
to
bioaccumulate
in
aquatic
organisms.

MITI
linear
biodegradability
(
modified
linear
biodegradation
method)
for
components
A
and
B
indicates
a
fast
biodegradation
is
highly
probable
in
soils
and
water.
These
compounds
do
not
likely
pose
a
concern
for
surface
and
ground
water
contamination
8.3
Environmental
Exposure
and
Risk
Most
uses
of
Aza
are
indoor
uses,
with
little
chance
of
exposure
to
the
environment.
Exposure
modeling
is
not
conducted
for
those
uses.
The
oil
production
uses
do
occur
outdoors;
however,
OPP
does
not
have
an
available
model
for
estimating
exposure
from
those
uses.
The
risk
from
offshore
oil
drilling
uses
of
Aza
was
previously
addressed
(
Environmental
Fate
and
Effects
Division
review,
7/
14/
83),
and
the
application
of
500­
2000
ppm
drilling
fluid
treatment
or
100­
1000
ppm
flooding
fluid
treatment
was
considered
A
unlikely
to
adversely
affect
aquatic
organisms
due
to
the
low
toxicity
and
large
dilution
factor.@
Discharge
of
waste
streams
occurring
from
terrestrial
oil
recovery
operations
would
be
regulated
at
the
local
level
in
order
to
prevent
undue
environmental
exposure.
44
The
indoor
uses
of
Aza
are
not
likely
to
pose
risk
to
fish,
wildlife
or
plants
due
to
the
low
likelihood
of
exposure
and
the
low
toxicity
of
the
compound.
The
offshore
oil
production
use
of
Aza
was
previously
addressed
(
Environmental
Fate
and
Effects
Division
review,
7/
14/
83),
and
the
application
of
500­
2000
ppm
drilling
fluid
treatment
or
100­
1000
ppm
flooding
fluid
treatment
was
considered
A
unlikely
to
adversely
affect
aquatic
organisms
due
to
the
low
toxicity
and
large
dilution
factor.@
The
Agency
assumes
that
the
waste
streams
occurring
from
terrestrial
oil
production
are
actively
managed
under
local
environmental
regulations
to
prevent
adverse
ecological
effects.
45
8.4
Endangered
Species
Considerations
The
Agency
has
developed
the
Endangered
Species
Protection
Program
to
identify
pesticides
whose
use
may
cause
adverse
impacts
on
endangered
and
threatened
species,
and
to
implement
mitigation
measures
that
address
these
impacts.
The
Endangered
Species
Act
requires
federal
agencies
to
ensure
that
their
actions
are
not
likely
to
jeopardize
listed
species
or
adversely
modify
designated
critical
habitat.
To
analyze
the
potential
of
registered
pesticide
uses
to
affect
any
particular
species,
EPA
puts
basic
toxicity
and
exposure
data
developed
for
risk
assessments
into
context
for
individual
listed
species
and
their
locations
by
evaluating
important
ecological
parameters,
pesticide
use
information,
the
geographic
relationship
between
specific
pesticide
uses
and
species
locations,
and
biological
requirements
and
behavioral
aspects
of
the
particular
species.
A
determination
that
there
is
a
likelihood
of
potential
impact
to
a
listed
species
may
result
in
limitations
on
use
of
the
pesticide,
other
measures
to
mitigate
any
potential
impact,
or
consultations
with
the
Fish
and
Wildlife
Service
and/
or
the
National
Marine
Fisheries
Service
as
necessary.

Due
to
the
low
likelihood
of
exposure
and
low
toxicity
of
Aza,
the
indoor
uses
of
the
compound
are
not
likely
to
adversely
affect
listed
species.
Likewise,
offshore
oil
production
use
of
Aza
is
considered
unlikely
to
adversely
affect
listed
species
due
to
the
low
toxicity
of
the
compound
and
the
large
dilution
factor
in
offshore
operations.
The
Agency
assumes
that
the
waste
streams
occurring
from
terrestrial
oil
production
are
actively
managed
under
local
environmental
regulations
to
prevent
adverse
ecological
effects,
and
are
therefore
not
likely
to
adversely
affect
listed
species
or
critical
habitats.
46
9.0
INCIDENT
REPORTS
The
following
databases
have
been
consulted
for
the
poisoning
incident
data
on
the
active
ingredient:

a.
OPP
Incident
Data
System
(
IDS)
­
The
Incident
Data
System
of
the
Office
of
Pesticide
Programs
(
OPP)
of
the
Environmental
Protection
Agency
(
EPA)
contains
reports
of
incidents
from
various
sources,
including
registrants,
other
federal
and
state
health
and
environmental
agencies,
and
individual
consumers,
submitted
to
OPP
since
1992.
Reports
submitted
to
the
Incident
Data
System
represent
anecdotal
reports
or
allegations
only,
unless
otherwise
stated.
Typically
no
conclusions
can
be
drawn
implicating
the
pesticide
as
a
cause
of
any
of
the
reported
health
effects.
Nevertheless,
sometimes
with
enough
cases
and/
or
enough
documentation
risk
mitigation
measures
may
be
suggested.

