Document ID: EPA-HQ-OPP-2006-0339-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-26T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
February
27,
2006
Memorandum
Subject:
Toxicology
Disciplinary
Chapter
for
the
Re­
Registration
Eligibility
Decision
(
RED)
Risk
Assessment
Active
Ingredient:
alkyl
dimethyl
benzyl
amoinium
chloride
(
ADBAC)
PC
Code
069105
DP
Barcode:

From:
Timothy
F.
McMahon,
Ph.
D
Senior
Toxicologist
Antimicrobials
Division
(
7510C)

To:
Jacqueline
McFarlane,
Chemical
Review
Manager
Regulatory
Management
Branch
I
Antimicrobials
Division
(
7510C)
Page
2
of
28
1.0
HAZARD
CHARACTERIZATION...................................
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defined.
2.0
REQUIREMENTS
..............................................................
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defined.
3.0
DATA
GAP(
S)
.....................................................................
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defined.
4.0
HAZARD
ASSESSMENT...................................................
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defined.
4.1
Acute
Toxicity........................................................................................................
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defined.
4.2
Subchronic
Toxicity
..............................................................................................
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not
defined.
4.3
Prenatal
Developmental
Toxicity........................................................................
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not
defined.
4.4
Reproductive
Toxicity
..........................................................................................
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not
defined.
4.5
Chronic
Toxicity....................................................................................................
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defined.
4.6
Carcinogenicity......................................................................................................
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defined.
4.7
Mutagenicity..........................................................................................................
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defined.
4.8
Neurotoxicity..........................................................................................................
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defined.
4.9
Metabolism.............................................................................................................
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defined.

5.0
Toxicity
Endpoint
Selection
................................................
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defined.
6.0
FQPA
Considerations..........................................................
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defined.
7.0
Summary
of
Doses
and
Endpoints
for
ADBAC
.................
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not
defined.
8.0
Toxicity
Profile
of
ADBAC..................................................
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defined.
9.0
References............................................................................
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3
of
28
1.0
HAZARD
CHARACTERIZATION
Pursuant
to
PR
Notice
88­
2,
grouping
of
quaternary
ammonium
compounds
was
allowed,
based
on
the
numerous
chemical
structures
that
represent
these
types
of
chemicals.
Grouping
was
allowed
into
4
broad
categories,
based
on
chemical
structure:
Group
I
quaternary
ammonium
compounds
(
alkyl
or
hydroxy
alkyl
substituted
compounds);
Group
II
non­
halogenated
benzyl
substituted
quaternary
ammonium
compounds
(
ADBAC
as
representative);
Group
III
di­
and
trichlorobenzyl
substituted
quaternary
ammonium
compounds;
and
Group
IV,
quaternary
ammonium
compounds
with
unusual
substituents.
ADBAC,
or
alkyl
dimethyl
benzyl
ammonium
chloride,
is,
as
stated
above,
a
member
of
the
Group
II
class
of
quaternary
ammonium
compounds.
Hazard
data
generated
for
ADBAC
is
representative
of
the
hazard
associated
with
this
class
of
quaternary
ammonium
chemicals.

In
an
acute
oral
toxicity
study
(
MRID
45109204),
the
acute
oral
LD50
of
ADBAC
(
82.26%
a.
i.)
was
determined
to
be
304.5
mg/
kg
(
both
sexes
combined)
and
was
assigned
Toxicity
Category
II.
In
an
acute
dermal
toxicity
study
(
MRID
45109202),
the
acute
dermal
LD50
of
ADBAC
(
82.26%
a.
i.)
was
determined
to
be
930
mg/
kg
(
both
sexes
combined)
and
was
assigned
Toxicity
Category
II.
In
an
acute
inhalation
toxicity
study
(
MRID
44885201),
the
acute
LC50
of
ADBAC
(
82.26%
a.
i.)
was
determined
to
be
0.054
<
LC50
<
0.51
mg/
L
and
was
assigned
a
Toxicity
Category
II.
The
primary
eye
irritation
study
was
waived
and
assigned
a
Toxcity
Category
I
for
technical
grade
ADBAC
(
80%
a.
i).
For
primary
dermal
irritation
(
MRID
45109201),
ADBAC
(
82.26%
a.
i.)
was
corrosive
to
rabbits
(
Toxicity
Category
I).
In
a
dermal
sensitization
study
(
MRID
45109203),
ADBAC
(
82.26%
a.
i.)
was
not
a
sensitizer
to
guinea
pigs.
In
a
photoallergy
(
light)
sensitization
study
(
MRID
40958501
and
MRID
44825002),
ADBAC
(
80%
a.
i.)
was
not
a
photosensitizer.

In
a
subchronic
oral
toxicity
study
in
rats
(
MRID
40746601),
ADBAC
was
found
to
have
a
low
order
of
toxicity,
in
that
manifestations
of
toxicity
were
non­
specific
(
decreased
body
weight
gain,
food
consumption),
and
occurred
at
relatively
high
doses
(
LOAEL
of
62
mg/
kg/
day
in
males,
308
mg/
kg/
day
in
females).
This
result
was
also
observed
in
chronic
toxicity
studies
in
rats
and
mice
(
MRIDs
41947501
and
41765201),
where
effects
were
also
non
­
specific
in
nature
(
decreased
body
weight
gain
and
food
consumption),
and
occurred
at
relatively
high
doses.
In
a
21­
day
dermal
toxicity
study
in
guinea
pigs
(
MRID
41105801),
no
significant
systemic
effects
were
observed
using
a
chemical
mixture
of
4%
ADBAC/
6%
DDAC,
but
denuding
of
the
epidermal
layer
was
observed
at
the
highest
tested,
1000
mg/
kg/
day.
In
a
90­
day
dermal
toxicity
study
in
rats
(
MRID
41499601)
using
technical
grade
ADBAC
,
dermal
applications
of
ADBAC
(
81.09%
a.
i.)
to
rats
did
not
elicit
systemic
or
dermal
toxicity
up
to
the
highest
dose
tested,
20
mg/
kg/
day,
before
dermal
irritation
became
significant.

ADBAC
has
been
examined
for
effects
on
development
of
the
mammalian
fetus
and
effects
on
reproductive
function.
In
developmental
studies
with
rats
(
range­
finding
MRID
42645101
and
main
study
MRID
42351501)
and
rabbits
(
range­
finding
MRID
42734401
and
main
study
MRID
42392801),
developing
fetuses
showed
no
increased
sensitivity
to
the
toxicity
of
ADBAC
in
relation
to
adult
animals.
In
a
2­
generation
reproductive
toxicity
study
(
MRID
41385001),
effects
on
rat
pups
were
observed
in
the
absence
of
maternal
toxicity,
raising
some
concern
for
the
effects
Page
4
of
28
of
ADBAC
on
reproductive
function.
However,
the
effects
observed
were
non­
specific
(
decreased
pup
body
weight
and
weight
gain
during
lactation),
and
there
were
no
effects
of
ADBAC
on
reproductive
indices.

In
a
chronic
toxicity
study
in
dogs
(
MRID
43221101),
groups
of
4
male
and
female
beagle
dogs
per
group
received
either
0,
120,
400,
or
1200
ppm
(
0,
3.79,
13.1,
or
33.8
mg/
kg/
day
in
males
and
0,
3.67,
14.6,
or
38.6
mg/
kg/
day
in
females)
alkyl
dimethyl
benzyl
ammonium
chloride
[
ADBAC,
80%
a.
i.]
as
a
direct
dietary
admix
for
one
year.
Systemic
toxicity
was
observed
at
13.1
mg/
kg/
day
in
males
and
14.6
mg/
kg/
day
in
females
as
reduced
body
weight
gain
(
approximately
10%
reduction)
after
52
weeks
of
exposure.
Food
consumption
was
decreased
in
the
1200
ppm
males
and
females
for
the
entire
study
period
(
approximately
15%
reduction
in
males
and
5%
reduction
in
females).
Based
on
the
data
in
this
study,
the
Systemic
Toxicity
NOAEL
was
120
ppm
(
3.79
mg/
kg/
day
in
males,
3.67
mg/
kg/
day
in
females)
and
the
LOAEL
was
400
ppm
(
13.1
mg/
kg/
day
in
males,
14.6
mg/
kg/
day
in
females)
based
on
reduced
body
weight
gain.

ADBAC
has
been
tested
for
carcinogenicity
in
long
term
studies
with
both
rats
(
MRID
41947501)
and
mice
(
MRID
41765201).
In
both
studies,
tested
to
adequate
dose
levels,
ADBAC
was
negative
for
induction
of
tumors
in
both
species.
This
result
is
supported
by
results
of
testing
in
a
battery
of
mutagenicity
studies,
including
an
HGPRT/
CHO
for
ward
mutation
assay
(
MRID
41012701),
an
in
vivo
bone
marrow
chromosome
aberration
assay
(
MRID
40311101,
supplement
MRID
43037701),
and
an
unscheduled
DNA
synthesis
(
UDS)
assay
(
MRIDs
42290801
and
42290802),
which
show
ADBAC
to
be
negative
for
mutagenic
effects.

The
metabolism
of
ADBAC
was
investigated
in
MRID
41087701.
The
majority
of
administered
radioactive
ADBAC
is
eliminated
in
feces
from
oral
administration.
Intravenous
administration
also
shows
elimination
of
a
significant
proportion
of
ADBAC
in
feces,
indicating
elimination
through
the
bile.
Tissue
retention
of
orally
administered
radioactivity
is
negligible.
Page
5
of
28
2.0
TOXICOLOGY
DATA
REQUIREMENTS
The
Toxicology
database
for
ADBAC
is
listed
in
the
following
table.

