Document ID: EPA-HQ-OPP-2006-0338-0013
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-26T04:00Z

US
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
April
20,
2006
MEMORANDUM
SUBJECT:
Didecyl
Dimethyl
Ammonium
Chloride
(
DDAC)
­
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
Kathryn
Montague,
Team
Leader
Risk
Assessment
and
Science
Support
Branch
(
RASSB)
Antimicrobials
Division
(
7510C)
and
Tracy
Lantz,
Chemical
Review
Manager
Velma
Noble,
Team
Leader
Regulatory
Management
Branch
I
Antimicrobials
Division
(
7510C)

PC
Code:
069149
On
February
10,
2000,
the
Health
Effects
Division
(
HED)
HIARC
reviewed
the
recommendations
of
the
toxicology
reviewer
for
didecyl
dimethyl
ammonium
chloride
(
DDAC)
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
DDAC
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
In
November
of
2005,
members
of
the
ADTC
met
with
the
HED
Hazard
Science
Policy
Council
to
discuss
revision
of
the
dermal
endpoints.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
3
Committee
Members
in
Attendance
HIARC
members
present:
Willam
Burnam,
Vicki
Dellarco,
Elizabeth
Doyle,
Pamela
Hurley,
Tina
Levine,
Elizabeth
Mendez,
David
Nixon,
Nicole
Paquette,
Jess
Rowland,
and
Brenda
Tarplee.
Also
in
attendance
were:
Winston
Dang
(
AD),
Tim
McMahon
(
AD)

HIARC
Data
Evaluation/
Report
Presentation:
_______________________________
Jonathan
Chen,
Ph.
D.

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.

ADTC
Data
Evaluation/
Report
Presentation:
___________________________________
Tim
McMahon,
Ph.
D.,
Chair
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
1.
INTRODUCTION
On
February
10,
2000,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
didecyl
dimethyl
ammonium
chloride
(
DDAC)
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
DDAC
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
In
December
of
2005,
the
Antimicrobials
Division=
s
ADTC
updated
the
dermal
endpoints
for
DDAC
based
on
the
recently
adopted
use
of
dermal
irritation
as
an
endpoint
for
short­
term
dermal
risk
assessments.

2.
HAZARD
IDENTIFICATION
2.1.
Acute
Reference
Dose
(
RfD)
Subpopulation
Females
13+

Study
Selected:
Developmental
Toxicology
­
Rat,
OPPTS
870.3700;
'
83­
3
MRID
No.:
41886701
Executive
Summary:
In
a
prenatal
developmental
toxicity
study
(
MRID
41886701),
twenty
five
bred
female
CD
7
(
Sprague­
Dawley)
rats
per
group
were
administered
DDAC
(
80.8%
a.
i.)
in
deionized
water
orally
by
gavage
at
doses
of
0,
1,
10,
or
20
mg/
kg/
day
on
gestation
days
(
GD)
6­
15,
inclusive.
On
GD
21,
dams
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
examined
externally,
viscerally,
and
skeletally
for
malformations/
variations.
Maternal
toxicity
was
observed
at
the
mid
and
high
dose
group
in
the
form
of
audible
respiration
with
the
high
dose
presenting
with
other
observations.
Further,
a
treatment
related
decrease
in
body
weight
gain
was
noted
during
the
dosing
period
(
gestation
day=
s
6­
15),
the
dosing
period
plus
post
dosing
period
(
gestation
days
6­
21)
and
for
the
corrected
body
weight
gains
for
the
high
dose.
There
was
also
low
food
efficiency
compared
with
controls
during
the
dosing
period
for
the
mid
and
high
dose
group.
The
maternal
LOAEL
is
10
mg/
kg/
day,
based
on
reductions
in
body
weight
gain
and
clinical
signs
of
toxicity
(
audible
respiration).
The
maternal
NOAEL
is
1
mg/
kg/
day.
Developmental
toxicity
was
noted
at
the
high
dose
in
the
form
of
increased
incidences
of
skeletal
variations.
Therefore,
the
developmental
toxicity
LOAEL
is
20
mg/
kg/
day
based
on
an
increased
incidence
of
skeletal
variations,
and
the
developmental
toxicity
NOAEL
is
10
mg/
kg/
day.

