Page
1
of
31
February
27,
2006
Memorandum
Subject:
Toxicology
Disciplinary
Chapter
for
the
Re­
Registration
Eligibility
Decision
(
RED)
Risk
Assessment
Active
Ingredient:
Didecyl
dimethyl
ammonium
chloride
(
DDAC)
PC
Code
069149
DP
Barcode:

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

To:
Tracy
Lantz,
Chemical
Review
Manager
Regulatory
Management
Branch
I
Antimicrobials
Division
(
7510C)
Page
2
of
31
1.0
HAZARD
CHARACTERIZATION.............................................................................
3
2.0
TOXICOLOGY
DATA
REQUIREMENTS
................................................................
6
3.0
DATA
GAPS..................................................................................................................
6
4.0
HAZARD
ASSESSMENT.............................................................................................
7
4.1
Acute
Toxicity........................................................................................................................................................
7
4.2
Subchronic
Toxicity..............................................................................................................................................
8
4.3
Prenatal
Developmental
Toxicity......................................................................................................................
10
4.4
Reproductive
Toxicity
........................................................................................................................................
11
4.5
Chronic
Toxicity..................................................................................................................................................
12
4.6
Carcinogenicity
...................................................................................................................................................
12
4.7
Mutagenicity........................................................................................................................................................
14
4.8
Neurotoxicity
.......................................................................................................................................................
14
4.9
Metabolism
and
Pharmacokinetics
..................................................................................................................
14
5.0
TOXICITY
ENDPOINT
SELECTION......................................................................
14
5.1
See
Section
7.1,
Summary
of
Toxicological
Doses
and
Endpoint
Selection,
Table
2..............................
15
5.2
Dermal
Absorption.............................................................................................................................................
15
5.3
Classification
of
Carcinogenic
Potential
..........................................................................................................
15
6.0
FQPA
CONSIDERATIONS
.......................................................................................
15
6.1
Developmental
Toxicity
Study
Conclusions
....................................................................................................
15
6.2
Reproductive
Toxicity
Study
Conclusions.......................................................................................................
16
6.3
Pre­
and/
or
Postnatal
Toxicity
...........................................................................................................................
16
6.4
Recommendation
for
a
Developmental
Neurotoxicity
Study........................................................................
16
7.0
SUMMARY
OF
TOXICOLOGICAL
DOSES
AND
ENDPOINTS
FOR
DDAC
FOR
USE
IN
HUMAN
RISK
ASSESSMENT................................................................................
17
7.1
Summary
Table
of
Toxicological
Dose
and
Endpoint
Selection
...................................................................
17
8.0
TOXICITY
PROFILE
TABLES
................................................................................
20
8.1
Acute
Toxicity
Profile
Table
(
Table
5).
............................................................................................................
20
LD50
=
4350
mg/
kg
(
combined)
......................................................................................................................................
21
LD50
=
4350
mg/
kg
(
males).............................................................................................................................................
21
LD50
=
4350
mg/
kg
(
females)..........................................................................................................................................
21
8.2
Subchronic,
Chronic
and
Other
Toxicity
Profiles
Table
(
Table
6)
..............................................................
23
9.0
REFERENCES............................................................................................................
27
Page
3
of
31
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,
DDAC
as
representative);
Group
II
non­
halogenated
benzyl
substituted
quaternary
ammonium
compounds;
Group
III
di­
and
trichlorobenzyl
substituted
quaternary
ammonium
compounds;
and
Group
IV,
quaternary
ammonium
compounds
with
unusual
substituents.
DDAC,
or
didecyl
dimethyl
ammonium
chloride,
is,
as
stated
above,
a
member
of
the
Group
I
class
of
quaternary
ammonium
compounds.
Hazard
data
generated
for
DDAC
is
representative
of
the
hazard
associated
with
this
class
of
quaternary
ammonium
chemicals.

DDAC
was
assigned
Toxicity
Category
II
in
two
acute
oral
toxicity
studies
in
rats,
MRIDs
41394404
[
65%
a.
i.;
LD50
=
262
mg/
kg
(
combined)]
and
42296101
[
80%
a.
i.;
LD50
=
238
mg/
kg
(
combined)].
DDAC
was
assigned
Toxicity
Category
III
in
two
acute
dermal
toxicity
studies
in
rabbits,
MRIDs
42053801
[
65%
a.
i.;
LD50
=
2930
mg/
kg
(
combined)]
and
00071158
[
50%
a.
i.;
LD50
=
4350
mg/
kg
(
combined)].
For
acute
inhalation
toxicity
(
MRID
00145074;
TRID
455201010),
the
LC50
of
DDAC
(
purity
not
reported)
was
reported
as
0.7
mg/
L;
Toxicity
Category
III
was
assigned.
For
primary
eye
irritation,
DDAC
was
found
to
be
corrosive
(
Toxicity
Category
I)
in
two
primary
eye
irritation
studies
in
rabbits,
MRIDs
41394404
[
65%
a.
i.]
and
42161602
[
80%
a.
i].
For
primary
dermal
irritation,
DDAC
(
80%
a.
i.)
was
found
to
be
corrosive
(
Toxicity
Category
I)
in
a
primary
dermal
irritation
study
in
rabbits
(
MRID
42161601).
For
dermal
sensitization,
DDAC
was
found
to
be
a
slight
sensitizer
in
one
dermal
sensitization
study
in
guinea
pigs
(
MRID
42161603
[
80%
a.
i.])
and
not
a
sensitizer
in
another
(
MRID
46367601
[
purity
not
reported]).

For
subchronic
toxicity,
the
database
includes
a
90­
day
oral
toxicity
test
in
rats
(
MRID
40966302),
a
90­
day
oral
study
in
dogs
(
MRID
40262901),
two
21­
day
dermal
toxicity
studies
with
product
formulations
(
MRIDs
41105801
and
45656601),
and
a
90­
day
dermal
toxicity
study
in
rats
using
the
technical
grade
(
MRID
41305901).
In
the
90­
day
rat
oral
feeding
study
(
MRID
40966302),
incidence
of
gross
pathological
observations
and
non­
neoplastic
lesions,
including
a
higher
incidence
of
glycogen
depletion
in
the
liver
and
contracted
spleens
were
observed.
In
the
21­
day
dermal
toxicity
study
in
guinea
pigs,
MRIDs
40565301
and
41105801,
a
1:
5
dilution
of
HS
sanitizing
solution
(
containing
6%
DDAC
and
4%
alkyl
dimethyl
benzyl
ammonium
chloride)
at
the
high
dose
(
1000
mg/
kg/
day)
resulted
in
skin
irritation
was
observed
in
week
2
of
the
study,
body
weights
decreased
in
week
3
of
the
study,
and
a
slight
elevation
of
basophils
and
eosinophils
as
well
as
a
slight
elevation
of
SGPT
and
SGOT.
In
a
21­
day
dermal
toxicity
study
in
rats
using
SS0853­
01
(
0.13%
a.
i.,
MRID
45656601),
no
toxicity
was
observed
at
any
dose
level
tested
.
In
the
90­
day
dog
feeding
study
(
MRID
40269201),
no
treatmentrelated
clinical
chemistry,
hematology,
urinalysis,
or
pathological
findings
were
observed.

In
the
90­
day
dermal
toxicity
test
in
rats
(
MRID
41305901),
systemic
toxicity
was
not
observed
and
clinical
and
gross
findings
(
erythema,
edema,
exfoliation,
excoriation
and
ulceration)
were
Page
4
of
31
limited
to
the
treated
skins.

For
developmental
toxicity,
the
data
from
two
developmental
toxicity
studies,
one
in
the
rat
(
MRID
41886701,
range­
finder
MRID
42746901)
and
another
in
the
rabbit
(
MRID
41018701),
do
not
indicate
increased
susceptibility
in
rats
or
rabbits
from
in
utero
and
postnatal
exposure
to
DDAC.
In
the
rat
developmental
toxicity
study
(
MRID
41886701),
developmental
toxicity
(
skeleton
variations)
was
observed
only
at
treatment
levels
which
also
resulted
in
maternal
toxicity
(
audible
respiration).
In
the
rabbit
developmental
toxicity
study,
developmental
toxicity
(
decreased
fetal
body
weight
and
increased
number
of
dead
fetuses)
occurred
at
levels
which
also
resulted
in
maternal
toxicity
(
hypo
activity,
audible
respiration,
and
decreased
body
weight
gain).
For
reproductive
toxicity,
the
toxicity
database
for
DDAC
includes
a
2­
generational
reproductive
toxicity
study
in
rats
(
MRID
41804501).
In
this
study,
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
1500
ppm
(
during
premating,
for
both
sexes
=
22,
56,
and
133
mg/
kg/
day).
The
effects
in
offspring
(
decreased
pup
body
weight/
weight
gain)
occurred
at
the
same
dose
level
as
maternal
effects
(
decreased
maternal
body
weight/
weight
gain
and
food
consumption),
1500
ppm.
The
NOAEL
for
this
study
is
750
ppm
(
56
mg/
kg/
day)
and
the
LOAEL
for
this
study
is
1500
ppm
(
113
mg/
kg/
day).

