Page
1
of
11
Appendix
A:
Executive
Summaries
and
Toxicological
Profile
of
4­
CPA
The
requirements
(
CFR
158.340)
for
a
food
use
for
4
chlorophenoxyacetic
acid
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
1:
Toxicology
data
requirements
for
a
food
use
pesticide
and
whether
or
not
they
have
been
satisfied.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
No
No
Yes
Yes
No
1
No
2
No
2
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
No
1
No
1
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
No3
No
1
No
1
No
1
No
1
­

870.5100
Mutagenicity
C
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5395
Mutagenicity
C
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
No
Yes
Yes
Yes
­

870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
No
4
No
4
No
No
No
­­­­­

870.7485
General
Metabolism/
rats
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
No
No1
­

1
A
data
waiver
was
granted
for
this
guideline
study.
2
Not
required
for
this
use
category.
3
Either
870.4200a
or
870.4300
can
fulfil
this
requirement.
4
Required
only
for
organophosphate
pesticides.
Page
2
of
11
Table
2:
Acute
Toxicity
Data
on
4CPA
(
Technical
Grade
4­
CPA)

Guideline
No.
Study
Type
MRID
#(
s)
Results
Toxicity
Category
870.1100
Acute
Oral
41837001
LD
50
=
2703
mg/
kg
III
870.1200
Acute
Dermal
42522601
LD
50
=
>
2000
mg/
kg
III
870.1300
Acute
Inhalation
42968201
LC
50
=
>
5.25
mg/
L
IV
870.2400
Primary
Eye
Irritation
42339101
Severe
irritation
I
870.2500
Primary
Skin
Irritation
42306801
Non­
irritating
IV
870.2600
Dermal
Sensitization
42339102
Not
a
sensitizer
NA
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

870.3100
90­
Day
Oral
Toxicity
­
Rat
EXECUTIVE
SUMMARY:
In
a
90­
day
oral
toxicity
study
(
MRID
42902501)
4­
chlorophenoxyacetic
acid
(
99.8%
a.
i.,
batch/
lot
#
HWI
TM
No.
0020A4)
was
administered
to
12
Crl:
CDBR
VAF/
PLUS
rats/
sex/
group
in
diet
at
dose
levels
of
0,
100,
2000
or
8000
ppm
(
equivalent
to
0,
6.6,
132.4
or
516.9
mg/
kg
bw/
day
for
males
and
0,
7.99,
153
or
625.9
mg/
kg
bw/
day
for
females).
Animals
were
subjected
to
the
following:
(
1)
observed
twice
daily,
(
2)
body
weights
measured
weekly,
(
3)
food
consumption
measured
weekly,
(
4)
ophthalmic
examination,
(
5)
hematology,
clinical
chemistry,
urinalysis
at
week
5
and
14,
and
(
6)
at
13
weeks,
fasted
and
sacrificed
for
organ
weights
and
gross
examination
and
microscopic
examination
of
selected
tissue
and
organs.
Male
body
weights
were
consistently
nominally
lower
(­
0.05%
by
week
7
to
­
1.8%
by
week
14)
than
control
weights
at
8000
ppm.
Significantly
lower
body
weights
(
p<
0.05)
were
seen
in
females
(­
9%
by
week
3
to
­
14%
by
week
14)
at
8000
ppm.
Body
weight
gain
was
significantly
decreased
in
males
and
females
dosed
at
8000
ppm
for
the
first
week
and
for
week
10
for
males
and
week
5
for
females.
Since
food
efficiency
was
less
than
controls
in
males
(­
8%)
and
females
(­
8%)
at
8000
ppm,
the
decrease
in
weight
may
have
been
due
to
toxicity
rather
than
decreased
food
consumption.
Alkaline
phosphatase
was
slightly,
but
statistically
elevated
at
5
weeks
(
29%)
and
14
weeks
(
57%)
in
females
only.
At
8000
ppm,
glucose
was
statistically
Page
3
of
11
significantly
lower
by
16%
in
females.
Urine
volumes
were
increased
in
males
(
17%
at
week
5
and
2%
at
week
14)
and
significantly
increased
in
females
(
233%
at
week
5
and
198%
at
week
14)
at
8000
ppm.
The
specific
gravity
of
urine
from
females
was
decreased
significantly
at
week
5
(­
2%)
and
week
14
(­
2%)
in
the
8000
ppm
group.
At
histological
examination,
an
increased
number
of
males
showed
liver
lymphohistiocytic
infiltration
(
1
in
control
and
5
at
8000
ppm)
and
individual
hepatocyte
necrosis
(
0
in
control
and
6
at
8000
ppm).
The
LOAEL
is
8000
ppm
(
517
mg/
kg/
day
for
males
and
626
mg/
kg/
day
for
females),
based
on
body
weight
decrement
in
males
and
females
and
lymphohistiocytic
infiltration
and
individual
hepatocyte
necrosis
in
males
and
increased
urine
volume
in
females.
The
NOAEL
is
2000
ppm
(
132
mg/
kg/
day
for
males
and
153
mg/
kg/
day
for
females).
This
90­
day
oral
toxicity
study
in
the
rodent
is
acceptable
guideline
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
rodent
species.
The
acceptability
of
the
study
is
unchanged
from
TXR#
0010794
and
the
NOAEL/
LOAEL
are
unchanged.