Table
1:
Toxicologic
Data
Requirements
for
ADBAC.

Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity
(
Rat)
MRID
45109204
870.1200
Acute
Dermal
Toxicity
(
Rat)
MRID
45109202
870.1300
Acute
Inhalation
(
Rat)
MRID
44885201
870.2400
Primary
Eye
Irritation
(
Rabbit)
MRID
40919701
and
supplement
MRID
44825001
870.2500
Primary
Dermal
Irritation
(
Rabbit)
MRID
45109201
870.2600
Dermal
Sensitization
(
Guinea
pig)
MRID
45109203
Photosensitization
(
Guinea
pigs)
MRID
40958501
and
supplement
MRID
44825002
yes
yes
yes
yes
yes
yes
no
yes
yes
yes
yes
yes
yes
NA
870.3100
Oral
Subchronic
(
Rat)
MRID
40746601
870.3200
21­
Day
Dermal
(
Guinea
pig)
MRID
41105801
870.3250
90­
Day
Dermal
(
Rat)
MRID
41499601
yes
yes
yes
yes
yes
yes
870.3700a
Developmental
Toxicity
(
Rat)
MRID
42645101
(
rangefinding
MRID
42351501
(
main
study)
870.3700b
Developmental
Toxicity
(
Rabbit)
MRID
42734401
(
range­
finding)
and
42392801
(
main
study)
870.3800
Reproduction
(
Rat)
MRID
41385001
yes
yes
yes
yes
yes
yes
870.4100
Chronic
Toxicity
(
dog)
MRID
43221101
yes
yes
870.4200b
Oncogenicity
(
Mouse)
MRID
41765201
870.4300
Chronic/
Oncogenicity
(
Rat)
MRID
41947501
yes
yes
yes
yes
870.5300
Mutagenicity 
Gene
Mutation
(
CHO)
MRID
41012701
870.5385
Mutagenicity 
In
vivo
bone
arrow
chromosomal
aberration
test
(
mouse)
MRID
40311101,
supplement
43037701
870.5550
Mutagenicity 
Unscheduled
DNA
synthesis
(
Rat
hepatocyte)
MRID
42290802
and
42290801
yes
yes
yes
yes
yes
yes
870.6100
...................................................................................................
870.6200
...................................................................................................
870.6300
...................................................................................................
no
no
no
­
­
­

870.7485
Metabolism
(
Rat)
MRID
40990701,
supplemental
MRIDs
41087701
and
44783401
yes
yes
Page
6
of
28
3.0
DATA
GAPS
A
dermal
absorption
study
is
not
available
for
ADBAC.
Until
data
are
received
that
adequately
address
this
science
issue,
the
value
of
10%
dermal
absorption
determined
by
the
HIARC
will
be
used.
Also,
a
repeated
dose
inhalation
toxicity
study
is
not
available
for
the
technical
grade
ADBAC.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
database
for
Acute
Toxicity:
The
acute
toxicity
data
for
ADBAC
are
considered
adequate
to
support
reregistration.
The
acute
toxicity
data
for
ADBAC
are
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Profile
for
ADBAC
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.1100
(
§
81­
1)
Acute
oral,
rat
(
Purity
82.26%)
MRID
45109204
LD50
=
304.5
mg/
kg
(
combined)

LD50
=
510.9
mg/
kg
(
males)
LD50
=
280.8
mg/
kg
(
females)
II
870.1200
(
§
81­
2)
Acute
dermal,
rat
(
Purity
82.26%)
MRID
45109202
LD50
=
930
mg/
kg
(
combined)

LD50
=
1100
mg/
kg
(
males)
LD50
=
704
mg/
kg
(
females)
II
870.1300
(
§
81­
3)
Acute
inhalation,
rat
(
Purity
82.26%)
MRID
44885201
0.054
<
LC50
<
0.51
mg/
L
II
870.2400
(
§
81­
4)
Primary
eye
irritation
waived
I
870.2500
(
§
81­
5)
Primary
dermal
irritation,
rabbit
(
Purity
82.26%)
MRID
45109201
Corrosive
I
870.2600
(
§
81­
6)
Dermal
sensitization,
guinea
pigs
(
Purity
82.26%)
MRID
45109203
Not
a
dermal
sensitizer.
NA
Non­
Photosensitization,
MRID
40958501
Not
a
NA
Page
7
of
28
Table
2.
Acute
Toxicity
Profile
for
ADBAC
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
Guideline
guinea
pigs
(
Purity
80%)
and
supplement
44825002
photosensitizer.

4.2
Subchronic
Toxicity
Adequacy
of
database
for
Subchronic
Toxicity:
The
database
for
subchronic
toxicity
of
ADBAC
is
considered
complete.
For
oral
toxicity,
the
database
includes
a
90­
day
oral
toxicity
test
in
rats
(
MRID
40746601).
For
dermal
toxicity,
there
is
a
21­
day
dermal
toxicity
study
in
guinea
pigs
(
MRID
40700700)
and
a
90­
day
dermal
toxicity
study
in
rats
(
MRID
41499601).

870.3100
Subchronic
(
Oral)
Toxicity
­
Rat
In
a
subchronic
oral
toxicity
study
in
rats
(
MRID
#
40746601),
male
and
female
rats
were
administered
ADBAC
(
79.7%
a.
i.)
in
the
diet
for
13
weeks
at
dose
levels
of
0,
100,
500,
1000,
4000,
or
8000
ppm.
Increased
mortality
was
observed
at
the
4000
and
8000
ppm
dose
groups
in
both
sexes.
Decreased
body
weight,
weight
gain,
food
consumption
and
increased
incidence
of
microscopic
lesions
[
congestion
and
edema
of
the
G.
I.
tract,
hemorrhaging
of
the
lungs
and
brain]
were
also
observed
in
males
and
females
at
4000
ppm.
The
Systemic
NOAEL
for
males
is
500
ppm
and
for
females
is
1000
ppm,
based
upon
decreased
body
weight
and
weight
gain
in
males
at
1000
ppm,
and
increased
mortality,
decreased
body
weight
gain
and
food
consumption,
and
increased
microscopic
lesions
in
female
rats
at
4000
ppm.

This
study
is
classified
as
acceptable.

870.3200
Subchronic
(
21­
day
dermal)
Toxicity
 
Guinea
pig
In
a
21­
day
dermal
toxicity
study
(
MRIDs
40565301
and
41105801),
a
1:
5
dilution
of
HSsanitizing
carpet
shampoo
(
containing
6%
didecyl
dimethyl
ammonium
chloride
and
4%
alkyl
dimethyl
benzyl
ammonium
chloride)
was
applied
to
a
2
inch
square
area
of
the
shaved
dorsal
trunk
of
5
male
and
5
female
guinea
pigs
at
doses
of
500
and1000
mg/
kg,
five
days
a
week,
for
21
days.
There
was
no
mortality
or
signs
of
clinical
toxicity
noted.
Signs
of
skin
irritation
were
noted
during
the
second
week
of
treatment
and
the
report
stated
that
the
response
intensified
during
the
third
week
of
treatment.
Body
weight
was
decreased
in
treated
males
and
females
by
7%
and
11%
vs
untreated
animals
at
week
3
at
1000
mg/
kg.
Results
of
hematology
and
clinical
chemistry
measurements
indicated
a
slight
elevation
of
basophils
and
eosinophils
as
well
as
a
slight
elevation
of
SGPT
and
SGOT
but
statistics
were
not
performed
on
these
data.
Histologically,
the
skin
irritation
was
described
as
a
denuded
non­
vascularized
epidermal
layer
at
the
application
site.
Although
this
study
was
identified
with
several
deficiencies
(
HED
document
007757,
from
the
1/
31/
90
review
by
Pamela
Hurley,
Ph.
D.),
the
data
are
useful
for
determining
a
level
of
concern
Page
8
of
28
for
dermal
irritation
and
systemic
effects
after
short­
term
exposure
to
ADBAC.
In
this
case,
the
500
mg/
kg
dose
level
produced
no
significant
dermal
or
systemic
effects,
and
is
considered
a
NOAEL
for
the
study
for
dermal
irritation
and
systemic
effects.

870.3250
Subchronic
(
90­
day
dermal)
Toxicity
 
Rat
In
a
90­
day
dermal
toxicity
study
(
MRID
41499601),
ADBAC
(
81.09%
a.
i.)
was
applied
at
dose
levels
of
0,
2,
6,
or
20
mg/
kg/
day
to
the
clipped
backs
of
Sprague­
Dawley
rats
for
6­
8
hours
per
day,
5
days
per
week,
for
13
weeks.
Although
higher
doses
were
tested
in
a
preliminary
rangefinding
study
(
6,
20,
60,
120,
and
200
mg/
kg/
day),
the
high
dose
selected
for
the
main
study
(
20
mg/
kg/
day)
was
chosen
on
the
basis
that
higher
concentrations
produced
skin
irritation
that
was
considered
greater
than
slight.

A
significant
and
dose­
related
decrease
in
reticulocyte
count
was
observed
in
the
6­
and
20­
mg/
kg/
day
females.
Decreases
in
reticulocyte
count
are
normally
associated
with
regenerative
responses
to
anemia.
However,
no
evidence
of
anemia
was
seen
in
other
hematological
parameters.
Furthermore,
the
decreased
levels
in
treated
females
were
similar
to
the
levels
observed
in
control
males.
Thus,
the
decreasing
reticulocyte
count
was
most
likely
not
a
biologically
significant
finding.
A
significant
increase
in
hyperkeratosis
was
observed
in
treated
skin
of
high
dose
females,
but
this
lesion
was
also
observed
in
increased
incidence
in
male
rats
at
all
doses
including
controls.