In
a
1­
year
dog
feeding
study
(
MRID
41970401),
beagle
dogs
were
given
doses
of
0,
3,
10,
or
20/
30
mg/
kg/
day
in
the
diet.
Treatment­
related
clinical
signs
(
soft/
mucoid
feces,
emesis)
were
observed
frequently
in
high­
dose
animals,
and
total
cholesterol
levels
were
significantly
decreased
in
high­
dose
females.

DDAC
was
not
carcinogenic
when
administered
in
the
diet
in
2­
year
chronic/
carcinogenicity
studies
in
rats
(
MRID
41965101)
and
mice
(
MRID
41802301).
In
the
rat
study,
an
increase
in
incidence
of
interstitial
cell
adenomas
in
the
tested
were
reported,
but
the
incidence
was
with
in
the
range
of
historical
controls.
In
the
mouse
study,
no
treatment­
related
effects
were
noted
in
the
incidence
of
clinical
signs,
deaths,
and
gross
and
histopathological
observations.

For
mutagenicity,
DDAC
was
negative
in
a
battery
of
tests.
In
the
Ames
test
(
MRID
40282201,
supplemental
information
MRID
44005801),
DDAC
was
not
mutagenic
with
or
without
metabolic
activation.
In
a
forward
gene
mutation
test
(
MRID
93014008,
reformat
of
40895202),
DDAC
was
negative
for
induction
of
gene
mutations
in
CHO
cells
at
the
HGPRT
locus
with
and
without
metabolic
activation.
In
an
in
vitro
chromosome
aberration
test
(
MRID
41252601),
DDAC
did
not
induce
chromosome
aberration
in
the
Chinese
hamster
ovary
(
CHO)
cells
with
or
without
metabolic
activation.
In
an
unscheduled
DNA
synthesis
(
UDS)
assay
(
MRID
93014007,
reformat
of
40895201),
DDAC
did
not
cause
UDS
in
primary
rat
hepatocytes.

Although
there
are
no
neurotoxicity
studies
available
in
the
database,
the
available
toxicity
for
DDAC
show
no
evidence
for
neurotoxic
effects.

In
a
rat
pharmacokinetics/
metabolism
study
(
MRID
41617101
and
addendum
MRID
41385101),
single
oral
doses
of
14C­
DDAC
(
5
or
50
mg/
kg)
or
repeated
dose
(
34
ppm
of
DDAC
in
the
diet
Page
5
of
31
for
14
days
and
then
one
single
dose
of
5
mg/
kg
of
14C­
DDAC)
were
given
to
both
male
and
female
rats.
DDAC
was
mostly
excreted
in
the
feces
within
3
days
principally
as
parent
compound
and
metabolites.
The
elimination
pattern
and
metabolic
profile
was
not
substantially
altered
by
the
dose
or
exposure
duration.
Male
and
female
rats
showed
similar
elimination
patterns,
but
females
metabolized
DDAC
more
extensively
than
males.
Four
major
metabolites
were
identified
as
oxidation
products
with
oxidation
confined
to
the
decyl
side
chains.
Page
6
of
31
2.0
TOXICOLOGY
DATA
REQUIREMENTS
The
Toxicology
database
for
DDAC
is
listed
in
the
following
table.

Table
1:
Toxicologic
Data
Requirements
for
DDAC.

Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity
(
Rat)
MRIDs
41394404,
42296101
870.1200
Acute
Dermal
Toxicity
(
Rabbit)
MRIDs
42053801,
00071158
870.1300
Acute
Inhalation
(
Rat)
MRID
00145074
870.2400
Primary
Eye
Irritation
(
Rabbit)
MRIDs
41394404,
42161602
870.2500
Primary
Dermal
Irritation
(
Rabbit)
MRIDs
42161601
870.2600
Dermal
Sensitization
(
Guinea
pig)
MRIDs
42161603,
46367601
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
Rat)
MRID
40966302
870.3150
Oral
Subchronic
(
Dog)
MRID
40262901
870.3250
90­
Day
Dermal
(
Rat)
MRID
41305901
yes
yes
yes
yes
yes
yes
870.3700a
Developmental
Toxicity
(
Rat)
MRID
41886701,
rangefinding
MRID
42746901
870.3700b
Developmental
Toxicity(
Rabbit)
MRID
41018701
870.3800
Reproduction
(
Rat)
MRID
41804501
yes
yes
yes
yes
yes
yes
870.4100
Chronic
(
Dog)
MRID
41970401
870.4300
Chronic/
Carcinogenicity
(
Rat)
MRID
41965101
870.4300
Chronic/
Carcinogenicity
(
Mouse)
MRID
41802301
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity
 
Bacterial
Reverse
Gene
Mutation
assay
MRIDs
40282201,
supplemental
information
44005801
870.5300
Mutagenicity
 
Forward
gene
mutation
test
(
HGPRT)
MRID
93014008,
reformat
of
40895202
870.5375
Mutagenicity
 
Chromosome
aberrations
(
CHO)
MRID
41252601
870.5550
Mutagenicity
 
Unscheduled
DNA
synthesis
in
primary
rat
hepatocytes
MRID
93014007,
reformat
of
40895201
yes
yes
yes
yes
yes
yes
yes
yes
870.6100
...................................................................................................
870.6200
...................................................................................................
870.6300
...................................................................................................
no
no
no
­
­
­

870.7485
Metabolism
and
Pharmacokinetics
MRID
41617101
and
addendum
MRID
41385101
yes
yes
3.0
DATA
GAPS
There
are
no
data
gaps
in
the
toxicity
database
for
DDAC.
Page
7
of
31
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
database
for
Acute
Toxicity:
DDAC
was
assigned
Toxicity
Category
II
in
two
acute
oral
toxicity
studies
in
rats,
MRIDs
41394404
[
65%
a.
i.;
LD50
=
262
mg/
kg
(
combined)]
and
42296101
[
80%
a.
i.;
LD50
=
238
mg/
kg
(
combined)].
DDAC
was
assigned
Toxicity
Category
III
in
two
acute
dermal
toxicity
studies
in
rabbits,
MRIDs
42053801
[
65%
a.
i.;
LD50
=
2930
mg/
kg
(
combined)]
and
00071158
[
50%
a.
i.;
LD50
=
4350
mg/
kg
(
combined)].
For
acute
inhalation
toxicity
(
MRID
00145074;
TRID
455201010),
the
LC50
of
DDAC
(
purity
not
reported)
was
reported
as
0.07
mg/
L;
Toxicity
Category
I
was
assigned.
For
primary
eye
irritation,
DDAC
was
found
to
be
corrosive
(
Toxicity
Category
I)
in
two
primary
eye
irritation
studies
in
rabbits,
MRIDs
41394404
[
65%
a.
i.]
and
42161602
[
80%
a.
i].
For
primary
dermal
irritation,
DDAC
(
80%
a.
i.)
was
found
to
be
corrosive
(
Toxicity
Category
I)
in
a
primary
dermal
irritation
study
in
rabbits
(
MRID
42161601).
Two
dermal
sensitization
studies
(
one
photoallergyl
sensitization
study
in
guinea
pigs
using
BARDAC
2280
80%
a.
i.
[
MRID
42161603])
and
another
dermal
sensitization
study
in
guinea
pigs
using
BARDAC
2280
80%
a.
i.
(
MRID
46367601)
show
that
DDAC
is
not
a
dermal
sensitizer.
The
acute
toxicity
data
for
DDAC
are
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Profile
for
DDAC
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.1100
(
§
81­
1)
Acute
oral,
rat
(
Purity
65%)
MRID
41394404
LD50
=
262
mg/
kg
(
combined)

