CHEMICAL
NAME
PC
Code:
030001
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:

Prepared
by:
Linda
L.
Taylor,
Ph.
D.
Reregistration
Branch
I
Health
Effects
Division
Reviewed
by:
Whang
Phang,
Ph.
D.
Reregistration
Branch
I
Health
Effects
Division
form:
FINAL
June
21,
2000
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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4
2.0
REQUIREMENTS
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6
3.0
DATA
GAP(
S)
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7
4.0
HAZARD
ASSESSMENT
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7
4.1
Acute
Toxicity
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7
4.2
Subchronic
Toxicity
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9
4.3
Prenatal
Developmental
Toxicity
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18
4.4
Reproductive
Toxicity
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24
4.5
Chronic
Toxicity
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27
4.6
Carcinogenicity
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30
4.7
Mutagenicity
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33
4.8
Neurotoxicity
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38
4.9
Metabolism.
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41
4.10
Special/
Other
Studies
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42
5.0
TOXICITY
ENDPOINT
SELECTION
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44
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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44
5.2
Dermal
Absorption
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44
5.3
Classification
of
Carcinogenic
Potential
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45
6.0
FQPA
CONSIDERATIONS
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45
6.1
Special
Sensitivity
to
Infants
and
Children
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45
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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45
7.0
OTHER
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46
8.0
REFERENCES
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48
9.0
APPENDICES
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9.1
Toxicity
Profile
Summary
Tables
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9.1.1
Acute
Toxicity
Table
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9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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9.2
Summary
of
Toxicological
Dose
and
Endpoints
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CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
3
1.0
HAZARD
CHARACTERIZATION
2,4­
Dichlorophenoxyacetic
acid
[
2,4­
D]
and
its
amine
salts
[
diethanolamine
(
DEA),
dimethylamine
(
DMA),
isopropylamine
(
IPA),
and
triisopropanolamine
(
TIPA)]
and
esters
[
butoxyethyl
ester
(
BEE),
ethylhexyl
ester
(
EHE),
and
isopropyl
ester
(
IPE)]
are
not
acutely
toxic
via
the
oral
[
Toxicity
Category
III],
dermal
[
Toxicity
Category
III],
and
inhalation
[
Toxicity
Category
III/
IV]
routes
of
exposure.
2,4­
D
and
its
amine
salts
and
esters
are
not
skin
irritants
[
Toxicity
Categories
III
and
IV]
and
none
is
a
skin
sensitizer.
The
acid
and
amine
salt
forms
of
2,4­
D
are
considered
severe
eye
irritants
[
Toxicity
Category
I],
but
the
ester
forms
are
not
eye
irritants
[
Toxicity
Category
III].

In
general,
2,4­
D
undergoes
limited
metabolism
primarily
involving
minor
conjugation
of
the
parent
acid
that
is
then
excreted
in
the
urine.
No
detectable
metabolites
of
2,4­
D
have
been
reported
in
the
rat;
i.
e.,
only
the
parent
acid
is
found
in
rat
urine.
In
addition
to
2,4­
D
itself,
2,4­
D
conjugates
have
been
found
in
the
urine
of
dogs,
humans,
mice,
and
hamsters
following
oral
exposure.
The
mechanisms
responsible
for
the
renal
clearance
of
2,4­
D
have
been
investigated
in
several
species
also.
This
phenoxy
herbicide
is
actively
secreted
by
the
proximal
tubules
in
a
manner
similar
to
paraaminohippuric
acid
[
PAH],
and
this
mechanism
of
renal
clearance
for
2,4­
D
is
consistent
with
results
seen
with
other
phenoxy
acids.
It
has
been
suggested
that
the
observed
dosedependent
non­
linear
pharmacokinetics
of
2,4­
D
are
primarily
due
to
the
saturation
of
this
renal
secretory
transport
system.
Due
to
a
limited
capacity
to
excrete
organic
acids,
the
dog
is
more
sensitive
to
the
effects
of
2,4­
D
than
the
rat
with
respect
to
repeated
dosing.

Following
subchronic
oral
exposure
at
dose
levels
of
2,4­
D
above
the
threshold
of
saturation
for
renal
clearance,
the
primary
target
organs
are
the
eye
[
retinal
degeneration,
cataract
formation],
thyroid
[
increased
thyroid
weight,
increased
T3/
decreased
T4,
and
follicular
cell
hypertrophy],
kidney
[
brush
border
loss
in
proximal
tubule],
adrenals
[
hypertrophy],
and
ovaries/
testes
[
atrophy].
These
changes
are
also
observed
following
exposure
to
the
amine
salts
and
esters
of
2,4­
D.
Systemic
toxicity
was
not
observed
following
repeated
dermal
exposure
to
2,4­
D,
EHE,
and
TIPA
at
or
above
the
limit
dose
or
following
repeated
dermal
exposure
to
BEE
and
IPA
at
the
highest
dose
tested.
Liver
toxicity
was
observed
following
repeated
dermal
exposure
to
DEA,
and
one
death
[
female]
occurred
following
dermal
exposure
to
DMA
at
a
high­
dose
level.

There
are
no
repeated
inhalation
exposure
data
available
on
2,4­
D.
The
only
reliable
way
to
characterize
inhalation
toxicity
and
to
quantify
inhalation
risk
is
through
the
use
of
inhalation
toxicity
studies.
In
general,
chemicals
tend
to
be
more
toxic
by
the
inhalation
route
than
by
the
oral
route
due
to
rapid
absorption
and
distribution,
bypassing
of
the
liver's
metabolic
protection
(
portal
circulation),
and
potentially
serious
portal­
ofentry
effects,
such
as
irritation,
edema,
cellular
transformation,
degeneration,
and
necrosis.
An
inhalation
risk
assessment
that
is
based
on
oral
data
generally
underestimates
the
inhalation
risk
because
it
cannot
account
for
these
factors.
However,
in
the
case
of
2,4­
D,
based
on
the
limited
metabolism
of
2,4­
D
via
the
oral
route,
the
moiety
to
which
the
body
would
be
exposed
would
be
the
same
for
both
routes
of
exposure.
With
regard
to
portal­
of­
entry
effects,
these
can
only
be
assessed
in
an
inhalation
study.
Therefore,
a
subchronic
inhalation
study
is
required
for
2,4­
D
pending
the
submission
of
an
acceptable
waiver
rationale.

Developmental
toxicity,
characterized
mainly
as
an
increased
incidence
of
skeletal
variations
in
the
rat,
was
observed
following
exposure
to
2,4­
D
and
its
amine
salts
and
esters.
Malformations
in
the
rat
were
observed
only
at
dose
levels
that
were
at
or
above
the
threshold
of
saturation
of
renal
clearance.
Similarly,
developmental
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
4
toxicity
was
observed
in
the
rabbit
only
following
high­
dose
exposures
above
the
renal
clearance
level
for
2,4­
D
[
abortions]
and
DEA
[
increased
number
of
litters
with
fetuses
with
7th
cervical
ribs.

Reproductive
toxicity,
characterized
as
an
increase
in
gestation
length,
was
observed
following
exposure
to
2,4­
D
at
a
dose
level
above
the
threshold
of
saturation
of
renal
clearance.
A
repeat
2­
generation
reproduction
study
[
using
the
new
protocol]
is
required
to
address
concerns
for
endocrine
disruption
[
thyroid
and
immunotoxicity
measures].

Neurotoxicity
was
demonstrated
following
exposure
to
2,4­
D
at
relatively
high
dose
levels.
Clinical
signs
of
neurotoxicity
[
ataxia,
decreased
motor
activity,
myotonia,
prostration,
lateral
recumbency,
and
impaired/
loss
of
the
righting
reflex,
cold
to
the
touch]
were
observed
in
pregnant
rabbits
following
exposure
to
2,4­
D
and
its
amine
salts
and
esters.
Neuropathology
[
retinal
degeneration]
was
observed
following
2,4­
D
exposure
in
several
studies
in
female
rats.
Incoordination
and
slight
gait
abnormalities
(
forepaw
flexing
or
knuckling)
were
observed
following
acute
dosing
and
increased
forelimb
grip
strength
was
observed
following
chronic
exposure
to
2,4­
D
at
dose
levels
that
exceeded
the
threshold
of
saturation
of
renal
clearance.
A
developmental
neurotoxicity
study
in
the
rat
is
required
on
2,4­
D.

2,4­
D
is
classified
as
a
Group
D
chemical
[
not
classifiable
as
to
human
carcinogenicity].
Based
on
the
overall
pattern
of
responses
observed
in
both
in
vitro
and
in
vivo
genotoxicity
tests,
2,4­
D
was
not
mutagenic,
although
some
cytogenic
effects
were
observed.

2,4­
D
affects
thyroid
hormone
homeostasis
following
oral
exposure,
and
there
is
a
concern
for
endocrine
disruption.
Effects
on
the
gonads
in
rats
[
decreased
testes
and
ovarian
weights,
atrophy
of
the
ovary,
uterus
and
testis,
degeneration
of
the
seminiferous
epithelium,
decreased
spermatozoa
in
epididymis,
testicular
degeneration,
increase
in
gestation
length]
and
dogs
[
increased
testes
weight,
juvenile
testes
and
prostate,
and
hypospermatogenesis]
are
seen
following
exposure
to
2,4­
D
and/
or
its
amine
salts
and
esters.
Although
there
are
data
on
thyroid
hormone
levels
in
the
adult
animal,
there
are
no
data
with
respect
to
thyroid
hormones
in
the
young;
therefore,
there
is
no
information
on
whether
the
young
are
more
sensitive
with
respect
to
this
endpoint.
There
is
no
developmental
neurotoxicity
[
DNT]
study
available
on
2,4­
D,
and
the
HIARC
determined
previously
that
a
DNT
study
is
required
[
HED
Document
No.
014234].
There
have
been
no
studies
on
2,4­
D
that
specifically
assess
its
endocrine
disruption
potential,
and
there
are
no
data
on
other
hormonal
effects.
Thyroid
effects
[
increased
thyroid
weight,
increased
T3/
decreased
T4,
and
follicular
cell
hypertrophy]
have
been
observed
in
the
rat
following
subchronic
exposure
to
2,4­
D
and
its
amine
salts
and
esters
and
following
chronic
exposure
to
2,4­
D
[
decreased
T4,
increased
thyroid
weight,
thyroid
masses,
and
follicular
cell
hyperplasia
(
males;
interim
sacrifice
only)/
hypertrophy
(
females;
interim
sacrifice
only)].
Additionally,
there
is
some
concern
for
immunotoxicity
following
exposure
to
2,4­
D.
There
are
clear
NOAELs
for
each
of
the
above­
mentioned
effects,
which
occur
only
at
high­
dose
levels;
above
the
doses
selected
for
overall
risk
assessment.
Therefore,
there
are
no
residual
uncertainties
with
regard
to
these
effects.
However,
the
HIARC
concluded
that
a
2­
generation
reproduction
study
using
the
current
protocol
is
required
to
address
both
the
concern
for
thyroid
effects
[
comparative
assessment
between
the
young
and
adult
animals]
and
immunotoxicity,
as
well
as
a
more
thorough
assessment
of
the
gonads
and
reproductive/
developmental
endpoints.
The
Task
Force
should
consult
the
Agency
on
the
protocol
for
this
study.
2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
and
non
food
use
for
2,4­
dichlorophenoxyacetic
acid
[
2,4­
D]
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
5
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
Table
1.

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
yesb
yes
yes
yes
­
no
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yesa
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Carcinogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Carcinogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
carcinogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity
C
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
C
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotoxicity
Screening
Battery
(
rat)
.
.
.
.
.
.
.
870.6200b
90
Day
Neurotoxicity
Screening
Battery
(
rat)
.
.
.
.
.
.
870.6300
Developmental
Neurotoxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
yes
yes
yes
­­

yes
yes
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
­­­

aa
repeat
2­
generation
reproduction
study
following
new
protocol
is
required
to
address
concerns
for
endocrine
disruption
[
thyroid
and
immunotoxicity
measures];
b
a
28­
day
inhalation
study
is
not
satisfied
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
6
3.0
DATA
GAP(
S)

There
are
three
datagaps:
(
1)
repeat
2­
generation
reproduction
study
following
new
protocol
to
address
concerns
for
endocrine
disruption
with
thyroid
and
immunotoxicity
measures;
(
2)
developmental
neurotoxicity
study;
and
(
3)
28­
day
inhalation
toxicity
study.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
The
acute
toxicity
data
indicate
that
2,4­
dichlorophenoxyacetic
acid
[
2,4­
D]
is
not
acutely
toxic
via
the
oral
[
Toxicity
Category
III],
dermal
[
Toxicity
Category
III],
or
inhalation
[
Toxicity
Category
III]
routes
of
exposure.
2,4­
Dichlorophenoxyacetic
acid
is
not
a
skin
irritant
[
Toxicity
Category
IV]
nor
a
skin
sensitizer
but
it
is
considered
a
severe
eye
irritant
[
Toxicity
Category
I].

After
oral
[
single
dose]
administration
of
2,4­
D
and
its
amine
salts
and
esters,
the
clinical
signs
of
toxicity
observed
consistently
were
ataxia,
myotonia,
and
decreased
limb
tone.
No
dermal
or
systemic
toxicity
was
observed
in
rabbits
dosed
dermally,
and
no
deaths
were
observed
after
inhalation.
Clinical
signs
of
toxicity
observed
during
inhalation
exposure
were
decreased
activity
and
closed
eyes.
All
rats
had
dried
white
material
on
their
fur,
presumably
test
material.
Signs
observed
at
the
end
of
and
during
the
week
after
inhalation
exposure
were
salivation,
lacrimation,
mucoid
nasal
discharge,
labored
breathing,
dried
red
or
brown
material
around
eyes
and
nose,
matted
fur,
and
staining
of
the
fur
in
the
anogenital
region.
There
were
no
significant
findings
post
mortem.

The
acute
toxicity
data
on
2,4­
dichlorophenoxyacetic
acid
are
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
2,4­
Dichlorophenoxyacetic
acid
Guideline
No.
Study
Type
MRID
#(
S)
Results
Toxicity
Category
870.1100
Acute
Oral
00101605
rat
LD
50
=
699
mg/
kg
III
870.1200
Acute
Dermal
00101596
rabbits
LD
50
>
2000
mg/
kg
III
870.1300
Acute
Inhalation
00161660
rat
LC
50
>
1.79
mg/
L
III
870.2400
Primary
Eye
Irritation
41125302
severe
eye
irritant
I
870.2500
Primary
Skin
Irritation
42232701
non­
irritating
IV
870.2600
Dermal
Sensitization
00161659
not
a
dermal
sensitizer
­

870.6200
Acute
Neurotoxicity
43115201
NOAEL
=
67
mg/
kg/
day
­

above
studies
satisfy
the
acute
toxicity
data
requirements
[
OPPTS
870.1100,
870.1200,
870.1300,
870.2400,
870.2500,
870.2600,
870.6200;
formerly
§
81­
1
through
§
81­
6,
§
81­
8]
for
2,4­
dichlorophenoxyacetic
acid.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
7
The
acute
toxicity
data
on
several
amine
salts
[
diethanolamine
(
DEA;
CAS
No.
5742­
19­
8),
dimethylamine
(
DMA;
CAS
No.
2008­
39­
1),
isopropylamine
(
IPA;
5742­
17­
6),
and
triisopropanolamine
(
TIPA;
32341­
80­
3)]
and
esters
[
butoxyethyl
ester
(
BEE;
1929­
7303),
ethylhexyl
ester
(
EHE;
1928­
43­
4),
and
isopropyl
ester
(
IPE;
94­
11­
1)]
of
2,4­
Dichlorophenoxyacetic
acid
[
2,4­
D;
CAS
No.
94­
75­
1]
are
summarized
below
in
Table
2a.