870.3150
90­
Day
Oral
Toxicity
­
Dog
EXECUTIVE
SUMMARY:
In
a
90­
day
oral
toxicity
study
(
MRID
42968301)
4­
chlorophenoxyacetic
acid
(
99.8%%
a.
i.,
batch/
lot
HWI
0020A4)
was
administered
to
4
Beagle
dogs/
sex/
group
in
the
diet
at
dose
levels
of
0,
20,
100
or
500
ppm
(
equivalent
to
0,
0.80,
3.3
or
18.6
mg/
kg/
day
for
males
and
0,
0.78,
4.0
or
17.4
mg/
kg/
day
for
females;
average
for
males
and
females;
0,
0.792,
3.67
and
18.0
mg/
kg
bw/
day).
Doses
were
based
on
a
4­
week
range­
finding
study
in
2
dogs/
sex/
group
dosed
at
0,
40,
200,
400,
800,
1600
or
3200
ppm
(
MRID
43045301).
In
this
range­
finding
study,
the
dogs
were
offered
test
material
for
3
hour
for
1
day
followed
by
basal
diet
for
2
days;
the
regimen
was
followed
subsequently
at
the
next
higher
dose
until
the
3200
ppm
dose
was
reached.
These
treated
dogs
were
then
offered
1600
ppm
for
the
remaining
ten
days
from
day
19
to
28.
In
this
range­
finding
study,
decreased
palatability
at
1600
and
3200
ppm
resulted
in
decreased
body
weight
and
changed
clinical
chemistries,
while
absolute
and
relative
organ
weight
changes
were
associated
with
decreased
nutritional
status
of
the
dogs.
No
specific
toxicity
was
seen
grossly
or
microscopically.
In
the
90­
day
study,
body
weights
and
food
consumption
were
measured
weekly
in
the
0,
20,
100
and
500
ppm
groups
(
MRID
42968301).
No
dose
related
statistical
differences
were
seen.
Male
body
weight
were
nominally
lower
throughout
the
study.
Males
showed
a
nominal
body
weight
gain
decrement
of
250
g
week
1­
13
(­
8%),
but
females
showed
a
nominal
25
g
body
weight
gain
week
1­
13
(+
1%)
at
500
ppm.
Male
food
consumption
was
statistically
significantly
depressed
week
9
and
12
at
the
100
ppm
dose
level.
There
was
no
dose
related
differences
in
food
consumption
or
food
efficiency
for
females
on
study.
Male
dogs
showed
a
nominal
­
19%
decreased
food
efficiency
for
the
first
4
weeks
of
the
study,
but
a
nominal
9%
increase
during
the
last
9
weeks
of
the
study
for
no
change
for
the
entire
13
week
study.
Clinical
observations,
hematology,
and
clinical
chemistry
data
showed
no
differences
by
study
termination.
The
author
stated
that
red
feces
and
vomiting
were
seen
in
all
dose
groups,
but
that
it
appeared
to
be
more
frequent
in
the
two
top
dose
levels.
No
dose
related
differences
were
Page
4
of
11
seen
in
organ
weights
or
relative
organ
weights
or
pathology
at
microscopic
examination.
Statistically
significant
ovarian
weight
increase
seen
in
the
left
ovary
at
20
and
500
ppm,
were
not
seen
in
the
combined
ovarian
weights.
The
ovarian
weight
changes
were
considered
incidental
and
not
dose
related.
The
study
showed
only
suggestive
body
weight
gain
decrement
at
500
ppm,
but
no
definitive
toxicity
in
any
parameter
.
Possibly
based
on
the
nominal
male
body
weight
gain
decrement,
the
study
author
concluded
that
the
LOAEL
was
500
ppm
(
HDT).
It
is
concluded
that
the
suggestive
toxicity
in
male
body
weight
gain
decrement
at
500
ppm
(
18.6
mg/
kg/
day)
may
have
approached
a
LOAEL.
However,
the
demonstrated
NOAEL
is
500
ppm
(
18.6
mg/
kg/
day
for
males
and
17.4
mg/
kg/
day
for
females
or
an
average
of
18.0
mg/
kg/
day
for
males
and
females).
A
LOAEL
was
not
demonstrated.
The
NOAEL
is
500
ppm
(
18.0
mg/
kg/
day)(
HDT).
This
90­
day
oral
toxicity
study
in
the
dog
is
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
nonrodent
species.
Although
the
study
shows
no
definitive
toxicity,
repeating
the
study
is
not
likely
to
produce
meaningful