LD50
=
331
mg/
kg
(
males)
LD50
=
238
mg/
kg
(
females)
II
870.1100
(
§
81­
1)
Acute
oral,
rat
(
Purity
80%)
MRID
42296101
LD50
=
238
mg/
kg
(
combined)
II
870.1200
(
§
81­
2)
Acute
dermal,
rabbit
(
Purity
65%)
MRID
42053801
LD50
=
2930
mg/
kg
(
combined)
LD50
=
3140
mg/
kg
(
males)
LD50
=
2730
mg/
kg
(
females)
III
870.1300
(
§
81­
3)
Acute
inhalation,
rat
(
Purity
not
reported)
MRID
00145074
TRID
455201010
LC50
(
combined)
=
0.07
mg/
L
I
Page
8
of
31
Table
2.
Acute
Toxicity
Profile
for
DDAC
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.2400
(
§
81­
4)
Primary
eye
irritation,
rabbit
(
Purity
65%
a.
i.)
MRID
41394404
Corrosive.
I
870.2400
(
§
81­
4)
Primary
eye
irritation,
rabbit
(
Purity
80%
a.
i.)
MRID
42161602
Corrosive.
I
870.2500
(
§
81­
5)
Primary
dermal
irritation,
rabbit
(
Purity
80%)
MRID
42161601
Corrosive.
I
870.2600
(
§
81­
6)
Dermal
sensitization,
guinea
pigs
(
Purity
80%)
MRID
46367601
Not
a
sensitizer.
NA
4.2
Subchronic
Toxicity
Adequacy
of
database
for
Subchronic
Toxicity:
The
database
for
subchronic
toxicity
of
DDAC
is
considered
complete.
For
oral
toxicity,
the
database
includes
two
studies,
a
90­
day
oral
toxicity
test
in
rats
(
MRID
40966302)
and
a
90­
day
oral
study
in
dogs
(
MRID
MRID
40262901).
For
dermal
toxicity,
there
are
two
21­
day
dermal
studies
using
DDAC
formulations,
one
in
the
rat
(
MRID
45656601)
and
one
in
the
guinea
pig
(
MRIDs
40565301
and
41105801)
and
there
is
a
90­
day
dermal
toxicity
study
using
DDAC,
technical
grade,
in
rats
(
MRID
41305901).

870.3100
Subchronic
(
Oral)
Toxicity
­
Rat
In
a
90­
day
rat
feeding
study
(
MRID
40966302),
male
and
female
rats
were
given
diets
containing
0,
100,
300,
600,
1000,
and
3000
ppm
(
respective
mg/
kg/
day
equivalents;
0,
6.2,
18.5,
36.8,
60.7
and
175
for
males;
0,
7.5,
22.3,
44.4,
74.3
and
225.5
for
females)
DDAC
for
13
weeks.
Highdose
animals
showed
increased
mortality,
decreased
mean
body
weights,
body
weight
gain
and
food
consumption,
and
increased
incidence
of
gross
pathological
observations
and
non­
neoplastic
lesions,
including
a
higher
incidence
of
glycogen
depletion
in
the
liver
and
contracted
spleens.
Additionally,
high­
dose
females
showed
sinus
erythrocytosis
and
lymphoid
hyperplasia
of
mesenteric
lymph
nodes.

From
the
results
of
this
study,
the
NOAEL
is
60.7
mg/
kg/
day
for
males
and
74.3
mg/
kg/
day
for
females.
The
LOAEL
is
175.4
mg/
kg/
day
for
males
and
225.5
mg/
kg/
day
for
females.
The
LOAEL
is
based
on
increased
mortality,
decreased
mean
body
weights,
body
weight
gain
and
food
consumption,
and
increased
incidences
of
gross
pathological
lesions.

This
study
is
classified
as
acceptable.
Page
9
of
31
870.3150
Subchronic
(
Oral)
Toxicity
­
Dog
In
a
90­
day
dog
feeding
study
(
MRID
40262901),
male
and
female
beagle
dogs
were
given
DDAC
at
doses
of
0,
5,
15
and
50
mg/
kg/
day.
High­
dose
animals
experienced
marked
decrease
in
body
weight
gain,
food
consumption
and
food
efficiency.
Clinical
chemistry,
hematology,
urinalysis,
and
pathological
results
did
not
reveal
any
treatment­
related
effects.

Based
on
decreased
body
weight
gain,
food
consumption
and
food
efficiency,
for
both
males
and
females,
the
NOAEL
is
15
mg/
kg/
day,
and
the
LOAEL
is
50
mg/
kg/
day.

This
study
is
classified
as
acceptable.

870.3250
Subchronic
(
21­
day
dermal)
Toxicity
 
Guinea
pig
In
a
21­
day
dermal
toxicity
study
(
MRIDs
40565301
and
41105801),
a
1:
5
dilution
of
HS­
sanitizing
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
and
1000
mg/
kg,
five
days
a
week,
for
21
days.
Actual
doses
to
the
skin
based
on
6%
DDAC
in
the
formulation
were
calculated
to
be
30
and
65
mg/
kg
a.
i.
(
communication
from
registrant).
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.
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
sloughing
of
the
stratum
corneum
as
a
result
of
defatting.

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
for
dermal
irritation
and
systemic
effects
after
short­
term
exposure
to
ADBAC.
In
this
case,
the
500
mg/
kg
dose
level
(
30
mg/
kg
a.
i.)
produced
no
significant
dermal
or
systemic
effects,
and
is
considered
a
NOAEL
for
the
study
for
dermal
irritation
and
systemic
effects.

870.3200
Subchronic
(
21­
day
dermal)
Toxicity
 
Rat
In
a
21­
day
dermal
toxicity
study
(
MRID
456566­
01),
SS0853.01
(
100%
pure)
was
administered
directly
to
the
skin
of
CD
[
Crl:
CD
(
SD)
IGS
BR]
rats
(
10/
sex/
group)
at
doses
of
100,
500,
and
1000
mg/
kg­
day.
The
dermal
route
of
exposure
was
chosen
because
it
is
a
possible
route
of
human
exposure.
Doses
for
this
study
were
determined
by
the
Sponsor
to
achieve
a
gradient
of
toxic
effects.
The
high­
dose
level
was
selected
per
OPPTS
870­
3200
and
was
considered
to
show
signs
of
toxicity.
The
mid­
dose
level
was
selected
as
an
additional
dose
in
order
to
evaluate
any
potential
toxicological
effects.
Page
10
of
31
No
treatment­
related
effects
on
clinical
observations
(
including
expanded
clinical
observations),
motor
activity,
dermal
irritation,
ophthalmic
observations,
body
weights
or
body
weight
changes,
food
consumption,
clinical
pathology
parameters,
terminal
body
weights,
mean
absolute
or
relative
organ
weights,
or
macroscopic
or
microscopic
observations
were
observed.
Analyses
of
hindlimb
strength,
food
consumption,
hematology
and
clinical
chemistry
parameters,
and
relative
organ
weights
showed
significantly
reduced
hindlimb
strength
in
female
rats
at
500
and
1000
mg/
kg/
day.
However,
there
were
no
other
indications
of
effects
on
motor
function
in
male
or
female
rats
at
any
dose
tested.
Numerous
microscopic
changes
in
the
liver
were
observed,
but
were
noted
to
be
test
system­
related
due
to
the
torso
wrapping
procedure.
The
systemic
NOAEL
for
SS0853­
01
is
1000
mg/
kg­
day
in
this
study,
and
the
systemic
LOAEL
is
>
1000
mg/
kg/
day.

This
study
is
classified
as
Acceptable
 
Guideline.

870.3250
Subchronic
(
90­
day
dermal)
Toxicity
 
Rat
In
a
90­
day
rat
dermal
study
(
MRID
41305901),
Sprague­
Dawley
rats
(
15/
sex/
group)
received
repeated
dermal
dosing
of
the
test
compound
at
0,
2,
6,
and
12
mg/
kg/
day
for
6
hours/
day,
5
days/
week
for
13
weeks.
No
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
hyperkeratosis,
acanthosis,
epidermitis,
dermatitis
and
ulceration
were
noted.

The
systemic
NOAEL
is
greater
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.

This
study
is
classified
as
Acceptable
 
Guideline.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
database
for
Prenatal
Developmental
Toxicity:
The
database
for
developmental
toxicity
of
DDAC
is
considered
complete.
The
database
includes
2
developmental
studies,
one
in
the
rat
(
MRID
41886701)
and
another
in
the
rabbit
(
MRID
41018701).