Table
2a.
Acute
Toxicity
Data
on
Amine
Salts
and
Esters
of
2,4­
Dichlorophenoxyacetic
Acid
Guideline
No.
Study
Type
MRID
#(
S)
Results
Toxicity
Category
870.1100
Acute
Oral
DEA
salt
DMA
salt
IPA
salt
IP
ester
TIPA
salt
BEE
ester
EHE
ester
41920901
00157512
00252291
41709901
41413501
40629801
41209001
rat
LD50
=
910
mg/
kg
rat
LD50
=
949
mg/
kg
rat
LD50
=
2322/
1646
mg/
kg
rat
LD50
=
1250
mg/
kg
rat
LD50
=
1220/
1074
mg/
kg
rat
LD50
=
866
mg/
kg
rat
LD50
=
896
mg/
kg
III
III
III
III
III
III
III
870.1200
Acute
Dermal
DEA
salt
DMA
salt
IPA
salt
IP
ester
TIPA
salt
BEE
ester
EHE
ester
41920911
00157513
00252291
41709902
41413502
40629802
41209002
rabbits
LD50
>
2000
mg/
kg
rabbit
LD50
>
2000
mg/
kg
rabbits
LD50
>
2000
mg/
kg
rabbits
LD50
>
2000
mg/
kg
rabbits
LD50
>
2000
mg/
kg
rabbits
LD50
>
2000
mg/
kg
rabbits
LD50
>
2000
mg/
kg
III
III
III
III
III
III
III
870.1300
Acute
Inhalation
DEA
salt
DMA
salt
IPA
salt
IP
ester
TIPA
salt
BEE
ester
EH
ester
41986601
00157514
40085501
40352701
41957601
40629803
42605202
rat
LC50
>
3.5
mg/
L
rat
LC50
>
3.5
mg/
L
rat
LC50
=
3.8
mg/
L
rat
LC50
>
4.97
mg/
L
rat
LC50
=
5.35
mg/
L
rat
LC50
=
4.6
mg/
L
rat
LC50
>
5.4
mg/
L
IV
IV
IV
IV
IV
IV
IV
870.2400
Primary
Eye
Irritation
DEA
salt
DMA
salt
IPA
salt
IP
ester
TIPA
salt
BEE
ester
EHE
ester
41920902
00157515
00252291
40352702
41413504
40629804
44725303
severe
eye
irritant
severe
eye
irritant
severe
eye
irritant
not
an
eye
irritant
severe
eye
irritant
not
an
eye
irritant
not
an
eye
irritant
I
I
III
I
III
III
870.2500
Primary
Skin
Irritation
DEA
salt
DMA
salt
IPA
salt
IP
ester
TIPA
salt
BEE
ester
EH
ester
41920903
00157516
00252291
40352703
41413505
40629805
41209005
slight
skin
irritant
slight
skin
irritant
slight
skin
irritant
very
mild
irritant
slight
skin
irritant
very
mild
irritant
not
a
skin
irritant
IV
IV
IV
IV
IV
IV
IV
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Guideline
No.
Study
Type
MRID
#(
S)
Results
Toxicity
Category
8
870.2600
Dermal
Sensitization
DEA
salt
DMA
salt
IPA
salt
IP
ester
TIPA
salt
BEE
ester
EH
ester
41920904
41642805
41233701
40352704
41413506
40629806
41209006
not
a
dermal
sensitizer
not
a
dermal
sensitizer
not
a
dermal
sensitizer
not
a
dermal
sensitizer
not
a
dermal
sensitizer
not
a
dermal
sensitizer
not
a
dermal
sensitizer
­

above
studies
satisfy
the
acute
toxicity
data
requirements
[
OPPTS
870.1100,
870.1200,
870.1300,
870.2400,
870.2500,
870.2600,
870.6200;
formerly
§
81­
1
through
§
81­
6,]
for
several
amine
salts
and
esters
of
2,4­
dichlorophenoxyacetic
acid.

4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
oral
and
dermal
toxicity
is
considered
complete.
No
additional
oral
or
dermal
studies
are
required
at
this
time.
There
is
no
subchronic
inhalation
study
available,
and
one
is
required.
The
subchronic
database
provides
evidence
that
the
kidney
[
increased
kidney
weight,
histopathological
lesions],
thyroid
[
decreased
thyroxine,
increased
thyroid
weight,
hypertrophy
of
follicular
cells],
liver
[
increased
liver
weight,
increased
ALT,
and
AST,
histopathological
lesions,
including
hypertrophy],
and
adrenal
[
increased
adrenal
weight,
histopathological
lesions]
are
target
organs
in
the
rat
following
subchronic
exposure
via
the
oral
route.
No
systemic
toxicity
was
observed
in
rabbits
following
repeated
exposure
via
the
dermal
route
at
dose
levels
up
to
the
limit
dose
[
1000
mg/
kg/
day].
In
the
dog,
the
kidney
and
thyroid
are
target
organs
[
elevated
blood
urea
nitrogen
and
creatinine,
decreased
glucose,
decreased
T4,
increased
kidney
and
thyroid
weights,
cellular
alterations
of
the
proximal
tubule].
Additionally,
decreased
testes
weight
and
hypospermatogenesis/
juvenile
testis
were
observed
in
both
dog
studies.
Effects
in
dogs
were
observed
at
lower
dose
levels
than
those
observed
in
rodents,
and
this
is
attributed
to
the
dog's
limited
capacity
to
eliminate
2,4­
D
and
other
organic
acids.
Subchronic
toxicity
following
exposure
to
the
amine
salts
and
esters
of
2,4­
D
was
similar
to
that
observed
following
2,4­
D
exposure.

870.3100
90­
Day
Oral
Toxicity
­
Rat
EXECUTIVE
SUMMARY:
In
a
subchronic
oral
toxicity
study
[
MRID
41991501],
10
Fischer
344
rats/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.1%
a.
i.]
via
the
diet
for
13
weeks
at
concentrations
of
0,
1
mg/
kg/
day,
15
mg/
kg/
day,
100
mg/
kg/
day,
and
300
mg/
kg/
day.

There
were
no
treatment­
related
deaths.
Clinical
signs
of
toxicity
occurred
mainly
in
the
high­
dose
females
and
included
hunched
posture
[
1
high­
dose
female
during
weeks
13­
14],
depressed
activity
[
all
high­
dose
females
during
first
week],
and
few/
no
feces
[
4
high­
dose
males
and
all
high­
dose
females
during
week
1;
5
high­
dose
females
during
week
12;
1
high­
dose
female
during
week
13].
There
was
a
dose­
related
increase
in
the
incidence
of
pale/
opaque
eyes
in
both
sexes
[
1/
10
controls,
2/
10
at
1,
15,
and
100
mg/
kg/
day
and
4/
10
at
300
mg/
kg/
day
in
males;
1/
10
controls,
2/
10
at
1
mg/
kg/
day,
1/
10
at
15
mg/
kg/
day,
4/
10
at
100
mg/
kg/
day,
and
8/
10
at
300
mg/
kg/
day
in
females].
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
9
Decreased
body
weights
were
observed
throughout
the
study
at
the
high­
dose
level
[
both
sexes],
with
the
magnitude
of
the
deficit
increasing
with
time
[
males
85%/
77%
and
females
79%/
72%
of
control
at
weeks
6/
13,
respectively],
and
decreased
body­
weight
gains
[
weeks
0­
6:
males
72%/
females
50%
of
control;
overall:
males
63%/
females
43%
of
control]
were
observed
in
both
sexes
at
the
highest
dose
level
throughout
the
study.
At
the
next
highest
dose
level,
decreased
body
weight
[
93%
of
control
at
13
weeks;
both
sexes]
and
body­
weight
gain
[
overall
males
91%/
females
89%
of
control]
were
observed.
A
corresponding
decrease
in
food
consumption
was
observed
in
both
sexes
at
the
two
highest
dose
levels.

Complete
cataract
formation
was
observed
in
7
high­
dose
[
300
mg/
kg/
day]
females
and
in
one
female
at
the
next
highest
[
100
mg/
kg/
day]
dose,
and
posterior
subcapsular
cataract
was
observed
in
5
high­
dose
females.
Treatment­
related
alterations
in
hematology
[
statistically
significant
decreases
in
RBC,
HGB,
HCT,
platelet
count,
absolute
and
corrected
leukocyte
counts,
and
lymphocyte
counts]
were
observed
at
the
6­
and/
or
13­
week
intervals
at
the
high­
dose
level
[
both
sexes],
and
decreased
platelet
counts
were
observed
in
both
sexes
at
the
next
highest
dose
level
at
week
13.
Alterations
in
clinical
chemistry
[
decreased
thyroxine
and
triiodothyronine
levels]
were
observed
at
100
and
300
mg/
kg/
day
at
both
intervals
in
one
or
both
sexes.

Changes
in
absolute
and/
or
relative
organ
weights
[
adrenals,
brain,
thymus,
heart,
kidneys,
testes
with
epididymides
(
males),
ovaries
(
females),
pituitary,
liver
(
increased),
thyroids/
parathyroids
(
increased)
were
observed
primarily
at
the
high­
dose
level
[
both
sexes],
and
many
of
these
changes
may
be
attributable
to
decreased
body
weight.
Gross
findings,
mainly
in
the
high­
dose
group,
included
small
testes
and
epididymis
and
opaque
eyes
[
females].
Treatment­
related
histopathological
changes
were
observed
primarily
in
the
high­
dose
group
and
included
centrilobular
hepatocellular
hypertrophy
[
liver],
bilateral
retinal
degeneration
and
cataract
formation
[
females],
atrophy
of
the
testes
[
males],
hypertrophy
of
the
zona
glomerulose
[
adrenal
cortex,
both
sexes]
and
follicular
cells
[
thyroid,
females],
atrophy
of
the
thymus
[
both
sexes]
and
spleen
[
both
sexes],
congestion
and
edema
of
the
bone
marrow
[
both
sexes],
brush
border
loss
in
proximal
tubular
cells
[
kidney,
both
sexes].
Many
of
the
lesions
correlated
well
with
the
alterations
observed
in
hematology
and
clinical
chemistry
parameters
and/
or
organ­
weight
data
of
the
high­
dose
groups.

The
NOAEL
is
15
mg/
kg/
day,
based
on
decreased
body
weight/
body­
weight
gain,
alterations
in
some
hematology
[
decreased
platelets
(
both
sexes)]
and
clinical
chemistry
[
decreased
T3
(
females)
and
T4
(
both
sexes)]
parameters,
and
cataract
formation
in
females
at
the
LOAEL
of
100
mg/
kg/
day.

This
subchronic
oral
toxicity
study
is
classified
Acceptable/
Guideline,
and
the
study
satisfies
the
guideline
requirement
[
OPPTS
870.3100;
§
82­
1(
a)]
for
a
subchronic
oral
toxicity
study
in
the
rodent.

The
following
table
summarizes
the
subchronic
oral
toxicity
studies
in
rats
available
for
2,4­
D
and
its
amine
salts
and
esters
for
comparison.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
10
Subchronic
Oral
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
in
Rats
Guideline
STUDY
RESULTS
870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1,
15,
100,
300
mg/
kg/
day]

MRID:
41991501
[
1991]

Classification:
Acceptable/
Guideline
2,4­
D
(
96.1%
a.
i.)
Systemic
Toxicity
NOAEL
=
15
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
100
mg/
kg/
day,
based
on
decreases
in
body
weight/
gain,
alterations
in
hematology
and
clinical
chemistry
parameters,
and
cataract
formation
in
females;

At
the
highest
dose
tested
[
HDT],
effects
listed
above
occurred
more
frequently
and/
or
to
a
greater
extent,
as
well
as
histopathological
lesions
in
eyes,
liver,
testes,
adrenals,
kidneys,
thymus,
bone
marrow,
spleen,
thyroids,
lungs.

870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1.5,
22,
145,
436
mg/
kg/
day]
{
1,
15,
100,
300
mg/
kg/
day}

MRID:
41928101
[
1991]

Classification:
Acceptable/
Guideline
BEE
ester
of
2,4­
D
(
94.6%
;
acid
equivalent

65%)
Systemic
Toxicity
NOAEL
=
22
{
15}
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
145
{
100}
mg/
kg/
day,
based
on
slight
increase
in
body
weight/
gain,
food
consumption,
alterations
in
some
hematological
and
clinical
chemistry
parameters,
changes
in
thyroid
hormone
concentrations
[
females]
and
histopathological
lesions
[
males]
in
thyroids.

At
the
highest
dose
tested
[
HDT;
436
{
300}
mg/
kg/
day],
one/
sex
were
sacrificed
moribund,
females
lost
weight
during
2nd
and
3rd
months
and
both
exhibited
lesions
in
the
thyroid,
liver,
and
kidney.

870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1.5,
27.1,
147.6,
442.8
mg/
kg/
day]
{
1,
18.4,
100,
300
mg/
kg/
day}

MRID:
41994001
[
1991]

Classification:
Acceptable/
Guideline
DEA
salt
of
2,4­
D
(
73.8%;
acid
equivalent
50.0%???)
Systemic
Toxicity
NOAEL
=
1.5
{
1}
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
27.1
{
18.4}
mg/
kg/
day,
based
on
decreased
body­
weight
gain,
food
consumption,
increased
relative
kidney
weight
[
females],
histopathological
lesions
in
kidneys
of
both
sexes.

At
the
highest
dose
tested
[
HDT;
442.8
{
300}],
3
of
each
sex
died
between
weeks
6­
9;
effects
observed
on
liver
[
increased
weight
(
females),
hypertrophy,
individual
cell
necrosis],
thyroid
[
follicular
cell
hypertrophy,
decreased
T4],
testes
[
decreased
weight,
degeneration
of
seminiferous
epithelium,
decreased
spermatozoa
in
epididymis,
decreased
secretory
content
(
prostate
and
seminal
vesicles)]
and
ovaries
[
decreased
weight,
atrophy]
at
the
two
highest
dose
levels.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Subchronic
Oral
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
in
Rats
Guideline
STUDY
RESULTS
11
870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1.5,
22.6,
150,
452
mg/
kg/
day]
{
1,
15,
100,
300
mg/
kg/
day}

MRID:
41896701
[
1991]

Classification:
Acceptable/
Guideline
EH
ester
of
2,4­
D
(
98%
;
63.25%
acid
equivalent)
Systemic
Toxicity
NOAEL
=
22.6
{
15}
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
150
{
100}
mg/
kg/
day,
based
on
alterations
in
clinical
chemistry
[
decreased
total
protein
(
both
sexes),
calcium
and
albumin
(
males),
globulin
and
T4
(
females),
increased
ALT
(
females)].

At
the
highest
dose
tested
[
HDT
452
{
300}
mg/
kg/
day],
deaths
in
both
sexes
between
weeks
7­
11,
clinical
signs
[
hunched
posture,
thin
appearance,
languid
behavior,
ataxia,
anorexia,
squinted
eyes,
opaque
eyes
(
females)],
decreased
body­
weight
gain,
negative
BWG
during
weeks
6­
13,
bilateral
cataracts
(
females),
retinal
degeneration
(
males),
alterations
in
hematology,
numerous
organ
weight
changes,
many
of
which
can
be
attributed
to
decreased
BW,
histopathological
lesions
[
centrilobular
hypertrophy,
bilateral
retinal
degeneration
and
cataract
formation,
atrophy
of
testes,
prostate,
seminal
vesicles,
hypertrophy
of
zona
glomerulose
(
adrenal
of
both
sexes),
thyroid
follicular
cells
hypertrophy,
lymphoid
hypoplasia
of
thymus
(
both
sexes)
and
spleen,
hypoplasia
of
bone
marrow,
vacuolation
of
tubular
cells
and
brush
border
loss
in
proximal
tubular
cells
(,
females)
kidney.

870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1.2,
18.1,
120,
361
mg/
kg/
day]
{
1,
15,
100,
300
mg/
kg/
day}

MRID:
41896702
[
1991]

Classification:
Acceptable/
Guideline
DMA
salt
of
2,4­
D
(
66.18%
;
55.5%
acid
equivalent)
Systemic
Toxicity
NOAEL
=
18.1
{
15}
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
120
{
100}
mg/
kg/
day,
based
on
decreased
body­
weight
gain,
food
consumption
in
females,
alterations
in
hematology
parameters
[
females],
decreased
T4/
T3
[
females]
increased
kidney
weight
in
males
and
decreased
ovarian
weights
in
females.