The
NOAEL
for
dermal
effects
and
the
NOAEL
for
systemic
effects
were
20
mg/
kg/
day.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
database
for
Prenatal
Developmental
Toxicity:
The
database
for
developmental
toxicity
of
ADBAC
is
considered
complete.
The
database
includes
2
developmental
studies,
one
in
the
rat
(
range­
finding
MRID
42645101
and
main
study
MRID
42351501)
and
another
in
the
rabbit
(
range­
finding
MRID
42734401
and
main
study
MRID
42392801).

870.3700
Prenatal
Developmental
Toxicity
(
Gavage)
Study
 
Rat
In
a
dose
range­
finding
study
for
developmental
toxicity
in
rats
(
MRID
#
42645101),
ADBAC
(
81.09%)
was
administered
at
doses
of
0,
25,
50,
100,
200,
or
400
mg/
kg/
day
to
CD
rats
(
5/
dose)
by
oral
gavage
on
gestation
days
6
through
15,
inclusive.
Doses
 
200
mg/
kg/
day
resulted
in
100%
mortality;
necropsy
findings
revealed
a
distended
and
change
in
color
of
the
stomach,
and
distended
intestines
filled
with
mucoid
fluid.
These
dams
also
exhibited
clinical
signs
including
loose
feces,
perioral
wetness
and
perioral
encrustation,
ataxia,
hypoactivity,
urogenital
area
wetness,
and
audible
respiration.
Maternal
toxicity
observed
at
100
mg/
kg/
day
was
manifest
as
significantly
increased
incidence
of
perioral
wetness.
The
maternal
NOAEL
and
LOAEL
are
50
and
100
mg/
kg/
day,
respectively.
The
NOAEL
for
developmental
toxicity
is
100
mg/
kg/
day
based
on
no
survival
of
dams
at
200
and
400
mg/
kg/
day.
Page
9
of
28
In
a
developmental
toxicity
study
in
rats
(
MRID
#
42351501),
female
Sprague­
Dawley
rats
(
25/
dose)
were
administered
ADBAC
(
81.09%
a.
i.)
by
gavage
at
doses
of
0,
10,
30,
and
100
mg/
kg
on
gestation
days
6
through
15
inclusive
for
assessment
of
developmental
toxicity.
There
was
no
mortality
in
maternal
animals
observed
at
any
dose
level.
At
100
mg/
kg/
day,
one
dam
exhibited
dehydration,
unkempt
appearance,
loose
feces,
and
perioral
wetness.
At
30
mg/
kg/
day,
one
dam
was
noted
with
perioral
wetness,
gasping,
loose
feces,
and
urine
stains.
Decreased
body
weight
gain
(
12­
13%)
was
observed
in
maternal
animals
at
30
mg/
kg/
day
during
gestation
days
6­
15.
Food
consumption
was
not
consistently
affected
by
treatment.
There
were
no
treatmentrelated
increases
in
the
incidence
of
fetal
external,
visceral,
or
skeletal
abnormalities
at
any
dose
level.
Based
on
the
results
of
this
study,
the
Maternal
NOAEL
is
10
mg/
kg/
day,
and
the
Maternal
LOAEL
is
30
mg/
kg/
day,
based
on
clinical
signs
and
decreased
body
weight
gain.
The
Developmental
toxicity
NOAEL
is
100
mg/
kg/
day,
and
the
Developmental
toxicity
LOAEL
is
>
100
mg/
kg/
day.
There
was
no
evidence
for
developmental
toxicity
of
ADBAC
in
this
study.

This
study
is
classified
as
acceptable.

870.3700
Prenatal
Developmental
Toxicity
(
Gavage)
 
Rabbit
In
a
dose
range­
finding
study
for
developmental
toxicity
in
rabbits
(
MRID
#
42734401),
ADBAC
(
81.09%)
was
administered
at
doses
of
0,
1,
3,
10,
30,
or
60
mg/
kg/
day
to
pregnant
New
Zealand
White
rabbits
(
5/
dose)
by
oral
gavage
on
gestation
days
6
through
18.
Mortality
was
observed
at
doses
of
30
and
60
mg/
kg/
day
(
2
and
5
does,
respectively).
Audible
respiration
was
observed
at
doses
greater
than
or
equal
to
10
mg/
kg/
day.
At
doses
greater
than
or
equal
to
30
mg/
kg/
day,
clinical
signs
included
hypoactivity,
perioral
wetness,
and
labored
breathing.
At
60
mg/
kg/
day,
clinical
signs
included
paralysis,
cold
extremities,
prostration,
slow
respiration,
emaciation,
loose
feces,
and
perioral
encrustation.
Decreased
body
weight
gain
and
food
consumption
were
observed
at
doses
greater
than
or
equal
to
10
mg/
kg/
day.
Developmental
toxicity
was
not
observed
at
any
of
the
doses
tested.
The
maternal
NOAEL
for
the
range­
finding
study
is
3
mg/
kg/
day
and
the
LOAEL
is
10
mg/
kg/
day,
based
on
clinical
signs
and
reduced
body
weight
gain
and
food
consumption.
There
was
no
evidence
of
developmental
toxicity
of
ADBAC
in
this
study.

In
a
developmental
toxicity
study
in
rabbits
(
MRID
#
42392801),
ADBAC
(
81.09%)
was
administered
at
doses
of
0,
1,
3,
or
9
mg/
kg/
day
to
pregnant
New
Zealand
White
rabbits
(
16/
dose)
by
oral
gavage
on
gestation
days
6
through
18,
inclusive.
There
was
no
mortality
or
abortions
at
any
dose
level.
Hypoactivity
and
labored
breathing
were
observed
at
9
mg/
kg/
day
in
2
of
15
rabbits.
There
were
no
effects
on
maternal
body
weight,
food
consumption,
cesarean
section
observations,
or
necropsy
observations.
In
offspring,
there
was
no
evidence
of
developmental
toxicity
at
any
dose
level
tested.
The
Maternal
NOAEL
is
3
mg/
kg/
day,
and
the
Developmental
NOAEL
is
9
mg/
kg/
day.
The
Maternal
LOAEL
is
9
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
and
the
Developmental
LOAEL
is
>
9
mg/
kg/
day.
There
was
no
evidence
of
developmental
toxicity
of
ADBAC
in
this
study.
Page
10
of
28
This
study
is
classified
as
acceptable.

4.4
Reproductive
Toxicity
Adequacy
of
database
for
Reproductive:
The
database
for
reproductive
toxicity
of
ADBAC
is
considered
complete.
The
database
includes
an
acceptable
2­
generation
reproduction
toxicity
study
in
rats,
MRID
41385001.

870.3800
Reproduction
and
Fertility
Effects
 
Rat
In
a
two­
generation
reproduction
toxicity
study
in
rats
(
MRID
#
41385001),
ADBAC
(
81.09%)
was
administered
in
the
diet
to
groups
of
male
and
female
Sprague­
Dawley
rats
(
28/
sex/
dose)
at
dose
levels
of
0,
300,
1000,
or
2000
ppm
over
two
generations.
After
10
weeks
of
dietary
treatment,
F0
parental
animals
were
mated.
F1
parental
animals
were
mated
after
15
weeks
of
dietary
treatment.
Mean
compound
consumption
was
20.7,
68.2,
and
134.7
mg/
kg/
day
for
F0
males,
and
25.5,
81.3,
and
164.7
mg/
kg/
day
for
F0
females.
For
the
F1
males,
mean
compound
consumption
was
19.1,
62.5,
and
125.4
mg/
kg/
day,
and
24.8,
78.5,
and
157.1
mg/
kg/
day
for
F1
females.

There
was
no
treatment­
related
mortality
in
parental
animals
at
any
dose
level,
and
there
were
no
reported
signs
of
clinical
toxicity
in
parental
animals.
Although
some
decrease
in
body
weight
was
observed
in
both
generations
at
the
top
dose,
the
significant
variability
observed
did
not
qualify
this
as
a
treatment­
related
effect.

In
pups
of
both
generations,
mean
body
weights
at
the
top
dose
were
significantly
reduced
during
lactation
and
post­
weaning
periods.
There
were
no
adverse
effects
noted
on
gestational
length,
mating,
fertility,
or
other
gestational
indices.

Based
on
the
results
of
this
study,
the
Parental
NOAEL
=
146
mg/
kg/
day,
and
the
Parental
LOAEL
>
146
mg/
kg/
day
(
highest
dose
tested).
The
Developmental/
Systemic
NOAEL
=
65.4/
79.9
mg/
kg/
day
(
M/
F),
and
the
Developmental
/
Systemic
LOAEL
=
130.1/
160.9
mg/
kg/
day
(
M/
F),
based
on
reduced
pup
body
weight
and
weight
gain
during
lactation
[
doses
for
both
the
F0
and
F1
pups
combined].

This
study
is
classified
as
acceptable.

4.5
Chronic
Toxicity
Adequacy
of
database
for
Chronic
Toxicity:
The
database
for
chronic
toxicity
of
ADBAC
is
considered
adequate,
including
a
chronic
toxicity
study
in
dogs
(
MRID
43221101)
and
a
combined
chronic
oral
toxicity/
carcinogencity
study
in
rats
(
MRID
41947501).