870.3700
Prenatal
Developmental
Toxicity
(
Gavage)
Study
 
Rat
In
a
rat
developmental
toxicity
study
(
MRID
41886701,
and
range­
finding
MRID
42746901),
female
Sprague­
Dawley
rats
(
25/
group)
were
administered
DDAC
(
80.8%
a.
i.)
in
deionized
water
orally
by
gavage
at
doses
of
0,
1,
10,
and
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
Page
11
of
31
observations.
Further,
a
treatment
related
decrease
in
body
weight
gain
was
noted
during
the
dosing
period
(
gestation
days
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
respiratory).
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.

This
study
is
classified
as
acceptable.

870.3700
Prenatal
Developmental
Toxicity
(
Gavage)
Study
 
Rabbit
In
a
rabbit
developmental
toxicity
study
(
MRID
410187­
01),
female
New
Zealand
White
rabbits
(
16/
group)
were
administered
DDAC
(
80.8%
a.
i.)
daily
via
gavage
at
dose
levels
of
0,
1,
3,
and
10
mg/
kg/
day
on
gestational
days
6­
18,
inclusive.
Maternal
toxicity
was
observed
at
the
mid
and
high
dose
group
in
the
form
of
hypo
activity,
labored
and/
or
audible
respiration,
and
decreased
body
weight
gain
during
the
dosing
period.
In
addition,
at
10
mg/
kg/
day,
there
was
an
increased
incidence
of
mortality.
Therefore,
the
maternal
LOAEL
is
3
mg/
kg/
day,
based
on
reductions
in
body
weight
gain
and
clinical
signs
of
toxicity
(
hypo
activity
and
audible
respiratory).

The
maternal
NOAEL
is
1
mg/
kg/
day.
Developmental
toxicity
was
noted
at
high
dose
in
the
form
of
decreased
fetal
body
weight
and
increased
number
of
dead
fetuses.
Therefore,
the
developmental
toxicity
LOAEL
is
10
mg/
kg/
day
based
on
decreased
fetal
body
weight
and
increased
number
of
dead
fetuses.
The
developmental
toxicity
NOAEL
is
3
mg/
kg/
day.

This
study
is
classified
as
acceptable.

4.4
Reproductive
Toxicity
Adequacy
of
database
for
Reproductive:
The
database
for
reproductive
toxicity
of
DDAC
is
considered
complete.
The
database
includes
an
acceptable
2­
generation
reproduction
toxicity
study
in
rats,
MRID
41804501.

870.3800
Reproduction
and
Fertility
Effects
 
Rat
In
a
two­
generation
reproduction
study
(
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,
and
1500ppm
(
during
premating,
for
both
sexes
=
22,
56,
and
113
mg/
kg/
day,
for
males
=
20,
50,
and
103
mg/
kg/
day
and
for
females
=
24,
61,
and
122
mg/
kg/
day).
No
compound­
related
mortalities
were
observed
in
either
sex
or
generation.
No
compound­
related
clinical
signs
were
observed
in
either
sex
or
generation.
Page
12
of
31
Based
on
decreased
body
weight/
weight
gain
and
food
consumption,
the
parental
Toxicity
NOAEL
=
750ppm
(
56
mg/
kg/
day);
LOAEL
=
1500ppm
(
113
mg/
kg/
day)
.
Based
on
decreased
pup
body
weight/
weight
gain,
the
reproductive
toxicity
NOAEL
=
750ppm
(
56
mg/
kg/
day);
LOAEL
=
1500ppm
(
113
mg/
kg/
day).

This
study
is
classified
as
acceptable.

4.5
Chronic
Toxicity
Adequacy
of
database
for
Chronic
Toxicity:
The
database
for
chronic
toxicity
of
DDAC
is
considered
adequate,
including
a
chronic
oral
toxicity
study
in
dogs
(
MRID
41970401).

870.4100
Chronic
Toxicity
(
Oral
feed)
 
Dog
In
a
chronic,
1­
year
toxicity
study
(
MRID
41970401),
males
and
female
beagle
dogs
were
administered
DDAC
(
80.8%
a.
i.)
at
dosage
levels
of
0,
3,
10
and
20/
30
mg/
kg/
day
(
dosing
at
30
mg/
kg/
day
was
not
tolerated
well
and
was
discontinued
on
day
31;
dosing
was
resumed
at
day
36
at
20mg/
kg/
day).
No
treatment­
related
deaths
occurred
during
the
study.
The
treatment­
related
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
high­
dose
females.
Gross
and
histopathological
findings
did
not
reveal
any
treatment­
related
effects.

Based
on
increased
incidence
of
clinical
observations
(
emesis
and
soft/
mucoid
feces)
in
males
and
females
and
decreased
total
cholesterol
levels
in
females,
the
NOAEL
for
both
male
and
females
is
10
mg/
kg/
day,
and
the
LOAEL
is
20
mg/
kg/
day.

This
study
is
classified
as
Acceptable
 
Guideline.

4.6
Carcinogenicity
Adequacy
of
database
for
Carcinogenicity:
The
database
for
the
carcinogenicity
of
DDAC
is
considered
adequate.
The
database
for
carcinogenicity
includes
two
combined
chronic/
carcinogenicity
studies,
one
in
the
rat
(
MRID
41965101)
and
one
in
the
mouse
(
MRID
41802301).

870.4300
Combined
Chronic
/
Carcinogenicity
(
Oral)
 
Rat
In
a
two­
year
rat
carcinogenicity
study
(
MRID
41965101),
60
Sprague­
Dawley
CD
rats
per
sex
per
group
were
fed
diets
containing
DDAC
(
80.8%
a.
i.)
at
0,
300,
750
or
1500
ppm
(
mg/
kg/
day
equivalents:
0,
13,
32,
and
64
for
males
and
0,
16,
41,
and
83
for
females)
for
two
years.
Highdose
animals
showed
significant,
but
slight
(<
10%)
decreases
in
mean
body
weight
during
the
Page
13
of
31
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,
an
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
1500ppm
(
11.7%,
6/
60).
However,
because
the
incidence
was
within
the
historical
incidence
range,
this
effect
was
not
considered
treatment
related.
(
See
Table
3)

Table
3:
Incidence
of
Testicular
Interstitial
Adenomas
in
Male
Sprague­
Dawley
Rats
for
the
Studies
conducted
at
Bushy
Run
Research
Center
since
1987
1,2
Study
Dates
of
In­
Life
Phase
Group3
DDAC
06/
3/
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/
13/
91
4/
59
7/
60
­
­

Historical
Control
#
3
04/
29/
91
to
05/
04/
93
1/
60
6/
60
­
­
­

Note:
1.
Data
provided
by
Bushy
Run
Research
Center
(
1995,
MRID
43613801).
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.

The
NOEL
for
both
sexes
is
750
ppm.
The
LOEL
for
both
sexes
is
1500
ppm,
based
on
increased
incidence
of
nonneoplastic
lesionsin
the
mesenteric
lymph
nodes.

This
study
is
classified
as
Acceptable
 
Guideline.

870.4300
Combined
Chronic/
Carcinogenicity
(
Oral)
 
Mouse
In
a
78­
week
mouse
feeding
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,
and
155.5
for
males
and
0,
18.6,
93.1,
and
193.1
for
females).
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
dose
level
tested,
DDAC
was
not
carcinogenic.
Page
14
of
31
This
study
is
classified
as
Acceptable
 
Guideline.

4.7
Mutagenicity
In
the
Ames
test,
with
or
without
the
microsomal
activation
(
S­
9
fraction),
DDAC
was
not
mutagenic
to
Salmonella
typhimurium
tester
strains
(
MRID
40282201
and
supplemental
information
MRID
44005801).

In
a
forward
gene
mutation
assays
(
MRID
93014008,
reformat
of
40895202)
demonstrated
that
DDAC
was
negative
for
induction
of
gene
mutations
in
CHO
cells
at
the
HGPRT
locus,
with
levels
of
DDAC
ranging
from
1­
10
µ
g/
ml
without
S9
induction
and
1­
26
µ
g/
ml
with
S9
induction.
Severe
toxicity
was
demonstrated
at
doses
of
 
10
µ
g/
ml
(­
S9)
and
 
25
µ
g/
ml
(+
S9).

In
an
in
vitro
chromosome
aberration
test
(
MRID
41252601),
DDAC
failed
to
induce
chromosome
aberrations
in
Chinese
hamster
ovary
(
CHO)
cells
harvested
26
hours
after
exposure
to
DDAC
at
concentrations
of
1­
8
µ
g/
ml
without
microsomal
fraction
(
S9)
induction
or
DDAC
at
concentrations
of
2­
8
µ
g/
ml
with
S9
induction.
Cytotoxic
effects
were
observed
at
DDAC
concentrations
16
µ
g/
ml
(
with
or
without
S9).