Dose
and
Endpoint
for
Establishing
RfD:
Developmental
NOAEL
of
10
mg/
kg/
day
based
on
increased
incidences
of
skeletal
variations
at
20
mg/
kg/
day.

Uncertainty
Factor
(
UF):
100X
(
10X
for
intraspecies
extrapolation;
and
10X
for
interspecies
extrapolation)
6
Acute
RfD
(
females
13+)
=
10
mg/
kg/
day
(
NOAEL)
=
0.1
mg/
kg/
day
100
(
UF)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
developmental
endpoint
is
presumed
to
occur
after
a
single
exposure.
Since
the
effect
developed
from
in
utero
exposure,
they
are
applicable
for
risk
assessment
for
female
13­
50
subpopulation
group
only.

2.2.
Acute
Reference
Dose
(
RfD)
General
Population
Including
Infants
and
Children+

Since
the
developmental
endpoint
selected
is
only
applicable
to
Females
13+,
another
endpoint
was
considered
for
the
general
population
including
infants
and
children.
However,
an
appropriate
endpoint
was
not
identified
for
this
population
subgroup.
The
maternal
toxicity
(
decreases
in
body
weight
gains)
observed
in
maternal
animals
in
the
rat
and
rabbit
studies
are
NOT
appropriate
since
the
effects
are
not
attributable
to
a
single
exposure
(
dose).
Other
oral
studies
did
not
indicate
endpoints
that
are
appropriate
for
this
exposure
period.

Study
Selected:
None
MRID
No.:
None
Executive
Summary:
None
Dose
and
Endpoint
for
Establishing
RfD:
None
Uncertainty
Factor
(
UF):
None
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
This
risk
assessment
is
NOT
required
for
this
subpopulation.

2.3.
Chronic
Reference
Dose
(
RfD)

Study
Selected:
Chronic
Oral
Toxicity
Study
­
Dog,
OPPTS
870.4100;
'
83­
1b)

MRID
No.:
41970401
Executive
Summary:
In
a
chronic
one
year
oral
toxicity
study
(
MRID
41970401),
male
and
female
beagle
dogs
were
given
test
compound
at
dosages
of
0,
3,
10,
or
20/
30
mg/
kg/
day
(
dosage
at
30
mg/
kg/
day
was
not
tolerated
well
and
was
discontinued
on
day
31,
dosing
was
resumed
on
day
36
at
20
mg/
kg/
day).
No
treatment­
related
deaths
occurred
during
the
study.
The
treatment­
related
7
clinical
signs
(
soft/
mucoid
feces,
emesis)
were
observed
frequently
in
high­
dose
animals.
Hematology
or
urinalysis
results
were
normal.
Total
cholesterol
levels
were
significantly
decreased
in
the
high­
dose
females.
Gross
and
histopathological
findings
did
not
reveal
any
treatment­
related
effects.
The
LOAEL
is
20/
30
mg/
kg/
day
based
on
increase
incidence
of
clinical
observations
(
emesis
and
soft/
mucoid
feces)
in
males
and
females
and
decreased
total
cholesterol
levels
in
females.
The
NOAEL
is
10
mg/
kg/
day.

Dose
and
Endpoint
for
Establishing
RfD:
NOAEL
of
10mg/
kg/
day
based
on
decreased
total
cholesterol
levels
in
females
at
20
mg/
kg/
day
(
LOAEL)

Uncertainty
Factor(
s):
100X
(
10X
for
intraspecies
extrapolation;
and
10X
for
interspecies
extrapolation)

Chronic
RfD
=
10
mg
/
kg
/
day
(
NOAEL)

100
(
UF)
0.1
mg
/
kg
/
day
=

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
lowest
NOAEL
in
the
most
sensitive
species
following
chronic
exposure
and
is
appropriate
for
chronic
dietary
risk
assessment.

2.4.
Occupational/
Residential
Exposure
2.4.1.
Dermal
Absorption
The
dermal
absorption
factor
is
not
required
since
route­
specific
studies
are
available
to
assess
the
need
for
endpoints.