information
on
this
unpalatable
test
material.
Dogs
suffered
from
malnutrition
at
higher
dose
levels
in
a
range­
finding
study
(
MRID#
43045301).
This
malnutrition
was
caused
by
the
unpalatable
test
material
in
the
diet
resulting
in
decreased
food
consumption.
The
acceptability
of
the
study
(
MRID
42968301)
is
not
changed
from
TXR#
10794,
however,
the
NOAEL
has
been
changed
from100
ppm
in
TXR#
10794
to
500
ppm
in
the
current
Executive
Summary,
with
no
LOAEL.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(
MRID
42322602)
4­
chlorophenoxyacetic
acid
(
99­
100%
a.
i.,
batch/
lot
#
HWI
0020A1
and
0020A2)
was
administered
to
25
Crl:
CDBR
VAF/
PLUS
rats/
group
by
gavage
at
dose
levels
of
0,
150,
300,
600
or
1000
mg/
kg
bw/
day
from
days
6
through
15
of
gestation.
Mean
body
weight
gains
of
dams
were
significantly
decreased
and
were
dose
related
during
gestational
days
6
through
9
(­
44%)
and
6
through
16
(­
14%)
at
300
mg/
kg/
day
and
greater.
Dams
at
1000
mg/
kg/
day
showed
yellow
staining
of
the
ano­
genital
area,
tremors,
uncoordinated
movements,
recumbent
posture,
languidness,
and
cold
to
touch.
Also
at
1000
mg/
kg/
day,
1
dam
died
and
3
were
killed
in
a
moribund
condition.
There
were
no
differences
among
control
and
treated
groups
in
pre­
or
post
implantation
loss,
resorptions
or
corpora
lutea.
Fetal
weights
were
significantly
lower
than
control
in
the
600
(­
8%)
and
1000
mg/
kg/
day
groups
(­
19%).
There
were
no
dose
related
soft
tissue
or
skeletal
malformations.
Statistically
significant
dose
related
increases
occurred
in
unossified
sternebrae
5
for
fetuses
at
all
dose
levels,
but
not
for
litters.
Litters
in
the
150
mg/
kg/
day
group
showed
the
same
incidence
as
concurrent
control
litters
and
historical
control
litters.
The
litter
incidence
did
not
reach
statistical
significance
below
the
600
mg/
kg/
day
dose
level.
At
the
1000
mg/
kg/
day
dose,
other
variations
increased,
increases
were
seen
in
misaligned
sternebrae
and
7th
cervical
ribs
in
fetuses
and
litters.
Page
5
of
11
The
LOAEL
for
developmental
effects
in
fetuses
and
litters
was
the
300
mg/
kg/
day
dose
level.
The
study
author
stated
that
the
LOAEL
for
developmental
effects
was
600
mg/
kg/
day
because
the
litter
incidence
was
significantly
increased
at
600
mg/
kg/
day.
Although
the
incidence
in
litters
was
not
significantly
affected
until
the
600
mg/
kg/
day
dose
level
was
reached,
the
increased
fetal
incidence
was
statistically
significant
at
300
mg/
kg/
day
(
27%
versus
13%
in
control)
and
showed
a
good
dose
related
response
and
the
litter
incidence
was
nominally
increased
at
300
mg/
kg/
day
(
52%
versus
73%
in
control)
and
showed
a
dose
related
response.
The
response
in
fetuses
and
litters
at
300
mg/
kg/
day
and
above
suggests
that
the
increased
litter
incidence
was
also
treatment
related.
The
maternal
LOAEL
is
300
mg/
kg
bw/
day,
based
on
decreased
body
weight
between
gestational
days
6
and
9
and
6
to
16.
The
maternal
NOAEL
is
150
mg/
kg
bw/
day.
The
developmental
LOAEL
is
300
mg/
kg
bw/
day,
based
on
unossified
sternebrae
5
(
incidence
was
statistically
significant
in
fetuses
and
nominally
increased
in
litters).
The
developmental
NOAEL
is
150
mg/
kg
bw/
day.
The
developmental
toxicity
study
in
the
rat
is
classified
acceptable/
guideline;
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
The
acceptability
of
the
study
and
NOAEL/
LOAEL
are
not
change
from
TXR#
009556.
The
developmental
effect
of
concern
is
presented
in
the
Table
below.