At
the
highest
dose
tested
[
HDT
{
300}
mg/
kg/
day],
changes
in
several
organ
weights,
histopathological
changes
[
bilateral
retinal
degeneration
and
cataracts
(
females),
centrilobular
hepatocellular
hypertrophy
(
females),
atrophy
of
testes,
hypertrophy
of
thyroid
follicular
cells
(
both
sexes),
brush
border
loss
in
proximal
tubular
cells
in
kidney
(
both
sexes),
and
hypoplasia
of
spleen
(
females)
and
bone
marrow
(
both
sexes)].
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Subchronic
Oral
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
in
Rats
Guideline
STUDY
RESULTS
12
870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1,
19,
127,
380
mg/
kg/
day]
{
1,
15,
100,
300
mg/
kg/
day}

MRID:
42021401
[
1991]

Classification:
Acceptable/
Guideline
IPA
salt
of
2,4­
D
(
45.1%;
acid
equivalent
35.6%)
Systemic
Toxicity
NOAEL
=
19
{
15}
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
127
{
100}
mg/
kg/
day,
based
on
decreased
body­
weight
gain,
food
consumption,
histopathological
lesions
in
kidneys
(
both
sexes),
adrenal
(
females),
and
thyroid
(
females).

At
the
highest
dose
tested
[
HDT;
380
{
300}
mg/
kg/
day],
females
displayed
alterations
in
hematology,
both
sexes
displayed
alterations
in
clinical
chemistry,
increased
liver
and
thyroid
weights,
decreased
testes
and
ovarian
weights,
lesions
in
eyes,
liver,
thyroids,
kidneys,
adrenals,
spleen,
thymus,
and
lungs,
testes.

870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
1.23,
18.4,
123,
369
mg/
kg/
day]
{
1,
15,
100,
300
mg/
kg/
day}

MRID:
43515901
[
1995]

Classification:
Acceptable/
Guideline
IP
ester
of
2,4­
D
(
97.1%
a.
i.;
81.6%
acid
equivalent)
Systemic
Toxicity
NOAEL
=
15
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
100
mg/
kg/
day,
based
on
decreased
body
weight/
body­
weight
gain
[
females),
increased
incidence
of
retinal
degeneration,
decreased
T4
(
both
sexes),
increased
TSH
(
females).

At
the
highest
dose
tested
[
HDT;
{
300}
mg/
kg/
day],
both
sexes
displayed
alterations
in
hematology
and
clinical
chemistry,
increased
liver
and
thyroid
weights,
decreased
brain,
testes,
ovarian,
thymus,
adrenal,
and
spleen
weights,
and
hepatocellular
hypertrophy,
atrophy
and
aspermatogenesis
in
testes,
thymus
atrophy,
hypocellular
bone
marrow.

870.3100
[
§
82­
1a]
Subchronic
oral
toxicity
­
Fischer
344
rats
[
2,
28,
187,
560
mg/
kg/
day]
{
1,
15,
100,
300
mg/
kg/
day}

MRID:
42021402
[
1991]

Classification:
Acceptable/
Guideline
TIPA
salt
of
2,4­
D
(
72.2%
;
acid
equivalent
38.7%)
Systemic
Toxicity
NOAEL
=
28
{
15}
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
187
{
100}
mg/
kg/
day,
based
on
alterations
in
some
hematology
and
clinical
chemistry
parameters,
histopathological
lesions
in
adrenal
(
females),
kidney
(
both
sexes),
and
eye
(
females).

At
the
highest
dose
tested
[
HDT,
560
{
300}
mg/
kg/
day],
decreased
body­
weight
gain,
in
addition
to
effects
listed
above,
increased
liver
weight,
decreased
testes
and
ovarian
weights,
histopathological
lesions
in
thyroids,
testes,
lung,
spleen,
thymus,
bone
marrow.
LOAEL
=
Lowest
Observable
Adverse
Effect
Level;
NOAEL
=
No
Observable
Adverse
Effect
Level;

{
acid
equivalent}

870.3150
90­
Day
Oral
Toxicity
­
Dog
EXECUTIVE
SUMMARY:
In
a
subchronic
oral
toxicity
study
[
MRID
42780001],
4
beagle
dogs/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.7%]
via
the
diet
for
13
weeks
at
concentrations
of
0,
0.5
mg/
kg/
day,
1.0
mg/
kg/
day,
3.75
mg/
kg/
day,
and
7.5
mg/
kg/
day.
The
dose
levels
were
selected
based
on
the
results
of
a
4­
week
range­
finding
study
[
MRID
42780004]
in
which
decreased
body
weight,
food
consumption,
alterations
in
clinical
chemistry
parameters,
and
distended
gall
bladders
were
observed
at

10
mg/
kg/
day.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
13
There
were
no
deaths,
and
no
treatment­
related
clinical
signs
were
observed.
Decreased
body
weights
were
observed
in
males
at
the
highest
dose
level
[
85%
of
control
at
week
14]
and
in
females
at
the
lowest
and
highest
dose
levels
[
91%
of
control]
at
week
14.
Body­
weight
gains
were
decreased
throughout
the
study
in
both
sexes
at
the
two
highest
dose
levels
but
there
was
no
dose­
response
[
overall
gain:
males
52%
and
55%
of
the
control
value/
females
53%
and
58%
of
the
control
value
at
3.75
and
7.5
mg/
kg/
day,
respectively].
Females
at
the
two
lowest
dose
levels
also
displayed
decreased
body­
weight
gains
[
overall
gain:
74%
and
79%
of
control
at
0.5
and
1.0
mg/
kg/
day,
respectively]
compared
to
the
control.
Decreased
food
consumption
was
observed
in
males
at
the
two
highest
dose
levels
and
in
all
female
groups
compared
to
their
respective
controls,
but
there
was
no
consistent
dose
response.

Ophthalmology
findings
were
comparable
among
the
groups
for
both
sexes.
There
were
no
apparent
treatmentrelated
alterations
in
hematology
among
the
groups
for
either
sex,
with
the
exception
of
decreased
platelet
counts.
Decreased
platelet
counts
[
73%
and
87%
of
control]
were
observed
in
males
at
the
high­
dose
level
at
both
[
week
4
and
week
13,
respectively]
time
points.
Elevations
in
blood
urea
nitrogen
[
two
highest
dose
levels,
both
sexes],
creatinine
[
three
highest
dose
levels,
both
sexes],
and
alanine
aminotransferase
[
two
highest
dose
levels,
both
sexes]
and
decreased
glucose
levels
[
two
highest
dose
levels,
females]
were
observed
at
week
4
and/
or
week
13;
however,
a
dose
response
was
not
always
apparent.
Although
no
corroborative
histopathological
changes
were
observed
in
the
liver
or
kidneys,
similar
changes
in
several
of
these
clinical
chemistry
parameters
have
been
observed
in
other
studies
on
both
2,4­
D
and
the
2,4­
D
salts
and
esters
in
rats
and
in
an
earlier
subchronic
toxicity
study
in
dogs
with
2,4­
D
[
MRID
41737301].
In
this
latter
study,
microscopic
lesions
were
observed
in
the
kidneys
of
both
sexes
at
10
mg/
kg/
day.

Males
at
the
two
highest
dose
levels
displayed
a
dose­
related
decrease
in
testes
weight
[
absolute,
relative
to
body,
and
relative
to
brain],
although
statistical
significance
was
not
attained
[
n=
4].
Decreased
adrenal
weight
[
absolute
and
relative
to
brain]
was
observed
in
both
sexes
at
the
highest
dose
level,
decreased
liver
weight
[
absolute
and
relative
to
brain]
was
observed
in
both
sexes
at
the
highest
dose
level,
and
decreased
heart
weight
[
absolute
and
relative
to
brain]
was
observed
in
both
sexes
at
the
two
highest
dose
levels,
but
there
was
no
dose
response.
Microscopically,
hypospermatogenesis/
juvenile
testis
was
observed
in
1
control,
1
mid­
high
[
3.75
mg/
kg/
day],
and
2
high­
dose
[
7.5
mg/
kg/
day]
males,
and
inactive,
juvenile
prostate
was
observed
in
one
male
in
the
control,
0.5
mg/
kg/
day,
1
mg/
kg/
day,
and
3.75
mg/
kg/
day
dose
groups
and
in
all
4
high­
dose
males.

The
NOAEL
is
1.0
mg/
kg/
day.
The
LOAEL
of
3.75
mg/
kg/
day
is
based
on
decreased
body­
weight
gain
(
both
sexes)
and
food
consumption
(
males),
as
well
as
alterations
in
clinical
chemistry
parameters
[
increased
BUN,
creatinine,
and
alanine
aminotransferase]
in
both
sexes,
and
decreased
testes
weight.

This
subchronic
oral
toxicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
3150;
§
82­
1(
b)]
for
a
subchronic
non­
rodent
oral
toxicity
study.

EXECUTIVE
SUMMARY:
In
a
subchronic
oral
toxicity
study
[
MRID
41737301],
5
beagle
dogs/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.1%]
via
capsules
for
13
weeks
at
concentrations
of
0,
0.3
mg/
kg/
day,
1.0
mg/
kg/
day,
3.0
mg/
kg/
day,
and
10
mg/
kg/
day.

Two
males
[
weeks
4,
13]
and
one
female
[
week
9]
at
the
high­
dose
level
were
sacrificed
moribund.
Treatmentrelated
clinical
signs
[
thin,
languid
appearance,
anorexia,
tremors]
were
observed
at
the
high­
dose
level
in
the
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
14
three
dogs
sacrificed
in
extremis.
Decreased
body
weights
were
observed
in
males
at
the
two
highest
dose
levels
[
83%
and
80%
of
control
at
3
and
10
mg/
kg/
day,
respectively]
and
in
females
at
the
high­
dose
level
[
86%
of
control]
at
week
13.
Body­
weight
gains
were
decreased
throughout
the
study
in
males
at
the
two
highest
dose
levels
[
weeks
0­
13:
56%
and
44%,
respectively].
The
mid­
and
high­
dose
females
displayed
decreased
bodyweight
gains
also
[
weeks
0­
13:
84%
and
52%
of
control,
respectively].
Decreased
food
consumption
was
observed
in
both
sexes
at
the
highest
dose
level
and
in
males
at
the
next
highest
dose
level
throughout
the
study.

Decreased
RBC,
hemoglobin,
hematocrit,
and
platelet
count
values
were
observed
in
both
sexes
at
the
highest
dose
level,
although
statistical
significance
was
not
always
attained
[
n=
4­
5].
Treatment­
related
alterations
in
clinical
chemistry
parameters
were
observed
mainly
at
the
two­
highest
dose
levels
in
both
sexes
at
various
times
during
the
dosing
period
[
increased
blood
urea
nitrogen
(
both
sexes),
creatinine
(
both
sexes),
alanine
aminotransferase
(
high­
dose
females;
males
not
statistically
significant);
decreased
T4
(
both
sexes
at
high­
dose;
not
statistically
significant),
and
glucose
(
high
dose,
both
sexes].
High­
dose
females
displayed
slightly
increased
kidney
and
thyroid
weights
[
absolute,
relative
to
body
and
brain
weights]
compared
to
the
control
group.
Decreased
testis
weight
was
observed
at
the
two­
highest
dose
levels,
and
two
of
the
3
surviving
high­
dose
males
and
one
of
the
2
high­
dose
males
sacrificed
moribund
displayed
hypospermatogenesis
and
giant
cell
formation.
Microscopic
lesions
[
cellular
alterations,
proximal
tubule]
were
observed
in
the
kidney
of
both
sexes
at
the
highdose
level
[
3
of
5
males
at
3
mg/
kg/
day,
3/
3
surviving
males
at
10
mg/
kg/
day,
1
of
4
surviving
females
at
10
mg/
kg/
day,
and
all
dogs
sacrificed
moribund].

The
NOAEL
is
1.0
mg/
kg/
day.
The
LOAEL
of
3.0
mg/
kg/
day
is
based
on
decreased
body
weight/
bodyweight
gain
and
food
consumption
(
males),
alterations
in
clinical
chemistry
parameters
[
increased
BUN
(
both
sexes),
creatinine
(
both
sexes)],
and
decreased
testis
weight
(
males).

This
subchronic
oral
toxicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
3150;
§
82­
1(
b)]
for
a
subchronic
non­
rodent
oral
toxicity
study.

The
following
table
summarizes
the
subchronic
oral
toxicity
studies
in
dogs
on
2,4­
D
and
two
esters
[
EHE
and
IPE]
and
one
amine
salt
[
DMA]
for
comparison.

Subchronic
Oral
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
in
Dogs
Guideline
STUDY
RESULTS
870.3150
[
§
82­
1b]
Subchronic
oral
(
capsule)
toxicity
­
dogs
[
0,
0.3,
1.0,
3.0,
and
10
mg/
kg/
day]

MRID:
41737301
[
1990]

Classification:
Acceptable/
Guideline
2,4­
D
(
96.1%
a.
i.)
Systemic
Toxicity
NOAEL
=
1
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
3
mg/
kg/
day,
based
on
decreased
body
weight/
body­
weight
gain
and
food
consumption
(
males),
alterations
in
clinical
chemistry
parameters
[
increased
BUN
(
both
sexes),
creatinine
(
males)],
and
decreased
testis
weight
in
males.

At
the
highest
dose
tested
[
HDT,
10
mg/
kg/
day],
mortality
[
2
males,
1
female
sacrificed
moribund],
hematology
alterations,
and
microscopic
lesions
of
the
kidneys
and
testes
[
hypospermatogenesis]
were
observed.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Subchronic
Oral
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
in
Dogs
Guideline
STUDY
RESULTS
15
870.3150
[
§
82­
1b]
Subchronic
oral
(
diet)
toxicity
­
dogs
[
0,
0.5,
1.0,
3.75,
and
7.5
mg/
kg/
day]

MRID:
42780001
[
1993]

Classification:
Acceptable/
Guideline
2,4­
D
(
96.1%
a.
i.)
Systemic
Toxicity
NOAEL
=
1
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
3.75
mg/
kg/
day,
based
on
decreased
body­
weight
gain
(
both
sexes)
and
food
consumption
(
males),
as
well
as
alterations
in
clinical
chemistry
parameters
[
increased
BUN,
creatinine,
and
alanine
aminotransferase]
in
both
sexes,
and
decreased
testes
weight
and
sl
ightly
higher
incidence
of
hypospermatogenesis/
juvenile
testis
and
inactive/
juvenile
prostate
were
observed.

870.3150
[
§
82­
1b]
Subchronic
oral
[
diet]
toxicity
­
dogs
{
0,
1,
3.75,
and
7.5
mg/
kg/
day}

MRID:
42780003
[
1993]

Classification:
Acceptable/
Guideline
EH
ester
of
2,4­
D
(
98%
;
63.25%
acid
equivalent)
Systemic
Toxicity
NOAEL
=
<
1
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
1
mg/
kg/
day,
based
on
increased
BUN
and
creatinine
values
at
all
dose
levels
at
study
termination
At
the
highest
dose
tested
[
HDT
7.5
mg/
kg/
day],
there
was
a
slightly
higher
incidence
of
hypospermatogenesis/
juvenile
testis
and
inactive/
juvenile
prostate
compared
to
the
control
dogs
870.3150
[
§
82­
1b]
Subchronic
oral
[
capsule]
toxicity
­
dogs
{
0,
0.3,
1.0,
3.0,
and
10.0
mg/
kg
bw/
day}

MRID:
43515501
[
1994]

Classification:
Acceptable/
Guideline
IP
ester
of
2,4­
D
(
97.1%
a.
i.)
Systemic
Toxicity
NOAEL
=
1
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
3
mg/
kg/
day,
based
on
increased
blood
urea
nitrogen,
creatinine,
aspartate
aminotransferase,
and
alanine
aminotransferase
values.