2.4.2.
Dermal
Exposure
NOTE:
studies
are
available
for
both
the
technical
grade
active
ingredient
(
80%
a.
i.)
and
two
formulated
products
of
DDAC
(
0.13%
and
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.

2.4.3
Short­
term
Dermal
Exposure
(
1­
30
days)

Study
Selected:
90­
Day
Dermal
Toxicity
Study
­
Rat,
870.3250;
'
82­
3
MRID
No.:
41305901
Executive
Summary:
In
a
subchronic
oral
toxicity
study
(
MRID
41305901),
fifteen
Sprague­
Dawley
rats
per
sex
per
group
received
repeated
dermal
dosing
of
test
compound
(
80%
a.
i.
diluted
to
0.1%)
at
0,
2,
6,
or
12
mg/
kg/
day
for
6
hours/
day,
5
days/
week
for
13
weeks.
No
8
treatment­
related
effects
were
noticed
in
mortality,
weight
gain,
food
consumption,
or
systemic
toxicity.
Toxicity
was
limited
to
treated
skin
of
mid­
dose
females
and
high­
dose
males
and
females.
The
clinical
and
gross
findings
(
erythema,
edema,
exfoliation,
excoriation
and
ulceration)
were
confirmed
by
histopathological
examination,
where
increased
incidence
of
hyperkertosis,
acanthosis,
epidermitis,
dermatitis
and
ulceration
were
noted
beginning
after
5
days
of
exposure.
The
systemic
NOAEL
is
grater
than
12
mg/
kg/
day
(
highest
dose
tested).
The
dermal
LOAEL
for
dermal
toxicity
is
6
mg/
kg/
day.
The
dermal
NOAEL
is
2
mg/
kg/
day.

Dose
and
Endpoint
for
Risk
Assessment:
Dermal
toxicity
NOAEL
of
2
mg/
kg/
day
based
on
increased
clinical
and
gross
findings
at
6
mg/
kg/
day
(
LOAEL).

Comments
about
Study/
Endpoint:.
The
HIARC
and
ADTC
selected
irritation
as
the
short­
term
endpoint
based
on
the
policy
adopted
for
use
of
dermal
irritation
as
a
short­
term
endpoint.
It
is
noted
from
the
90­
day
dermal
toxicity
study
that
no
systemic
toxicity
was
seen
at
the
highest
dose
tested
but
dermal
irritation
was
present
after
5
days
of
exposure.
It
is
further
noted
that
a
second
dermal
toxicity
study
is
available
(
MRID
40565301
and
41105801)
in
which
a
dilution
of
a
product
containing
6%
DDAC
and
4%
ADBAC
was
studied
for
21
daysin
guinea
pigs.
However,
the
rat
study
was
chosen
for
the
short­
term
endpoint
because
between
these
two
studies,
the
concentration
evoking
the
irritation
response
was
lower
in
the
rat
study
(
8
µ
g/
cm2)
than
in
the
guinea
pig
study
(
500
µ
g/
cm2)
and
occurred
within
the
same
time
frame
(
rat
response
observed
after
5
days,
guinea
pig
response
observed
after
approximately
10
days).

Short­
term
Dermal
Exposure­
formulated
product,
0.13%
a.
i.

Study
Selected:
none
Comments
about
Study/
Endpoint:
There
is
an
available
21­
day
dermal
toxicity
study
for
a
formulation
of
DDAC
at
0.13%
(
MRID
45656601).
.
This
study
shows
no
dermal
irritancy
or
systemic
effects
up
to
and
including
a
limit
dose
of
1000
mg/
kg.