Doses
0
150
mg/
kg/
day
300
mg/
kg/
day
600
mg/
kg/
day
1000
mg/
kg/
day
Percentage
with
unossified
sternebrae
5
in
each
group,
*
p=>
0.05,
**
p=>
0.01
Fetuses
13
20*
27*
35*
81**

Litters
52
50
73
80*
100*

The
range
in
historical
control
litter
incidence
of
unossified
sternebrae
5
is
0­
50%.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Summary
of
the
rabbit
range­
finding
study:
No
definitive
study
was
conducted.
A
1965
range­
finding
study
was
conducted
in
pregnant
rabbits
on
5
animals/
group
at
0,
5,
10
or
25
mg/
kg/
day
(
MRID#
00144733;
TXR#
005712).
However,
since
maternal
weight
for
controls
was
not
reported,
it
is
impossible
to
determine
maternal
weight
decrement.
Total
litter
weight
was
reported
but
no
individual
fetal
weights.
The
viability
index
was
nominally
decreased
(
11%
compared
with
control)
at
the
HDT,
but
no
statistics
were
reported.
The
study
was
considered
unacceptable/
not
upgradable
for
these
and
other
reasons.
The
study
report
authors
however,
stated
that
no
effects
were
observed
in
fetuses
or
dams.
A
data
waiver
was
granted
for
the
study
requirement.
Page
6
of
11
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
Due
to
a
data
waiver,
no
additional
study
is
required
at
this
time.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
EXECUTIVE
SUMMARY:
4­
CPA
(
technical)
was
administered
in
the
diet
to
20
female
and
10
male
Sprague
Dawley
rat
per
group
at
0,
25,
125
or
250
ppm
for
60
days
to
the
parental
generation,
mated
2:
1
to
produce
Fa
and
Fb
litters
for
three
generations
(
MRID#
00083274).
After
weaning
the
F3a
and
F3b
litters,
the
study
was
terminated.
Animals
were
kept
on
diet
continuously
except
females
were
rested
for
10
days
after
weaning
the
first
litter;
the
second
litter
was
used
for
F1
and
F2
parents.
Thus
females
producing
the
litter
from
which
parents
were
to
be
selected
for
the
next
generation
were
not
dosed
for
10
days
prior
to
mating.
No
dose
related
effects
occurred
in
offspring
or
parents.
However,
since
the
highest
dose
administered
was
only
12.5%
of
the
NOAEL
in
the
90­
day
study
in
rats,
the
dose
levels
administered
were
too
low
to
show
any
effects.
The
NOAEL
in
the
90­
day
study
in
rats
2000
ppm.
A
number
of
mothers
died
and/
or
cannibalized
their
offspring.
For
example,
from
the
F2a
group
from
control
to
the
high
dose
14
to
3
mothers
died
with
loss
of
their
litters
and
30
to
64
pups
were
cannibalized
in
control
and
each
dose
group.
The
pup
viability
index
was
too
variable
to
show
dose
related
effects,
if
there
were
any
to
see;
it
was
lower
in
control
(
38%)
than
in
the
high
dose
group
(
49%)
at
day
21
of
lactation.
There
appeared
to
be
no
dose
relationship
with
variable
numbers
per
generation
and
among
groups.
The
authors
speculated
that
a
respiratory
disease
in
the
colony
may
have
been
responsible.
Parts
of
the
report
that
were
readable
suggested
that
no
effects
in
parents
or
offspring
were
seen
in
the
study
at
the
HDT
of
12.5
mg/
kg/
day.
However,
the
parts
of
the
submission
that
could
verify
these
results
were
unreadable.
This
study
is
unacceptable/
not
upgradable
for
a
multi
generation
study
of
reproduction
in
the
rat.
The
study
was
conducted
at
a
dose
that
was
insufficient
to
cause
any
effects.
[
Note:
The
NOAEL/
LOAEL
=
2000/
8000
ppm
(
ca.
132/
517
mg/
kg/
day)
in
the
90­
day
subchronic
study
in
rats.]
In
addition,
dietary
concentrations
were
no
measured,
equal
numbers
of
males
and
females
were
not
used,
dosing
was
not
continuous
and
the
data
too
variable
for
assessment.

Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
mutagenicity
is
considered
adequate
based
on
pre­
1991
mutagenicity
guidelines.
All
three
studies
conducted
at
toxic
doses
were
negative.
Page
7
of
11
Gene
Mutation
Guideline
#
870.5100,
Reverse
mutation
in
S.
typhimurium
MRID
41837002
Acceptable
A
dose
range
of
0­
5000

g/
plate
of
4CPA
was
used
for
strains
TA98,
TA100,
TA
1535,
TA
1537,
and
TA
1538
of
S.
typhimurium.
The
test
was
negative
up
to
cytotoxic
doses
of
5000

g/
plate
with
no
activation
(
­
S9),
and
up
to
doses
of
5000

g/
plate
with
activation
(+
S9)
where
no
cytotoxicity
was
seen.

Guideline#
870.5300,
Gene
mutation
MRID
41837004
Acceptable
4­
CPA
(
99%)
was
evaluated
for
potential
to
induced
forward
mutations
at
the
TK+/­
locus
in
L5178Y
TK+/­
cells
in
two
independently
performed
trials.
Without
S9
activation,
4­
CPA
was
not
mutagenic
at
doses
of
100,
500,
1000,
1600,
2000,
2500,
3000,
3500,
or
4000

g/
mL:
higher
levels
(
5000

g/
mL)
were
severely
cytotoxic.
In
the
presence
of
S9
activation
at
10,
50,
100,
250,
300,
750,
1000,
1300,
1600
or
2000

g/
mL
(
cytotoxic
at
doses

1300

g/
mL),
non­
dose
related
increases
in
mutation
frequency
(
MF)
were
obtained
in
both
trials.
Although
there
was
a
tendency
for
elevated
MFs
at
doses
ranging
from
300
to
1600

g/
mL
+
S9,
doubling
of
the
MF
over
concurrent
controls
was
only
seen
at
600

g/
mL
(
Trial
1)
and
1000

g/
mL
(
Trial
2).
The
evidence
suggesting
a
mutagenic
response,
was
however,
insufficient
to
conclude
the
4­
CPA
was
positive.
The
test
material
was
not
mutagenic
in
this
in
vitro
mammalian
cell
assay.

Cytogenetics
Guideline
#
870.5395,
In
vivo
mammalian
erythrocyte
micronucleus
test
MRID
41837003
Acceptable
In
an
ICR
mouse
bone
marrow
micronucleus
assay,
5/
sex/
group
were
treated
gavage
with
4­
chlorophenoxyacetic
acid
(
99%)
at
doses
of
0,
450,
900
or
1800
mg/
kg­
bw.
Bone
marrow
cells
were
harvested
at
24,
48
and
72
hours
post­
treatment.

There
were
signs
of
toxicity,
languidness
and
prostration,
and
most
animals
died
within
24
hours
at
1800
mg/
kg
during
the
study.
Hematopoiesis
was
adversely
affected
at
1800
mg/
kg.
There
were
5000
polychromatic
erythrocytes
and
<
5
micronucleated
polychromatic
erythrocytes
(
MPE)
per
group
with
no
dose
response.
4­
CPA
was
tested
at
an
adequate
dose
based
on
mortality.
The
positive
control
induced
the
appropriate
response.
There
was
no
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
after
any
treatment
time.

