
1
US
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
April
20,
2006
MEMORANDUM
SUBJECT:
Alkyl
dimethyl
benzyl
ammonium
chloride
(
ADBAC)
­
Report
of
the
Antimicrobials
Division
Toxicity
Endpoint
Committee
(
ADTC)
and
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC).

FROM:
Timothy
F.
McMahon,
Ph.
D.;
Chair,
ADTC
Michelle
Centra,
Pharmacologist;
Executive
Secretary,
ADTC
Antimicrobials
Division
(
7510C)

TO:
Steve
Malish,
Ph.
D.,
Toxicologist
Risk
Assessment
and
Science
Support
Branch
Antimicrobials
Division
(
7510C)

and
Jacqueline
McFarlane,
Chemical
Review
Manager
Ben
Chambliss,
Team
Leader
Mark
Hartman,
Chief
Regulatory
Management
Branch
I
Antimicrobials
Division
(
7510C)

PC
Code:
069105
On
October
14,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
evaluated
the
toxicology
data
base
of
ADBAC,
established
a
Reference
Dose
2
(
RfD)
and
selected
the
toxicological
endpoints
for
acute
and
chronic
dietary
exposure
as
well
as
occupational
and
residential
exposure
risk
assessments.
The
HIARC
also
addressed
the
potential
enhanced
sensitivity
of
infants
and
children
from
exposure
to
ethyl
parathion
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
On
May
15,
2000,
the
HIARC
re­
affirmed
the
chronic
RfD
value
chosen
from
the
two­
year
rat
chronic
toxicity/
carcinogenicity
study
(
document
#
014155).
In
December
of
2005,
the
Antimicrobials
Division
=

s
ADTC
updated
the
dermal
endpoints
for
ADBAC
based
on
the
recently
adopted
use
of
dermal
irritation
as
an
endpoint
for
short­
term
dermal
risk
assessments.
The
conclusions
of
these
meetings
are
presented
in
this
report.
3
Committee
Members
in
Attendance
HIARC
members:
David
Anderson;
Bill
Burnam;
Virginia
Dobozy;
Karen
Hamernik;
Pam
Hurley;
Tina
Levine;
Sue
Makris
Nancy
McCarroll;
Nicole
Paquette;
Kathleen
Raffaele;
Jess
Rowland;
P.
V.
Shah;
and
Pauline
Wagner.
Member(
s)
in
absentia:
none.
Data
was
presented
by
Tim
McMahon
of
the
Antimicrobials
Division.

ADTC
members:
Michelle
Centra,
Jonathan
Chen,
Ph.
D.,
Stephen
Dapson,
Ph.
D.,
Roger
Gardner,
Karen
Hamernik,
Ph.
D.,
Timothy
Leighton,
Tim
McMahon,
Ph.
D.,
Melba
Morrow,
D.
V.
M.,
John
Redden,
Najm
Shamim,
Ph.
D.,
Sanyvette
Williams­
Foy,
D.
V.
M.

DATA
EVALUATION/
PRESENTATION:
_______________________________________
Timothy
F.
McMahon,
Ph.
D.,
Chair
DRAFT
DOCUMENT
PREPARATION:
_______________________________________
Timothy
F.
McMahon,
Ph.
D.,
Chair
FINAL
DOCUMENT
PREPARATION:
_______________________________________
Michelle
Centra,
Executive
Secretary
4
COMMITTEE
MEMBERS
(
Signature
indicates
concurrence
unless
otherwise
stated)

Stephen
Dapson
_________________________________________

Jonathan
Chen
_________________________________________

Roger
Gardner
_________________________________________

Karen
Hamernik
_________________________________________

Tim
McMahon
(
Chair)
_________________________________________

Melba
Morrow
_________________________________________

John
Redden
_________________________________________

SanYvette
Williams
_________________________________________

Michelle
Centra
(
Executive
Secretary)
_________________________________________

Najm
Shamim
_________________________________________

Timothy
Leighton
_________________________________________
5
6
I.
INTRODUCTION
ADBAC
is
one
member
a
group
of
approximately
30
chemical
structures,
all
related
by
a
core
chemical
aromatic
structure
and
differing
only
in
the
length
and
relative
composition
of
the
alkyl
carbon
chains
and
benzyl
ring
bonded
to
the
nitrogen
atom.
Based
on
this
close
chemical
relationship,
the
Agency,
in
PR
Notice
88­
2,
allowed
these
related
chemicals
to
be
grouped
together
as
a
class,
and
also
allowed
Toxicology
data
for
ADBAC
(
P.
C.
code
069105)
to
represent
the
Toxicology
data
for
the
whole
class.
ADBAC
type
chemicals
are
used
as
antimicrobial
pesticides
on
a
wide
variety
of
sites,
including
food
uses,
wood
treatment,
eating
establishments,
and
hospitals.
The
HIARC
was
asked
to
select
endpoints
for
ADBAC
as
there
has
been
no
formal
risk
assessment
for
this
group
of
chemicals.