2.4.4
Intermediate
(
30
days­
6
months)
and
Long­
Term
(>
6
months)
Dermal
(
Exposure
Study
Selected:
none
Comments
about
Study/
Endpoint:
The
available
data
show
no
appropriate
endpoint
for
intermediate­
and
long­
term
dermal
risk.
Use
of
irritation
as
an
endpoint
for
the
short­
term
is
protective
of
any
dermal
or
systemic
effects
from
longer
term
exposures.
9
2.4.5
Inhalation
Exposure
(
All
Durations)

When
DDAC
is
applied
with
a
spraying
system
(
e.
g.
sprayer),
inhalation
may
be
a
potential
exposure
route.
Since
no
inhalation
studies
are
available,
committee
selected
the
oral
NOAEL
for
this
risk
assessment.
Since
the
dose
identified
for
inhalation
risk
assessments
are
from
oral
studies,
route­
to­
route
extrapolation
should
be
as
follows:

Step
I:
The
inhalation
exposure
component
(
i.
e.,
µ
g
a.
i./
day)
using
a
100%
(
default)
absorption
rate
and
application
rate
should
be
converted
to
an
equivalent
oral
dose
(
mg/
kg/
day)

Step
II:
To
calculate
the
MOE
=

s
,
the
equivalent
oral
dose
converted
from
Step
I
should
then
be
compared
to
the
oral
NOAEL
of
10
mg/
kg/
day
for
short
term
exposure
study
(
MRID
418867­
01),
and
the
oral
NOAEL
of
10
mg/
kg/
day
for
intermediate
and
chronic
oral
exposure
based
on
chronic
dog
study
(
MRID
419704­
01).

3.0
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessments
For
acute
and
chronic
dietary
exposures,
the
standard
UF
of
100
is
applied.
The
special
hazardbased
FQPA
safety
factor
is
reduced
to
1x.

For
incidental
oral
and
dermal
assessments,
the
MOE
of
100
is
applied
and
for
inhalation
assessments,
an
MOE
of
100
is
applied.
An
additional
database
UF
of
10x
is
applied
for
route­
toroute
extrapolation
from
an
oral
endpoint.

4
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
4.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.
41965101
Discussion
of
Tumor
Data:
In
a
chronic/
carcinogenicity
study
(
MRID
41965101),
60
Sprague­
Dawley
CD
rats
per
sex
per
group
were
fed
diets
containing
DDAC
(
Batch
#
B­
1889,
80.8%
a.
i.)
At
0,300,750
or
1500
ppm
(
mg/
kg/
day
equivalents:
0,13,32,
or
64
for
males
and
0,
16,
41,
or
83
for
females)
for
two
years.
High­
dose
animals
showed
significant,
but
slight
(<
10%)
decreases
in
mean
body
weight
during
the
study.
Treatment
related
effects
consisted
of
increased
incidence
of
sinusoidal
blood,
hemosiderosis
and
histiocytosis
in
the
mesenteric
lymph
nodes
of
high
dose
animals.
In
addition,
a
treatment­
related
increase
in
the
incidence
of
interstitial
cell
adenomas
in
testes
was
reported.
In
this
study,
the
incidences
of
this
tumor
for
control
and
treated
animals
are
:
Control
1
(
5%,
3/
60);
Control
2
(
5%
3/
60),
300ppm
(
12.5%,
1/
8),
750ppm
(
17.9%,
5/
28),
and
10
1500ppm
(
11.7%,
6/
60).
However,
because
the
incidence
within
the
historical
incidence
range,
this
chemical
is
not
considered
carcinogenic
in
this
study.
(
See
Table
1)

Adequacy
of
the
Dose
Levels
Tested:
The
high
dose
tested
(
HDT)
in
the
study
is
appropriated
for
carcinogenicity
testing
based
on
slight
but
statistically
significant
decrease
in
mean
body
weight
(<
10%)
and
some
histopathological
changes.

Table
1:
Incidence
of
Testicular
Interstitial
Adenomas
in
Male
sprague­
Dawley
Rats
for
the
Studies
conducted
at
Bushy
Run
Research
Center
since
1987
1,2
Group3
Study
Dates
of
In­
Life
Phase
C1
C2
L
M
H
DDAC
06/
13/
88
to
06/
19/
90
3/
60
3/
60
1/
18
5/
28
7/
60
Historical
Control
#
1
03/
22/
88
to
03/
27/
90
3/
59
1/
60
­
­
­

Historical
Control
#
2
03/
08/
89
to
03/
27/
91
4/
59
7/
60
­
­
­

Historical
Control
#
3
04/
22/
91
to
05/
04/
93
1/
60
6/
60
­
­
­

1.
Data
provided
by
Bushy
Run
Research
Center
(
1995,
MRID
436138­
01).
2.
All
rats
were
from
Charles
River
Breeding
Laboratories,
Portage
MI.
3.
C1
­
Control
Group
1;
C2
­
Control
Group
2;
L
­
Low­
dose
Group;
M
­
Mid
­
dose
Group;
and
H­
High­
dose
group.

