Document ID: EPA-HQ-OPP-2005-0310-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-02T05:00Z

FILE
NAME:
company.
wpt
(
7/
1/
2005)
(
xml)
Template
Number
P25
COMPANY
FEDERAL
REGISTER
DOCUMENT
SUBMISSION
TEMPLATE
(
1/
1/
2005)

EPA
Registration
Division
contact:
Pauline
Wagner,
(
703)
308­
6164
TEMPLATE:

[
Stepan
Company]

[
5E7003]

EPA
has
received
a
pesticide
petition
([
5E7003])
from
[
Stepan
Company],
[
951
Bankhead
Highway,
Winder,
GA
30680]
proposing,
pursuant
to
section
408(
d)
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA),
21
U.
S.
C.
346a(
d),
to
amend
40
CFR
part
180.

1.
by
establishing
a
tolerance
for
residues
of
2.
to
establish
an
exemption
from
the
requirement
of
a
tolerance
for
[
Amine
oxides,
when
used
as
an
inert
ingredient
in
a
pesticide
product]
in
or
on
the
raw
agricultural
commodity.
EPA
has
determined
that
the
petition
contains
data
or
information
regarding
the
elements
set
forth
in
section
408(
d)(
2)
of
the
FFDCA;
however,
EPA
has
not
fully
evaluated
the
sufficiency
of
the
submitted
data
at
this
time
or
whether
the
data
supports
granting
of
the
petition.
Additional
data
may
be
needed
before
EPA
rules
on
the
petition.

A.
Residue
Chemistry
1.
Plant
metabolism.
No
plant
metabolism
studies
have
been
submitted
in
support
of
this
petition
since
an
exemption
from
tolerance
is
being
requested.
In
addition,
amine
oxides
(
AOs)
degrade
readily
and
completely
under
aerobic
and
anaerobic
conditions.
[
MRID
46647301]

2.
Analytical
method.
Since
the
petitioner
has
requested
a
tolerance
exemption,
a
residue
analytical
method
for
amine
oxides
in
food
crops
is
not
required.

3.
Magnitude
of
residues.
Due
to
the
low
toxicity
exhibited
by
the
AOs,
in
either
acute,
subchronic
or
chronic
studies,
and
the
complete
degradation
of
AOs,
no
field
residue
studies
were
conducted.
2
B.
Toxicological
Profile
1.
Acute
toxicity.
The
available
toxicity
studies
for
Ninox
HCDO,
an
AO,
(
known
also
under
the
trade
name
of
Ammonyx
®
HCDO)
[
10]
cites
an
acute
oral
LD
50
of
500
­
1000
mg/
kg
in
the
rat.
The
acute
oral
toxicity
reported
for
the
rat
corresponds
to
Toxicity
Category
III.
The
acute
dermal
LD
50
was
found
to
be
greater
than
2174
mg/
kg
bw
in
the
rat.
This
corresponds
to
Toxicity
Category
III.
An
acute
dermal
irritation
test
in
the
rabbit
produced
moderate
irritation.
The
acute
eye
irritation
test
in
rabbits
was
irritating
to
eyes
but
cleared
by
day
14,
placing
it
in
Toxicity
Category
II.
For
skin
sensitization,
a
Magnusson
and
Kligman
maximization
study
was
performed
on
the
guinea
pig.
Ninox
HCDO
produced
0%
sensitization
rate
and
is
classified
as
a
non­
sensitizer.[
1,
2,
3,
4,
5]

Technical
information
provided
by
Stepan
indicated
that
the
several
closely
related
AOs
all
have
oral
LD
50
values
greater
than
5
g/
kg
(
practically
non­
toxic).
[
MRID
46647301]
The
Material
Safety
Data
Sheet
(
MSDS)
for
Ammonyx
®
MO
indicates
the
it
is
non­
mutagenic,
extremely
irritating
to
the
eyes
and
moderately
irritating
to
skin
in
concentrated
form
(
30%)
but
only
mildly
irritating
to
eyes
when
dilute
(
2.5%
to
5%).
The
corresponding
Product
Bulletin
indicated
that
Ammonyx
®
MO
is
moderately
irritating
to
skin
and
minimally
irritating
to
eyes
(
2%
preparation).
[
MRID
46647301]

Another
chemical
information
sheet
listed
a
rat
oral
LD
50
of
>
2,000
mg/
kg.
[
13]
A
material
safety
data
sheet
for
another
product
indicated
that
a
closely
related
chemical
had
an
oral
LD
50
of
>
2,000
mg/
kg.
[
MRID
46647301]