870.4100
Chronic
Toxicity
(
Oral)
 
Dog
Page
11
of
28
In
a
chronic
toxicity
study
in
dogs
(
MRID
43221101),
groups
of
4
male
and
female
beagle
dogs
per
group
received
either
0,
120,
400,
or
1200
ppm
(
0,
3.79,
13.1,
or
33.8
mg/
kg/
day
in
males
and
0,
3.67,
14.6,
or
38.6
mg/
kg/
day
in
females)
alkyl
dimethyl
benzyl
ammonium
chloride
[
ADBAC,
80%
a.
i.]
as
a
direct
dietary
admix
for
one
year.
Systemic
toxicity
was
observed
at
400
ppm
and
above
in
female
dogs
and
at
1200
ppm
in
males
as
reduced
body
weight
gain
(
approximately
10%
reduction)
after
52
weeks
of
exposure.
Food
consumption
was
decreased
in
the
1200
ppm
males
and
females
for
the
entire
study
period
(
approximately
15%
reduction
in
males
and
5%
reduction
in
females).
Based
on
the
data
in
this
study,
the
Systemic
Toxicity
NOAEL
was
120
ppm
(
3.79
mg/
kg/
day
in
males,
3.67
mg/
kg/
day
in
females)
and
the
LOAEL
was
400
ppm
(
13.1
mg/
kg/
day
in
males,
14.6
mg/
kg/
day
in
females)
based
on
reduced
body
weight
gain.

870.4300
Chronic
Toxicity/
Carcinogenicity
(
Oral)
 
Rat
In
a
chronic
toxicity
/
carcinogenicity
study
(
MRID
#
41947501),
ADBAC
(
81%
purity)
was
administered
in
the
diet
to
groups
of
male
and
female
Sprague­
Dawley
rats
(
50/
sex/
dose)
at
dose
levels
of
0,
300,
1000,
and
2000
ppm
(
nominal
doses
of
13,
44,
and
88
mg/
kg/
day
in
males;
17,
57,
and
116
mg/
kg/
day
in
females)
for
104
weeks.
Significant
decreases
in
group
mean
body
weight
were
observed
in
male
rats
at
the
2000
ppm
dose
level
during
weeks
1­
26
of
the
study
and
then
sporadically
thereafter.
Body
weights
of
high
dose
female
rats
were
also
significantly
decreased
during
weeks
1­
60
of
the
study.
Body
weight
gain
was
decreased
11%
on
average
in
high
dose
males
and
14%
in
high
dose
females.
There
were
no
significant
treatment­
related
effects
on
clinical
chemistry,
hematology,
or
urinalysis.
No
treatment­
related
non
neoplastic
gross
or
microscopic
lesions
were
evident
in
any
of
the
treated
groups
of
rats.
There
was
no
evidence
of
carcinogenicity
of
ADBAC
in
this
study.
The
Systemic
toxicity
NOAEL
=
1000
ppm,
(
44
mg/
kg/
day
[
M];
57
mg/
kg/
day
[
F]),
and
the
Systemic
toxicity
LOAEL
=
2000
ppm
(
88
mg/
kg/
day
[
M];
116
mg/
kg/
day
[
F],
based
on
decreased
body
weight
and
weight
gain.
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity
/
carcinogenicity
study
in
rats.

4.6
Carcinogenicity
Adequacy
of
database
for
Carcinogenicity:
The
database
for
the
carcinogenicity
of
ADBAC
is
considered
adequate.
The
database
for
carcinogenicity
includes
the
104
week
chronic
toxicity/
carcinogenicity
study
in
rats
(
MRID
41947501)
described
in
4.5
and
an
additional
carcinogenicity
study
in
the
mouse
(
MRID
41765201).
Results
of
both
studies
showed
ADBAC
to
be
negative
for
carcinogenicity.

870.4200
Carcinogenicity
(
Oral)
 
Mouse
Page
12
of
28
In
a
carcinogenicity
study
in
mice
(
MRID
#
41765201),
ADBAC
(
81%
purity)
was
administered
in
the
diet
to
male
and
female
CD­
1
mice
(
60
sex/
dose)
at
levels
of
0,
100,
500,
or
1500
ppm
for
78
weeks
(
nominal
doses
of
14.9,
73.4
and
229.3
mg/
kg/
day
in
males;
17.8,
92.1
and
288.6
mg/
kg/
day
in
females).
No
significant
differences
in
the
incidence
of
mortality
were
observed
in
treated
animals
versus
controls.
No
clinical
signs
of
toxicity
were
observed
at
any
dose
level
tested.
Significant
reductions
in
group
mean
body
weight
were
observed
at
the
high
dose
in
male
and
female
mice
throughout
the
treatment
period
with
no
significant
reduction
in
food
intake.
There
were
no
significant
treatment­
related
effects
on
organ
weights,
macroscopic,
or
microscopic
pathology
in
treated
mice
at
any
dose
level.
ADBAC
was
negative
for
carcinogenicity
in
this
study.
The
Systemic
LOAEL
=
1500
ppm
in
male
and
female
mice
(
229.3
/
288.6
mg/
kg/
day),
based
on
reduced
body
weight.
The
Systemic
NOAEL
=
500
ppm
in
male
and
female
mice
(
73.4
/
92.1
mg/
kg/
day).
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
in
mice.

4.7
Mutagenicity
ADBAC
has
been
tested
for
mutagenicity
in
an
HGPRT
assay
in
CHO
cells
for
forward
mutations
(
MRID
41012701),
an
in
vivo
bone
marrow
chromosome
aberration
assay
(
MRID
40311101,
supplemental
MRID
43037701),
and
an
unscheduled
DNA
synthesis
assay
(
MRID
42290802
and
4229080).
Results
of
all
of
these
studies
were
negative
for
ADBAC.

4.8
Neurotoxicity
Adequacy
of
database
for
Neurotoxicity:
There
are
no
studies
specifically
examining
the
Neurotoxicity
of
ADBAC.
Based
on
the
lack
of
evidence
for
Neurotoxicity
of
ADBAC,
specific
neurotoxicity
studies
are
not
required
for
ADBAC
at
this
time.

4.9
Metabolism
and
Pharmacokinetics
Adequacy
of
database
for
Metabolism
and
Pharmacokinetics:
Disposition
of
ADBAC
was
examined
in
male
and
female
Sprague­
Dawley
rats
(
MRID
40990701,
supplemental
MRIDs
41087701
and
44783401)
following
a
10
mg/
kg
single
dose
by
the
oral
or
intravenous
route,
following
exposure
to
100
ppm
ADBAC
for
14
days
in
the
diet,
or
after
a
single
oral
dose
of
50
mg/
kg.
Ring­
labeled
test
material
was
used.
Following
oral
administration,
from
5­
8%
of
the
administered
dose
was
eliminated
in
urine
and
90­
98%
in
feces.
No
apparent
differences
in
disposition
were
noted
between
sexes.
Following
intravenous
administration,
males
eliminated
31%
of
the
dose
in
urine
and
44%
in
feces,
while
females
eliminated
21%
in
urine
and
55%
in
feces
following
intravenous
administration.
After
oral
administration,
from
0.03­
0.58%
of
the
administered
dose
was
accounted
for
in
tissues.
After
intravenous
administration,
tissue
residues
accounted
for
33­
36%
of
the
dose
and
were
observed
mainly
in
the
carcass.
The
results
of
this
study
indicate
that
a
majority
of
an
administered
dose
of
ADBAC
is
eliminated
in
feces
and
involves
biliary
excretion.
Page
13
of
28
5.0
Toxicity
Endpoint
Selection
5.1
See
Section
7.1,
Summary
of
Toxicological
Doses
and
Endpoint
Selection,
Table
2.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
10%

Based
upon
the
structure,
molecular
weight,
ionized
state,
and
lack
of
lipophilicity,
that
dermal
absorption
of
ADBAC
would
not
exceed
10%.
This
value
will
be
used
in
dermal
risk
assessments.

5.3
Classification
of
Carcinogenic
Potential
ADBAC
has
been
tested
for
carcinogenicity
in
both
rats
and
mice
in
studies
reviewed
by
the
Agency.
Results
of
both
studies
show
ADBAC
to
be
negative
for
carcinogenicity.

1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
In
a
chronic
toxicity
/
carcinogenicity
study
(
MRID
#
41947501),
ADBAC
(
81%
purity)
was
administered
in
the
diet
to
groups
of
male
and
female
Sprague­
Dawley
rats
(
50/
sex/
dose)
at
dose
levels
of
0,
300,
1000,
and
2000
ppm
(
nominal
doses
of
13,
44,
and
88
mg/
kg/
day
in
males;
17,
57,
and
116
mg/
kg/
day
in
females)
for
104
weeks.
Significant
decreases
in
group
mean
body
weight
were
observed
in
male
rats
at
the
2000
ppm
dose
level
during
weeks
1­
26
of
the
study
and
then
sporadically
thereafter.
Body
weights
of
high
dose
female
rats
were
also
significantly
decreased
during
weeks
1­
60
of
the
study.
Body
weight
gain
was
decreased
11%
on
average
in
high
dose
males
and
14%
in
high
dose
females.
There
were
no
significant
treatment­
related
effects
on
clinical
chemistry,
hematology,
or
urinalysis.
No
treatment­
related
non
neoplastic
gross
or
microscopic
lesions
were
evident
in
any
of
the
treated
groups
of
rats.
There
was
no
evidence
of
carcinogenicity
of
ADBAC
in
this
study.
The
Systemic
toxicity
NOAEL
=
1000
ppm,
(
44
mg/
kg/
day
[
M];
57
mg/
kg/
day
[
F]),
and
the
Systemic
toxicity
LOAEL
=
2000
ppm
(
88
mg/
kg/
day
[
M];
116
mg/
kg/
day
[
F],
based
on
decreased
body
weight
and
weight
gain.
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity
/
carcinogenicity
study
in
rats.