Other
Genotoxicity
Guideline
#,
study
type
MRID
00141673
classification
Dose
range
and
brief
conclusions
of
study
(
see
gene
mutation
summary
instructions)
Page
8
of
11
REFERENCES:

00083274
Booz­
Allen
Applied
Research
(
1964)
The
Effect
of
4­
Chlorophenoxyacetic
Acid
on
Reproduction
in
the
Rat:
Project
No.
4031.
(
Unpublished
study,
including
letter
dated
Nov
3,
1965
from
R.
A.
Turner
to
Nathan
G.
Fox,
received
Nov
16,
1965
under
PP0360;
submitted
by
Chun
King
Corp.,
Duluth,
Minn.;
CDL:
090390­
A)

00144733
Turner,
R.
(
1965)
A
Study
of
the
Effect
of
P­
chlorophenoxyacetic
Acid
on
Teratogenicity
in
the
Rabbit:
BSL4054.
Unpublished
study
prepared
by
Biological
Science
Laboratory,
Foster
D.
Snell,
Inc.
14
p.

41837001
Glaza,
S.
(
1991)
Acute
Oral
Toxicity
Study
of
4­
Chlorophenoxyacetic
Acid
in
Rats:
Final
Report:
Lab
Project
Number:
HLA/
00801531.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
53
p.

42306801
Glaza,
S.
(
1992)
Primary
Dermal
Irritation
Study
of
4­
Chlorophenoxyacetic
Acid
in
Rabbits:
Lab
Project
Number:
HWI
20200490.
Unpublished
study
prepared
by
Hazleton
Wisconsin,
Inc.
21
p.

42322602
Henwood,
SM
(
1992)
Teratology
Study
with
4­
Chlorophenoxyacetic
acid.
Laboratory
name
Hazelton
Wisconsin,
Inc.
Laboratory
report
number,
HWI
6341­
101
(
May
14,
1992)
Unpublished
42339101
Glaza,
S.
(
1992)
Primary
Eye
Irritation
Study
of
4­
Chlorophenoxyacetic
Acid
in
Rabbits:
Lab
Project
Number:
HWI
20200491.
Unpublished
study
prepared
by
Hazleton
Wisconsin,
Inc.
36
p.

42339102
Glaza,
S.
(
1992)
Dermal
Sensitization
Study
of
4­
Chlorophenoxyacetic
Acid
in
Guinea
Pigs­­
Closed
Patch
technique:
Final
Report:
Lab
Project
Number:
HWI
20200492.
Unpublished
study
prepared
by
Hazleton
Wisconsin,
Inc.
33
p.

42522601
Glaza,
S.
(
1992)
Acute
Dermal
Toxicity
Study
of
4­
Chlorophenoxyacetic
Acid
in
Rabbits:
Final
Report:
Lab
Project
Number:
HWI
20700133.
Unpublished
study
prepared
by
Hazleton
Wisconsin,
Inc.
28
p.

42902501
Henwood,
SM
(
1993)
13­
Week
Dietary
Toxicity
Study
with
4­
Chlorophoxyacetic
acid
in
Rats.
Laboratory
name
Hazleton
Wisconsin,
Inc.
Laboratory
report
HWI
6341­
102.
Unpublished
42968201
Nachreiner,
D.
(
1993)
4­
Chlorophenoxyacetic
Acid:
Acute
Dust
Inhalation
Toxicity
Study
in
Rats:
Revised
Report:
Lab
Project
number:
92N1192
REVISED:
92N1192.
Unpublished
study
prepared
by
Union
Carbide
and
Plastics
Co.,
Bushy
Run
Research
Center.
58
p.
Page
9
of
11
42968301
Henwood,
SM
(
1993)
13­
Week
Dietary
Study
with
4­
Chlorophenoxyacetic
Acid
in
Dogs.
Laboratory
name
Hazleton
Wisconsin,
Inc.
Laboratory
report
number,
HWI
6341­
108.
September
30,1993.
Unpublished
43045301
Hewood,
SM
(
1992)
Dietary
Escalating
Dose
Tolerance
Study
with
4­
Chlorophenoxyacetic
acid
in
Dogs.
Laboratory
name
Hazleton
Wisconsin,
Inc.
Laboratory
report
number,
HWI
6341­
106.
September
11,
1992.
Unpublished
Other
References:

Clock,
Mary
(
1994);
Memorandum
to
Jay
Ellenburger;
Dated
12/
22/
94.
The
HED
Chapter
of
the
Regististration
Eligibility
Decision
Document
(
RED)
for
4­
chlorophenoxyacetic
acid
(
4CPA),
019401
(
TXR#
011819)

USEPA
(
1997)
Regregistration
Eligibility
Decision
(
RED)
4­
Chlorophenoxyacetic
Acid
(
4CPA).
EPA
738­
R­
97­
001
March
1997
Toxicity
Profile
Summary
Tables
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
42902501
Acceptable/
guideline
0,
100,
2000
or
8000
ppm
M:
0,
6.6,
132.4,
516.9
mg/
kg/
day
F:
0,
7.99,
153,
625.9
mg/
kg/
day
NOAEL
=
M/
F;
132/
153
mg/
kg/
day
LOAEL
=
M/
F;
517/
626
mg/
kg/
day
based
on
based
on
body
weight
decrement
in
males
and
females
and
lymphohistiocytic
infiltration
and
individual
hepatocyte
necrosis
in
males
and
increased
urine
volume
in
females.