b.
Poison
Control
Centers
­
As
the
result
of
a
data
purchase
by
EPA,
OPP
received
Poison
Control
Center
data
covering
the
years
1993
through
1996
for
all
pesticides.
Most
of
the
national
Poison
Control
Centers
(
PCCs)
participate
in
a
national
data
collection
system,
the
Toxic
Exposure
Surveillance
System,
which
obtains
data
from
about
65­
70
centers
at
hospitals
and
universities.
PCCs
provide
telephone
consultation
for
individuals
and
health
care
providers
on
suspected
poisonings,
involving
drugs,
household
products,
pesticides,
etc.

c.
California
Department
of
Pesticide
Regulation
­
California
has
collected
uniform
data
on
suspected
pesticide
poisonings
since
1982.
Physicians
are
required,
by
statute,
to
report
to
their
local
health
officer
all
occurrences
of
illness
suspected
of
being
related
to
exposure
to
pesticides.
The
majority
of
the
incidents
involve
workers.
Information
on
exposure
(
worker
activity),
type
of
illness
(
systemic,
eye,
skin,
eye/
skin
and
respiratory),
likelihood
of
a
causal
relationship,
and
number
of
days
off
work
and
in
the
hospital
is
provided.

d.
National
Pesticide
Telecommunications
Network
(
NPTN)
­
NPTN
is
a
toll­
free
information
service
supported
by
OPP.
A
ranking
of
the
top
200
active
ingredients
for
which
telephone
calls
were
received
during
calendar
years
1984­
1991,
inclusive,
has
been
prepared.
The
total
number
of
calls
was
tabulated
for
the
categories
human
incidents,
animal
incidents,
calls
for
information,
and
others.

e.
Published
Incident
Reports
­
Searches
for
incident
reports
associated
with
AZArelated
human
health
hazards
published
in
the
scientific
literature
were
conducted.
47
Examination
of
these
databases
for
incidents
related
to
human
exposure
from
azadioxabicyclooctane
showed
no
reports
on
file
from
any
of
these
databases.

10.0
Data
Gaps
Human
Hazard:
For
assessment
of
human
hazard
and
risk,
several
data
gaps
were
identified
by
the
ADTC.
Due
to
the
potential
for
inhalation
exposure
in
the
occupational
setting,
a
repeated
dose
(
90­
day)
inhalation
toxicity
study
should
be
performed
with
Azadioxabicyclooctane.
The
oral
study
used
for
selection
of
the
inhalation
endpoint
does
not
adequately
characterize
potential
inhalation
hazard
and
was
used
with
added
uncertainty
factors
(
10x)
in
the
absence
of
inhalation
data.
A
route­
specific
study
would
reduce
or
eliminate
this
uncertainty.

With
respect
to
indirect
food
uses,
the
Agency
has
established
an
interim
two­
tiered
system
for
toxicology
testing
requirements
in
order
to
complete
a
risk
assessment
for
indirect
food
uses
of
antimicrobial
pesticide
chemicals
for
which
the
FDA
has
established
a
food
additive
regulation
that
specifically
states
that
the
use
is
"
safe",
but
for
which
the
Agency
requires
its
own
assessment.
Tier
I
toxicology
data
requirements
would
apply
to
all
indirect
food
additives
that
result
in
residue
concentrations
in
food
ranging
from
0­
200ppb.
The
requirements
would
consist
of
an
acute
toxicity
testing
battery,
a
subchronic
toxicity
study
in
the
rodent,
a
developmental
toxicity
study
in
the
rodent
(
rat),
and
a
mutagenicity
testing
battery.
Each
of
these
data
requirements
has
been
fulfilled
for
AZA.
The
Agency
also
conducts
a
literature
search
and
can
also
conduct
a
Structure
Activity
Relationship
analysis
(
SAR)
if
appropriate.