At
the
highest
dose
tested
[
HDT
10
mg/
kg/
day],
males
displayed
decreased
BW/
BWG,
decreased
absolute
and
relative
testes
and
ovarian
weights
and
decreased
absolute
adrenal
(
male)
weights
.

870.3150
[
§
82­
1b]
Subchronic
oral
[
diet]
toxicity
­
dogs
{
0,
1,
3.75,
and
7.5
mg/
kg/
day}

MRID:
42780002
[
1993]

Classification:
Acceptable/
Guideline
DMA
salt
of
2,4­
D
(
66.18%
;
55.5%
acid
equivalent)
Systemic
Toxicity
NOAEL
=
1
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
3.75
mg/
kg/
day,
based
on
decreased
body­
weight
gain
and
food
consumption,
as
well
as
alterations
in
clinical
chemistry
parameters
[
increased
BUN,
creatinine]
in
both
sexes.

At
the
highest
dose
tested
[
HDT;
7.5
mg/
kg/
day],
decreased
platelet
counts
and
slightly
higher
incidence
of
hypospermatogenesis/
juvenile
testis
and
inactive/
juvenile
prostate
were
observed
in
the
males.
LOAEL
=
Lowest
Observable
Adverse
Effect
Level;
NOAEL
=
No
Observable
Adverse
Effect
Level;
{
acid
equivalent}

870.3200
21/
28­
Day
Dermal
Toxicity
B
Rat
EXECUTIVE
SUMMARY:
In
a
21­
day
dermal
toxicity
study
[
MRID
41735304],
5
Hra:
(
NZW)
SPF
rabbits/
sex/
group
were
administered
the
2,4­
dichlorophenoxyacetic
acid
[
96.1%]
via
dermal
application
[
neat
material
(
powder)
spread
evenly
on
4"
x
4"
gauze
pad
and
moistened
with
0.5
mL
distilled
water
[
6
hours/
day,
7
days/
week
for
21
days
at
concentrations
of
0
[
distilled
water],
10,
100,
and
1000
mg/
kg/
day.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
16
Treatment
had
no
adverse
effect
on
survival,
clinical
signs,
mean
body
weight,
hematology,
clinical
chemistry,
urinalysis,
gross
pathology,
or
histopathology.
At
the
high­
dose
level,
increased
kidney
weights
[
absolute
and
relative]
were
observed
in
both
sexes,
but
statistical
significance
was
attained
in
the
females
only,
and
there
were
no
corroborating
changes
in
clinical
chemistry
parameters
or
histopathology
in
the
kidneys.
2,4­
D
was
only
slightly
irritating
to
the
skin
of
the
rabbits,
inducing
very
slight
erythema
and
epidermal
scaling,
with
the
females
displaying
a
higher
incidence
than
males.

The
NOAEL
for
dermal
and
systemic
toxicity
is
1000
mg/
kg/
day,
the
highest
dose
tested.

This
21­
day
dermal
toxicity
study
is
classified
ACCEPTABLE/
Guideline
and
satisfies
the
guideline
requirement
[
§
82­
2;
870.3200]
for
a
21­
day
dermal
toxicity
study.

The
following
table
summarizes
the
subchronic
dermal
studies
on
2,
4­
D
and
its
amine
salts
and
esters
for
comparison.

Subchronic
Dermal
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
Guideline
STUDY
RESULTS
870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
10,
100,
1000
mg/
kg/
day]

MRID:
41735301,
41735304
[
1990]

Classification:
Acceptable/
Guideline
2,4­
D
(
96.1%
a.
i.)
Dermal
Toxicity
NOAEL
1000
mg/
kg/
day,
HDT
Dermal
Toxicity
LOAEL
=
>
1000
mg/
kg/
day,
no
adverse
effects
observed
at
the
limit
dose
Systemic
Toxicity
NOAEL
=
1000
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
>
1000
mg/
kg/
day,
no
adverse
effects
observed
at
the
limit
dose
870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
50,
150,
500
mg/
kg/
day]
{
32,
96,
321
mg/
kg/
day}

MRID:
41407901
[
1990]

Classification:
Acceptable/
Guideline
BEE
ester
of
2,4­
D
(
94.6%
;

65%
acid
equivalent)
Dermal
Toxicity
NOAEL
=
500
mg/
kg/
day
[
HDT
Dermal
Toxicity
LOAEL
=
not
determined.

Systemic
Toxicity
NOAEL
=
500
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
no
effects
observed
at
HDT
[
500
mg/
kg/
day]

870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
15,
148,
443
mg/
kg/
day]
{
9,
92,
276
mg/
kg/
day}?

MRID:
41920905
[
1991]

Classification:
Acceptable/
Guideline
DEA
salt
of
2,4­
D
(
73.09%;

45.6%
acid
equivalent)
Dermal
Toxicity
NOAEL
15
mg/
kg/
day
Dermal
Toxicity
LOAEL
=
148
mg/
kg/
day,
based
on
microscopic
dermal
lesions.

Systemic
Toxicity
NOAEL
=
148
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
443
mg/
kg/
day,
based
on
liver
toxicity
[
increased
AST,
ALT,
AP,
liver
weight,
liver
lesions].
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Subchronic
Dermal
Toxicity
of
2,4­
D
and
its
Salts
and
Esters
Guideline
STUDY
RESULTS
17
870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
18,
180.1,
540.5
mg/
kg/
day]
{
10,
100,
300
mg/
kg/
day}

MRID:
41735303,
41735306
[
1990]

Classification:
Acceptable/
Guideline
DMA
salt
of
2,4­
D
(
66.18%
;
55.5%
acid
equivalent)
Dermal
Toxicity
NOAEL
18
mg/
kg/
day
Dermal
Toxicity
LOAEL
=
180.1
mg/
kg/
day,
based
on
microscopic
dermal
lesions
Systemic
Toxicity
NOAEL
=
180.1
mg/
kg/
day
Systemic
Toxicity
LOAEL
=
540.5
mg/
kg/
day,
based
on
one
female
death.

870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
16.3,
162.8,
1627.5
mg/
kg/
day]
{
10,
100,
1000
mg/
kg/
day}

MRID:
41735302,
41735305
[
1990]

Classification:
Acceptable/
Guideline
EH
ester
of
2,4­
D
(
98%
;
62.8%
acid
equivalent)
Dermal
Toxicity
NOAEL
16.3
mg/
kg/
day
Dermal
Toxicity
LOAEL
=
162.5
mg/
kg/
day,
based
on
histopathological
lesions
of
the
skin.

Systemic
Toxicity
NOAEL
=
1627.5
mg/
kg/
day
[
HDT]
Systemic
Toxicity
LOAEL
=
not
determined,
based
on
no
effects
at
greater
than
the
limit
dose.

870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
50,
125,
350
mg/
kg/
day]
{
39,
98,
275
mg/
kg/
day}

MRID:
41407903
[
1990]

Classification:
Acceptable/
Guideline
IPA
salt
of
2,4­
D
(
50.2%;

39%
acid
equivalent)
Dermal
Toxicity
NOAEL
50
mg/
kg/
day
Dermal
Toxicity
LOAEL
=
125
mg/
kg/
day,
based
on
microscopic
dermal
lesions.

Systemic
Toxicity
NOAEL
=
350
mg/
kg/
day
[
HDT]
Systemic
Toxicity
LOAEL
=
not
determined,
based
on
no
effects
at
HDT.

870.3200
[
§
82­
2]
21­
Day
dermal
toxicity
­
rabbits
[
100,
350,
1000
mg/
kg/
day
{
55,
193,
553
mg/
kg/
day}

MRID:
41407902
[
1989]

Classification:
Acceptable/
Guideline
TIPA
salt
of
2,4­
D
(
72.2%
;

37%­
38%
acid
equivalent)
Dermal
Toxicity
NOAEL
=
1000
mg/
kg/
day
[
HDT]
Dermal
Toxicity
LOAEL
=
not
determined,
based
on
no
effects
at
the
limit
dose.

Systemic
Toxicity
NOAEL
=
1000
mg/
kg/
day
[
HDT]
Systemic
Toxicity
LOAEL
=
not
determined,
based
on
no
effects
at
the
limit
dose.
LOAEL
=
Lowest
Observable
Adverse
Effect
Level;
NOAEL
=
No
Observable
Adverse
Effect
Level
870.3465
90­
Day
Inhalation
B
Rat
Adequacy
of
data
base
for
Inhalation
Toxicity:
The
data
base
for
subchronic
inhalation
toxicity
is
considered
incomplete.
A
28­
day
inhalation
study
in
the
rat
is
required.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Developmental
toxicity
was
observed
in
the
rat,
as
evidenced
by
the
increased
incidence
of
skeletal
malformations
and
variations
observed
at
the
same
dose
level
that
resulted
in
maternal
toxicity,
which
manifested
as
decreased
body­
weight
gain.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
18
Similar
developmental
toxicity
as
seen
in
the
rat
was
not
observed
in
the
rabbit.
The
only
developmental
toxicity
observed
in
rabbits
was
abortion,
which
occurred
in
2
does
at
the
highest
dose
tested.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
[
MRID
00130407;
00130408],
pregnant
Fischer
344
rats
[
35/
group]
were
administered
2,4­
dichlorophenoxyacetic
acid
[
97.5%]
via
gavage
at
dose
levels
of
0
[
corn
oil],
8
mg/
kg/
day,
25
mg/
kg/
day,
and
75
mg/
kg/
day
from
gestation
day
[
GD]
6
through
gestation
day
15.

There
were
no
treatment­
related
deaths.
Two
[
one
control
and
one
low­
dose]
dams
delivered
prematurely
on
gestation
day
19,
and
in
both
instances
the
offspring
produced
were
of
similar
size
and
development
as
those
from
full­
term
delivery.
Clinical
signs
were
comparable
among
the
groups.
Body
weights
were
comparable
among
the
groups
throughout
the
study,
but
dams
at
the
high­
dose
level
displayed
a
decrease
in
body­
weight
gain
during
the
dosing
period
[
79%
of
control
for
GD
6­
15;
57%
of
control
for
GD
6­
10],
although
statistical
significance
was
not
attained.
The
corrected
body­
weight
gain
was
comparable
among
the
groups.
Food
consumption
data
were
not
reported.

There
was
a
slight
decrease
in
pregnancy
rate
with
increasing
dose
[
85%,
85%,
80%
and
77%].
The
numbers
of
corpora
lutea,
implantations,
and
live
fetuses
were
comparable
among
the
groups,
and
there
were
no
dead
fetuses.
The
number
of
resorptions,
as
well
as
pre­
and
post­
implantation
losses,
were
not
adversely
affected
by
treatment.
The
number
of
the
dams
with
100%
resorptions
was
2,
0,
1,
and
1
[
control,
low­,
mid­,
and
highdose
groups,
respectively].
One
control,
2
low­,
4
mid­,
and
2
high­
dose
dams
had
late
resorptions.
Fetal
body
weight
and
crown­
rump
length
were
comparable
among
the
groups,
as
was
the
sex
ratio.

There
were
no
statistically­
significant
or
treatment­
related
differences
in
the
incidence
of
fetal
external
or
visceral
malformations.
There
was
an
increased
incidence
of
skeletal
malformations/
variations
at
the
high­
dose
level
that
included
the
presence
of
7th
cervical
ribs
[
4
fetuses
in
3
litters
vs
none
in
the
control],
the
presence
of
14th
rudimentary
ribs
[
4
fetuses
in
3
litters
vs
none
in
the
control],
malaligned
sternebrae
[
15
fetuses
in
10
litters
vs
7
fetuses
in
7
litters
of
the
control],
reduced
ossification
of
the
vertebral
arches
[
6
fetuses
in
5
litters
vs
2
fetuses
in
1
litter
of
the
control],
and
unossified
sternebrae
#
5
or
#
6
[
73
fetuses
in
22
litters
(
3.32
fetuses/
litter)
vs
62
fetuses
in
24
litters
(
2.58
fetuses/
litter)].
Although
none
of
the
increases
attained
statistical
significance,
they
were
attributed
to
treatment
since
some
of
the
findings
[
maligned
sternebrae,
14th
rudimentary
ribs,
and
reduced
ossification
of
vertebral
arches]
were
also
observed
in
the
F1b
pups
of
dams
fed
2,4­
D
at
80
mg/
kg/
day
[
actual
dose

75
mg/
kg/
day]
in
the
2­
generation
reproduction
study
in
the
same
strain
of
rat.
Additionally,
skeletal
variations
of
the
ribs
[
2nd
wavy
ribs,
lumbar
ribs]
and
missing
sternebrae
were
observed
in
another
developmental
toxicity
study
using
a
different
strain
of
rat
[
Sprague­
Dawley]
at
a
comparable
dose
of
87.5
mg/
kg/
day
[
2,4­
D].

The
maternal
toxicity
NOAEL
is
25
mg/
kg/
day,
and
the
maternal
toxicity
LOAEL
is
75
mg/
kg/
day,
based
on
decreased
body­
weight
gain.

The
NOAEL
for
developmental
toxicity
is
25
mg/
kg/
day,
and
the
developmental
toxicity
LOAEL
is
75
mg/
kg/
day,
based
on
the
increased
incidence
of
skeletal
abnormalities.

This
developmental
toxicity
study
is
classified
Acceptable/
Guideline,
and
it
satisfies
the
guideline
requirement
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
19
[
OPPTS
870.3700;
§
83­
3(
a)]
for
a
developmental
toxicity
study
in
the
rodent.

The
following
table
provides
summaries
of
the
rat
developmental
toxicity
studies
on
2,4­
D
and
its
amine
salts
and
esters
for
comparison.

Developmental
Toxicity
of
2,4­
D
and
its
Esters
and
Salts
in
Rats
Guideline
STUDY
RESULTS
870.3700
[
§
83­
3a]
Developmental
Toxicity
­
Fischer
344
rats
[
0,
8,
25,
and
75
mg/
kg/
day]

MRID
00130407,
00130408
[
1983]

Classification:
Acceptable/
Guideline
2,4­
D
(
97.5%
a.
i
.)
Maternal
NOAEL:
25
mg/
kg/
day
Maternal
LOAEL:
75
mg/
kg/
day,
based
on
decreased
bodyweight
gains.
Survival
was
not
affected
by
treatment.

Developmental
NOAEL:
25
mg/
kg/
day
Developmental
LOAEL:
75
mg/
kg/
day,
based
on
skeletal
abnormalities.

870.3700
[
§
83­
3a]
Developmental
toxicity
­
CD
®
[
Sprague­
Dawley
derived]
rats
[
0,
25,
75,
185
mg/
kg/
day]
{
10.2,
50.8,
101.6
mg/
kg/
day}
MRID
41527101;
41527104
[
1990]

Classification:
Acceptable/
Guideline
BEE
ester
of
2,4­
D
(
95.6%;
acid
equivalent
65.1­
65.8%)
Maternal
NOAEL:
75
mg/
kg/
day
Maternal
LOAEL:
185
mg/
kg/
day,
based
on
decreased
bodyweight
gain
on
days
6­
16,
decreased
food
consumption,
RBC,
increased
reticulocytes.
There
were
no
deaths.

Developmental
NOAEL:
75
mg/
kg/
day
Developmental
LOAEL:
185
mg/
kg/
day,
based
on
an
increased
incidence
of
skeletal
variations
[
incompletely
ossified
supraoccipital,
squamosal(
s),
maxilla,
and
4th
sternebrae,
and
14
rib
pairs,
short
ribs,
rudimentary
first
lumbar
rib(
s),
and
unilateral
14th
rib(
s)]

870.3700
[
§
83­
3a]
Developmental
toxicity
­
Sprague­
Dawley
Crl:
CD
BR
VAF/
Plus
rats
[
0,
15,
75,
and
150
mg/
kg/
day]
{
10.2,
50.8,
and
101.6
mg/
kg/
day}
MRID
41920906;
41986602
[
1990]

Classification:
Acceptable/
Guideline
DEA
salt
of
2,4­
D
(
73.09%;
acid
equivalent

49.5%)
Maternal
NOAEL:
15
mg/
kg/
day
Maternal
LOAEL:
75
mg/
kg/
day,
based
on
decreased
bodyweight
gain.
There
were
no
deaths.