In
an
in
vitro
mutagenicity
test
(
MRID
93014007,
reformat
of
40895201),
DDAC
did
not
induce
unscheduled
DNA
Synthesis
(
UDS)
in
primary
rat
hepatocytes
treated
with
DDAC
at
doses
up
to
2.00
µ
g/
ml.
Higher
concentrations
(
4.0
µ
g/
mL)
of
DDAC
were
severely
cytotoxic.

4.8
Neurotoxicity
Adequacy
of
database
for
Neurotoxicity:
Although
a
neurotoxicity
study
is
not
available
in
the
database,
the
available
toxicity
data
for
DDAC
show
no
evidence
for
neurotoxic
effects.

4.9
Metabolism
and
Pharmacokinetics
Adequacy
of
database
for
Metabolism
and
Pharmacokinetics:
In
a
rat
pharmacokinetics/
metabolism
study
(
MRID
41617101
and
addendum
41385101),
single
oral
doses
of
14C­
DDAC
(
5
or
50
mg/
kg)
or
repeated
dose
(
34
ppm
of
DDAC
in
the
diet
for
14
days
and
then
one
single
dose
of
5
mg/
kg
of
14C­
DDAC)
were
gave
to
both
male
and
female
rats.
DDAC
was
mostly
excreted
in
the
feces
within
3
days
principally
as
parent
compound
and
metabolites.
The
elimination
pattern
and
metabolic
profile
was
not
substantially
altered
by
the
dose
or
exposure
duration.
Male
and
female
rats
showed
similar
elimination
patterns,
but
females
metabolized
DDAC
more
extensively
than
males.
Four
major
metabolites
were
identified
as
oxidation
products
with
oxidation
confined
to
the
decyl
side
chains.

5.0
TOXICITY
ENDPOINT
SELECTION
Page
15
of
31
5.1
See
Section
7.1,
Summary
of
Toxicological
Doses
and
Endpoint
Selection,
Table
2.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
The
dermal
absorption
factor
is
not
required
since
route
appropriate
toxicity
data
are
available
for
DDAC.

5.3
Classification
of
Carcinogenic
Potential
DDAC
is
not
likely
to
be
a
human
carcinogen
based
on
following
reasons:

1.
All
the
DDAC
mutagenicity
studies
were
negative;
2.
and
DDAC
was
not
carcinogenic
in
the
rat
and
mouse
carcinogenic
studies
(
MRIDs
41965­
01
and
418023­
01)

Therefore,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
data
and
classified
DDAC
as
not
likely
to
be
a
human
carcinogen
based
on
the
lack
of
evidences
of
carcinogenicity
in
mice
or
rats
(
EPA,
2000).

6.0
FQPA
CONSIDERATIONS
There
is
no
evidence
DDAC
will
induce
neurotoxic
effects.
In
addition,
there
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
to
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.
Therefore,
DDAC
will
not
cause
FQPA
concern.

6.1
Developmental
Toxicity
Study
Conclusions
In
the
developmental
toxicology
­
Rabbits
(
MRID
#:
410187­
01),
female
New
Zealand
White
Rabbits
(
16/
dose)
were
administered
DDAC
(
81%
a.
i.)
via
gavage
on
gestation
days
6
 
18,
inclusive,
at
dose
levels
of
0,
1,
3,
or
10
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
1
mg/
kg/
day;
LOAEL
=
3
mg/
kg/
day
based
on
increased
incidence
of
clinical
signs
(
hypo
activity,
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
reported.

In
the
developmental
toxicology
­
Rats
(
MRID
#:
418867­
01),
female
Sprague­
Dawley
CD
Rats
(
25/
dose)
were
administered
DDAC
via
gavage
on
gestation
days
6
 
15,
inclusive,
at
dose
levels
of
0,
1,
10
and
20
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
1
mg/
kg/
day;
LOAEL
=
10
Page
16
of
31
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain.
The
developmental
toxicity
NOAEL
=
10
mg/
kg/
day;
LOAEL
=
20
mg/
kg/
day
based
on
several
variations
were
reported
(
split
anterior
arch
of
the
atlas,
poorly
ossified
thoracic
centrum,
bilobed
thoracic
centrum,
unilateral
short
rib,
poorly
ossified
parietal,
and
poorly
ossified
sternebrae).

6.2
Reproductive
Toxicity
Study
Conclusions
In
the
two
generation
Reproductive
toxicity
­
Rats
(
MRID
#:
418045­
01),
Sprague­
Dawley
CD
Rats
(
28/
sex/
dose)
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
were
reported.

6.3
Pre­
and/
or
Postnatal
Toxicity
A.
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.

B.
Proposed
Hazard­
based
Special
FQPA
Safety
Factor(
s):
The
HIARC
recommended
that
the
FQPA
safety
factor
be
removed
for
DDAC
because
there
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
to
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.

6.4
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
Committee
concluded
that
evidence
does
not
support
a
need
for
a
Developmental
Neurotoxicity
study.
Page
17
of
31
7.0
SUMMARY
OF
TOXICOLOGICAL
DOSES
AND
ENDPOINTS
FOR
DDAC
FOR
USE
IN
HUMAN
RISK
ASSESSMENT
7.1
Summary
Table
of
Toxicological
Dose
and
Endpoint
Selection
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
increased
incidence
of
clinical
signs
in
males
and
females
and
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
Target
MOE
=
100
(
10x
interspecies
extrapolation,
10x
intraspecies
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
Target
MOE
=
100
(
10x
interspecies
extrapolation,
10x
intraspecies
variation)
FQPA
SF
=
1
Chronic
Toxicity
Study
­
Dog
MRID
41970401
LOAEL
=
20
mg/
kg/
day
based
on
increased
incidence
Page
18
of
31
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE/
UF,
Special
FQPA
SF
for
Risk
Assessment
Study
and
Toxicological
Effects
of
clinical
signs
in
males
and
females
and
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
Dermal,
Short­
term
(
TGAI
80%
diluted
to
0.1%)
NOAEL(
dermal)
=
2
mg/
kg/
day
(
8.0
Fg/
cm2)
b
Target
MOE
=
100
(
10x
interspecies
extrapolation,
10x
intraspecies
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)

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

Inhalation,
Short­
Term
NOAEL
=
10
mg/
kg/
daya
Target
MOE
=
100
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
routeextrapolation

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
Target
MOE
=
100
(
10x
interspecies
extrapolation,
10x
intraspecies
variation,
10x
routeextrapolation

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
increased
incidence
of
clinical
signs
in
males
and
females
and
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.
Page
19
of
31
b
TGAI­
based
dermal
endpoint
=
(
2
mg/
kg
rat
x
0.2
kg
rat
x
1000
ug/
mg)
/
50cm2
area
of
rat
dosed
=
8.0
µ
g/
cm2
.
Page
20
of
31
8.0
TOXICITY
PROFILE
TABLES
8.1
Acute
Toxicity
Profile
Table
(
Table
5).

Table
5.
Acute
Toxicity
Profile
for
DDAC.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
DDAC
purity
65%
MRID
41394404
Acceptable
Females:
0,
100,
200,
or
400
mg/
kg
Males:
0,
100,
200,
283,
336,
or
400
mg/
kg
Rats
(
5/
sex/
dose)
Toxicity
Category
II
LD50
=
262
mg/
kg
(
combined)
LD50
=
331
mg/
kg
(
males)
LD50
=
238
mg/
kg
(
females)

Signs
of
toxicity
included
sluggishness,
lacrimation,
diarrhea,
and
a
brown
stain
on
the
periurogenital
fur,
red
discharge
on
the
facial
fur
and
emaciation.
Deaths
occurred
at
1
to
4
days.
Survivors
recovered
at
2
to
5
days.
Necropsy
of
rats
that
died
revealed
discolored
stomachs
(
yellow
or
red
to
purple),
hemorrhaged
stomachs,
one
stomach
adhering
to
liver,
red
to
brown
intestines,
dark
red
livers,
and
thoracic
cavities
filled
with
red
to
clear
liquid.
Two
males
had
blood
in
the
urine.
In
survivors,
there
were
no
remarkable
gross
lesions.
870.1100
(
§
81­
1)
Acute
Oral
Toxicity
 