Tier
II
studies
would
be
triggered
by
the
presence
of
significant
(
i.
e.
=
200ppb)
residues
in
food
or
evidence
of
significant
toxicity
from
the
Tier
I
data
set,
which
may
include
developmental
/
reproductive,
or
other
systemic
toxicity
such
as
presence
of
neoplastic
growth
or
significant
target
organ
toxicity.
In
such
cases,
chronic
toxicity
and
carcinogenicity
testing
would
be
required
in
addition
to
the
above
Tier
I
studies.

For
AZA,
the
Agency
assigned
additional
uncertainty
factors
to
portions
of
the
risk
assessment
in
the
absence
of
reproductive
toxicity
data
to
assess
indirect
food
use
risk
of
the
chemical
(
specifically,
the
FQPA
hazard­
based
factor
was
retained
at
10x).
Submission
of
a
reproductive
toxicity
study
could
possibly
reduce
or
remove
this
additional
uncertainty
factor.
The
subchronic
toxicity
in
the
non­
rodent
will
also
be
held
in
reserve
but
if
submitted
would
also
be
useful
in
refining
risk
from
indirect
food
uses
of
azadioxabicyclooctane
An
acceptable
dermal
sensitization
study
for
AZA
must
also
be
submitted.

Occupational
and
Residential
Exposure:
The
use
of
the
Chemical
Manufacturers
Association
(
CMA)
surrogate
data
were
noted
to
have
the
following
deficiencies
with
regard
to
assessment
of
48
exposure:

a)
The
inhalation
concentrations
were
typically
below
the
detection
limits,
and
the
unit
exposures
for
the
inhalation
exposure
route
could
not
be
accurately
calculated.

b)
The
CMA
Unit
exposure
data
was
used
for
each
of
the
worker
scenarios
assessed.
These
data
are
of
poor
quality
because
they
are
based
on
limited
number
of
replicates
(
i.
e.,
2)
which
does
not
meet
the
Agency's
standard
of
15.
AD
requests
that
exposure
confirmatory
data
be
collected
to
show
that
the
exposures
assessed
in
this
memo
using
the
CMA
data
are
valid.

The
following
are
also
noted
with
respect
to
the
PHED
database
and
residential
SOPs:

The
following
factors
concerning
PHED
and
the
residential
SOPs
should
also
be
noted:

a)
The
job
functions
where
pesticides
are
commonly
used
may
be
different
from
those
job
functions
where
antimicrobial
chemicals
are
used
(
i.
e.,
representativeness
issue).

b)
The
basic
assumption
underlying
the
PHED
database
is
that
exposure
to
pesticide
handlers
is
primarily
a
function
of
the
physical
parameters
associated
with
handling
and
applying
of
the
product
rather
than
the
chemical
properties
of
the
individual
active
ingredients.
Therefore,
it
is
important
to
recognize
the
potential
effects
the
chemical
properties
of
azadioxabicyclooctane
may
have
on
the
exposure
rates.

c)
No
information
regarding
the
amount
of
end
use
product
handled
daily
was
provided
by
the
registrant.
The
AD
SOP
was
used
for
developing
a
value
to
use
in
this
assessment.

Ecological
Hazard:
The
following
were
identified
as
data
gaps
and/
or
deficiencies
with
respect
to
ecological
hazard
and
environmental
risk
for
azadioxabicyclooctane:

a)
Data
on
acute
toxicity
to
freshwater
fish
at
present
do
not
fulfill
the
850.1075
data
requirement.
49
11.0
REFERENCES
Toxicology
41641601
(
MRID
#):
Dilley,
J.
V.
(
Unknown).
Acute
oral
toxicity
of
Nuosept
95
in
rats
(
Interim
progress
report).
SRI
International.

41641602
(
MRID
#):
Hersham,
R.
J.
(
1984).
Summary
of
results
of
a
primary
eye
irritation
study.
Bioresearch
Incorporated.

41641603
(
MRID
#):
Unwin,
S.
E.
(
1983).
Primary
dermal
irritation
test
of
Nuosept
®
95
in
New
Zealand
White
albino
rabbits.
Midwest
Research
Institute.

41641605
(
MRID
#):
Elliot,
P.
H.,
et
al.
(
1985).
Twenty­
one
Day
Dermal
Toxicity
Study
in
Rabbits
with
Nuosept
95/
Nuosept
C.
Huntingdon
Research
Centre.