Two
studies
reported
on
skin
corrosivity
results.
An
In
Vitro
skin
corrosivity
assay
by
Botham
et
al.
showed
that
one
AO
(
Coco(
C
12
)
dimethylamine
oxide
)(
30%)
was
non­
corrosive,
as
expected,
to
epidermal
surfaces
of
skin
discs
obtained
from
humanely
killed
young
rats.
[
MRID
46647301]
The
other
study
reviewed
was
also
an
In
Vitro
examination
of
many
compounds
including
3
AOs.
This
study
found
that
one
of
the
chemicals
(
1­
tetradecanamine,
N,
N­
dimethyl­
N­
oxide)
was
corrosive
while
the
other
two
chemicals
tested
(
Amines,
coco
alkyldimethyl,
N­
oxide
and
Amines,
(
hydrogenated
tallow
alkyl)
dimethyl,
N­
oxide)
tested
as
irritants
in
this
assay.
The
latter
compound
is
a
wax
at
room
temperature
while
the
other
two
are
liquids.
[
MRID
46647301]

The
acute
toxicity
of
Ninox
HCDO
was
tested
against
the
freshwater
fish
rainbow
trout
with
a
96­
hour
LC
50
of
0.75
mg
ai/
L.
The
No
Observed
Effect
Concentration
(
NOEC)
was
0.56
mg
ai/
L.
[
8]

The
acute
toxicity
of
Ninox
HCDO
was
tested
against
Daphnia
magna
with
a
48­
hour
EC
50
of
0.96
mg
ai/
L
and
a
NOEC
of
0.32
mg
ai/
L.
[
9]

2.
Genotoxicity.
In
a
study
by
Inoue
et
al.,
the
genotoxicity
of
two
alkyl
dimethyl
amine
oxides
was
evaluated
in
two
in
vitro
assays
(
hamster
embryo
transformation
assay
and
Ames
mutagenicity
assay).
[
MRID
46647301]
For
one
of
the
molecules,
N,
N­
dimethyldodecylamine
oxide,
treatment
levels
ranged
from
0.1
to
20
µ
g/
ml
in
three
different
cultures
for
8
days
at
37
°
C.
The
other
molecule,
N,
N­
dimethyltetradecylamine
oxide,
was
evaluated
under
the
same
incubation
conditions
and
treatment
levels
ranging
from
0.1
to
10
µ
g/
ml.
The
incubations
were
done
in
triplicate.
There
3
was
no
apparent
treatment­
related
effect
upon
the
transformation
of
these
cells,
however,
the
response
of
3­
methylchloranthrene
was
minimal
as
well.
This
casts
doubt
on
the
results
of
this
study.
On
the
other
hand,
the
Salmonella
mutagenicity
(
Ames
test)
showed
clearly
that
neither
chemical
resulted
in
an
increase
in
reverse
mutation.
In
this
test,
the
two
test
materials
were
preincubated
for
20
minutes
and
then
incubated
for
48
hours
at
37
°
C
with
Salmonella
typhimurium
at
concentrations
ranging
from
10
to
200
µ
g/
plate
under
conditions
of
non­
activation
and
activation.
[
MRID
46647301]

In
an
oncogenicity
mouse
study,
Cardin
et
al.,
mice
were
exposed
to
alkyldimethylamine
oxides
(
ADAO)
in
a
dermal
application
of
0.1
ml
of
0,
0.05,
0.13
or
0.26%
w/
v
ADAO
in
aqueous
solution.
[
MRID
46647301]
Mice
were
treated
once
daily
three
times
per
week
for
104
weeks.
There
were
no
compound­
related
skin
or
systemic
neoplasms
noted
and
no
skin
tumors
were
observed
.
In
the
high
dose
mice
there
was
some
compound­
related
dermal
irritation
observed
in
the
high
dose
group.

A
study
was
done
with
ten
different
surfactants
(
including
two
AOs)
by
Inoue,
et
al.
and
two
other
compounds
to
determine
the
capacity
of
these
chemicals
to
transform
and
mutagenize
Syrian
golden
hamster
embryo
cells.
The
hamster
embryo
cells
used
in
this
study
were
cryopreserved
primary
cultures
that
were
used
as
the
source
of
target
and
feeder
cells
for
an
in
vitro
bioassay
of
carcinogenesis.
None
of
the
ten
surfactants,
including
N,
N­
Dimethyldodecylamine
oxide
(
C
12
)
and
N,
N­
Dimethyltetradecylamine
oxide
(
C
14
),
induced
in
vitro
transformation
of
hamster
embryo
cells
and
neither
were
they
mutagenic
in
Salmonella
typhimurium.
[
MRID
46647301]