2.
Carcinogenicity
Study
in
Mice
In
a
carcinogenicity
study
in
mice
(
MRID
#
41765201),
ADBAC
(
81%
purity)
was
administered
in
the
diet
to
male
and
female
CD­
1
mice
(
60
sex/
dose)
at
levels
of
0,
100,
500,
or
1500
ppm
for
78
weeks.
No
significant
differences
in
the
incidence
of
mortality
were
observed
in
treated
animals
versus
controls.
No
clinical
signs
of
toxicity
were
observed
at
any
dose
level
tested.
Significant
Page
14
of
28
reductions
in
group
mean
body
weight
were
observed
at
the
high
dose
in
male
and
female
mice
throughout
the
treatment
period
with
no
significant
reduction
in
food
intake.
There
were
no
significant
treatment­
related
effects
on
organ
weights,
macroscopic,
or
microscopic
pathology
in
treated
mice
at
any
dose
level.
ADBAC
was
negative
for
carcinogenicity
in
this
study.
The
Systemic
LOAEL
=
1500
ppm
in
male
and
female
mice
(
229.3
/
288.6
mg/
kg/
day),
based
on
reduced
body
weight.
The
Systemic
NOAEL
=
500
ppm
in
male
and
female
mice
(
73.4
/
92.1
mg/
kg/
day).
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
in
mice.

6.0
FQPA
Considerations
6.1
Developmental
Toxicity
Study
Conclusions
In
both
the
developmental
toxicity
study
in
the
rat
and
rabbit,
there
was
no
evidence
of
increased
susceptibility
to
offspring
in
these
studies.

6.2
Reproductive
Toxicity
Study
Conclusions
There
was
no
evidence
of
a
primary
reproductive
toxicity
effect
of
ADBAC
based
on
the
available
data.

6.3
Pre­
and/
or
Postnatal
Toxicity
A.
Determination
of
Susceptibility
The
HIARC
determined
from
the
available
data
that
there
was
no
evidence
for
increased
susceptibility
of
offspring
to
the
toxic
effects
of
ADBAC.

B.
Proposed
Hazard­
based
Special
FQPA
Safety
Factor(
s):

The
HIARC
recommended
that
the
FQPA
safety
factor
be
reduced
to
1x
for
ADBAC,
based
upon
the
existence
of
a
complete
developmental
and
reproductive
toxicity
database
and
the
lack
of
evidence
for
increased
susceptibility
in
these
data.

6.4
Recommendation
for
a
Developmental
Neurotoxicity
Study
There
are
no
studies
specifically
examining
neurotoxicity
of
ADBAC.
However,
there
was
no
evidence
of
neurotoxicity
from
the
available
studies
on
ADBAC.
The
HIARC
expressed
concern
that
some
quaternary
ammonium
compounds
could
have
the
potential
for
neurotoxicity,
depending
upon
the
length
of
the
alkyl
chains.
However,
for
ADBAC,
neurotoxicity
studies
will
not
be
required
at
this
time.

A
developmental
neurotoxicity
study
is
not
recommended,
based
on
the
lack
of
evidence
for
Page
15
of
28
neurotoxicity
of
ADBAC
in
the
available
database.

7.0
Summary
of
Toxicological
Doses
and
Endpoints
for
ADBAC
for
Use
in
Human
Risk
Assessment
7.1
Summary
Table
of
Toxicological
Dose
and
Endpoint
Selection
(
Table
3)

EXPOSURE
SCENARIO
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE/
UF,
Special
FQPA
SF
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
general
pop.,
females
13+)
No
appropriate
endpoint
was
identified
in
the
database.
This
risk
assessment
is
not
required.

FQPA
SF
=
1
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
Chronic
toxicity/
carcinogenicity
­
rat
MRID
41947501
LOAEL
=
88
mg/
kg/
day,
based
on
decreased
body
weight
and
weight
gain
Chronic
Dietary
NOAEL
=
44
mg/
kg/
day
Chronic
RfD
=
0.44
mg/
kg/
day
Incidental
Oral
(
short­
term)
NOAEL
=
10
mg/
kg/
day
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
Developmental
Toxicity
­
Rat
MRID
42351501
LOAEL
=
30
mg/
kg/
day,
based
on
clinical
signs
and
decreased
body
weight
gain.

Incidental
Oral
(
intermediate­
term)
NOAEL
=
10
mg/
kg/
day
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
Developmental
Toxicity
­
Rat
MRID
42351501
LOAEL
=
30
mg/
kg/
day,
based
on
decreased
body
weight
and
food
consumption.

Short­
Term
Dermal
(
formulated
product
(
4%
a.
i.))
b
NOAEL=
500
mg/
kg/
day
(
333
:
g
ai/
cm2)
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
21­
day
dermal
toxicity­
guinea
pigs
MRID
41105801
LOAEL
=
40
mg
ai/
kg/
day,
based
on
denuded
non­
vascularized
epidermal
layer.
Page
16
of
28
EXPOSURE
SCENARIO
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE/
UF,
Special
FQPA
SF
for
Risk
Assessment
Study
and
Toxicological
Effects
Intermediate­
term
dermal
technical
grade
a.
i.
(
80%
a.
i.)
c
NOAEL
=
20
mg/
kg/
day
(
80
:
g
ai/
cm2)
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
90­
day
dermal
toxicity
in
rats
MRID
41499601
highest
dose
(
20
mg
ai/
kg/
day)
tested
before
irritation
became
significant
at
day
43.

Short­
Term
Dermal
(
technical
grade
a.
i.)
No
endpoint
identified
from
the
available
data
on
dermal
irritation.
Dermal
irritation
in
the
90­
day
dermal
toxicity
study
was
not
evident
until
day
43
(
MRID
41499601).

Long­
Term
Dermal
(
technical
grade
a.
i.)
No
appropriate
endpoint
identified.
No
systemic
effects
observed
up
to
20
mg/
kg/
day,
highest
dose
of
technical
grade
that
could
be
tested
without
irritation
effects.

Inhalationa
(
all
exposure
durations)
NOAEL=
3
mg/
kg/
day
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation,
10x
route­
extrapolation)

Note
­
an
additional
10x
is
necessary
for
route
extrapolation.
If
risk
estimates
are
below
an
MOE
of
1000,
a
confirmatory
inhalation
toxicity
study
may
be
required
Developmental
toxicity
­
rabbit
MRID
42392801
LOAEL
=
9
mg/
kg/
day,
based
on
clinical
signs
of
toxicity
in
maternal
animals.

UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
Level
of
concern,
NA
=
Not
Applicable.
aAn
additional
uncertainty
factor
of
10x
is
applied
for
use
of
an
oral
endpoint
for
route­
to­
route
extrapolation
to
determine
if
a
confirmatory
inhalation
toxicity
study
is
warranted.
b
Formulated­
based
dermal
endpoint
=
(
20
mg/
kg
guinea
pig
x
0.43
kg
guinea
pig
x
1000
ug/
mg)
/
25.8cm2
area
of
guinea
pig
dosed
=
333
µ
g
ai/
cm2
.
c
TGAI­
based
dermal
endpoint
=
(
20
mg
ai/
kg
rat
x
0.2
kg
rat
x
1000
ug/
mg)
/
50cm2
area
of
rat
dosed
=
80
µ
g
ai/
cm2
Page
17
of
28
8.0
Toxicity
Profile
Tables
8.1
Acute
Toxicity
Profile
Table
(
Table
4).

Table
4.
Acute
Toxicity
Profile
for
ADBAC.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
Purity
82.26%
MRID
45109204
Acceptable
Females:
0,
100,
250,
500,
or
510
mg/
kg
Males:
0,
500,
510,
525,
600,
or
750
mg/
kg
Rats
(
5/
sex/
dose)
Toxicity
Category
II
LD50
=
304.5
mg/
kg
(
combined)
LD50
=
510.9
mg/
kg
(
males)
LD50
=
280.8
mg/
kg
(
females)

Two
200
mg/
kg
females,
four
500
mg/
kg/
females,
three
males,
and
four
females
in
the
510
mg/
kg
group
and
all
males
in
the
525,
600,
and
750
mg/
kg
groups
were
dead
by
Day
6.
Breathing
abnormalities,
decreased
activity,
wobbly
gait,
salivation,
apparent
hypothermia,
soft/
mucoid
stools,
diarrhea,
decreased/
no
defacation,
fecal/
urine
stain,
piloerection,
rough
haircoat,
hunched
postures,
dehydration,
ocular
discharge,
decreased
food
consumption,
and/
or
dark
material
around
the
facial
area
were
noted
from
most
of
the
rats
with
recovery
by
Day
13
or
earlier.
Two
surviving
510
mg/
kg
males
lost
weight
during
the
first
week
of
study,
but
gained
weight
during
the
second
week.
All
other
surviving
rats
gained
weight
during
the
study.
The
decedents
had
abnormal
content
and/
or
reddened
mucosa
in
the
digestive
tract,
dark
red
thymus,
and/
or
fluid
contents
in
the
thoracic
cavity,
abnormal
content
in
the
small
intestines
and/
or
thickened
stomach
mucosa.
870.1200
(
§
81­
2)
Acute
Dermal
Toxicity
 