Rats
DDAC
Purity
80%
MRID
42296101
Acceptable
Range­
finding:
Rats
(
5/
sex/
dose)
administered
single
oral
dose
of
BARDAC
2280
undiluted
at
0.16,
0.4,
1.0,
or
4.0
g/
kg
or
as
a
20%
w/
v
formulation
in
water
at
0.0632
g/
kg
Main
study:
Rats
(
5/
sex/
dose)
given
single
oral
dose
of
DDAC
in
5%
w/
v
formulation
in
water
at
0.1,
0.2,
0.3,
or
0.5
g/
kg
Identification
of
NOAEL
following
single
dose:
Single
oral
doses
of
DDAC
in
5%
w/
v
formulation
in
water
at
0.01
(
5/
sex),
0.02
(
2/
sex),
or
0.03
(
2/
sex)
g/
kg
Toxicity
Category
II
LD50
=
238
mg/
kg
(
combined)

NOAEL
=
10
mg/
kg
The
observations
for
the
third
phase
of
the
study
ranged
from
minimal
effects
to
no
clear
treatment­
related
effects.
The
most
prevalent
clinical
signs
during
the
observation
period
included
urine
and
fecal
stains,
saliva
discharge
and
stains,
dried
red
stains
on
muzzle
and
around
the
eyes,
eye
squinting,
piloerection,
ataxia,
body
tremors,
labored
and
shallow
respiration,
slight
to
severe
depression,
viscous
red
blood­
like
discharge
from
the
mouth,
bloated
appearance
to
the
abdomen,
and
spasms
in
the
abdominal
area.
With
the
exception
of
one
animal,
all
animals
that
survived
the
observation
period
exhibited
no
gross
pathologic
findings.

870.1200
(
§
81­
2)
Acute
Dermal
Toxicity
 
Rabbits
DDAC
Purity
65%
MRID
42053801
Acceptable
0,
2000,
2830,
or
4000
mg/
kg
Rabbits
(
5/
sex/
dose)
Toxicity
Category
III
LD50
=
2930
mg/
kg
(
combined)
LD50
=
3140
mg/
kg
(
males)
LD50
=
2730
mg/
kg
(
females)

Skin
reactions
included
erythema,
edema,
necrosis,
ulceration,
ecchymoses,
fissuring,
alopecia,
desquamation,
and
scabs.
Signs
of
systemic
toxicity
observed
were
sluggishness,
prostration
(
in
2),
diarrhea
(
in
1),
and
persistent
weight
loss
(
with
emaciation
in
some
animals).
Four
rabbits
died
at
3
to
3.5
hours.
However,
most
deaths
occurred
at
2
to
7
days.
Necropsy
of
the
decedents
revealed
dark
red
lungs,
hemorrhaged
intestines
(
in
1),
gas
or
liquid­
filled
intestines
(
in
2),
dark
purple
thymus,
and
purple
and
enlarged
kidneys
(
in
1).
Gross
lesions
apparent
in
survivors
at
necropsy
included
dark
red
lungs
(
in
1),
enlarged
spleen,
tan
or
purple
kidneys
(
1
with
multiple
red
foci),
an
excessive
amount
Page
21
of
31
Table
5.
Acute
Toxicity
Profile
for
DDAC.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
of
blood
in
the
kidneys
(
of
1),
and
a
trace
amount
of
blood
in
the
urine
of
1.
870.1200
(
§
81­
2)
Acute
Dermal
Toxicity
 
Rabbits
DDAC
Purity
50%
MRID
00071158
Acceptable
0,
2000,
5000,
or
8000
mg/
kg
Rabbits
(
3/
sex/
dose)
Toxicity
Category
III
LD50
=
4350
mg/
kg
(
combined)
LD50
=
4350
mg/
kg
(
males)
LD50
=
4350
mg/
kg
(
females)

870.1300
(
§
81­
3)
Acute
Inhalation
Toxicity
 
Rats
Purity
not
reported
MRID
00145074,
TRID
455201010
Acceptable
0,
0.05,
0.09,
0.03,
0.25,
or
4.54
mg/
L
(
for
4
hours),
orr
1.36
mg/
L
(
for
2
hours)

Rats
(
5/
sex/
dose)
Toxicity
Category
III
LC50
=
0.07
mg/
L
At
necropsy,
no
gross
lesions
were
observed
in
48
of
the
60
test
rats.
Abnormalities
of
the
liver,
ear,
skin,
urinary
bladder,
kidneys,
stomach,
intestine,
cecum,
and
lungs
were
noted
among
the
remaining
rats.
870.2400
(
§
81­
4)
Primary
eye
irritation
 
Rabbits
DDAC
Purity
80%
MRID
41394404
Acceptable
0.1
mLof
NP­
1
Plus
(
concentrate)

Rabbits
(
2
animals)
Toxicity
Category
I
Corrosive.
Instillation
of
0.1
mL
of
NP­
1
Plus
(
concentrate)
resulted
in
severe
corneal
opacity;
it
was
impossible
to
score
the
iris
throughout
the
test.
Necrosis
of
the
conjuncticas
and
the
nictitating
membrane
was
apparent
at
one
hour
prohibiting
the
scoring
of
conjunctival
redness.
Moderate
chemosis
of
the
conjunctivae
was
observed
in
bathocytes
at
one
hour
developing
into
severe
swelling
at
24
hours.
Each
rabbit
also
exhibited
a
purulent
ocular
discharge
at
24
hours.
Because
of
the
persistent
severe
irritation
evident
aat
48
hours,
both
animals
were
sacrificed.
870.2400
(
§
81­
4)
Primary
eye
irritation
 
Rabbits
DDAC
Purity
80%
MRID
42161602
Acceptable
0.1
mL
of
BARDAC
(
80%
a.
i.)
for
1
hour
1
male
rabbit
Toxicity
Category
I
Corrosive.
The
total
irritation
score
for
the
single
animal
was
94
(
110
maximum)
at
the
one
hour
interval.
The
test
material
produced
extreme
corneal
opacity,
ititis,
and
conjunctival
irritation
after
1
hour.
The
eye
of
this
animal
also
appears
misshapen.
Due
to
the
evidence
of
corrosion
(
misshapen
eye)
exhibited
in
this
single
animal,
the
study
was
terminated
following
the
1
hour
reading
without
testing
additional
animals.
870.2500
(
§
81­
5)
Primary
dermal
irritation
 
Rabbits
DDAC
Purity
80%
MRID
42161601
Acceptable
0.5
mL
BARDAC
(
80%
a.
i.),
4
hours
1
male
rabbit
Toxicity
Category
I
Corrosive.
Severe
irritation
persisted
24
hours
following
application.
Changes
noted
in
the
coloration
and/
or
texture
of
the
skin
included
coriaceousness,
blanching,
green­
brown
discoloration,
brown/
dark
red
discoloration,
and
necrosis.
Due
to
the
evidence
of
corrosion
exhibited
in
this
animal
at
the
24
hour
reading,
this
study
was
terminated
without
testing
additional
animals.

870.2600
(
§
81­
6)
Dermal
sensitization
 
Guinea
pigs
DDAC
Purity
80%
MRID
421616303
Acceptable
Induction:
0.1%
w/
v
test
material,
followed
by
UVA
and
UVB
irradiation
Challenge
Period:
10­
14
days
Challenge
dose:
0.1%
w/
v,
followed
by
UVA
and
UVB
irradiation
Control:
No
induction,
received
Not
a
photosensitizer.

The
incidence
of
grade
1
responses
in
the
test
group
(
1/
10)
was
comparable
to
the
incidence
of
grade
1
responses
in
the
naïve
control
group
(
2/
10).
The
test
material
was
not
considered
to
have
caused
photosensitization.

The
positive
control
without
irradiation
did
not
clearly
exhibit
contact
sensitization.
Page
22
of
31
Table
5.
Acute
Toxicity
Profile
for
DDAC.
Guideline
No./
Study
Type/
Test
Substance
(%
a.
i.)
MRID
No.
(
Year)/
Citation/
Classification/
Doses
Results
challenge
dose
of
0.1%
w/
v,
followed
by
UVA
and
UVB
irradiation
Guinea
pigs
(
5/
sex)
870.2600
(
§
81­
6)
Dermal
sensitization
 
Guinea
pigs
DDAC
Purity
80%
MRID
46367601
Acceptable
Induction:
0.25,
0.5,
or
0.75%
w/
w
mixture
in
distilled
water,
once
a
week
for
3
weeks
Challenge
Period:
27
days
Challenge
dose:
or
0.1%
w/
w
mixture
in
distilled
water
Control:
10
guinea
pigs,
no
induction,
received
challenge
dose
of
0.1%
w/
w
Guinea
pigs
(
20)
Not
a
sensitizer.