4.2
Carcinogenicity
Study
in
Mice
MRID
No.
41802301
Discussion
of
Tumor
Data:
In
a
carcinogenicity
study
(
MRID
41802301),
60
CD­
1
mice
per
sex
per
group
were
fed
diets
containing
DDAC
(
Batch
#
B­
1889,
80.8%
a.
i.)
at
levels
of
0,100,
500
or
1000
ppm
(
mg/
kg/
day
equivalents:
0,
15.0,
76.3,
or
155.5
for
males
and
0,
18.6,
93.1,
or
193.1
for
females)
for
78
week.
No
treatment­
related
effects
were
noted
in
the
incidence
of
clinical
signs,
deaths,
gross
and
histopathological
observations.
Hematological
values
were
comparable
among
all
study
groups.
The
NOAEL
for
both
male
and
females
is
500
ppm
(
76.3
mg/
kg/
day
for
males
and
93.1
mg/
kg/
day
for
females),
and
the
LOAEL
is1500ppm
(
155.5
mg/
kg/
day
for
males;
193.1
mg/
kg/
day
for
females).
The
LOAEL
is
based
on
decreases
in
mean
body
weights
and
body
weight
gains.
At
the
level
tested,
the
chemical
is
not
carcinogenic.
11
Adequacy
of
the
Dose
Levels
Tested:
The
HDT
induce
statistically
significant
decreases
($
10%)
in
mean
body
weight).

4.3
Classification
of
Carcinogenic
Potential
The
HIARC
classified
DDAC
as
not
likely
to
be
a
human
carcinogen
based
on
the
lack
of
evidences
of
carcinogenicity
in
mice
or
rats.

5.
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
­­
Acute
delayed
neurotoxicity
study
in
hen
(
if
applicable)?
No
­­
Acute
and
subchronic
neurotoxicity
studies
(
if
applicable)?
No
­­
Developmental
toxicity
studies
in
Rat
&
Rabbits
Yes
­
Two­
Generation
Reproduction
Study
Yes
­
Developmental
neurotoxicity
study
(
if
applicable)
No
5.2
Neurotoxicity
Based
on
the
available
data,
the
committee
concluded
that
there
is
no
evidence
DDAC
will
induce
neurotoxic
effects.
Developmental
Toxicity
In
the
developmental
toxicology
­
Rabbits
(
MRID
#:
410187­
01),
16/
dose
New
Zealand
White
Rabbits
were
fed
by
gavage
on
gestation
days
6
­
18
at
dose
level
of
0,1,3
or
10
mg/
kg/
day
of
DDAC
(
81%
a.
i.).
The
maternal
toxicity
NOAEL
=
1
mg/
kg/
day;
LOAEL
=
3
mg/
kg/
day
based
on
increased
clinical
signs
(
hypoactivity,
labored
and/
or
audible
respiration)
and
decreased
body
weight
gain
during
the
dosing
period.
The
developmental
toxicity
NOAEL
=
3
mg/
kg/
day;
LOAEL
=
10
mg/
kg/
day
based
on
decreased
fetal
body
weight
and
an
increased
number
of
dead
fetuses
were
reported.

In
the
developmental
toxicology
­
Rats
(
MRID
#:
418867­
01),
25/
dose
Sprague­
Dawley
CD
Rats
were
fed
by
gavage
on
gestation
days
6
­
15
at
dose
level
of
0,1,10
and
20
mg/
kg/
day
of
DDAC
(
80.8%
a.
i.).
The
maternal
toxicity
NOAEL
=
1
mg/
kg/
day;
LOAEL
=
10
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain.
The
developmental
toxicity
NOAEL
=
10
mg/
kg/
day;
12
LOAEL
=
20
mg/
kg/
day
based
on
several
variations
were
reported
(
split
anterior
archof
the
atlas,
poorly
ossified
thoracic
centrum,
bilobed
thoracic
centrum,
unilateral
short
rib,
poorly
ossified
parietal,
and
poorly
ossified
sternebrae).