Rats
Purity
82.26%
MRID
45109202
Acceptable
0,
500,
1000,
or
2000
mg/
kg
Rats
(
5/
sex/
dose)
Toxicity
Category
II
LD50
=
930
mg/
kg
(
combined)
LD50
=
1100
mg/
kg
(
males)
LD50
=
704
mg/
kg
(
females)

Five
2000
mg/
kg/
females
were
found
dead
on
Day
1.
One
500
mg/
kg
female,
one
male
and
four
females
in
the
1000
mg/
kg
group,
and
five
2000
mg/
kg
were
found
dead
by
Day
4.
Irregular
respirations,
hunched
postures,
hypoactivity,
coldness
to
the
touch,
reduced
fecal
volume,
tremors,
ataxia,
and/
or
dypsnea
were
noted
for
the
decedents
prior
to
death.
Hypoactivity,
hunched
postures,
reduced
fecal
volume,
and/
or
irregular
respiration
were
noted
for
some
of
the
surviving
rats
with
recovery
by
Day
3.
Erythema
and
edema
were
noted
at
dose
site
from
most
of
the
rats.
Eschar
was
also
noted
at
the
dose
site
from
surviving
rats.
All
surviving
rats
had
normal
body
weight
gains.
No
gross
abnormalities
were
noted
from
the
surviving
rats
and
one
female
decedent
in
the
1000
mg/
kg/
group.
The
other
decedents
had
slightly/
moderately
red
lungs,
discolored
livers,
and/
or
red/
black/
green/
yellow
intestines.
870.1300
(
§
81­
3)
Acute
Inhalation
Toxicity
 
Rats
Purity
82.26%
a.
i.
MRID
44885201
Acceptable
0.054
or
0.51
mg/
L
Rats
(
5/
sex/
dose)
Toxicity
Category
II
0.054
<
LC50
>
0.51
mg/
L
0.054
mg/
L
group:
All
animals
survived.
Animal
displayed
ocular
and
nasal
discharge,
irregular
respiration,
dypsnea,
hunched
posture,
and
hypoactivity.
Irregular
respiration
and/
or
hypoactivity
persisted
in
several
rats
upon
removal
from
the
exposure
chamber
and
some
animals
also
developed
facial
staining
or
Page
18
of
28
Table
4.
Acute
Toxicity
Profile
for
ADBAC.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
reduced
fecal
volume.
All
rats
recovered
from
the
above
symptoms
by
Day
2
and
appeared
active
and
healthy
for
the
remainder
of
the
study,
gaining
bodyweight
over
the
entire
14­
day
observation
period.
No
gross
abnormalities
were
noted
in
animals
when
necropsied.

0.51
mg/
L
group:
All
animals
died.
During
exposure,
animals
exhibited
ocular
and
nasal
discharge,
irregular
respiration,
dypsnea,
gasping,
hunched
posture,
and
hypoactivity
prior
to
death.
Gross
necropsy
of
one
animal
revealed
discoloration
and
edema
of
the
lungs.
Gross
abnormalities
were
not
noted
in
the
other
animals.
870.2400
(
§
81­
4)
Primary
eye
irritation
 
Rabbits
waived
Toxicity
Category
I
870.2500
(
§
81­
5)
Primary
dermal
irritation
 
Rabbits
Purity
82.26%
MRID
45109201
Acceptable
0.5
mL
BQ451­
8,
40
hours
1
female
rabbit
Toxicity
Category
I
Corrosive.
The
rabbit
had
well­
defined
erythema
one
hour
after
patch
removal.
The
erythema
intensified
to
severe
by
24
hours
and
persisted
through
72
hours.
Moderate
edema
was
noted
on
the
rabbit
one
hour
after
patch
removal,
but
reduced
to
slight
by
24
hours
through
72
hours.
The
application
site
showed
superficial
eschar
by
24
through
48
hours
and
signs
of
dermal
corrosion
by
72
hours.
The
primary
dermal
irritation
index
was
5.8.

870.2600
(
§
81­
6)
Dermal
sensitization
 
Guinea
pigs
Purity
82.26%
MRID
45109203
Acceptable
Induction:
0.4
mL
of
2%
w/
w
test
material
in
distilled
water
with
occlusive
25
mm
Hilltop
Chamber
for
6
hours,
once/
week,
3
weeks
Challenge
Period:
27
days
Challenge
dose:
0.4
mL
of
0.5%
w/
w
test
material
in
distilled
water
under
occlusion
for
6
hours.

Control:
0.4
mL
of
0.5%
w/
w
test
material
in
distilled
water
at
challenge
only.

Guinea
pigs
(
20
test
animals,
10
controls;
24
males,
6
females)
Not
a
Sensitizer.

Faint
usually
confluent
to
moderate
erythema
was
noted
on
all
animals
after
the
first
induction.
Very
faint
usually
nonconfluent
to
moderate
erythema
was
noted
on
19/
20
animals
and
severe
erythema
was
noted
on
1/
20
animals
after
the
second
induction.
Faint
usually
confluent
to
severe
erythema
was
noted
on
all
animals
after
the
third
induction.
Eschar
was
noted
on
2/
20
animals
48
hours
after
the
third
induction.
Desquammation
was
noted
on
one
animal
24
hours
after
the
third
induction
with
resolution
by
48
hours.
After
three
weekly
inductions,
dermal
irritation
suggestive
of
sensitization
was
not
observed
on
the
test
animals
after
challenge.
The
study
report
included
DNCB
positive
control
study
which
was
carried
out
within
six
months
of
the
current
study.
The
results
were
appropriate.

Non­
Guideline
Photoallergy
 
Guinea
pigs
Purity
80%
MRID
40958501,
supplement
MRID
44825002
Acceptable
­
Nonguideline
Primary
irritation
study:
(
4
guinea
pigs/
sex/
dose)
0.3
mL
of
0,
0.5,
1,
2.5,
5,
10,
25,
50,
or
100
percent
in
distilled
water
for
4
hours,
followed
by
UV
irradiation
30
minutes
later
in
half
of
the
exposed
animals
Sensitization
study:
(
5
guinea
pigs/
sex/
group)
treated
for
4
hours,
followed
by
UV
radiation
exposure
approximately
30
Not
a
Photoallergen
at
the
dose
levels
tested.

Primary
irritation:
Severe
irritation
was
observed
in
animals
exposed
to
10,
25,
50,
or
100%
ADBAC.

Photosensitization
test:
In
the
test
material
group,
there
was
a
0
of
10
incidence
of
grade
1
responses
and
a
6
of
10
incidences
of
grade
+
responses
following
the
challenge
dose.
The
24
and
48
hour
severity
indices
were
0.3
and
0.1,
respectively.

In
the
vehicle
control,
there
was
a
0
of
10
incidence
of
grade
1
responses
and
a
4
of
10
incidence
grade
+
responses
following
the
challenge
dose.
The
24
and
48
Page
19
of
28
Table
4.
Acute
Toxicity
Profile
for
ADBAC.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
minutes
following
dosing
in
all
animals
Induction:
Test
group:
0.3
mL
of
0.5%
ADBAC,
lowered
to
0.25%
for
doses
5
to
9
Vehicle
control:
0.3
mL
of
vehicle
Naïve
control:
No
application
Positive
control:
0.3
mL
of
musk
ambrette
(
25%
in
acetone)
Monday,
Wednesday,
Friday
for
3
weeks
(
9
doses)

Challenge
Period:
12
days
Challenge
dose:
Test
group:
0.3
mL
of
0.5%
ADBAC
Vehicle
control:
0.3
mL
of
0.5%
ADBAC
Naïve
control:
0.3
mL
of
0.5%
ADBAC
Positive
control:
0.3
mL
of
musk
ambrette
(
25%
in
acetone)
Single
dose
hour
severity
indices
were
0.2
and
0.1,
respectively.

In
the
naïve
test
group,
there
was
a
0
of
10
incidence
of
grade
1
response
and
a
5
of
10
incidence
of
grade
+
responses
following
the
challenge
dose.
The
24
and
48
hour
severity
indices
were
0.3
and
0.3,
respectively.

In
the
positive
control
animal
group,
there
was
a
2
of
10
incidence
of
grade
1
response
and
a
7
of
10
incidence
of
grade
+
responses
following
the
challenge
dose.
The
24
and
48
hour
severity
indices
were
0.6
and
0.6,
respectively.

There
was
no
significant
difference
in
the
mean
body
weight
between
the
test
material
animal
group
and
the
vehicle
control
or
the
naïve
control
during
the
study.
Page
20
of
28
8.2
Subchronic,
Chronic
and
Other
Toxicity
Profiles
Table
(
Table
5)

Table
5:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
ADBAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3100
(
§
82­
1)
90­
Day
Oral
(
Feed)
 
Rat
79.7%
a.
i.
MRID
40746601
Acceptable
 
Guideline
(
15/
sex/
dose)
0,
100,
500,
1000,
[
0,
6.3,
31.2
and
62.0
mg/
kg/
day
for
males
and
0,
7.9,
38.3
and
76.7
mg/
kg/
day
for
females]
4000,
or
8000
ppm
Systemic
toxicity:
NOAEL
=
500
ppm
[
31.2
mg/
kg/
day]
(
males)
=
1000
ppm
[
76.7
mg/
kg/
day]
(
females)
LOAEL
=
1000
ppm
[
62.0
mg/
kg/
day]
(
males),
based
on
decreased
body
weight
and
weight
gain
=
4000
ppm
[>
76.7
mg/
kg/
day]
(
females),
based
on
increased
mortality,
decreased
body
weight
gain,
and
food
consumption,
and
increased
microscopic
lesions.