In
another
short­
term
surfactant
genotoxicity
test
by
Yam
et
al.
over
200
surfactants
(
including
N,
Ndimethyldodecylamine
oxide
and
N,
N­
dimethyltetradecylamine
oxide)
were
examined
in
nine
shortterm
genotoxicity
assay
systems.
The
tests
used
included
the
Salmonella/
microsome
mutation
assay,
bacterial
DNA
repair
tests,
mitotic
recombination
in
Saccharomyces
cerevisiae,
the
mouse
lymphoma
cell­
mutation
assay,
unscheduled
DNA
synthesis
and
sister
chromatid
exchange
assays
in
mammalian
cells,
mammalian
chromosome
damage
tests
in
vitro
and
in
vivo,
the
dominant
lethal
test
in
rodents
and
mammalian
cell
transformation
tests.
The
results
of
all
tests
were
overwhelmingly
negative
indicating
that
surfactants
(
including
AOs)
have
negligible
potential
to
cause
genetic
damage.
[
MRID
46647301]

In
a
chromosome
aberration
test
performed
on
Ninox
HCDO,
the
test
material
was
shown
to
be
nonclastogenic
to
human
lymphocytes
in
vitro.
The
test
material
did
not
induce
any
statistically
significant
increases
in
the
frequency
of
cells
with
aberrations
in
two
separate
experiments.
[
6]
An
Ames
test
was
conducted
with
Ninox
HCDO.
No
toxicologically
significant
increases
in
the
frequency
of
revertant
colonies
were
recorded
for
any
of
the
bacterial
strains,
with
any
dose
of
the
test
material,
either
with
or
without
metabolic
activation.
The
test
material
was
considered
to
be
nonmutagenic
[
7]

3.
Reproductive
and
developmental
toxicity.
Amine
oxides
are
being
investigated
for
use
as
a
antimicrobial/
spermicide
for
use
in
the
female
genital
tract.
In
a
study
by
Mauck
et
al.,
an
experimental
product
containing
myristamine
oxide
along
with
cetyl
betaine
(
0.5%,
1.0%
and
1.7%)
4
was
tested
in
a
phase
I
vaginal
safety
study
compared
with
a
marketed
spermicide.
The
tested
product
exhibited
less
irritation
at
the
two
lower
concentrations
than
at
the
1.7%
concentration
and
less
than
was
experienced
by
the
marketed
spermicide
(
Extra
Strength
Gynol
II
®
)
.
The
tested
antimicrobial
was
not
detected
in
the
plasma
of
any
volunteer.
[
MRID
46647301]
The
same
experimental
product,
known
as
C31G
vaginal
gel,
was
studied
for
distribution
in
the
female
genital
tract
using
magnetic
resonance
imaging.
Coverage
of
vaginal
mucosa
at
18
minutes
was
excellent
while
coverage
after
6
hours
was
substantially
decreased
with
60%
of
maximal
linear
coverage
and
41%
surface
contact.
There
was
very
minimal
coverage
noted
at
24
hours
following
insertion.
[
MRID
46647301]

4.
Subchronic
toxicity.
The
data
on
AOs
is
similar
to
that
obtained
on
other
classes
of
surfactants
based
on
fatty
amines,
alcohols
and
fatty
acids
previously
assessed
by
EPA,
all
of
which
exhibit
low
acute
toxicity,
show
no
likelihood
of
significant
toxicity
in
subchronic
and
chronic
studies,
and
are
not
teratogenic,
mutagenic,
or
carcinogenic.
[
MRID
46647301]

5.
Chronic
toxicity.
Chronic
toxicity
studies
showed
a
fish
302­
day
NOEC
of
420
µ
g/
L
and
a
21­
day
NOEC
on
Daphnia
of
700
µ
g/
L.
In
algae,
a
study
with
Chlorella
showed
a
72
hour
NOEC
of
700
µ
g/
L
while
a
study
with
Anabaena
showed
a
10
day
NOEC
value
of
1100
µ
g/
L.
[
MRID
46647301]

The
data
on
AOs
is
similar
to
that
obtained
on
other
classes
of
surfactants
based
on
fatty
amines,
alcohols
and
fatty
acids
previously
assessed
by
EPA,
all
of
which
exhibit
low
acute
toxicity,
show
no
likelihood
of
significant
toxicity
in
subchronic
and
chronic
studies,
and
are
not
teratogenic,
mutagenic,
or
carcinogenic.
[
MRID
46647301]