Developmental
NOAEL:
15
mg/
kg/
day
Developmental
LOAEL:
75
mg/
kg/
day,
based
on
an
increased
incidence
of
skeletal
variations/
malformations
[
reduced
ossification
of
skull,
14th
rudimentary
rib(
s),
7th
cervical
rib(
s),
bent
rib(
s)].

870.3700
[
§
83­
3a]
Developmental
Toxicity
­
Crl:
CD
®
BR
VAF/
Plus
®
rats
[
15,
60.2,
and
120.4
mg/
kg/
day]
{
12.5,
50,
and
100
mg/
kg/
day}

MRID
41735201
[
1990]

Classification:
Acceptable/
Guideline
DMA
salt
of
2,4­
D
(
66.18%;
acid
equivalent
55.5%)
Maternal
NOAEL:
12.5
mg/
kg/
day
Maternal
LOAEL:
50
mg/
kg/
day,
based
on
decreased
bodyweight
gain
and
food
consumption.
There
were
no
deaths.

Developmental
NOAEL:
50
mg/
kg/
day
Developmental
LOAEL:
100
mg/
kg/
day,
based
on
decreased
fetal
body
weight,
increased
incidence
of
wavy
ribs
and/
or
incompletely­
ossified
ribs.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Developmental
Toxicity
of
2,4­
D
and
its
Esters
and
Salts
in
Rats
Guideline
STUDY
RESULTS
20
870.3700
[
§
83­
3a]
Developmental
Toxicity
­
Sprague­
Dawley
Crl:
CD
BR
VAF/
Plus
rats
[
15,
45,
135
mg/
kg/
day]
{
10,
30,
and
90
mg/
kg/
day}

MRID
42304601;
42304602
[
1992]

Classification:
Acceptable/
Guideline
EH
ester
of
2,4­
D
(
95%;
acid
equivalent
63.25%)
Maternal
NOAEL:
10
mg/
kg/
day
Maternal
LOAEL:
30
mg/
kg/
day,
based
on
decreased
bodyweight
gain
[
GD
6­
9]
and
an
increased
incidence
of
clinical
signs
[
perivaginal
staining].
There
were
no
deaths.

Developmental
NOAEL:
10
mg/
kg/
day
Developmental
LOAEL:
30
mg/
kg/
day,
based
on
an
increased
incidence
of
delayed
sternebrae
ossification.

870.3700
[
§
83­
3a]
Developmental
Toxicity
­
Sprague­
Dawley
Crl:
CD
®
BR
rats
[
0,
12.3,
36.7,
and
123
mg/
kg/
day]
{
10,
30,
and
100
mg/
kg/
day}

MRID
43523101;
43523001
[
1995]

Classification:
Acceptable/
Guideline
IP
ester
of
2,4­
D
(
97.1%;
78.9%
acid
equivalent)
Maternal
NOAEL:
10
mg/
kg/
day
Maternal
LOAEL:
30
mg/
kg/
day,
based
on
decreased
bodyweight
gain
and
food
consumption
during
the
dosing
period.

At
the
highest
dose
tested
[
100
mg/
kg/
day],
one
death,
clinical
signs
[
rocking,
lurching,
or
swaying,
decreased
defecation,
clear
matting
on
the
ventral
abdominal
and
thoracic
areas,
red
material
on
the
urogenital
area,
and
ptosis],
and
one
litter
with
100%
resorptions
were
observed.
decreased
body­
weight
gain
[
GD
6­
9]
and
an
increased
incidence
of
clinical
signs
[
perivaginal
staining].
There
were
no
deaths.

Developmental
NOAEL:
30
mg/
kg/
day
Developmental
LOAEL:
100
mg/
kg/
day,
based
on
decreased
fetal
body
weight,
an
increased
incidence
of
skeletal
malformations
[
7th
cervical
ribs
and
14th
rudimentary
ribs],
and
a
decreased
percent
of
female
fetuses.

870.3700
[
§
83­
3a]
Developmental
Toxicity
­
CD
®
[
Sprague­
Dawley­
derived]
rats
[
0,
22,
65,
and
190
mg/
kg/
day]
{

17,
51,
150
mg/
kg/
day}

MRID
41527103;
41527106
[
1990]

Classification:
Acceptable/
Guideline
IPA
salt
of
2,4­
D
(
50.2%;
acid
equivalent
39.5%)
Maternal
NOAEL:
65
{
51}
mg/
kg/
day
Maternal
LOAEL:
190
{
150}
mg/
kg/
day,
based
on
decreased
body­
weight
gain
[
GD
6­
9],
food
consumption
[
GD
6­
11].
],
and
there
was
one
death
[
GD
7].

Developmental
NOAEL:
65
{
51}
mg/
kg/
day
Developmental
LOAEL:
190
{
150}
mg/
kg/
day,
based
on
a
slight
increase
in
the
incidence
of
skeletal
malformations/
variations
and
external
malformations.

870.3700
[
§
83­
3a]
Developmental
Toxicity
­
CD
®
[
Sprague­
Dawley
­
derived]
rats
[
0,
32.5,
100,
and
325
mg/
kg/
day]
{
17.4,
53.6,
174.2
mg/
kg/
day}

MRID
41527102;
41527105
[
1978]

Classification:
Acceptable/
Guideline
TIPA
salt
of
2,4­
D
(
72.2%;
acid
equivalent
38.7?%)
Maternal
NOAEL:
not
determined
Maternal
LOAEL:
32.5
mg/
kg/
day,
based
on
decreased
bodyweight
gain
on
days
6­
9.
At
HDT
[
325
mg/
kg/
day],
there
were
2
deaths
[
GD
9,
11]
and
2
moribund
sacrifices
[
GD
9,
12].

Developmental
NOAEL:
32.5
mg/
kg/
day
Developmental
LOAEL:
100
mg/
kg/
day,
based
on
a
significant
increase
in
the
incidence
of
skeletal
malformations
and
fetal
incidence
of
total
skeletal
variations.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
21
[
active
ingredient;
a.
i.];
{
acid
equivalent;
a.
e.}

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
[
MRID
41747601],
artificially­
inseminated
female
New
Zealand
White
rabbits
[
20/
group]
were
administered
2,4­
Dichlorophenoxyacetic
acid
[
96.1%]
at
dose
levels
of
0
[
aqueous
0.5%
methylcellulose],
10
mg/
kg/
day,
30
mg/
kg/
day,
and
90
mg/
kg/
day
from
gestation
day
6
through
gestation
day
18.
NOTE:
All
dose
concentrations
were
corrected
for
the
96.1%
purity
of
the
test
material.

There
were
no
treatment­
related
deaths.
Two
high­
dose
does
aborted
[
days
21
and
24].
Treatment­
related
clinical
signs
of
toxicity
were
observed
in
the
two
does
that
aborted
[
days
21
and
24,
after
13
doses
each]
and
included
ataxia
in
both
[
days
16­
19
and
after
day
13],
and
decreased
motor
activity,
loss
of
righting
reflex,
extremities
that
were
cold
to
the
touch,
and
dried
feces
in
doe
that
aborted
on
day
21.
Body
weights
were
comparable
among
the
groups
throughout
the
study,
but
body­
weight
gains
were
decreased
at
the
high­
dose
level
[
73%
of
control]
during
the
dosing
period
[
days
6­
19;
statistical
significance
was
not
attained].
During
days
7­
8,
the
low­
and
mid­
dose
groups
showed
no
body­
weight
gain,
and
the
high­
dose
group
displayed
a
negative
body­
weight
gain
[­
0.01
grams]
compared
to
the
control
[+
0.01
gram].
During
days
15­
19,
the
high­
dose
group
displayed
no
body­
weight
gain,
and
corrected
body­
weight
gain
was
decreased
at
the
high­
dose
level
[
77%
of
control;
statistical
significance
was
not
attained]
also.
Food
consumption
was
comparable
among
the
groups.

Pregnancy
rates
were
comparable
among
the
groups.
Comparable
numbers
of
corpora
lutea,
implantations,
and
live
fetuses
were
observed
among
the
groups,
and
there
were
no
dead
fetuses.
One
control
doe
had
100%
resorptions.
The
number
of
resorption
and
pre­
and
post­
implantation
losses
were
comparable
among
the
groups
also.
Gravid
uterine
weights
were
comparable
among
the
groups.

Mean
fetal
body
weight
was
comparable
among
the
groups.
At
the
high­
dose
level,
there
was
a
significant
increase
in
the
percent
of
live
male
fetuses
[
71.2%]
compared
to
the
control
[
52.8%]
and
other
dose
groups
[
low:
54.4%;
mid:
59.4%].
At
the
high­
dose
level,
the
fetal
incidence
[
3
fetuses
of
one
litter;
p<
0.01]
of
hindlimbs
turned
inward
was
increased
compared
to
the
control
(
0)
and
other
treatment
groups
(
0),
and
the
same
fetuses
displayed
domed
head
[
hydrocephaly].
This
finding
is
not
considered
treatment­
related.
There
were
no
apparent
differences
in
the
incidence
of
external,
visceral,
or
skeletal
variations,
anomalies,
retardations,
or
malformations
among
the
groups.

The
maternal
toxicity
NOAEL
is
30
mg/
kg/
day,
based
on
abortions,
decreased
body­
weight
gain,
and
clinical
signs
of
toxicity
[
decreased
motor
activity,
ataxia,
loss
of
righting
reflex,
extremities
cold
to
the
touch]
at
the
maternal
toxicity
LOAEL
of
90
mg/
kg/
day.

The
developmental
toxicity
NOAEL
is
30
mg/
kg/
day,
based
on
abortions
at
the
developmental
toxicity
LOAEL
of
90
mg/
kg/
day.

This
developmental
toxicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.3700/
§
83­
3
(
b)]
for
a
developmental
toxicity
study
in
rabbits.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
22
The
following
table
provides
summaries
of
the
rabbit
developmental
toxicity
studies
on
2,4­
D
and
its
amine
salts
and
esters
for
comparison.

Developmental
Toxicity
of
2,4­
D
and
its
Esters
and
Salts
in
Rabbits
Guideline
STUDY
RESULTS
870.3700
[
§
83­
3b]
Developmental
Toxicity
­
rabbits
[
0,
10,
30,
and
90
mg/
kg/
day]

MRID
41747601
[
1990]

Classification:
Acceptable/
Guideline
2,4­
D
(
96.1%
a.
i
.)
Maternal
NOAEL:
30
mg/
kg/
day
Maternal
LOAEL:
90
mg/
kg/
day,
based
on
clinical
signs
[
ataxia,
decreased
motor
activity,
loss
of
righting
reflex,
cold
extremities],
abortion
(
2),
decreased
body­
weight
gains.
Survival
was
not
affected
by
treatment.

Developmental
NOAEL:
30
mg/
kg/
day
Developmental
LOAEL:
90
mg/
kg/
day,
based
on
abortions.

870.3700
[
§
83­
3b]
Developmental
Study
­
rabbits
[
0,
15,
45,
110
mg/
kg/
day]
{
10,
30,
75
mg/
kg/
day}

MRID
42158703;
42158706
[
1990]

Classification:
Acceptable/
Guideline
BEE
ester
of
2,4­
D
(
95.6%;
acid
equivalent
65.8
Maternal
NOAEL:
15
mg/
kg/
day
Maternal
LOAEL:
45
mg/
kg/
day,
based
on
mortality/
morbidity,
clinical
signs
[
decreased
activity,
prostration,
myotonia,
transient
lateral
recumbency,
cold
to
touch,
perineal
soiling/
blood,
red
urine],
and
decreased
body­
weight
gain.
Deaths:
mid
dose
[
sacrificed
day
21,
another
died
day
24];
high
dose
[
4
sacrificed
(
days
14,
15,
18,
21),
4
died
(
days
11,12,13,19].

Developmental
NOAEL:
110
mg/
kg/
day
[
HDT].

870.3700
[
§
83­
3b]
Developmental
Toxicity
­
rabbits
[
0,
15,
30,
and
60
mg/
kg/
day]
{
10.2,
20.3,
40.6
mg/
kg/
day}

MRID
42055501,
42013501
[
1991]

Classification:
Acceptable/
Guideline
DEA
salt
of
2,4­
D
(
73.09%;
acid
equivalent
49.5%
Maternal
NOAEL:
15
mg/
kg/
day
Maternal
LOAEL:
30
mg/
kg/
day,
based
on
decreased
bodyweight
gain
and
food
consumption.
At
HDT,
one
doe
died,
slight
increase
in
resorptions/
post
implantation
loss].

Developmental
NOAEL:
30
mg/
kg/
day
Developmental
LOAEL:
60
mg/
kg/
day,
based
on
the
number
of
litters
with
fetuses
with
7th
cervical
rib(
s).

870.3700
[
§
83­
3b]
Developmental
Toxicity
­
rabbits
[
12,
36.1,
108.4
mg/
kg/
day]
{
10,
30,
and
90
mg/
kg/
day}

MRID
42224001
[
1991]

Classification:
Acceptable/
Guideline
DMA
salt
of
2,4­
D
(
66.18%;
acid
equivalent
55.5%)
Maternal
NOAEL:
30
mg/
kg/
day
Maternal
LOAEL:
90
mg/
kg/
day,
based
on
mortality/
morbidity,
clinical
signs
of
toxicity
[
decreased
motor
activity,
ataxia,
impaired/
loss
of
righting
reflex,
myotonia],
and
decreased
body­
weight
gain
and
food
consumption.
At
HDT,
2
found
dead
[
day
10],
2
found
dead
day
18,
one
sacrificed
day
17.
Clinical
signs
occurred
by
day
7.

Developmental
NOAEL:
90
mg/
kg/
day
[
HDT].
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Developmental
Toxicity
of
2,4­
D
and
its
Esters
and
Salts
in
Rabbits
Guideline
STUDY
RESULTS
23
870.3700
[
§
83­
3b]
Developmental
Toxicity
­
rabbits
[
15.1,
45.2,
and
113
mg/
kg/
day]
{
10,
30,
and
75
mg/
kg/
day}

MRID
42304603,
42304604
[
1992]

Classification:
Acceptable/
Guideline
EH
ester
of
2,4­
D
(
95%;
acid
equivalent
63.25%)
Maternal
NOAEL:
30
mg/
kg/
day
Maternal
LOAEL:
75
mg/
kg/
day,
based
on
mortality/
morbidity,
clinical
signs
of
toxicity
[
decreased
motor
activity,
ataxia,
impaired/
loss
of
righting
reflex,
bradypnea],
and
decreased
body­
weight
gain
in
does
that
died.
Two
does
were
sacrificed
moribund
[
days
15,
16].
Since
no
deaths
were
observed
at
50
mg/
kg/
day
in
the
rangefinding
study,
the
one
mid­
dose
death
at
day
21
was
not
considered
treatment­
related
Developmental
NOAEL:
75
mg/
kg/
day
[
HDT].

870.3700
[
§
83­
3b]
Developmental
Toxicity
­
rabbits
[
13,
38,
and
95
mg/
kg/
day]
{
10,
30,
75
mg/
kg/
day}

MRID
42158702;
42158704
[
1991]

Classification:
Acceptable/
Guideline
IPA
salt
of
2,4­
D
(
50.1%;
acid
equivalent
39.6%)
Maternal
NOAEL:
could
not
be
determined.
Maternal
LOAEL:
13
{
10}
mg/
kg/
day,
based
on
decreased
body­
weight
gain
throughout
the
dosing
period.
At
mid­
and
high­
dose
levels
[
38
{
30}
and
95
{
75}
mg/
kg/
day],
there
were
2
mid­
dose
[
days
16,
24]
and
3
high­
dose
[
days
12,
20,
21]
death
and
4
high­
dose
does
were
sacrificed
moribund
[
days
12,
13,
14,
20]
and
clinical
signs
[
lateral
recumbency,
cold
extremities,
myotonia,
perineal
staining,
blood
in
urine].