II.
HAZARD
IDENTIFICATION
A1.
Acute
Reference
Dose
(
RfD)­
general
population
Study
Selected:
none
An
endpoint
representing
a
single
dose
effect
was
not
identified
in
the
database
for
ADBAC.
This
risk
assessment
is
not
required.

Comments
A
developmental
toxicity
study
in
rabbits
was
also
available
that
showed
clinical
signs
of
toxicity
in
maternal
rabbits
at
a
dose
of
9
mg/
kg/
day.
However,
these
effects
did
not
occur
until
late
in
the
dosing
regimen
(
days
18­
29
of
gestation).
The
HIARC
concluded
that
these
effects,
while
treatment
related,
did
not
represent
effects
after
a
single
dose
of
ADBAC.

A2.
Acute
Reference
Dose
(
RfD)­
females
13+

An
endpoint
appropriate
for
this
subpopulation
was
not
identified
in
the
database.
There
were
no
developmental
effects
from
administration
of
ADBAC
in
this
study.
Body
weight
effects
are
not
considered
to
be
the
result
of
a
single
dose.
7
B.
Chronic
RfD
Type
of
Study:
Chronic
Toxicity
/
Carcinogenicity
in
Rats,
OPPTS
870.4300;
§
83­
5
MRID
No.:
41947501
Executive
Summary:
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.

Dose
Proposed
for
Consideration:
NOAEL
of
44
mg/
kg/
day,
based
on
decreased
body
weight
and
weight
gain
in
male
rats
at
88
mg/
kg/
day.

Uncertainty
Factor(
s):
100
(
10x
interspecies
extrapolation,
10x
intraspecies
variation)

Chronic
RfD
=
44
mg/
kg/
day
[
NOAEL]
=
0.44
mg/
kg/
day
100
[
UF]

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
none.

This
risk
assessment
is
required.

C.
Occupational/
Residential
Exposure
1.
Dermal
Absorption
Dermal
Absorption
Factor:

The
HIARC
determined
that,
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
if
needed.
8
2
.
Incidental
Oral
(
Short­
term)

Study
Selected:
Developmental
Toxicity
­
rat
§
870.3700
MRID
No.:
42351501
Executive
Summary:
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
treatment­
related
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.

Dose
and
Endpoint
for
Risk
Assessment:
The
maternal
NOAEL
of
10
mg/
kg/
day
was
selected,
based
on
decreased
body
weight
observed
at
30
mg/
kg/
day.
A
Margin
of
Exposure
of
100
is
acceptable
for
this
endpoint.

Comments
about
Study/
Endpoint:
none
Incidental
Oral
(
Intermediate­
term)

Type
of
Study:
same
as
for
incidental
oral
short­
term­
see
above.

3.
Short­
Term
Dermal
­
(
1­
7
days)
9
NOTE:
two
endpoints
are
derived
for
short­
term
dermal.
One
endpoint
is
for
the
technical
grade
active
ingredient
(
81%
a.
i.)
,
and
one
endpoint
is
for
a
representative
formulated
product
(
4%
a.
i.).
Use
of
dermal
irritation
as
an
endpoint
has
recently
been
adopted
as
a
working
policy
measure
for
the
Health
Effects
Division
and
the
Antimicrobials
Division
(
meeting
of
the
HED
Hazard
Science
Policy
Council,
November
30,
2005).
Therefore,
endpoints
for
the
technical
and
formulated
product
are
determined
separately
as
needed.

Short­
term
dermal
endpoint­
formulated
product,
4%
a.
i.