Increased
mortality
was
observed
at
the
4000
and
8000
ppm
dose
groups
in
both
sexes
which
did
not
allow
for
daily
compound
consumption
to
be
calculated.
Decreased
body
weight,
weight
gain,
food
consumption
and
increased
incidence
of
microscopic
lesions
[
congestion
and
edema
of
the
g.
i.
tract,
hemorrhaging
of
the
lungs
and
brain]
were
also
observed
in
males
and
females
at
>
4000
ppm.

870.3200
(
§
82­
2)
21­
Day
Dermal
 
Guinea
pig
HS
Sanitizing
Shampoo
(
4%
a.
i.)
MRID
41105801
Acceptable
 
Guideline
5
guinea
pigs/
sex/
dose
0,
500,
1000
mg/
kg/
day
in
HSsanitizing
carpet
shampoo
at
a
1:
5
dilution,
24­
hour
exposure,
5
days
per
week,
for
3
weeks
Systemic
toxicity:
NOAEL
=
500
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day,
based
on
decreases
in
body
weight
in
females
Dermal
toxicity:
NOAEL
=
500
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day,
based
on
denuding
of
the
epidermal
layer
Over
the
course
of
the
study,
body
weight
losses
of
between
6­
11%
were
observed
in
male
and
female
guinea
pigs.
There
were
no
reported
mortalities
or
clinical
signs
of
toxicity.
Slight
reduction
in
food
consumption
(
2­
5%)
was
observed
over
the
course
of
this
study.
There
were
no
significant
treatment­
related
effects
on
hematology
or
clinical
chemistry.
Histological
examination
of
the
skin
showed
that
the
nonvascularized
epidermal
layer
was
denuded,
while
the
dermal
or
corium
layer
and
basement
membrane
appeared
normal.
There
were
no
treatment­
related
effects
reported
on
the
liver
and
kidney.

870.3250
(
§
82­
3)
90­
day
dermal
­
Rat
ADBAC
purity
81.09%
MRID
41499601
Core
­
Supplementary
Rats
(
15/
sex/
dose)
0,
2,
6,
or
20
mg/
kg/
day,
6­
8
hours/
day,
5
days/
week,
13
weeks
Systemic
and
Dermal
toxicity
NOAEL
>
=
20
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
20
mg/
kg/
day
(
not
established)

A
significant
and
dose­
related
decrease
in
reticulocyte
count
was
observed
in
the
6­
and
20­
mg/
kg/
day
females.
Decreases
in
reticulocyte
count
are
normally
associated
with
regenerative
responses
to
anemia.
However,
no
evidence
of
anemia
was
seen
in
other
hematological
parameters.
Furthermore,
the
decreased
levels
in
treated
females
were
similar
to
the
levels
observed
in
control
males.
Thus,
the
decreasing
reticulocyte
count
was
most
likely
not
a
biologically
significant
finding.
Page
21
of
28
Table
5:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
ADBAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Range­
finding
Developmental
(
gavage)
­
Rat
ADBAC
purity
81.09%
MRID
42645101
Acceptable
­
Guideline
CD
rats
(
5/
dose)
0,
25,
50,
100,
200,
or
400
mg/
kg/
day,
GD
6­
15,
inclusive
Maternal
Toxicity
NOAEL
=
50
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day,
based
on
significantly
increased
incidence
of
perioral
wetness.

Developmental
Toxicity
NOAEL
=
100
mg/
kg/
day
LOAEL
=
200
mg/
kg/
day,
based
on
no
survival
of
dams.

Doses
 
200
mg/
kg/
day
resulted
in
100%
mortality;
necropsy
findings
revealed
a
distended
and
change
in
the
color
of
the
stomach,
and
distended
intestines
filled
with
mucoid
fluid.
These
dams
also
exhibited
clinical
signs
including
loose
feces,
perioral
wetness
and
perioral
encrustation,
ataxia,
hypoactivity,
urogenital
area
wetness,
and
audible
respiration.
Maternal
toxicity
observed
at
100
mg/
kg/
day
was
manifest
as
significantly
increased
incidence
of
perioral
wetness.

870.3700
(
§
83­
3)
Developmental
(
gavage)
­
Rat
ADBAC
purity
81.09%
MRID
42351501
Acceptable
­
Guideline
Females
rats
(
25/
dose)
0,
10,
30,
or
100
mg/
kg/
day,
GD
6­
15,
inclusive
Maternal
Toxicity
NOAEL
=
10
mg/
kg/
day
LOAEL
=
30
mg/
kg/
day,
based
on
clinical
signs
and
decreased
body
weight
gain.

Developmental
Toxicity
NOAEL
>=
100
mg/
kg/
day,
highest
dose
tested.
LOAEL
>
100
mg/
kg/
day,
not
established.

There
was
no
mortality
in
maternal
animals
observed
at
any
dose
level.
At
100
mg/
kg/
day,
one
dam
exhibited
dehydration,
unkempt
appearance,
loose
feces,
and
perioral
wetness.
At
30
mg/
kg/
day,
one
dam
was
noted
with
perioral
wetness,
gasping,
loose
feces,
and
urine
stains.
Decreased
body
weight
gain
(
12­
11%)
was
observed
in
maternal
animals
at
30
and
100
mg/
kg/
day
during
gestation
days
6­
15.
Food
consumption
was
not
consistently
affected
by
treatment.
There
were
no
treatment­
related
increases
in
the
incidence
of
fetal
external,
visceral,
or
skeletal
abnormalities
at
any
dose
level.

There
was
no
evidence
for
developmental
toxicity
of
ADBAC
in
this
study.

Range­
finding
Developmental
(
gavage)
­
Rabbit
ADBAC
purity
81.09%
MRID
42734401
Acceptable
­
Guideline
Females
rabbits
(
5/
dose)
0,
1,
3,
10,
30
or
60
mg/
kg/
day,
GD
6­
18
inclusive
Maternal
Toxicity
NOAEL
=
3
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day,
based
on
clinical
signs
and
reduced
body
weight
gain
and
food
consumption
Mortality
was
observed
at
doses
of
30
and
60
mg/
kg/
day
(
2
and
5
does,
respectively).
Audible
respiration
was
observed
at
doses
greater
than
or
equal
to
10
mg/
kg/
day.
At
doses
greater
than
or
equal
to
30
mg/
kg/
day,
clinical
signs
included
hypoactivity,
perioral
wetness,
and
labored
breathing.
At
60
mg/
kg/
day,
clinical
signs
included
paralysis,
cold
extremities,
prostration,
slow
respiration,
emaciation,
loose
feces,
and
perioral
encrustation.
Decreased
body
weight
gain
and
food
consumption
were
observed
at
doses
greater
than
or
equal
to
10
mg/
kg/
day.
Page
22
of
28
Table
5:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
ADBAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Developmental
toxicity
was
not
observed
at
any
of
the
doses
tested.

870.3700
(
§
83­
3)
Developmental
(
gavage)
­
Rabbit
ADBAC
purity
81.09%
MRID
42392801
Acceptable
­
Guideline
Females
rabbits
(
16/
dose)
0,
1,
3,
or
9
mg/
kg/
day,
GD
6­
18
Maternal
Toxicity
NOAEL
=
3
mg/
kg/
day
LOAEL
=
9
mg/
kg/
day,
based
on
clinical
signs
of
toxicity.

Developmental
Toxicity
NOAEL
>=
9
mg/
kg/
day,
highest
dose
tested.
LOAEL
>
9
mg/
kg/
day,
not
established.

There
was
no
mortality
or
abortions
at
any
dose
level.
Hypoactivity
and
labored
breathing
were
observed
at
9
mg/
kg/
day
in
2
of
15
rabbits.
There
were
no
effects
on
maternal
body
weight,
food
consumption,
cesarean
section
observations,
or
necropsy
observations.
In
offspring,
there
was
no
evidence
of
developmental
toxicity
at
any
dose
level
tested.

There
was
no
evidence
for
developmental
toxicity
of
ADBAC
in
this
study.

870.8700
(
§
83­
4)
Reproduction
(
Feed)
 
Rat
ADBAC
purity
81.09%
MRID
41385001
Acceptable
 
Guideline
Rats
(
28/
sex/
dose)
0,
300,
1000,
or
2000
ppm
F0:
0,
20.7,
68.2,
or
134.7
mg/
kg/
day
(
males)
0,
25.5,
81.3,
or
164.7
mg/
kg/
day
(
females)
F1:
0,
19.1,
62.5,
or
125.4
mg/
kg/
day
(
males)
0,
24.8,
78.5,
or
157.1
mg/
kg/
day
(
females)
Parental
toxicity:
NOAEL
>=
146
mg/
kg/
day,
highest
dose
tested
LOAEL
>
146
mg/
kg/
day,
not
established
Developmental/
systemic
toxicity:
NOAEL
=
65.4
mg/
kg/
day
(
males)
=
79.9
mg/
kg/
day
(
females)
LOAEL
=
130.1
mg/
kg/
day
(
males)
=
160.9
mg/
kg/
day
(
females),
based
on
reduced
pup
body
weight
and
weight
gain
during
lactation
(
doses
combined
for
both
F0
and
F1
generations)

There
was
no
treatment­
related
mortality
in
parental
animals
at
any
dose
level,
and
there
were
no
reported
signs
of
clinical
toxicity
in
parental
animals.
Although
some
decrease
in
body
weight
was
observed
in
both
generations
at
the
top
dose,
the
significant
variability
observed
did
not
qualify
this
as
a
treatment­
related
effect.