Developmental
NOAEL:
95
{
75}
mg/
kg/
day
[
HDT].

870.3700
[
§
83­
3b]
Developmental
Toxicity
­
rabbits
[
19,
56,
and
140
mg/
kg/
day]
{
10,
30,
75
mg/
kg/
day}

MRID
42158701;
42158705
[
1991]

Classification:
Acceptable/
Guideline
TIPA
salt
of
2,4­
D
(
73.1%;
acid
equivalent
39.2%)
Maternal
NOAEL:
19
{
10}
mg/
kg/
day
Maternal
LOAEL:
56
{
30}
mg/
kg/
day,
based
on
mortality/
morbidity,
clinical
signs
of
toxicity
[
lateral
recumbency,
myotonia,
perineal
staining,
blood
in
urine],
and
decreased
body­
weight
gain.
Deaths:
one
mid­
dose
doe
[
day
18];
3
highdose
does
were
sacrificed
moribund
[
days
12,
14,
15].

Developmental
NOAEL:
140
{
75}
mg/
kg/
day
[
HDT]

[
active
ingredient];
{
acid
equivalent}

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
existing
data
base
meets
the
guideline
for
reproductive
toxicity.
However,
a
2­
generation
reproduction
study
using
the
current
protocol
is
required
to
address
both
the
concern
for
thyroid
effects
[
comparative
assessment
between
the
young
and
adult
animals]
and
immunotoxicity,
as
well
as
a
more
thorough
assessment
of
the
gonads
and
reproductive/
developmental
endpoints.
At
dose
levels
above
the
saturation
of
renal
clearance,
reproductive
toxicity
was
observed
in
the
rat,
as
evidenced
by
the
increased
duration
of
gestation
of
the
F0
dams
producing
the
F1b
litters.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
EXECUTIVE
SUMMARY:
In
a
2­
generation
reproduction
study
[
MRID
00150557;
00163996],
30
male/
30
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
24
female
F0
Fischer
344
rats/
sex/
group
were
administered
2,4­
D
[
97.5%
a.
i.]
via
the
diet
for
105
days
prior
to
mating
and
through
gestation
and
lactation
of
two
litters
and
for
30
days
after
weaning
the
last
litter
at
target
dose
levels
of
0,
5,
20,
and
80
mg/
kg/
day.
Rats
were
mated,
one
male
with
one
female.
The
resulting
F1a
litters
were
weaned
at
day
28
post
partum.
After
a
2­
week
rest
period,
the
F0
parental
rats
were
re­
bred
using
different
male/
female
combinations
to
produce
the
F1b
litters,
from
which
30
males/
30
females/
group
were
selected
to
become
the
F1
parents.
The
F1
generation
[
30
rats/
sex/
group]
was
administered
the
test
material
at
target
dose
levels
of
0,
5,
and
20
mg/
kg/
day
[
high­
dose
level
dropped
due
to
excess
toxicity;
there
were
an
insufficient
number
of
F1b
pups]
in
utero
and
continuously
via
the
milk
or
feed
for
125
days
postnatally
and
prior
to
mating
and
through
gestation
and
lactation
of
two
litters
[
F2a
and
F2b]
and
for
30
days
after
weaning
the
last
litter.

There
were
no
apparent
treatment­
related
deaths,
and
clinical
signs
were
comparable
among
the
groups
throughout
the
study.
During
the
pre­
mating
dosing
period,
body
weights
of
the
F0
parental
animals
were
slightly
lower
[
males
95%­
97%
(
by
week
6)/
females
95%­
96%
(
by
week
13)
of
control]
at
the
high­
dose
level
for
both
sexes.
Body­
weight
gains
of
the
F0
high­
dose
males
were
decreased
initially
[
weeks
2­
3
(
86%
of
control]
and
overall
[
weeks
0­
13
and
weeks
0­
40
(
93%
of
control],
as
were
those
of
the
high­
dose
females
[
weeks
0­
1
(
79%
of
control);
weeks
0­
13
(
92%
of
control)
and
weeks
0­
40
(
94%
of
control)]
compared
to
the
controls.

The
high­
dose
F0
dams
displayed
a
significantly
lower
body
weight
throughout
[
F1A
litter]
gestation
(
94%­
95%
of
control)
and
by
gestation
day
20
during
F1b
pregnancy
[
90%
of
control].
The
high­
dose
F0
dams
displayed
significantly
reduced
body­
weight
gains
compared
to
the
controls
during
both
gestation
periods,
with
the
greater
deficit
being
observed
during
the
second
gestation
period
[
F1a
litters:
days
0­
7
(
67%*
of
control);
days
13­
20
(
95%
of
control;
days
0­
20
(
87%
of
control);
F1b
litters:
days
0­
7
(
70%*
of
control);
days
13­
20
(
59%**
of
control);
days
0­
20
(
67%**
of
control)].
The
high­
dose
F0
dams
displayed
decreased
body
weight
on
day
7
of
lactation
[
both
litters;
92%­
93%
of
control],
but
body
weights
were
significantly
increased
compared
to
the
controls
at
day
28
of
lactation
[
F1a
(
108%/
F1b
111%
of
control].
Body­
weight
gains
were
significantly
reduced
during
lactation
days
1­
7
for
both
litters
[
F1a
(
40%
of
control);
F1b
(
6%
of
control)].
Overall,
however,
the
high­
dose
dams
displayed
positive
body­
weight
gain
during
lactation
days
1­
28
compared
to
negative
bodyweight
gains
in
the
control
and
other
dose
groups.

Food
consumption
[
g/
rat/
day]
during
the
pre­
mating
period
was
slightly
lower
[
94%­
95%
of
control]
in
the
high­
dose
females
during
a
few
weeks,
but
on
a
g/
kg/
day
basis,
both
sexes
at
the
high­
dose
level
displayed
a
slight
increase
[
104%
of
control]
in
food
consumption
compared
to
the
controls.
During
the
first
week
of
the
two­
week
rest
period
following
the
weaning
of
the
first
litter,
the
F0
dams
displayed
a
significant
decrease
in
food
consumption
[
83%­
84%
of
control].
Food
consumption
was
decreased
at
the
high­
dose
level
during
both
gestation
periods
[
F1a
during
first
2
weeks
(
91%­
93%
of
control);
F1b
during
third
week
(
82%
of
control)].
A
significant
decrease
in
food
consumption
was
observed
throughout
lactation
[
both
litters]
at
the
high­
dose
level
[
F1a
litter
(
58%
of
control
for
days
1­
28);
F1b
litter
(
71%­
83%
of
control)].
At
necropsy,
no
treatmentrelated
adverse
effects
were
observed
at
any
dose
level,
although
the
F0
females
displayed
increased
kidney
weights
at
all
dose
levels
but
there
was
no
dose
response.

There
were
no
apparent,
treatment­
related,
adverse
effects
on
body
weights
or
body­
weight
gains
of
the
F1
parental
animals
during
the
pre­
mating
dosing
period
at
the
two
remaining
dose
levels,
although
the
mid­
dose
[
20
mg/
kg/
day;
the
highest
dose
in
the
F1
generation]
males
displayed
an
initial
decrease
in
body­
weight
gain
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
25
[
weeks
35­
36
(
91%**
of
control)
and
weeks
36­
37
(
89%**
of
control)].
At
20
mg/
kg/
day,
there
were
no
significant
differences
in
body
weights
in
the
F1
dams
during
gestation
[
F2a
litters
95%­
99%;
F2b
litters
95%­
96%
of
control]
or
body­
weight
gains
F2a
litters
85%
(
days
7­
13);
F2b
litters
83%
(
days
0­
7);
86%
(
days
13­
20);
90%
(
days
0­
20)
of
control],
and
comparable
body
weights/
gains
were
observed
during
lactation
[
both
litters].
Food
consumption
was
comparable
among
the
groups
[
both
sexes]
throughout
the
study.
At
necropsy,
no
treatment­
related
adverse
effects
were
observed
at
either
dose
level,
although
the
F1
males
and
females
displayed
slightly
increased
kidney
weights
at
the
20
mg/
kg/
day
dose
level,
and
the
females
at
this
dose
level
displayed
a
slight
increase
in
liver
weight.

F0
Generation.
No
apparent
adverse
effect
was
observed
on
fertility.
Pre­
coital
intervals
were
comparable
among
the
groups.
The
duration
of
gestation
was
significantly
increased
in
the
high­
dose
[
80
mg/
kg/
day]
F0
females
producing
the
F1b
pups
[
22.5
days
vs
21.9
days].
The
gestation
survival
index
was
comparable
among
the
groups
for
the
F1a
pups
but
significantly
decreased
for
the
F1b
litters
[
31.7%
vs
97.8%].
There
was
a
significant
decrease
in
the
number
of
F1a
female
fetuses
at
the
high­
dose
level
[
39%
vs
54%].
The
number
of
F1b
pups
born
dead/
dying
by
day
1
[
110]
was
significantly
increased
at
the
high­
dose
level
compared
to
the
control
[
5].
F1a
litter
size
was
slightly
lower
at
the
high­
dose
level
compared
to
the
control
[
9.0
vs
10.1],
but
F1b
litter
size
was
significantly
lower
than
the
control
[
5.1**
vs
9.5].
F1a
pup
viability
was
comparable
throughout
weaning,
but
F1b
pup
viability
was
significantly
lower
throughout
the
weaning
period.
There
was
a
significant
decrease
in
F1b
pup
survival
to
lactation
day
4
at
the
high­
dose
level
[
86.3%]
compared
to
the
control
[
100%]
and
other
dose
levels
[
98%
and
99.6%],
as
well
as
survival
to
lactation
day
28
[
71.4%
vs
100%
(
control)
and
other
dose
groups
99.4%
and
100%].
Decreased
pup
body
weight
[
F1a
males
89%/
females
90%
of
control
(
day
1),
75%/
81%
of
control
(
day
28);
F1b
males
78%/
females
85%
of
control
(
day
1),
73%/
76%
of
control
(
day
28)]
and
body­
weight
gains
[
F1a
males
68%/
females
70%
of
control
(
days
1­
4),
75%/
80%
of
control
(
days
4­
28);
F1b
males
26%/
females
43%
of
control
(
days
1­
4),
76%/
78%
of
control
(
days
4­
28)]
were
observed
at
the
high­
dose
level,
with
the
F1b
litters
displaying
the
greater
effect.
At
the
mid­
dose
level,
there
was
a
slight
decrease
in
body
weight
[
F1a
males
93%/
females
94%
of
control
(
day
28);
F1b
males
84%/
females
87%
of
control
(
day
28)]
and
body­
weight
gains
[
F1a
males
92%/
females
93%
of
control
(
days
4­
28);
F1b
males
83%/
females
85%
of
control
(
days
4­
28)],
with
the
deficits
being
greater
in
the
F1b
litters.

Skeletal
anomalies
and
reduced
ossification
were
observed
in
the
high­
dose
F1b
pups
[
80
mg/
kg/
day]
that
were
dead
at
birth
[
only
dose
level
examined].

F1
Generation.
No
apparent
adverse
effect
was
observed
on
fertility
at
either
dose
level.
Pre­
coital
intervals
and
gestation
lengths
were
comparable
among
the
groups.
The
gestation
survival
index
and
the
viability
index
were
comparable
among
the
groups
for
both
the
F2a
and
F2b
litters.
Litter
size,
body
weights,
and
the
sex
ratio
were
comparable
among
the
groups
in
both
the
F2a
and
F2b
litters.

Degenerative
changes
in
the
tubules
of
the
cortical
region
[
high­
dose
F0
males]
and
outer
medullary
regions
[
mid­
and
high­
dose
F0
males,
mid­
dose
F1
males
(
highest
dose
tested
in
this
generation)]
of
the
kidneys
were
found
in
a
subsequent
histopathological
examination.
The
original
reviewer
noted
that
these
effects
on
the
kidney
were
not
found
originally
but
during
a
subsequent
re­
examination
of
the
tissues,
casting
doubt
on
the
quality
of
the
histopathological
examination
of
the
reproductive
organs.
However,
the
RfD/
QA
Peer
Review
Committee
determined
that,
based
on
the
lack
of
effects
on
reproductive
organs
in
the
chronic
and
subchronic
studies
at
similar
or
higher
dose
levels,
reevaluation
of
these
tissues
[
testes
and
ovaries]
is
not
necessary
[
HED
Document
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
26
No.
011908,
dated
5/
9/
96].

The
NOAEL
for
parental
toxicity
is
5
mg/
kg/
day
(
target
dose;
actual
dose
range
3.8­
13.5
mg/
kg/
day)
and
the
parental
LOAEL
is
20
mg/
kg/
day
(
target
dose;
actual
dose
range
14­
48
mg/
kg/
day),
based
on
decreased
female
body
weight/
body­
weight
gain
(
F1)
and
male
renal
tubule
alteration
(
F0
and
F1).

The
NOAEL
for
reproductive
toxicity
is
20
mg/
kg/
day
(
target
dose;
actual
dose
range
18­
35
mg/
kg/
day),
and
the
LOAEL
for
reproductive
toxicity
is
80
mg/
kg/
day
(
target
dose;
actual
dose
range
69­
114
mg/
kg/
day),
based
on
an
increase
in
gestation
length.

The
NOAEL
for
offspring
toxicity
is
5
mg/
kg/
day
(
target
dose;
actual
dose
range
7.2­
13.5
mg/
kg/
day),
and
the
LOAEL
for
offspring
toxicity
is
20
mg/
kg/
day
(
target
dose;
actual
dose
range
26­
48
mg/
kg/
day),
based
on
decreased
pup
body
weight
[
F1b].
At
80
mg/
kg/
day
(
target
dose;
actual
dose
range
76.1­
133
mg/
kg/
day),
there
was
an
increase
in
pup
deaths.

This
2­
generation
reproduction
study
is
classified
Acceptable/
guideline.
This
study
satisfies
the
guideline
requirement
(
OPPTS
870.3800;
§
83­
4)
for
a
2­
generation
reproduction
study.
However,
as
noted
above,
a
2­
generation
reproduction
study
using
the
current
protocol
is
a
data
requirement
for
2,4­
D.
The
latter
study
is
required
to
address
both
the
concern
for
thyroid
effects
[
comparative
assessment
between
the
young
and
adult
animals]
and
immunotoxicity,
as
well
as
for
a
more
thorough
assessment
of
the
gonads
and
reproductive/
developmental
endpoints.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
At
doses
above
saturation
of
renal
clearance,
the
kidney
[
increased
kidney
weight,
proximal
tubule
degeneration],
thyroid
[
increased
thyroid
weight,
decreased
T4,
hyperplasia,
hypertrophy],
testes
[
decreased
testes
weight,
atrophy],
ovaries
[
decreased
ovarian
weight],
and
eyes
[
lens
opacity,
cataracts,
retinal
degeneration]
are
target
organs
in
the
rat
following
chronic
exposure
to
2,4­
D.
In
the
dog,
decreased
brain
weight
[
females],
increased
incidence
of
kidney
lesions,
and
aspermatogenesis
and
testes
degeneration
were
observed.

870.4100a
(
870.4300)
Chronic
Toxicity
B
Rat
EXECUTIVE
SUMMARY:
In
a
combined
chronic
toxicity/
carcinogenicity
study
[
MRID
43612001;
44284501],
50
Fischer
344
rats/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.4%]
via
the
diet
for
up
to
24
months
at
concentrations
of
0,
5
mg/
kg/
day,
75
mg/
kg/
day,
and
150
mg/
kg/
day.
The
achieved
doses
were
4.77,
73.15,
and
144.98
mg/
kg/
day
[
males]
and
4.89,
73.11,
and
143.52
mg/
kg/
day
[
females],
respectively.
Additionally,
10
rats/
sex/
group
were
sacrificed
at
12
months
[
interim
sacrifice].
NOTE:
The
interim
sacrifice
data
were
reported
in
MRID
43293901,
HED
Document
No.
011614,
along
with
the
chronic
neurotoxicity
screening
battery
substudy.