870.3150
90­
Day
oral
toxicity
in
dogs
42968301
Acceptable/
guideline
0,
20,
100
or
500
ppm
M;
0,
0.80,
3.3
and
18.6
mg/
kg/
day
F;
0,
0.78,
4.0
or
17.4
mg/
kg/
day
Average
for
males
and
females;
0,
0.792,
3.67
and
18.0
mg/
kg/
day.
NOAEL
=
M/
F
18.0
mg/
kg/
day
(
HDT)
LOAEL
=
None
mg/
kg/
day
based
on
no
effects
at
the
top
dose.
There
was
a
nominal
body
weight
decrement
at
the
top
dose,
which
was
insufficient
to
be
considered
a
toxic
effect.
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
10
of
11
870.3200
21/
28­
Day
dermal
toxicity
­
No
study
available
870.3250
90­
Day
dermal
toxicity
­
No
study
available
870.3465
90­
Day
inhalation
toxicity
­
No
study
available
870.3700a
Prenatal
developmental
in
rats
42322602
Acceptable
0,
150,
300,
600
or
1000
mg/
kg/
day
Maternal
NOAEL
=
150
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day
based
on
body
weight.
Developmental
NOAEL
=
150
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day
based
on
unossified
sternebrae
5
(
incidence
was
statistically
significant
in
fetuses
and
nominal
in
litters).

870.3700b
Prenatal
developmental
in
rabbits
00144733
Unacceptable
0,
5,
10,
25
mg/
kg/
day
(
range­
finding
study,
5
rabbits/
group)
Maternal
NOAEL
=
25
mg/
kg/
day
LOAEL
=
Not
determined.
Developmental
NOAEL
=
25
mg/
kg/
day
LOAEL
=
Not
determined.

870.3800
Reproduction
and
fertility
effects
00083274
Unacceptable
0,
25,
50,
250
ppm
0,
1.25,
2.5,
12.5
mg/
kg/
day
Parental/
Systemic
NOAEL
=
12.5
mg/
kg/
day
LOAEL
=
Not
determined.
Reproductive
NOAEL
=
12.5
mg/
kg/
day
LOAEL
=
Not
determined.
Offspring
NOAEL
=
12.5
mg/
kg/
day
LOAEL
=
Not
determined.

870.4100a
Chronic
toxicity
rodents
Unavailable
No
study
available
870.4100b
Chronic
toxicity
dogs
Unavailable
No
study
available
870.4200
Carcinogenicity
rats
Unavailable
No
study
available
870.4300
Carcinogenicity
mice
Unavailable
No
study
available
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Page
11
of
11
870.5100,
Gene
Mutation,
reverse
mutation
in
S.
typhimurium
41837002
Acceptable
0,
100,
333,
667,
1000,
3300
or
5000

g/
plate
Negative
without
activation
at
cytotoxic
doses
and
negative
with
activation
at
5000

g/
plate.

870.5300,
Gene
Mutation,
Mouse
L5178Y
lymphoma
cells
41837004
Acceptable
0­
4000

g/
mL
­
S9
0­
2000

g/
mL
+
S9
Negative
­
S9
and
+
S9
at
cytotoxic
doses.

870.5395,
Cytogenetics,
In
vivo
mouse
erythrocyte
micronucleus
test
41837003
Acceptable
0,
450,
900
or
1800
mg/
kg
Negative
at
toxic
doses.

870.6200a
Acute
neurotoxicity
screening
battery
­
NA
870.6200b
Subchronic
neurotoxicity
screening
battery
­
NA
870.6300
Developmental
neurotoxicity
­
NA
870.7485
Metabolism
and
pharmacokinetics
­
NA
870.7600
Dermal
penetration
­
NA
Special
studies
­
NA
NA
=
Not
available