Study
Selected:
21­
Day
Dermal
Toxicity
­
Guinea
Pigs,
OPPTS
870.3200
MRID
No.:
40700700;
41105801
Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
MRID
40700700;
41105801),
a
dose
of
1000
mg/
kg/
day
(
limit
dose)
of
ADBAC
,
contained
within
HS­
sanitizing
carpet
shampoo
at
a
1:
5
dilution,
was
tested
in
male
and
female
guinea
pigs,
5
days
per
week,
for
3
weeks.
Each
exposure
was
for
24
hours
to
groups
of
5
guinea
pigs/
sex/
dose.
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
non­
vascularized
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.
The
Systemic
LOAEL
=
1000
mg/
kg/
day,
based
on
decreases
in
body
weight
in
female
guinea
pigs.
The
Systemic
NOAEL
<
1000
mg/
kg/
day
(
not
achieved).
The
Dermal
LOAEL
=
1000
mg/
kg/
day,
based
on
denuding
of
the
epidermal
layer.
The
Dermal
NOAEL
was
not
achieved.
Although
a
systemic
NOAEL
was
not
achieved
in
this
study,
the
results
are
relevant
for
assessing
risk
from
dermal
exposure.
Based
on
the
lack
of
a
NOAEL
in
this
study,
an
additional
3x
uncertainty
factor
is
recommended
under
FIFRA
for
this
risk
assessment
Dose
and
Endpoint
Selected:
For
this
risk
assessment,
the
systemic
LOAEL
of
1000
mg/
kg/
day
was
selected,
based
on
the
observation
of
a
denuded
non­
vascularized
epidermal
layer
in
this
study.

Comments
about
Study/
Endpoint:
an
additional
3x
uncertainty
factor
that
would
normally
be
applied
under
FIFRA
for
use
of
a
LOAEL
was
not
used
based
on
the
fact
that
the
LOAEL
was
at
a
limit
dose
and
that
a
4%
formulation
was
used
in
this
study.
10
Short­
term
dermal
endpoint­
technical
grade
active
ingredient,
81%
a.
i.

Study
selected:
none
No
endpoint
was
identified
from
the
available
data
on
dermal
irritation
from
the
technical
test
material.
Dermal
irritation
in
the
90­
day
technical
a.
i.
dermal
toxicity
study
was
not
evident
until
day
43
(
MRID
41499601).

4.
Intermediate­
Term
Dermal,
technical
a.
i.
(
30
days­
6
months)

Study
Selected:
90­
day
Dermal
Toxicity
Study
in
Rats
(
MRID
41499601)

Executive
Summary:
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
range­
finding
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
systemic
and
dermal
effects
was
determined
to
be
20
mg/
kg/
day.

Endpoint
selected:
NOAEL
of
20
mg/
kg/
day
5.
Long­
Term
Dermal
(>
6
months)

No
appropriate
endpoint
was
identified
in
the
database.

6.
Inhalation
Exposure
(
All
Time
periods).
11
In
the
absence
of
route­
specific
data,
the
developmental
toxicity
study
in
the
rabbit
(
MRID
#
42392801)
was
selected.

Executive
Summary:
In
a
developmental
toxicity
study
in
rabbits
(
MRID
#
42392801),
ADBAC
(
81.09%)
was
administered
at
doses
of
0,
1,
3,
and
9
mg/
kg/
day
to
pregnant
New
Zealand
White
rabbits
(
16/
dose)
by
oral
gavage
on
gestation
days
6
through
18.
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.

The
acute
inhalation
toxicity
of
ADBAC
is
toxicity
category
II;
thus
there
is
concern
for
repeated
inhalation
exposure
to
ADBAC
based
upon
its
known
irritant
properties.
While
an
oral
endpoint
is
selected
for
the
present,
the
HIARC
recommended
the
conduct
of
a
subchronic
inhalation
toxicity
study.
The
registrant
is
in
the
process
of
conducting
subchronic
inhalation
studies
for
ADBAC.

Comments
about
Study/
Endpoint:.
Because
an
oral
endpoint
was
selected,
route­
to­
route
extrapolation
as
described
below
should
be
used
for
this
risk
assessment:

The
inhalation
exposure
component
using
100%
as
the
default
absorption
should
be
converted
to
an
equivalent
oral
dose
(
mg/
kg/
day)

The
oral
equivalent
dose
should
then
be
compared
to
the
oral
Maternal
NOAEL
of
3
mg/
kg/
day
(
from
the
developmental
toxicity
study
in
the
rabbit)
to
derive
the
MOE
for
all
time
points.

D.
Margins
of
Exposures
for
Occupational/
Residential
Exposure
Risk
Assessments
For
short­,
intermediate­,
and
long­
term
occupational
risk
assessments,
a
MOE
of
100
is
adequate.
For
short­,
intermediate­,
and
long­
term
residential
oral
and
dermal
risk
assessments,
an
MOE
of
100
is
adequate.
For
inhalation
risk
assessments,
a
database
uncertainty
factor
of
10x
is
necessary
for
route
extrapolation.
If
risk
estimates
are
below
an
MOE
of
1000
for
inhalation
exposures,
a
confirmatory
repeat
dose
inhalation
toxicity
study
may
be
required.
12
III.
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
Executive
Summary
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
Executive
Summary
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
was
observed
in
treated
animals
vs
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
or
macroscopic/
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.
13
IV.
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
42290801).
Results
of
all
of
these
studies
were
negative
for
ADBAC.