In
pups
of
both
generations,
mean
body
weights
at
the
top
dose
were
significantly
reduced
during
lactation
and
post­
weaning
periods.
There
were
no
adverse
effects
noted
on
gestational
length,
mating,
fertility,
or
other
gestational
indices.

870.4100
(
§
83­
1)
Chronic
Toxicity
(
feed)
­
Dog
ADBAC
purity
80%
MRID
43221101
Acceptable
 
Guideline
Dogs
(
4/
sex/
dose)
0,
120,
400,
or
1200
ppm
[
0,
3.79,
13.1,
or
33.8
mg/
kg/
day
(
males),
0,
3.67,
14.6,
or
38.6
mg/
kg/
day
(
females)]
for
1
year
Systemic
Toxicity
NOAEL
=
120
ppm
=
3.79
mg/
kg/
day
(
males)
=
3.67
mg/
kg/
day
(
females)
LOAEL
=
400
ppm
=
13.1
mg/
kg/
day
(
males)
=
14.6
mg/
kg/
day
(
females),
based
on
decreased
body
weight
gain.

Systemic
toxicity
was
observed
at
400
ppm
and
above
in
female
dogs
and
at
1200
ppm
in
males
as
reduced
body
weight
gain
(
approximately
10%
reduction)
after
52
weeks
of
exposure.
Food
consumption
was
decreased
in
Page
23
of
28
Table
5:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
ADBAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
the
1200
ppm
males
and
females
for
the
entire
study
period
(
approximately
15%
reduction
in
males
and
5%
reduction
in
females).

870.4300
(
§
83­
5)
Combined
Chronic
Toxicity/
Carcinogenicity
(
feed)
­
Rat
ADBAC
purity
81%
MRID
41947501
Acceptable
 
Guideline
Rats
(
50/
sex/
dose)
0,
300,
1000,
or
2000
ppm
[
0,
13,
44,
or
88
mg/
kg/
day
(
males),
0,
17,
57,
or
116
mg/
kg/
day
(
females)]
for
104
weeks
Systemic
Toxicity
NOAEL
=
1000
ppm
=
44
mg/
kg/
day
(
males)
=
57
mg/
kg/
day
(
females)
LOAEL
=
2000
ppm
=
88
mg/
kg/
day
(
males)
=
116
mg/
kg/
day
(
females),
based
on
decreased
body
weight
and
weight
gain.

Significant
decreases
in
group
mean
body
weight
were
observed
in
male
rats
at
the
2000
ppm
dose
level
during
weeks
1­
26
of
the
study
and
then
sporadically
thereafter.
Body
weights
of
high
dose
female
rats
were
also
significantly
decreased
during
weeks
1­
60
of
the
study.
Body
weight
gain
was
decreased
11%
on
average
in
high
dose
males
and
14%
in
high
dose
females.
There
were
no
significant
treatment­
related
effects
on
clinical
chemistry,
hematology,
or
urinalysis.
No
treatmentrelated
non
neoplastic
gross
or
microscopic
lesions
were
evident
in
any
of
the
treated
groups
of
rats.

There
was
no
evidence
of
carcinogenicity
of
ADBAC
in
this
study.

870.4200
(
§
82­
2)
Carcinogenicity
(
feed)
­
Mouse
ADBAC
purity
81%
MRID
41765201
Mice
(
60/
sex/
dose)
Acceptable
­
Guideline
0,
100,
500,
or
1500
ppm
[
14.9,
73.4
and
229.3
mg/
kg/
day
(
males);
17.8,
92.1
and
288.6
mg/
kg/
day
(
females)]
for
78
weeks
Systemic
Toxicity
NOAEL
=
500
ppm
=
73.4
mg/
kg/
day
(
males)
=
92.1
mg/
kg/
day
(
females)
LOAEL
=
1500
ppm
=
229.3
mg/
kg/
day
(
males)
=
288.6
mg/
kg/
day
(
females),
based
on
decreased
body
weight.

No
significant
differences
in
the
incidence
of
mortality
were
observed
in
treated
animals
versus
controls.
No
clinical
signs
of
toxicity
were
observed
at
any
dose
level
tested.
Significant
reductions
in
group
mean
body
weight
were
observed
at
the
high
dose
in
male
and
female
mice
throughout
the
treatment
period
with
no
significant
reduction
in
food
intake.
There
were
no
significant
treatment­
related
effects
on
organ
weights,
macroscopic,
or
microscopic
pathology
in
treated
mice
at
any
dose
level.

There
was
no
evidence
of
carcinogenicity
of
ADBAC
in
this
study.

870.5300
(
§
84­
2)
Mammalian
cell
forward
gene
mutation
 
HGPRT
locus
in
CHO
cells
ADBAC
purity
80%
MRID
41012701
HGPRT
locus
in
CHO
cells
Acceptable
0,
1.0,
2.0,
5.0,
10.0,
20.0,
50.0,
100.0,
200.0,
500.0,
or
5000.0
µ
g/
ml,
with
and
without
metabolic
activation
Negative
Mutant
frequencies
of
all
cultures
treated
with
the
test
material
were
within
the
acceptable
range
for
background
mutant
frequencies
(
0
to
15
x
10­
6).
In
all
of
the
assays,
no
culture
had
a
mutant
frequency
that
was
statistically
elevated
over
background
levels
and
greater
than
15
x
10­
6.
Three
toxic
cultures
in
one
nonactivation
trial
did
achieve
statistical
significance.
The
significant
mutant
frequencies
were
within
the
acceptable
background
range
and
were
not
confirmed
at
equitoxic
dose
levels
in
the
independent
nonactivation
trial.
The
Page
24
of
28
Table
5:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
ADBAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
significant
cultures,
in
that
one
trial
were
apparently
due
to
normal
assay
variation.
ADBAC
was
considered
negative
for
inducing
forward
mutations
at
the
HGPRT
locus
in
CHO
cells
under
the
S9
metabolic
activation
and
nonactivation
conditions
of
this
assay.

870.5385
(
§
84­
2)
In
vivo
mammalian
bone
marrow
chromosome
aberration
test
 
Mouse
ADBAC
purity
80%
MRID
40311101,
supplement
43037701
Mice
(
5/
sex/
group)
Acceptable
Single
dose
of
400
mg/
kg,
sacrificed
at
24,
48,
or
72
hours
later
Solvent
control:
deionized
water
Positive
control:
Cyclosphosphamide
(
CP,
30
mg/
kg)
Negative
One
mouse
of
the
72­
hour
group
was
found
dead
on
the
third
day
after
treatment.
The
PCE/
NCE
ratio
was
reduced
in
all
test
groups
(
as
well
as
the
positive
controls),
but
no
alteration
in
MN
from
solvent
control
value
was
found
in
any
timed
test
group.

By
contrast,
the
CP­
group
evidenced
a
significant
increase
in
MN­
PCE.

870.5550
(
§
84­
2)
Unscheduled
DNA
synthesis
 
Rat
hepatocytes
ADBAC
purity
80%
MRID
42290802
and
42290801
Rat
hepatocytes
Acceptable
Tritiated
thymidine
(
38Ci/
mmol)
for
18.8
hours
together
with
0.538,
1.08,
2.15,
4.31,
5.38,
6.46,
7.00,
7.54,
8.07,
or
8.61
ug/
mL
ADBAC
Solvent
control:
deionized
water
Positive
control:
AAF,
0.10
ug/
mL
Negative
The
test
article
was
lethal
at
8.61
ug/
mL,
and
progressively
cytotoxic
at
doses
equal
to
or
above
4.31
ug/
mL.
Treatments
producing
moderate
levels
of
cytotoxicity
(
62.7%
relative
survival
and
greater)
as
well
as
non­
toxic
doses
were
analyzed
for
UDS.
None
of
these
analyzable
treatments
induced
silver
grain
labeling
different
from
solvent
control.
In
contrast,
the
mutagen
2­
AAF
induced
large
increases
in
nuclear
labeling
in
the
absence
of
significant
toxicity.

870.7485
(
§
85­
1)
Metabolism
and
Pharmacokinetics
­
rats
ADBAC
purity
30%
MRID
40990701,
supplements
41087701
and
44783401
Acceptable
Group
1:
Single
dose
10
mg/
kg
(
oral
or
intravenous)
Group
2:
100
ppm
ADBAC
in
diet
for
14
days
Group
3:
Single
oral
dose
of
50
mg/
kg
Ring­
labeled
test
material
was
used.
Following
oral
administration,
from
5­
8%
of
the
administered
dose
was
eliminated
in
urine
and
90­
98%
in
feces.
No
apparent
differences
in
disposition
were
noted
between
sexes.
Following
intravenous
administration,
males
eliminated
31%
of
the
dose
in
urine
and
44%
in
feces,
while
females
eliminated
21%
in
urine
and
55%
in
feces
following
intravenous
administration.
After
oral
administration,
from
0.03­
0.58%
of
the
administered
dose
was
accounted
for
in
tissues.
After
intravenous
administration,
tissue
residues
accounted
for
33­
36%
of
the
dose
and
were
observed
mainly
in
the
carcass.
The
results
of
this
study
indicate
that
a
majority
of
an
administered
dose
of
ADBAC
is
eliminated
in
feces
and
involves
biliary
excretion.
Page
25
of
28
9.0
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