Erythema
scores
ranged
from
0.05
to
0.10
in
the
test
animals
and
from
0.05
to
0.20
in
the
controls.
A
positive
response
was
not
observed
in
any
of
the
test
or
control
animals.
Page
23
of
31
8.2
Subchronic,
Chronic
and
Other
Toxicity
Profiles
Table
(
Table
6)

Table
6:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
DDAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3100
(
§
82­
1)
90­
Day
Oral
(
Diet)
 
Rat
DDAC
purity
80.8%
MRID
40966302
Acceptable
 
Guideline
0,
100,
300,
600,
1000,
or
3000
ppm
[
0,
6.2,
18.5,
36.8,
60.7,
or
175.4
mg/
kg
(
males),
0,
7.5,
22.3,
44.4,
74.3,
or
225.5
mg/
kg/
day
(
females)]
Systemic
toxicity:
NOAEL
=
1000
ppm
=
60.7
mg/
kg/
day
(
males)
=
74.3
mg/
kg/
day
(
females)
LOAEL
=
3000
ppm
=
175.4
mg/
kg/
day
(
males)
=
225.5
mg/
kg/
day
(
females),
based
on
increased
mortality,
decreased
mean
body
weights,
body
weight
gain
and
food
consumption,
and
increased
incidences
of
gross
pathological
lesions.
High­
dose
animals
showed
increased
mortality,
decreased
mean
body
weights,
body
weight
gain
and
food
consumption,
and
increased
incidence
of
gross
pathological
observations
and
non­
neoplastic
lesions,
including
a
higher
incidence
of
glycogen
depletion
in
the
lover
and
contracted
spleens.
Additionally,
high­
dose
females
showed
sinus
erythrocytosis
and
lymphoid
hyperplasia
of
mesenterin
lymph
nodes.

870.3100
(
§
82­
1)
90­
Day
Oral
(
Feed)
 
Dog
DDAC
purity
not
reported
MRID
40262901
Acceptable
 
Guideline
0,
5,
15,
or
50
mg/
kg/
day
Systemic
toxicity:
NOAEL
=
15
mg/
kg/
day
LOAEL
=
50
mg/
kg/
day,
based
on
decreased
body
weight
gain,
food
consumption,
and
food
efficiency.

High­
dose
animals
experienced
marked
decrease
in
body
weight
gain,
food
consumption,
and
food
efficiency,
for
both
males
and
females.

870.3200
(
§
82­
3)
21­
day
dermal
 
Guinea
pig
1:
5
solution
with
DDAC
purity
4%
MRID
40565301
and
41105801
Acceptable
­
Nonguideline
Guinea
pigs
(
5/
sex/
dose)
0,
500,
or
1000
mg/
kg/
day,
5
days/
week,
21
days
Systemic
Toxicity
NOAEL
=
500
mg/
kg/
day
LOAEL
>
1000
mg/
kg/
day,
based
on
decreased
body
weights,
a
slight
elevation
of
basophils
and
eosiniphils
as
well
as
a
slight
elevation
of
SGPT
and
SGOT.
Dermal
Toxicity
NOAEL
=
500
mg/
kg/
day
LOAEL
=
1000
mg/
kg/
day,
based
on
sloughing
of
the
stratum
corneum
as
a
result
of
defatting.

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.
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
sloughing
of
the
stratum
corneum
as
a
result
of
defatting.

870.3200
(
§
82­
3)
21­
day
dermal
 
Rat
SS0853.01
(
DDAC
0.13%)
MRID
45656601
Acceptable
­
Guideline
Rats
(
10/
sex/
dose)
0,
100,
500,
or
1000
mg/
kg/
day
Systemic
Toxicity
NOAEL
=
1000
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
1000
mg/
kg/
day
(
not
established)

No
treatment­
related
effects
on
clinical
observations
(
including
expanded
clinical
observations),
motor
Page
24
of
31
Table
6:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
DDAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
activity,
dermal
irritation,
ophthalmic
observations,
body
weights
or
body
weight
changes,
food
consumption,
clinical
pathology
parameters,
terminal
body
weights,
mean
absolute
or
relative
organ
weights,
or
macroscopic
or
microscopic
observations
were
observed.
Analyses
of
hindlimb
strength,
food
consumption,
hematology
and
clinical
chemistry
parameters,
and
relative
organ
weights
showed
significantly
reduced
hindlimb
strength
in
female
rats
at
500
and
1000
mg/
kg/
day.
However,
there
were
no
other
indications
of
effects
on
motor
function
in
male
or
female
rats
at
any
dose
tested.
Numerous
microscopic
changes
in
the
liver
were
observed,
but
were
noted
to
be
test
system­
related
due
to
the
torso
wrapping
procedure.
The
systemic
NOAEL
for
SS0853­
01
is
1000
mg/
kgday
in
this
study,
and
the
systemic
LOAEL
is
>
1000
mg/
kg/
day
870.3250
(
§
82­
3)
90­
day
dermal
­
Rat
DDAC
purity
80.8%
MRID
41305901
Acceptable
­
Guideline
Rats
(
15/
sex/
dose)
0,
2,
6,
or
12
mg/
kg/
day,
6
hours/
day,
5
days/
week,
13
weeks
Systemic
Toxicity
NOAEL
>
=
12
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
20
mg/
kg/
day
(
not
established)

Dermal
Toxicity
NOAEL
=
2
mg/
kg/
day
LOAEL
=
6
mg/
kg/
day,
based
on
effects
on
treated
skin,
including
erythema,
edema,
exfoliation,
excoriation,
hyperkeratosis,
acanthosis,
epidermitis,
dermatitis,
and
ulceration.

No
treatment­
related
effects
were
noticed
in
mortality,
weight
gain,
food
consumption,
or
systemic
toxicity.

Toxicity
was
limited
to
the
treated
skin
of
mid­
dose
females
and
the
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
hyperkeratosis,
acanthosis,
epidermitis,
dermatitis,
and
ulceration
were
noted.

870.3700
(
§
83­
3)
Developmental
(
gavage)
­
Rat
DDAC
purity
80.8%
MRID
41886701,
range­
finding
MRID
42746901
Acceptable
­
Guideline
Females
rats
(
25/
dose)
0,
1,
10,
or
20
mg/
kg/
day,
GD
6­
15,
inclusive
Maternal
Toxicity
NOAEL
=
1
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day,
based
on
decreased
body
weight
gain
and
clinical
signs
(
audible
respiration)

Developmental
Toxicity
NOAEL
=
10
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day,
based
on
increased
incidence
of
skeletal
variations.

Maternal
toxicity
was
observed
at
the
mid­
and
highdose
groups
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
(
GD
6­
15),
the
dosing
period
plus
post­
dosing
(
GD
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
groups.

Developmental
toxicity
was
noted
at
the
high
dose
in
the
form
of
increased
incidences
of
skeletal
variations.
Page
25
of
31
Table
6:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
DDAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3700
(
§
83­
3)
Developmental
(
gavage)
 
Rabbit
DDAC
purity
80.8%
MRID
41018701
Acceptable
 
Guideline
Females
rabbits
0,
1,
3,
or
10
mg/
kg/
day,
GD
6­
18,
inclusive
Maternal
Toxicity
NOAEL
=
1
mg/
kg/
day
LOAEL
=
3
mg/
kg/
day,
based
on
reductions
in
body
weight
gain
and
clinical
signs
of
toxicity
(
hypo
activity
and
audible
respiration).

Developmental
Toxicity
NOAEL
=
3
mg/
kg/
day
LOAEL
=
10
mg/
kg/
day,
based
on
decreased
fetal
body
weight
and
increased
number
of
dead
fetuses.

At
the
10
mg/
kg/
day
dose
level,
4/
16
does
died
prior
to
GD
12.
There
were
no
abortions
at
any
dose
level.
Hypoactivity
and
labored
breathing
were
observed
at
3
mg/
kg/
day
in
2
of
15
rabbits.
There
were
no
effects
on
cesarean
section
observations,
or
necropsy
observations
at
scheduled
necropsy
Developmental
toxicity
was
noted
at
the
high
dose
in
the
form
of
decreased
fetal
body
weight
and
increased
number
of
dead
fetuses.