There
were
no
treatment­
related
deaths
or
clinical
signs
of
toxicity.
Decreased
body
weight
was
observed
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
27
throughout
the
study
at
the
high­
dose
level
in
both
sexes
[
males
92%­
96%/
females
74%­
90%
of
control]
and
at
the
mid­
dose
level
in
females
[
86%­
90%
of
control].
At
week
13,
decreased
body
weight
was
very
slight
in
the
high­
dose
males
[
96%
of
control]
and
somewhat
greater
in
the
high­
dose
females
[
90%
of
control].
At
study
termination,
both
sexes
displayed
decreased
body
weight
at
the
high­
dose
level
[
males
92%/
females
74%
of
control]
with
the
females
displaying
a
greater
effect
than
males.
The
mid­
dose
females
also
displayed
a
decrease
in
body
weight
at
study
termination
[
86%
of
control].
Body­
weight
gains
were
decreased
throughout
the
study
in
females
[
3­
month
interval
(
86%
and
74%
of
control);
6­
month
interval
(
88%
and
71%
of
control),
and
overall
(
77%
and
52%
of
control)]
at
the
mid­
and
high­
dose
levels,
respectively.
Similarly,
high­
dose
males
displayed
decreased
body­
weight
gains
throughout
the
study
[
83%­
87%
of
control].
Consistent
with
the
decreased
bodyweight
gains
was
a
decrease
in
food
consumption,
which
was
observed
at
the
mid­
dose
level
in
females
[­
3.9%]
and
in
both
sexes
at
the
high­
dose
level
[
males
(­
4.7%)/
females
(­
11.6%)].

Ophthalmology
findings
at
study
termination
consisted
of
increased
incidences
of
constricted
blood
vessels,
fundus
and
hyper­
reflective,
fundus
in
the
high­
dose
males
and
an
increased
incidence
of
lens
opacity
in
the
highdose
females
compared
to
the
control
and
lower
dose
groups.
Decreased
RBC,
HCT,
and
HGB
values
were
observed
at
various
time
points
in
the
mid­
and
high­
dose
females,
and
platelet
counts
were
decreased
at
various
time
points
in
both
sexes
at
the
mid­
and
high­
dose
levels.
Elevations
in
creatinine
were
observed
in
both
sexes
at
the
mid­
and
high­
dose
levels
throughout
the
study,
except
at
termination
when
comparable
levels
were
observed
among
the
male
groups.
Increased
aspartate
aminotransferase
[
mid­
and
high­
dose
males],
alanine
aminotransferase
[
mid­
and
high­
dose
males],
and
alkaline
phosphatase
[
mid­
and
high­
dose,
both
sexes],
and
decreased
glucose
levels
[
mid­
dose
females,
high­
dose
both
sexes],
cholesterol
[
mid­
and
high­
dose,
both
sexes],
and
triglycerides
[
mid­
dose
females
and
high­
dose
both
sexes]
were
observed
throughout
the
study,
although
a
dose
response
was
not
always
apparent.
There
was
a
dose­
related
decrease
in
T4
values
throughout
the
study
in
both
sexes
at
the
mid­
and
high­
dose
levels,
and
the
females
displayed
the
greater
effect
except
at
study
termination.

Thyroid
weights
were
increased
in
the
mid­
dose
females
and
in
both
sexes
at
the
high­
dose
level
at
the
12­
month
interim
sacrifice.
At
study
termination,
thyroid
weights
were
increased
in
both
sexes
at
the
mid­
and
high­
dose
levels,
although
the
mid­
dose
males
did
not
attain
statistical
significance
and
the
increase
at
the
mid­
dose
level
[
both
sexes]
was
greater
than
at
the
high­
dose
level.
Decreased
testes
weights
were
observed
at
the
high­
dose
level
at
both
the
interim
and
terminal
sacrifices
and
at
the
mid­
dose
level
at
study
termination,
although
statistical
significance
was
not
attained
at
the
mid
dose.
Decreased
ovarian
weights
were
observed
at
the
high­
dose
level
at
both
sacrifice
times
and
in
the
mid­
dose
females
at
study
termination.
The
decreases
in
testes
and
ovarian
weights
are
consistent
findings
in
other
studies
on
2,4­
D
and
its
salts/
esters.
Kidney
weights
were
increased
only
at
the
interim
sacrifice
in
males
at
the
mid­
and
high­
dose
levels
[
dose­
related].

Gross
pathology
findings
included
decreased
fat
in
high­
dose
females
at
both
sacrifice
times,
multifocal
pale
foci
in
the
lungs
[
interim:
1
mid­
dose,
10
high­
dose
females;
terminal:
4
high­
dose
males,
one
control,
4
mid­,
40
high­
dose
females],
and
lens
opacity
in
high­
dose
females
at
termination.
Microscopically,
there
were
increased
incidences
of
lesions
in
the
bone
marrow
[
decreased
hematopoiesis
in
high­
dose
females
at
the
interim
sacrifice],
eyes
[
retina
degeneration
in
1
male
and
9
females
at
high
dose],
kidney
[
proximal
tubule
degeneration
in
midand
high­
dose
males
and
females],
liver
[
altered
tinctorial
properties
in
mid­
dose
females
and
both
sexes
at
high
dose],
lungs
[
multifocal
alveolar
histiocytosis
in
mid­
dose
females
and
both
sexes
at
high
dose],
adipose
tissue
[
atrophy
in
mid­
dose
female,
both
sexes
at
high
dose],
testes
[
atrophy
at
high
dose],
and
thyroid
[
hyperplasia­
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
28
high­
dose
males;
hypertrophy
and
epithelial
cells­
high­
dose
females]
at
the
interim
sacrifice.
At
study
termination,
there
were
increased
incidences
of
cataracts
and
retina
degeneration
of
the
eyes
in
both
sexes
at
the
high­
dose
level,
and
the
severity
of
the
retina
degeneration
was
increased
also.
In
the
liver,
there
was
an
increased
incidence
of
increased
size
of
the
hepatocytes
with
altered
tinctorial
properties
in
both
sexes
at
the
high­
dose
level.
In
the
lungs,
both
the
incidence
and
severity
of
inflammation
were
increased
at
the
high­
dose
level
in
both
sexes,
and
the
incidence
of
atrophy
of
the
adipose
tissue
was
increased
at
the
high­
dose
level
in
both
sexes
at
termination.
Tumor
incidence
was
not
affected
by
treatment.

The
NOAEL
is
5
mg/
kg/
day.
The
LOAEL
of
75
mg/
kg/
day
is
based
on
decreased
body­
weight
gain
(
females)
and
food
consumption
(
females),
alterations
in
hematology
[
decreased
RBC
(
females),
HGB
(
females),
platelets
(
both
sexes)]
and
clinical
chemistry
parameters
[
increased
creatinine
(
both
sexes),
alanine
and
aspartate
aminotransferase
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
T4
(
both
sexes),
glucose
(
females),
cholesterol
(
both
sexes),
and
triglycerides
(
females)],
increased
thyroid
weights
(
both
sexes
at
study
termination),
decreased
testes
and
ovarian
weights,
and
microscopic
lesions
in
the
lungs
(
females).
At
the
high­
dose
level,
there
were
microscopic
lesions
in
the
eyes,
liver,
adipose
tissue,
and
lungs.
There
was
no
treatment­
related
increase
in
the
incidence
of
any
tumor.

This
chronic
toxicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
4100
(
a);
§
83­
1
(
a)]
for
a
chronic
toxicity
study
in
the
rat.

NOTE:
The
study
was
performed
to
address
whether
the
finding
of
an
increased
incidence
of
astrocytomas
of
the
brain
found
in
the
1986
rat
study
[
MRID
00160876]
was
attributable
to
2,4­
D.
The
HED
Carcinogenicity
Peer
Review
Committee
[
CPRC;
TXR
No.
0050017]
concluded
that
the
doses
used
in
the
1986
rat
study
were
not
adequate
to
assess
the
carcinogenic
potential
of
2,4­
D.
In
the
1986
study,
there
was
a
significant
trend
for
astrocytomas
in
male
rats
but
no
pair­
wise
significance.
The
incidence
in
both
the
treated
and
control
males
exceeded
the
historical
control
incidence
for
this
tumor.
Additionally,
the
CPRC
concluded
that
the
high­
dose
level
in
the
1986
study
was
not
adequate.
The
current
repeat
chronic
toxicity/
carcinogenicity
study
in
rats
was
performed
at
higher
dose
levels.
There
was
one
astrocytoma
in
the
brain
of
males
at
the
high
dose
vs
none
in
the
control.
There
was
one
tumor
each
in
the
control
and
high­
dose
female
group.
However,
all
of
the
brains
of
the
rats
in
the
low­
and
mid­
dose
groups
were
not
examined.
The
HED
Carcinogenicity
Peer
Review
Committee
[
CPRC;
TXR
No.
0050017]
requested
that
the
slides
of
the
low­
and
mid­
dose
brains
of
the
males
be
evaluated.
These
additional
data
were
submitted
[
MRID
44284501].
It
was
determined
that
there
was
no
increased
incidence
of
astrocytomas
at
any
dose
in
the
new
study.

870.4100b
Chronic
Toxicity
­
Dog
EXECUTIVE
SUMMARY:
In
a
chronic
oral
toxicity
study
[
MRID
43049001],
5
beagle
dogs/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.7%]
via
the
diet
for
52
weeks
at
concentrations
of
0,
1
mg/
kg/
day,
5
mg/
kg/
day,
and
7.5
mg/
kg/
day.
The
target
high­
dose
level
of
10
mg/
kg/
day
was
reduced
to
7.5
mg/
kg/
day
during
week
8,
due
to
loss
of
body
weight/
failure
to
gain
weight
early
in
the
study.

There
were
no
treatment­
related
deaths
or
clinical
signs.
One
female
at
5
mg/
kg/
day
was
sacrificed
on
Day
130
in
a
moribund
condition;
however,
death
was
attributed
to
an
abdominal
inflammatory
condition.
Decreased
body
weight
was
observed
throughout
the
study
at
the
high­
dose
level
in
both
sexes,
with
females
displaying
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
29
the
greater
effect.
By
week
3,
high­
dose
females
displayed
a
13%
deficit
in
body
weight
compared
to
the
control
females.
At
the
high­
dose
level
at
8
weeks
when
the
dose
level
was
lowered,
both
sexes
at
the
high­
dose
level
displayed
decreased
body
weight
compared
to
the
controls
[
males
90%/
females
82%
of
control].
At
week
13,
the
high­
dose
males
were
94%
of
control
and
the
high­
dose
females
were
82%
of
control.
At
study
termination,
both
sexes
displayed
decreased
body
weight
at
the
mid­
[
males
89%/
females
87%
of
control]
and
high­[
males
87%/
females
75%
of
control]
dose
levels
compared
to
the
controls.
The
low­
dose
females
also
displayed
a
decrease
[
87%
of
control]
in
body
weight
at
study
termination.
Body­
weight
gain
was
decreased
throughout
the
study
in
females
at
all
dose
levels
[
weeks
1­
13
(
75%,
70%,
and
35%
of
control);
1­
52
(
73%,
64%,
and
36%
of
control)
at
the
low­,
mid­,
and
high­
dose
levels,
respectively].
Similarly,
males
displayed
decreased
bodyweight
gains
throughout
the
study
(
except
the
low­
dose
group
during
weeks
1­
13)
compared
to
the
control,
although
there
was
no
dose­
response
[
weeks
1­
13
(
100%,
70%,
74%
of
control);
1­
52
(
78%,
63%,
67%
of
control].
Food
consumption
was
decreased
throughout
most
of
the
study,
mainly
at
the
high­
dose
level
[
both
sexes],
but
statistical
significance
was
not
attained.

Ophthalmology
findings
were
comparable
among
the
groups
for
both
sexes.
There
were
no
apparent
treatmentrelated
alterations
in
hematology
or
urinalysis
among
the
groups
for
either
sex.
Elevations
in
blood
urea
nitrogen,
creatinine,
and
alanine
aminotransferase,
and
decreased
glucose
levels
[
mid­
dose
males,
high­
dose
both
sexes]
were
observed
throughout
the
study
[
mid­
and
high­
dose
levels,
both
sexes],
although
a
dose
response
was
not
always
apparent,
especially
in
the
males.
Alkaline
phosphatase
was
decreased
in
both
sexes
at
the
highdose
level
at
week
4.
Similar
alterations
in
these
clinical
chemistry
parameters
have
been
observed
in
subchronic
studies
in
rats
and
dogs
on
2,4­
D,
and
its
amine
salts
and
esters.

There
was
a
dose­
related
decrease
in
absolute
brain
weight
in
females,
with
statistical
significance
being
attained
at
the
mid­
and
high­
dose
levels.
Males
at
the
high
dose
also
displayed
decreased
brain
weight,
but
statistical
significance
was
not
attained.
In
general,
the
organ­
weight
effects
observed
can
be
attributed
to
the
lower
body
weight,
although
the
decreased
testes
weights
at
the
high­
dose
level
and
decreased
ovarian
weights
at
the
midand
high­
dose
levels
are
consistent
findings
in
other
studies
on
2,4­
D
and
its
salts/
esters.
Microscopically,
liver
[
perivascular,
chronic
active
inflammation
(
males
1/
5,
1/
5,
3/
5,
4/
5;
females
0/
5,
0/
4,
4/
5,
3/
5
with
increasing
dose)
and
sinusoidal
lining
cell
pigment
(
females;
1/
5,
2/
4,
5/
5,
4/
5
with
increasing
dose)]
and
kidney
[
minimal
increase
in
the
frequency
and
average
severity
of
pigment
in
the
tubular
epithelium
(
males
2/
5,
4/
5,
5/
5,
5/
5;
females
1/
5,
1/
4,
5/
5,
5/
5
with
increasing
dose)]
lesions
were
observed
at
the
mid­
and
high­
dose
levels
in
both
sexes.
Aspermatogenesis
and
degeneration
were
observed
in
one
male
at
the
high­
dose
level
compared
to
none
in
the
other
groups.

The
NOAEL
is
1
mg/
kg/
day.
The
LOAEL
of
5
mg/
kg/
day
is
based
on
decreased
body­
weight
gain
(
both
sexes)
and
food
consumption
(
females),
as
well
as
alterations
in
clinical
chemistry
parameters
[
increased
BUN,
creatinine,
and
alanine
aminotransferase,
decreased
glucose]
in
both
sexes,
decreased
brain
weight
in
females,
and
histopathological
lesions
in
the
liver
and
kidneys.

This
chronic
oral
toxicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
4100;
§
83­
1(
b)]
for
a
chronic,
non­
rodent,
oral
toxicity
study.

4.6
Carcinogenicity
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
30
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
There
was
no
increase
in
the
incidence
of
any
tumor
type
in
either
sexes
or
species.

870.4200a
Carcinogenicity
Study
­
rat
EXECUTIVE
SUMMARY:
see
under
Chronic
Toxicity
above.

This
chronic
toxicity/
carcinogenicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
4300;
§
83­
5]
for
a
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
EXECUTIVE
SUMMARY:
In
a
carcinogenicity
study
[
MRID
40061801],
50
B
6
C
3
F
1
CRL
BR
mice/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
97.5%]
via
the
diet
for
104
weeks
at
concentrations
of
0,
1
mg/
kg/
day,
15
mg/
kg/
day,
and
45
mg/
kg/
day.
Additionally,
10
mice/
sex/
group
were
sacrificed
at
52
weeks
[
interim
sacrifice].

No
treatment­
related
effect
was
observed
on
survival
in
either
sex,
and
there
were
no
treatment­
related
clinical
signs
of
toxicity.
Males
at
the
high­
dose
level
displayed
a
slight
decrease
[
94%
of
control]
in
body
weight
at
study
termination,
but
body
weight
was
comparable
among
the
female
groups.
Body­
weight
gain
during
the
first
week
of
exposure
was
decreased
at
the
high­
dose
level
in
both
sexes
[
males
50%/
females
12%].
Thereafter,
the
females
displayed
comparable
body­
weight
gains
among
the
groups.
The
high­
dose
males
displayed
decreased
body­
weight
gains
during
the
0­
13
week
[
91%
of
control]
and
0­
104
week
[
84%
of
control,
p<
0.05]
intervals,
and
the
low­
[
91%
of
control,
p<
0.05]
and
mid­
[
89%
of
control,
0.05]
dose
males
displayed
lower
body­
weight
gains
overall
[
weeks
0­
104]
also.
There
was
no
apparent
adverse
effect
of
treatment
on
food
consumption
in
either
sex.