41641606
reformat
of
00109245
(
MRID
#):
Sasmore,
DP.
(
1980).
Final
Report:
Effect
of
Nuosept
95
in
Rats
90­
Day
Toxicity
Study
­
Contains
dose
range
study
for
Dominant
Lethal
Study
(
OPPTS
870.3100).
SRI
International.

41671801
(
MRID
#):
Liggett,
M.
P.
and
L.
A.
McRae.
(
1990).
Acute
dermal
toxicity
to
rabbits
of
Nuosept
95
(
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report).
Huntingdon
Research
Centre
Ltd.

41699001
(
MRID
#):
Smith,
J.
A.,
et
al.
(
1988).
A
Study
of
the
Effect
of
Nuosept
95
on
Pregnancy
of
the
Rat.
Huntingdon
Research
Centre.

41728601
(
MRID
#):
O'Loughlin,
K.
G.
(
1990).
Measurement
of
micronuclei
in
bone
marrow
erythrocytes
of
Swiss­
Webster
mice
following
two
treatments
with
Nuosept
95.
SRI
International.

42650901
(
MRID
#):
Cholakis,
J.
M.
and
H.
Sprinz.
(
1983).
Acute
inhalation
toxicity
of
Nuosept
95
in
Sprague­
Dawley
rats.
Midwest
Research
Institute.

42711001
(
MRID
#):
Hamilton,
C.
M.
(
1983).
Measurement
of
unscheduled
DNA
synthesis
in
male
Fischer­
344
rat
hepatocytes
following
in
vivo
treatment
with
Nuosept
95.
SRI
International.

93050017
reformat
of
00088956
(
MRID
#):
Haworth,
S.
R.
(
1979).
Salmonella/
mammalianmicrosome
plate
incorporation
mutagenesis
assay.
An
Evaluation
of
Carcinogenic
Potential
of
NUOSEPT
®
95
Employing
the
C3H/
10T
½
Cell
Transformation
Assay.
EG&
G
Mason
Research
Institute.

93050018
reformat
of
00088974
(
MRID
#):
Van
Goethen,
D.
(
1979).
Mutagenicity
studies
on
Nuosept
95
Salmonella/
microsome
test.
Midwest
Research
Institute.
50
93050019
reformat
of
00088957
(
MRID
#):
Haworth,
S.
R.
(
1979).
Bacterial
DNA
damage/
repair
suspension
assay.
EG&
G
Mason
Research
Institute.

93050020
reformat
of
00088958
(
MRID
#):
Van
Goethen
(
1979).
Bacterial
DNA
repair
assay.
Midwest
Research
Institute.

93050021
reformat
of
00088959
(
MRID
#):
Myhr,
B.
(
1980).
Evaluation
of
Nuosept
®
95
in
the
primary
rat
hepatocyte
unscheduled
DNA
synthesis
assay.
Litton
Bionetics,
Inc.

93050022
reformat
of
00088960
(
MRID
#):
Thilagar,
A.,
et
al.
(
1979).
An
Evaluation
of
Carcinogenic
Potential
of
NUOSEPT
®
95
Employing
the
C3H/
10T
½
Cell
Transformation
Assay.
EG&
G
Mason
Research
Institute.

93050023
reformat
of
00088961
(
MRID
#):
Schechtman,
M.
(
1980).
Activity
of
T1597
in
an
in
vitro
Mammalian
Cell
transformation
Assay
in
the
Absence
of
Exogenous
Metabolic
Activation.
Microbiological
Associates.

93050024
reformat
of
00088962
(
MRID
#):
Thilagar,
A.,
et
al.
(
1980).
An
Evaluation
of
Carcinogenic
Potential
of
R­
1162
(
NUOSEPT
®
95)
Employing
the
C3H/
10T
½
Cell
Transformation
System.
EG&
G
Mason
Research
Institute.

93050025
reformat
of
00088963
(
MRID
#):
Thilagar,
A.
(
1980).
An
Evaluation
of
Carcinogenic
Potential
of
R­
1143
(
NUOSEPT
®
95)
Employing
the
C3H/
10T
½
Cell
Transformation
System.
EG&
G
Mason
Research
Institute.

93050026
reformat
of
00088953
(
MRID
#):
Rushbrook
and
Jorgenson
(
1979).
Dominant
lethal
study
of
Nuosept
95.
SRI
International.

McMahon,
Timothy,
et
al.
(
2005).
Azadioxabicyclooctane
­
Report
of
the
Antimicrobial
Division
Toxicology
Endpoint
Selection
Committee.