6.
Animal
metabolism.
A
rat
metabolism
study
was
done
with
dodecyldimethylamine
oxide
(
DDAO)
by
the
Proctor
&
Gamble
Company.
[
MRID
46647301]
In
the
study
rats
were
treated
by
oral
gavage
with
100
mg/
kg
of
radiolabelled
DDAO
(
two
different
radiolabelled
molecules
used,
(
1)[
methyl­
14C]
DDAO
and
(
2)[
1­
dodecyl­
14C]
DDAO).
Urine
was
the
predominant
path
of
excretion,
(
2)
54%,
while
loss
as
CO
2
was
approximately
half
that
much
(
2)
23.1%
(
1)
13.1%.
Excretion
in
feces
constituted
from
9.4%
to
12.1%
of
the
administered
dose
for
either
test
material.
The
liver
had
the
highest
level
of
residue
72
hours
after
dosing
(
males
1.1
to
1.25%,
females
1.48%
of
the
administered
dose).
Intraperitoneal
administration
did
not
alter
the
excretion
profile
compared
with
oral
administration.
Two
human
subjects
dosed
orally
with
(
2)
showed
a
similar
excretion
profile
as
the
rat.
Very
low
levels
were
recovered
in
the
feces.
An
interspecies
comparison
was
made
of
percutaneous
absorption
to
the
skin
of
rats,
mice,
rabbits
and
humans.
The
greatest
percentage
of
absorption
was
demonstrated
by
the
rabbit,
followed
by
the
rat,
mouse
and
human.
Therefore,
dermal
uptake
of
DDAO
was
significantly
less
for
humans
as
compared
to
other
species.

In
another
metabolism
study
done
by
Turan
et
al.,
[
MRID
46647301]
rats,
rabbits,
and
humans
were
5
dosed
orally
with
[
1­
dodecyl­
14C]
DDAO.
Elimination
of
the
radiolabelled
material
was
determined
over
at
least
a
48
hour
period.
Urine
was
the
primary
excretion
pathway
in
all
of
the
species
(
range:
43.9
to
65.7%
of
the
dose).
CO
2
was
eliminated
at
19.2%
to
32%
of
the
dose.
Radiolabel
in
the
feces
consisted
2.5
to
9.4%.
None
of
the
parent
material
was
recovered
from
urine
samples
and
the
label
was
mostly
excreted
within
the
first
24
hours
after
dosing
(
75.2%
to
87.9%
recovered).

7.
Metabolite
toxicology.
The
amine
oxides
do
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.

8.
Endocrine
disruption.
The
amine
oxides
do
not
belong
to
a
class
of
chemicals
known
or
suspected
of
having
adverse
effects
on
the
endocrine
system.
There
is
no
evidence
that
amine
oxides
have
any
effect
on
endocrine
function.

C.
Aggregate
Exposure
1.
Dietary
exposure.
A
dietary
exposure
assessment
for
AOs
has
not
been
conducted
because
the
AOs,
as
a
class
of
compounds,
do
not
present
any
toxicological
effects
of
concern.
In
addition,
Section
408
of
the
Federal
Food,
Drug,
and
Cosmetic
Act
(
FFDCA)
requires
the
US
EPA
to
consider
available
information
concerning
exposure
from
a
chemical
in
food
and
all
other,
non­
occupational
avenues,
including
that
from
drinking
water
and
residential
or
other
indoor
uses.
In
the
case
of
the
AOs,
potential
exposure
from
the
FDA­
approved
uses
of
these
compounds
dwarfs
that
from
the
pesticidal
uses.
Also,
AOs
degrade
readily
and
completely
under
aerobic
and
anaerobic
conditions.

i.
Food.
Crop
levels
of
AOs
have
not
been
determined
since
a
tolerance
exemption
is
being
requested.
Human
exposure
to
AOs
from
FDA­
approved
sources,
and
from
cosmetics,
may
be
reasonably
expected
to
be
much
greater
than
that
for
the
use
of
these
compounds
in
pesticide
formulations.
Except
in
cases
of
extreme
dosages,
the
amine
oxides
are
of
low
toxicity
to
mammals
and
only
mildly
irritating.
Amine
oxides
are
a
component
of
many
non­
pesticidal
consumer
products
currently
marketed
in
the
United
States.
They
are
widely
used
in
consumer
products
used
by
children
and
adults,
including
such
products
as
bath
products,
cleansing
preparations,
moisturizers,
other
skin
care
preparations,
and
shampoos.
These
products
have
a
long,
safe
use
history.
[
MRID
46647301]

ii.
Drinking
water.
Amine
oxides
are
a
component
of
many
non­
pesticidal
consumer
products
currently
marketed
in
the
United
States.
They
are
widely
used
in
consumer
products
used
by
children
and
adults,
including
such
products
as
bath
products,
cleansing
preparations,
moisturizers,
other
skin
care
preparations,
and
shampoos.
These
products
have
a
long,
safe
use
history.
[
MRID
46647301]