870.8700
(
§
83­
4)
Reproduction
(
Feed)
 
Rat
DDAC
purity
80.8
%
MRID
41804501
Acceptable
 
Guideline
Rats
(
28/
sex/
dose)

Premating:
0,
300,
750,
or
1500
ppm
[
0,
20,
50,
or
103
mg/
kg/
day
(
males),
0,
24,
61,
or
122
mg/
kg/
day
(
females)]
Parental
toxicity:
NOAEL
=
750
ppm
=
56
mg/
kg/
day
LOAEL
=
1500
ppm
=
113
mg/
kg/
day,
based
on
decreased
body
weight/
weight
gain
and
food
consumption
Reproductive
toxicity:
NOAEL
=
750
ppm
=
56
mg/
kg/
day
LOAEL
=
1500
ppm
=
113
mg/
kg/
day,
based
on
decreased
pup
body
weight/
weight
gain
No
compound­
related
mortalities
were
observed
in
either
sex
or
generation.
Decreased
body
weight/
weight
gain
were
observed
in
parental
animals
and
pups
in
both
generations.

870.4100
(
§
83­
1)
Chronic
Toxicity
(
feed)
­
Dog
DDAC
purity
80.8%
MRID
41970401
Acceptable
 
Guideline
Dogs
(
4/
sex/
dose)
0,
3,
10,
or
20/
30
mg/
kg/
day
Systemic
Toxicity
NOAEL
=
10
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day,
based
on
increased
incidence
of
clinical
observations
(
emesis
and
soft/
mucoid
feces)
in
males
and
females
and
decreased
total
cholesterol
levels
in
females
Dosing
at
30
mg/
kg/
day
was
not
tolerated
well
and
was
discontinued
on
Day
31;
dosing
was
resumed
at
Day
36
at
20
mg/
kg/
day.

No
treatment­
related
deaths
occurred
during
the
study.
The
treatment­
related
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
highdose
females.
Gross
and
histopathological
findings
did
not
reveal
any
treatment­
related
effects.
870.4300
(
§
83­
5)
Combined
Chronic/
Carcinogenicity
(
feed)
­
Rat
MRID
41965101
Rats
(
60/
sex/
dose)
Acceptable
­
Guideline
High­
dose
animals
showed
significant,
but
slight
(<
10%)
decreases
in
mean
body
weight
during
the
study.
Treatment­
related
effects
consisted
of
increased
Page
26
of
31
Table
6:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
DDAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
DDAC
purity
80.8%
0,
300,
750,
or
1500
ppm
for
2
years
[
0,
13,
32,
or
64
mg/
kg/
day
(
males)
and
0,
16,
41,
or
83
mg/
kg/
day
(
females)]
incidence
of
sinusoidal
blood,
hemosiderosis
and
histiocytosis
in
the
mesenteric
lymph
nodes
of
high
dose
animals.
In
addition,
an
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);
300
ppm
(
12.5%,
1/
8),
750
ppm
(
17.9%,
5/
28),
and
1500
ppm
(
11.7%,
7/
60).
However,
because
the
incidence
was
within
the
historical
incident
range,
this
effect
was
not
considered
treatment­
related.

870.4300
(
§
83­
5)
Combined
Chronic/
Carcinogenicity
(
feed)
­
Mouse
DDAC
purity
80.8%
MRID
41802301
Mice
(
60/
sex/
dose)
Acceptable
­
Guideline
0,
100,
500,
or
1000
ppm
for
78
weeks
[
0,
15.0,
76.3,
or
155.5
mg/
kg/
day
(
males),
0,
18.6,
93.1,
or
193.1
mg/
kg/
day
(
females)]
Systemic
Toxicity
NOAEL
=
500
ppm
=
76.3
mg/
kg/
day
(
males)
=
93.1
mg/
kg/
day
(
females
LOAEL
=
1000
ppm
=
155.5
mg/
kg/
day
(
males)
=
193.1
mg/
kg/
day
(
females),
based
on
decreases
in
mean
body
weight
and
body
weight
gains.

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.

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

870.5100
(
§
84­
2)
Bacterial
reverse
mutation
test
DDAC
purity
50%
MRID
40282201
and
supplemental
information
MRID
44005801
Acceptable
Strains
TA1535,
TA1537,
and
TA1538
exposed
to
3.9,
7.8,
15.6,
31.2,
62.5,
or
125
ug/
plate
with
and
without
metabolic
activation
Strains
TA98
and
TA100
exposed
to
31.2,
62.5,
125,
250,
500,
or
1000
ug/
plate
with
and
without
metabolic
activation
Negative
Cytotoxicty
was
seen
at
concentrations
 
65.5
ug/
plate
without
S9
and
at
125
or
250
ug/
plate
with
S9.
All
strains
responded
in
the
expected
manner
to
the
appropriate
positive
control.
There
was
no
indication
of
a
mutagenic
effect
at
any
dose
with
or
without
metabolic
activation.

870.5300
(
§
84­
4)
Mammalian
cell
forward
gene
mutation
 
CHO
cells
DDAC
purity
80.8%
MRID
93014007
93014008,
reformat
of
40895202
CHO
cells
Acceptable
10
doses,
ranging
from
1.0
to
13.0
ug/
mL
were
applied
without
metabolic
activation
Doses
ranging
from
1.0
to
40.0
ug/
mL
applined
in
the
presence
of
metabolic
activation
(
S9)
Vehicle
control:
deionized
water
Negative
The
mutant
frequency
of
the
nonactivation
vehicle
and
positive
controls
in
each
trial
were
acceptable.

870.5375
(
§
84­
2)
In
Vitro
mammalian
chromosome
aberration
test
DDAC
purity
80%
MRID
41252601
Acceptable
0,
2,
4,
8,
or
16
ug/
mL
in
the
presence
of
metabolic
activation
for
6
hours
0,
1,
2,
4,
or
8
ug/
mL
in
the
absence
of
metabolic
activation
for
24
hours
Negative
There
was
no
reproducible
evidence
that
P0151
induces
chromosomal
aberrations
in
either
the
presence
or
absence
of
metabolic
activation.
There
was
no
indication
of
chromosomal
ploidy
changes
in
cultures
exposed
to
P0151
in
either
the
presence
or
absence
of
S9
mix.
Concurrent
positive
controls
demonstrated
the
sensitivity
of
the
test
system
and
the
metabolic
activity
of
Sp
mix.
Page
27
of
31
Table
6:
Subchronic,
Chronic
and
Other
Toxicity
Profiles
for
DDAC.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.5550
(
§
84­
2)
Unscheduled
DNA
synthesis
assay
DDAC
purity
80.8%
MRID
93014007,
reformat
of
40895201
Acceptable
Rat
hepatocytes
Test
concentrations
ranged
from
0.050
to
10.0
ug/
mL
Negative
The
test
material
was
lethal
at
concentrations
exceeding
4.00
ug/
mL
and
excessively
toxic
at
4.00
ug/
mL.
Moderately
high
toxicity
was
observed
at
2.00
ug/
mL
(
74.6%
survival),
however
normal
cellular
morphology
was
observed
and
analysis
could
be
performed.

The
test
material
did
not
induce
significant
changes
in
the
nuclear
labeling
of
rat
primary
hepatocytes
for
an
applied
concentration
range
of
2.00
to
0.050
ug/
mL
870.7485
(
§
85­
1)
Metabolism
­
Rat
DDAC
purity
40%
MRID
41617101
and
addendum
MRID
41385101
Rats
(
5/
sex/
dose)
Acceptable
Experiment
1:
Single
oral
dose
of
5
or
50
mg/
kg
of
14C­
DDAC
Experiment
2:
Repeat
dose
of
34
ppm
in
feed
for
14
days,
followed
by
a
single
dose
of
5
mg/
kg
of
14C­
DDAC.
The
pharmacokinetics
data
collectively
indicate
that
DDAC
is
poorly
absorbed
by
the
oral
route
but
is
principally
eliminated
as
parent
compound
and
metabolites
(
possibly
due
to
intestinal
micro
flora)
in
the
feces.
Most
DDAC
is
excreted
within
3
days
after
dosing.
The
elimination
pattern
and
metabolic
profile
is
not
substantially
altered
by
the
dose
or
exposure
duration.
Males
and
females
show
similar
elimination
with
females
but
differ
somewhat
in
the
extent
of
metabolism
with
females
metabolizing
DDAC
more
extensively.
Four
major
metabolites
were
identified
by
mass
spectrometry
as
oxidation
products
with
oxidation
confined
to
the
two
decyl
side
chains.
A
plausible
metabolic
scheme
was
proposed.

9.0
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