Human
Exposure
Antimicrobials
Division
Standard
Operating
Procedure.
Summary
of
Antimicrobial
Standard
Operating
Procedure
(
SOP)
Assumptions
for
Residential
and
Occupational
Exposure
Assessments,
January
2005.

CMA.
1992.
Chemical
Manufacturers
Association
Antimicrobial
Exposure
Assessment
Study.
Popendorf,
W,
Selim,
M.,
Kross,
B.
The
University
of
Iowa.
MRID
425875­
01.
December
8,
1992.
51
Dang,
W.
1997.
"
The
Use
of
Models
for
Estimating
Exposure
and
Risk
of
Antimicrobials
in
Metalworking
Fluids"

PHED
Surrogate
Exposure
Guide.
1997.
Estimates
of
Worker
Exposure
from
the
Pesticide
Handler
Exposure
Database
Version
1.1.
May
1997.

U.
S.
EPA.
1999.
Evaluation
of
the
Chemical
Manufacturers
Association
Antimicrobial
Exposure
Assessment
Study
(
Amended
on
December
8,
1992).
Memorandum
from
Siroos
Mostaghimi,
Ph.
D.,
Environmental
Engineer
to
Julie
Fairfax,
PM
#
36.
November
4,
1999.

Dietary
Exposure
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.

Environmental
Fate
430607­
01
John
Cross,
Aqueous
Hydrolysis
of
Neusept
95,
EPL
Bio­
Analytical
Services,
Harrison
IL,
1993.

Ecological
Effects
MRID
41684801.
Hakin,
B.,
M.
Rodgers,
A.
Anderson
and
I.
S.
Dawe.
1990.
Nuosept
95:
LC50
to
Bobwhite
Quail.
Unpublished
data.
Conducted
by
Huntingdon
Research
Centre,
Ltd.,
for
Huls
America,
Inc.

ACC#
250533.
Ward,
G.
S.
1983.
Acute
Toxicity
of
Nuosept
95
to
Embryo­
larvae
of
Eastern
oysters
(
Crassostrea
virginica).
Unpublished
data.
Conducted
by
EG&
G
Bionomics
for
Nuodex,
Inc.

ACC#
247878.
Truslow
Farms,
Inc.
1974.
Eight­
day
Dietary
LC50
­
Bobwhite
quail
Nuosept
95.
Unpublished
data.
Conducted
by
Truslow
Farms,
Inc.,
for
Tenneco
Chemicals.

­­­­­­­­­­­­­­­­­.
­­­­­­­­­­­­­­­­­­­­­­­.
Eight­
day
Dietary
LC50
­
Mallard
duck
Nuosept
95.
Unpublished
data.
Conducted
by
Truslow
Farms,
Inc.,
for
Tenneco
Chemicals.

MRID
#
93050015.
Bently,
R.
E.
and
B.
H.
Sleight.
1974.
Acute
Toxicity
of
Nuosept
95
Preservative
to
Bluegill
and
Rainbow
Trout.
Unpublished
data.
Conducted
by
EG&
G
Bionomics,
Inc.,
for
Huls
America,
Inc.
(
formerly
Nuodex,
Inc.,
formerly
Tenneco
Chemicals,
Inc.).
Also
submitted
by
Creanova,
Inc.,
1990.
52
­­­­­­­­­­­­­­­­­.
­­­­­­­­­­­­­­­­­­­­­.
Acute
Toxicity
of
Nuosept
95
to
Mysid
Shrimp
(
Mysidopsis
bahia).
Unpublished
data.
Conducted
by
EG&
G
Bionomics
for
Nuodex,
Inc.

­­­­­­­­­­­­­­­­­
­­­­­­­­­­­­­­­­­­­­
Acute
Toxicity
of
Nuosept
95
to
Sheepshead
Minnows
(
Cyprinodon
variegatus).
Unpublished
data.
Conducted
by
EG&
G
Bionomics
for
Nuodex,
Inc.

­­­­­­­­­­­­­­­­­.
Suprenant,
D.
C.
1983.
Acute
Toxicity
of
Nuospet
95
to
the
Water
Flea
(
Daphnia
magna).
Unpublished
data.
Conducted
by
EG&
G
Bionomics
for
Nuodex,
Inc.
Also
submitted
as
MRID
#
930500­
16
by
Creanova,
Inc.,
2002.

U.
S.
Environmental
Protection
Agency
(
EPA).
2002.
ECOTOX
User
Guide:
ECOTOXicology
Database
System.
Version
3.0.
Available:
http://
www.
epa.
gov/
ecotox/