Minimal,
if
any
residues
of
AOs
are
expected
to
occur
in
drinking
water
since
AOs
degrade
readily
and
completely
under
aerobic
and
anaerobic
conditions.
The
OECD
test
method
303
showed
>
99.8%
6
removal
of
AO
from
sewage
while
wastewater
treatment
plant
monitoring
studies
in
the
U.
S.,
Netherlands
and
Japan
have
shown
an
average
98%
removal
of
amine
oxides.
[
MRID
46647301]

2.
Non­
dietary
exposure.
Amine
oxides
are
a
component
of
many
non­
pesticidal
consumer
products
currently
marketed
in
the
United
States.
They
are
widely
used
in
consumer
products
used
by
children
and
adults,
including
such
products
as
bath
products,
cleansing
preparations,
moisturizers,
other
skin
care
preparations,
and
shampoos.
These
products
have
a
long,
safe
use
history.
[
MRID
46647301]

D.
Cumulative
Effects
The
amine
oxides
are
structurally
related
to
other
classes
of
chemicals,
all
of
which
are
of
lowtoxicity
and
which
resemble
natural
products.
Consequently,
the
separate
or
combined
risks
are
expected
to
be
low.
[
MRID
46647301]

E.
Safety
Determination
1.
U.
S.
population.
There
are
no
data
that
point
to
any
concern
for
increased
risk
to
the
U.
S.
population
from
exposure
to
AOs.
Amine
oxides
are
widely
used
in
consumer
products
used
by
children
and
adults,
including
such
products
as
bath
products,
cleansing
preparations,
moisturizers,
other
skin
care
preparations,
and
shampoos.
These
products
have
a
long,
safe
use
history.
[
MRID
46647301]

2.
Infants
and
children.
There
are
no
data
that
point
to
any
concern
for
increased
risk
to
infants
or
children
from
exposure
to
AOs.
Amine
oxides
are
widely
used
in
consumer
products
used
by
children
and
adults,
including
such
products
as
bath
products,
cleansing
preparations,
moisturizers,
other
skin
care
preparations,
and
shampoos.
These
products
have
a
long,
safe
use
history.
[
MRID
46647301]

F.
International
Tolerances
No
Codex
Maximum
Residue
Levels
(
MRL)
are
established
for
the
amine
oxides.
7
References:

1.
Sanders,
A.,
Ninox
HCDO:
Acute
oral
toxicity
study
in
the
rat
­
acute
toxic
class
method,
SPL
project
number:
625/
046.
May
19,
2000.

2.
Sanders,
A.,
Ninox
HCDO:
Acute
dermal
toxicity
(
limit
test)
in
the
rat,
SPL
project
number:
625/
047.
May
19,
2000.

3.
Sanders,
A.,
Ninox
HCDO:
Acute
dermal
irritation
test
in
the
rabbit,
SPL
project
number:
625/
048.
May
19,
2000.

4.
Sanders,
A.,
Ninox
HCDO:
Acute
eye
irritation
test
in
the
rabbit,
SPL
project
number:
625/
049.
May
19,
2000.

5.
Sanders,
A.,
Ninox
HCDO:
Magnusson
and
Kligman
maximisation
study
in
the
guinea
pig,
SPL
project
number:
625/
050.
May
22,
2000.

6.
Wright,
N.
P.,
Ninox
HCDO:
Chromosome
aberration
test
in
human
lymphocytes
in
vitro,
SPL
project
number:
625/
053.
November
16,
2000.

7.
Thompson,
P.
W.,
Ninox
HCDO:
Reverse
mutation
assay
"
Ames
test"
using
Salmonella
typhimurium
and
Escherichia
coli,
SPL
project
number:
625/
052.
May
31,
2000.

8.
Wetton,
P.
M.
and
Mullee,
D.
M.,
Ninox
HCDO:
Acute
toxicity
to
rainbow
trout
(
Oncorhnychus
mykiss),
SPL
project
number:
625/
054.
May
16,
2000.

9.
Wetton,
P.
M.
and
Mullee,
D.
M.,
Ninox
HCDO:
Acute
toxicity
to
Daphnia
magna,
SPL
project
number:
625/
055.
May
16,
2000.

10.
Personal
conversation,
Herbert
M.
Collins,
Stepan
Company,
10/
10/
2005.