5.3
Reproductive
Toxicity
In
the
two
generation
Reproductive
toxicity
­
Rats
(
MRID
#:
418045­
01),
28/
sex/
dose
(
both
F0
and
F1)
Sprague­
Dawley
CD
Rats
were
fed
a
diet
containing
DDAC
(
80.8%
a.
i.)
at
dosage
levels
of
0,
300,
750,
or
1500ppm
(
during
premating,
for
males
=
20,
50,
or
103
mg/
kg/
day
and
for
females
=
24,
61,
or
122
mg/
kg/
day).
Reproductive
Toxicity
NOAEL
=
750ppm
(
56
mg/
kg/
day);
LOAEL
=
1500ppm
(
113
mg/
kg/
day)
based
on
decreased
pup
body
weight/
weight
gain
and
food
consumption
were
reported.

5.4
Determination
of
Susceptibility
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
to
rat
or
rabbit
fetus
following
in
utero
exposure
in
the
prenatal
developmental
toxicity
studies
or
in
the
offspring
when
exposed
to
adults
in
the
two
generation
reproductive
study.

5.5
Recommendation
for
a
Developmental
Neurotoxicity
Study
Committee
concluded
that
evidence
do
not
support
a
need
for
a
Developmental
Neurotoxicity
study.

6.
HAZARD
CHARACTERIZATION
Didecyl
dimethyl
ammonium
chloride
(
DDAC)
is
an
active
ingredient
for
Z­
1.
Z­
1
is
intended
to
be
sold
as
a
non­
public
health
product
that
kills
odor
causing
bacteria
on
hard
to
launder
fabrics.
DDAC
is
corrosive
and
is
of
moderate
acute
toxicity
by
oral,
dermal,
or
inhalation
routes
of
exposure.
DDAC
is
a
severe
eye
irritant.
DDAC
is
a
weak
dermal
sensitizer.

In
rats
and
dogs
subchronic
oral
studies,
at
median
and
high
dietary
doses
above
the
limit
dose,
decreases
in
body
weight
and
food
consumption
have
been
observed.
In
the
dog
chronic
oral
study,
at
high
dosage
group,
emesis
and
soft
mucoid
feces
were
observed
in
males
and
females
and
deceased
total
cholesterol
was
noticed
in
females.
In
a
90
day
dermal
toxicity
study
in
rats,
DDAC
technical
(
80%
a.
i.)
did
not
produce
any
systemic
toxicity
but
caused
significant
dermal
irritation
at
a
dose
of
6
mg/
kg/
day
(
0.15
Fg/
cm2).
A
formulation
testing
0.13%
DDAC
showed
no
evidence
of
dermal
or
systemic
toxicity,
while
another
study
using
a
4%
DDAC
formulation
showed
dermal
irritation
at
1000
13
mg/
kg/
day.

There
is
a
battery
of
negative
mutagenicity
studies
for
DDAC.
DDAC
is
negative
for
carcinogenicity
in
feeding
studies
in
rats
and
mice
at
doses
above
the
limit
dose
and
was
classified
as
"
not
likely"
to
be
a
human
carcinogen
by
the
HIARC.
DDAC
induced
developmental
and
offspring
effects
in
both
the
developmental
study
and
reproduction
study
in
rats,
but
only
at
dosage
levels
higher
than
those
causing
maternal
toxicity.
On
the
basis
of
this
finding,
the
HIARC
concluded
that
there
was
no
evidence,
to
suggest
that
DDAC
was
associated
with
increase
susceptibility
to
reproductive
and
developmental
toxicity.
14
7.
ACUTE
TOXICITY
ENDPOINTS:

Acute
Toxicity
of
DDAC
(
Didecyl
dimethyl
ammonium
chloride)

Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
(
80%
a.
i.)
42296101
LD50
(
combined)
=
238
mg/
kg
II
81­
2
Acute
Dermal
(
65%
a.
i.)
42053801
LD50
(%)
=
3140mg/
kg;
LD50
(&)
=
2730mg/
kg;
LD50
(
combined)
=
2930
mg/
kg
III
81­
3
Acute
Inhalation
(
purity
not
reported)
00145074
LC50
=
0.07mg/
L
I
81­
4
Primary
Eye
Irritation
(
80%
a.
i.)
42161602
Severe
eye
irritant
I
81­
5
Primary
Skin
Irritation
(
80%
a.
i.)
42161601
Severe
dermal
irritant
I
81­
6
Dermal
Sensitization
(
80%
a.
i.)
42161603
Not
a
sensitizer
15
8.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION­
DDAC
The
doses
and
toxicological
endpoints
selected
for
DDAC
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
NOAEL(
development
al)
=
10
mg/
kg/
day
FQPA
SF
=
1
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intraspecies
variation)
Prenatal
Developmental
Toxicity
­
Rat
MRID
41886701
LOAEL
=
20
mg/
kg/
day
based
on
increased
incidence
of
skeletal
variations.
Acute
Dietary
(
Females
13+)

Acute
RfD
=
0.1
mg/
kg/
day
(
Females
age
13+)

Acute
dietary
(
general
pop.)
an
acute
dietary
endpoint
for
the
general
population
was
not
identified
in
the
database
for
DDAC.

NOAEL
=
10
mg/
kg/
day
FQPA
SF
=
1
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation
Chronic
Toxicity
Study
­
Dog
MRID
41970401
LOAEL
=
20
mg/
kg/
day
based
on
decreased
total
cholesterol
levels
in
females.
Chronic
Dietary
(
general
population)

Chronic
RfD
=
0.1
mg/
kg/
day
Non­
Dietary
Exposures
Incidental
Oral
Short­
Term
NOAEL(
development
al)
=
10
mg/
kg/
day
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
Prenatal
Developmental
Toxicity
­
Rat
MRID
41886701
LOAEL
=
20
mg/
kg/
day
based
on
increased
incidence
of
skeletal
variations.

Incidental
Oral
Intermediate­
Term
NOAEL
=
10
mg/
kg/
day
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
Chronic
Toxicity
Study
­
Dog
MRID
41970401
LOAEL
=
20
mg/
kg/
day
based
on
decreased
total
cholesterol
levels
in
females.

Dermal,
Short­
term
(
formulated
product,
0.13%
a.
i.)
No
endpoint
identified.
No
dermal
or
systemic
effects
identified
in
the
21­
day
dermal
toxicity
study
(
MRID
45656601)
up
to
and
including
the
limit
dose
of
1000
mg/
kg/
day
16
Dermal,
Short­
term
(
TGAI
80%
diluted
to
0.1%)
NOAEL(
dermal)
=
2
mg/
kg/
day
(
8
Fg/
cm2)
c
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
90­
day
Dermal
Toxicity
­
Rat
MRID
41305901
LOAEL
=
6
mg/
kg/
day
based
on
increased
clinical
and
gross
findings
(
erythema,
edema,
exfoliation,
excoriation,
and
ulceration)
beginning
on
day
4­
5
of
treatment.

Dermal,
Intermediate­
and
Long­
term
(
formulated
product)
No
appropriate
endpoint
identified.

Inhalation,
Short­
Term
NOAEL
=
10
mg/
kg/
daya
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation,
10x
route­
extrapolation)

DB
UF­
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.
Prenatal
Developmental
Toxicity
­
Rat
MRID
41886701
LOAEL
=
20
mg/
kg/
day
based
on
increased
incidence
of
skeletal
variations.

Inhalation,
Intermediate­
and
Long­
Term
NOAEL
=
10
mg/
kg/
daya
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation,
10x
route­
extrapolation)

DB
UF­
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.
Chronic
Toxicity
Study
­
Dog
MRID
41970401
LOAEL
=
20
mg/
kg/
day
based
on
decreased
total
cholesterol
levels
in
females.

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.
c
TGAI­
based
dermal
endpoint
=
(
2
mg/
kg
rat
x
0.2
kg
rat
x
1000
ug/
mg)
/
50cm2
area
of
rat
dosed
=
8
µ
g/
cm2
.