V.
FQPA
CONSIDERATIONS
1.
Neurotoxicity:

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.

2.
Developmental
Toxicity
In
both
the
developmental
toxicity
study
in
the
rat
and
rabbit,
there
was
no
evidence
of
increased
susceptibility
to
offspring
in
these
studies.

3.
Reproductive
Toxicity:

There
was
no
evidence
of
a
primary
reproductive
toxicity
effect
of
ADBAC
based
on
the
available
data.

4.
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.

5.
Recommendation
for
a
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
is
not
recommended,
based
on
the
lack
of
evidence
for
neurotoxicity
of
ADBAC
in
the
available
database.
14
6.
Determination
of
the
FQPA
Safety
Factor:

The
HIARC
recommended
that
the
FQPA
safety
factor
be
removed
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.
15
VI.
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.
16
VII.
HAZARD
CHARACTERIZATION
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
studies
with
rats
and
rabbits,
developing
fetuses
showed
no
increased
sensitivity
to
the
toxicity
of
ADBAC
in
relation
to
adult
animals.
In
a
reproductive
toxicity
study,
effects
on
rat
pups
were
observed
in
the
absence
of
maternal
toxicity,
raising
some
concern
for
the
effects
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.

ADBAC
has
been
tested
for
carcinogenicity
in
long
term
studies
with
both
rats
and
mice.
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,
which
show
ADBAC
to
be
negative
for
mutagenicity.

The
metabolism
of
ADBAC
has
been
investigated.
The
majority
of
administered
radioactive
17
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.

VIII.
ACUTE
TOXICITY
Table
2.
Acute
Toxicity
of
ADBAC
Technical
Grade
Guideline
Number
Test
Substance
MRID
Results
Toxicity
Category
870.1100
Acute
oral,
rat
BQ451­
8
Biocide
(
Purity
82.26%)
45109204
LD50
=
304.5
mg/
kg
(
combined)

LD50
=
510.9
mg/
kg
(
males)
LD50
=
280.8
mg/
kg
(
females)
II
870.1200
Acute
dermal,
rat
BQ451­
8
Biocide
(
Purity
82.26%)
45109202
LD50
=
930
mg/
kg
(
combined)

LD50
=
1100
mg/
kg
(
males)
LD50
=
704
mg/
kg
(
females)
III
870.1300
Acute
inhalation,
rat
(
Purity
82.26%)
44885201
0.054
<
LC50
<
0.51
mg/
L
II
870.2400
Primary
Eye
Irritation
Waived
N/
A
I
870.2500
Primary
Dermal
Irritation,
,
rabbit
BQ451­
8
Biocide
(
Purity
82.26%)
45109201
Corrosive
I
870.2600
Dermal
sensitization,
guinea
pigs
BQ451­
8
Biocide
(
Purity
82.26%)
45109201
Not
a
dermal
sensitizer
N/
A
18
IX
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION­
ADBAC
The
doses
and
toxicological
endpoints
selected
for
ADBAC
are
summarized
below.

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+)
An
acute
dietary
endpoint
was
not
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
decreased
body
weight
and
food
consumption.

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
clinical
signs
and
decreased
body
weight
gain.

Short­
Term
Dermal
(
formulated
product
(
4%
a.
i.))
NOAEL=
20
mg/
kg/
day
(
333
µ
g/
cm2)
b
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
21­
day
dermal
toxicity­
guinea
pigs
MRID
41105801
LOAEL
=
40
mg/
kg/
day,
based
on
denuded
non­
vascularized
epidermal
layer.

Intermediate­
term
dermal
(
technical
grade
a.
i.
(
80%
a.
i.))
NOAEL
=
20
mg/
kg/
day
(
80
µ
g/
cm2)
c
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
90­
day
dermal
toxicity
in
rats
MRID
41499601
highest
dose
(
20
mg/
kg/
day)
tested
before
irritation
became
significant.
Irritation
not
observed
until
day
43.
19
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
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
routeextrapolation

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/
cm2
.
c
TGAI­
based
dermal
endpoint
=
(
20
mg/
kg
rat
x
0.2
kg
rat
x
1000
ug/
mg)
/
50cm2
area
of
rat
dosed
=
80
µ
g/
cm2
.