Hematology
parameters
were
comparable
among
the
groups
[
both
sexes].
There
was
no
ophthalmoscopic
assessment,
and
thyroid
toxicity
was
not
assessed
in
this
study.

Increased
kidney
weights
were
observed
in
the
high­
dose
females
at
both
the
52­
week
and
terminal
sacrifices.
Kidney
weights
of
the
high­
dose
males
were
slightly
increased
at
the
terminal
sacrifice
only.
Adrenal
weights
were
decreased
at
all
dose
levels
in
the
males
at
the
52­
week
sacrifice,
but
there
was
no
dose
response.
At
study
termination,
the
mid­
and
high­
dose
males
displayed
a
significant
increase
in
adrenal
weight.

Gross
pathology
findings
were
comparable
among
the
groups
[
both
sexes].
Microscopically,
there
was
an
increased
incidence
of
lesions
in
the
kidney
of
males
at
the
mid­
and
high­
dose
levels
[
histomorphologic
alteration
in
the
renal
tubule
epithelium,
characterized
as
a
cytoplasmic
homogeneity
due
to
the
reduction
of
cytoplasmic
vacuoles
normally
present]
in
unscheduled
deaths
and
at
both
the
interim
and
terminal
sacrifices.
This
kidney
lesion
was
not
observed
in
females.
No
microscopic
lesions
were
observed
in
the
adrenal.
There
was
no
treatment­
related
increase
in
any
tumor
type
in
either
sex.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
31
The
NOAEL
is
1
mg/
kg/
day.
The
LOAEL
of
15
mg/
kg/
day
is
based
on
treatment­
related
increase
in
kidney
weights
in
both
sexes
and
microscopic
renal
lesions
in
males.
There
was
no
treatment­
related
increase
in
the
incidence
of
any
tumor
type.

This
carcinogenicity
study
is
classified
Unacceptable
because
the
high
dose
[
45
mg/
kg/
day]
is
considered
inadequate
to
assess
the
carcinogenic
potential
of
2,4­
D.
It
was
previously
classified
Core
Minimum
in
the
original
DER;
however,
the
HED
Carcinogenicity
Peer
Review
Committee
[
HED
TXR
No.
0050017]
concluded
that
a
repeat
carcinogenicity
study
in
mice
be
performed
at
higher
dose
levels
to
adequately
assess
the
carcinogenic
potential
of
2,4­
D.
The
current
study
does
not
satisfy
the
guideline
requirement
[
OPPTS
870.
4200b;
§
83­
2]
for
a
carcinogenicity
study
in
the
mouse.
The
repeated
study
[
MRIDs
43879801
and
43597201]
employed
dosages
from
5­
120
mg/
kg/
day
for
males
and
5­
300
mg/
kg/
day
for
females.
The
study
has
been
reviewed
under
a
separate
DER
[
TXR
No.
011934],
and
the
results
indicated
no
treatment­
related
increase
in
any
tumor
incidence
relative
to
controls.

EXECUTIVE
SUMMARY:
In
a
carcinogenicity
study
[
MRID
43879801
and
43597201],
50
B
6
C
3
F
1
CRL
BR
mice/
sex/
group
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.4%]
via
the
diet
for
104
weeks
at
concentrations
of
0,
5
mg/
kg/
day
[
both
sexes],
62
[
males]/
150
[
females]
mg/
kg/
day,
and
120
[
males]/
300
[
females]
mg/
kg/
day.
Additionally,
10
mice/
sex/
group
were
sacrificed
at
52
weeks
[
interim
sacrifice].

There
were
no
treatment­
related
deaths
or
clinical
signs
of
toxicity
in
either
sex.
Body
weight,
body­
weight
gain,
and
food
consumption
were
comparable
among
the
male
groups
throughout
the
study.
Females
at
the
high­
dose
level
displayed
a
slightly
lower
body
weight
at
the
3­
and
6­
month
intervals
[
96%
of
control].
Body­
weight
gains
were
decreased
significantly
at
all
dose
levels
in
the
females
at
the
3­
month
interval
[
93%,
94%,
and
86%
of
control
at
the
low­,
mid­,
and
high­
dose,
respectively],
and
the
high­
dose
females
continued
to
display
a
reduced
body­
weight
gain
at
the
6­
month
[
91%
of
control]
and
12­
month
[
91%
of
control]
intervals.
There
were
no
consistent
changes
in
food
consumption
in
the
female
groups.

Ophthalmology
and
hematology
parameters
[
RBC,
HGB,
HCT,
platelets]
were
comparable
among
the
groups
[
both
sexes];
no
thyroid
parameters
were
monitored.

There
was
a
dose­
related
increase
in
kidney
weights
in
both
sexes.
In
males,
increased
kidney
weights
[
absolute
and
relative]
were
observed
at
the
mid­
and
high­
dose
levels
at
the
terminal
sacrifice
only.
In
females,
increased
kidney
weights
were
observed
at
the
mid­
and
high­
dose
levels
at
both
the
interim
and
terminal
sacrifices.

Gross
pathology
findings
were
comparable
among
the
groups
[
both
sexes].
Microscopically,
there
was
an
increased
incidence
of
lesions
in
the
kidneys
of
both
sexes
at
the
mid­
and
high­
dose
levels.
In
males
at
the
interim/
terminal
sacrifices,
renal
lesions
were
characterized
as
degeneration
with
regeneration
of
the
descending
limb
of
the
proximal
tubule
in
the
mid­
[
20%/
50%]
and
high­
dose
[
100%/
96%]
males
vs
none
in
the
low
dose
or
control
males;
decreased
vacuolization
of
the
renal
proximal
tubule
in
mid­
[
80%/
78%]
and
high­
dose
[
100%/
96%]
males
vs
0%
in
the
low­
dose
and
control
males.
Additionally
at
the
terminal
sacrifice,
there
was
an
increased
incidence
of
mineralization
of
the
tubule(
s)
in
the
mid­
[
58%]
and
high­
[
72%]
dose
males
compared
to
the
low
and
control
groups
[
38%
and
32%,
respectively].
In
females,
the
renal
lesions
were
characterized
by
hypercellularity
in
the
descending
part
of
the
proximal
tubule
at
both
the
interim
and
terminal
sacrifices
at
the
mid­
[
80%/
64%]
and
high­
dose
[
100%/
50%]
levels
vs
0%
in
the
low­
and
control
females.
There
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
32
was
no
treatment­
related
increase
in
any
tumor
type
in
either
sex.

The
NOAEL
is
5
mg/
kg/
day.
The
LOAEL
of
62
mg/
kg/
day
[
males]/
150
mg/
kg/
day
[
females]
is
based
on
an
increased
absolute
and/
or
relative
kidney
weights
and
an
increased
incidence
of
renal
microscopic
lesions.
There
was
no
treatment­
related
increase
in
the
incidence
of
any
tumor
type.

This
carcinogenicity
study
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
4200b;
§
83­
2
(
b)]
for
a
carcinogenicity
study
in
the
mouse.

NOTE:
In
the
mouse
study,
there
was
an
increase
in
hemangiosarcomas
of
the
spleen
in
male
mice
at
the
low
and
mid
doses,
which
was
not
sustained
at
the
highest
dose;
however,
the
slides
from
all
male
mice
at
the
low
and
mid
doses
were
not
evaluated.
The
HED
Carcinogenicity
Peer
Review
Committee
[
CPRC;
TXR
No.
0050017]
requested
that
the
slides
of
the
low­
and
mid­
dose
spleens
of
the
males
be
evaluated.
These
additional
data
were
submitted
[
MRID
44284502].
The
spleen
of
35
male
mice
in
the
low­
dose
[
5
mg/
kg/
day]
group
and
33
in
the
mid­
dose
[
62.5
mg/
kg/
day]
group
were
examined
by
light
microscopy.
No
neoplasms
were
observed.
When
all
of
the
data
on
the
50
male
mice/
group
were
combined,
there
was
no
dose­
related
increase
in
hemangiosarcomas
or
in
possible
preneoplastic
lesions,
such
as
extramedullary
hematopoiesis.
It
was
concluded
that
the
additional
data
do
not
alter
the
findings
of
the
study.
There
was
another
mouse
carcinogenicity
study
[
MRID
40061801]
conducted
at
dosages
of
1,
15,
and
45
mg/
kg/
day.
No
treatment­
related
increase
in
tumor
incidence
was
found;
however,
this
latter
study
was
classified
unacceptable
because
the
high
dose
was
considered
inadequate
to
assess
the
carcinogenic
potential
of
2,4­
D.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
mutagenicity
is
considered
adequate
based
on
pre
1991
mutagenicity
guidelines.
2,4­
Dichlorophenoxyacetic
acid
has
been
evaluated
extensively
[
open
literature]
in
a
range
of
in
vivo
and
in
vitro
assays
that
have
included
tests
with
human
cells.
Overall,
the
pattern
of
responses
observed
in
both
in
vivo
and
in
vitro
tests
indicates
that
2,4­
dichlorophenoxyacetic
acid
was
not
mutagenic,
although
some
cytogenetic
effects
were
observed.
The
available
studies
on
the
amine
salts
and
esters
show
a
similar,
nonmutagenic,
response.

Ames
tests,
with
and
without
metabolic
activation,
were
negative
consistently.
Negative
results
were
also
observed
in
a
mouse
bone
marrow
micronucleus
assay
and
in
UDS
assays
in
rat
hepatocytes.
Conflicting
results
were
obtained
in
Drosophila;
positive
effects
were
observed
in
larvae,
and
negative
results
were
observed
in
adults
after
feeding
or
injection.
Conflicting
results
were
also
seen
in
in
vitro
mammalian
cell
cytogenetics
assays:
2,4­
dichlorophenoxyacetic
acid
was
negative
for
structural
chromosomal
damage
up
to
an
insoluble
level
but
positive
in
the
presence
of
metabolic
activation
at
high
doses.
The
positive
evidence,
however,
tends
to
be
weak
and
generally
not
supported
by
the
data
from
in
vivo
cytogenetic
assays.
Overall,
the
pattern
of
responses
observed
in
both
in
vivo
and
in
vitro
tests
indicates
that
2,4­
dichlorophenoxyacetic
acid
was
not
mutagenic,
although
some
cytogenetic
effects
were
observed.

2,4­
dICHLOROPHENOXYACETIC
ACID
[
2,4­
D
aCID]
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
33
Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41409801
classification:
Acceptable
2,4­
D
100­
1000

g/
plate
w/
S9;
66.7­
6670

g/
plate
w/
out
S9.
No
evidence
of
bacterial
mutation
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
Guideline
870.5300,
hamster
V79
fibroblasts,
HPRT
locus
Pavlica,
et
al.,
1991
classification:
N/
A
2,4­
D
10­
100

g/
mL.
Positive
Cytogenetics
Guideline
870.5385,
in
vitro
chromosome
aberration
[
human
lymphocytes];
Mustonen,
et
al.
1986
classification:
N/
A
2,4­
D
0.125­
0.35
mM;
0.125­
1.250
mM.
No
evidence
of
increased
chromosome
aberrations
in
human
lymphocytes.

Guideline
870.5385,
in
vivo
chromosome
aberration
[
Wistar
rat
bone
marrow]
Adhikari
&
Grover,
1988
classification:
N/
A
2,4­
D
0,
17.5,
35,
70
mg/
kg/
day
ip
2X.
Equivocal
[+
at
top
2
doses,
but
results
were
similar
to
DMSO
control].

Guideline
870.5385,
in
vivo
chromosome
aberration
[
Charles
River
rat
bone
marrow]
Turkula
&
Jalal,
1987
classification:
N/
A
2,4­
D
0­
350
mg/
kg
ip
for
4
or
24
hours/
3
replicates.
Equivocal
[+

75
mg/
kg
but
only
in
one
replicate].

Guideline
870.5395,
micronucleus
assay;
MRID
41409804,
41870101
classification:
Acceptable
2,4­
D
(
96.1%)
40­
400

g/
kg.
ICR
mouse
(
bone
marrow).
Negative
Other
Genotoxicity
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay;
MRID
41409807;
classification:
Acceptable
2,4­
D
(
96.1%)
0.969­
2890

g/
mL
Fisher
344
primary
rat
hepatocytes.
No
evidence
of
induction
of
unscheduled
DNA
synthesis.

The
following
tables
provide
summaries
of
the
mutagenicity
studies
on
the
2,4­
D
amine
salts
and
esters
for
comparison.

BUTOXYETHYL
ESTER
[
BEE]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41388204,
41797903,
42015701
classification:
Acceptable
BEE
5­
5000

g/
plate
w/
S9;
1.6­
1667

g/
plate
w/
out
S9.
No
evidence
of
bacterial
mutation
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
34
Guideline
870.5300,
HPRT
locus
(
CHO)
cells
[
in
vitro]
MRID
43394201
classification:
Acceptable
BEE
Doses:
200­
700
and
600­
1000
µ
g/
mL
without
S9;
150­
1400
µ
g/
mL
with
S9
activation
[
Aroclor­
induced
rat
liver];
cytotoxic
at

800
µ
g/
mL
without
S9
activation;
non­
cytotoxic
with
S9.
There
was
no
evidence
of
mutagenic
effect
at
any
dose
level
with
or
without
activation.

Cytogenetics
Guideline
870.5375,
in
vitro
chromosome
aberration
[
rat
lymphocytes];
MRID
43327305
classification:
Unacceptable
need
new
study
BEE
Doses:
87.5,
175,
350,
700,
and
1400
µ
g/
mL
with
or
without
metabolic
activation.
Negative.

Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
41478301,
42015704,
42015701,
42015707
classification:
Unacceptable
BEE
Doses:
37.5,
125,
or
375
mg/
kg;
did
not
cause
a
significant
increase
in
frequency
of
micronucleated
polychromatic
erythrocytes
(
MPEs);
however,
no
evidence
of
compound
toxicity
in
the
test
animals
or
cytotoxicity
in
the
target
organ.

Other
Genotoxicity
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
41498101.
classification:
Unacceptable
BEE
5.0
to
500
µ
g/
mL;
did
not
induce
an
appreciable
increase
in
the
net
nuclear
grain
counts
in
two
independent
unscheduled
DNA
(
UDS)
assays,
but
technical
problems
preclude
accurate
assessment
of
results;
excessively
high
background
cytoplasmic
and
nuclear
grain
counts
in
all
groups
make
it
difficult
to
distinguish
between
a
positive
and
negative
genotoxic
response.

DIETHANOLAMINE
[
DEA]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41920910
classification:
Acceptable
DEA
500,
1000,
2500,
5000,
10000,
14000

g/
plate
[
equivalent
to
369,
738,
1845,
3690,
7380,
10332

g/
plate
2,4­
D
DEA].
Not
mutagenic
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
Cytogenetics
Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
41920908
classification:
Acceptable
DEA
Doses
(
oral):
60,
200,
600
mg/
kg;
equivalent
to
44.28,
147.6,
442.8
mg/
kg.
Not
clastogenic;
no
significant
increase
in
frequency
of
micronucleated
polychromatic
erythrocytes
(
MPEs);
toxic
signs
in
males
at
HDT
included
ataxia,
languidness,
and
squinted
eyes.

Other
Genotoxicity
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
35
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
41920909
classification:
Acceptable
DEA
Doses
[
10
to
500
µ
g/
mL;
equivalent
to
7.38
to
369
µ
g/
mL].
Negative;
no
appreciable
increase
in
net
nuclear
grain
counts
of
treated
rat
hepatocytes.

DIMETHYLAMINE
[
DMA]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41409802
classification:
Acceptable
DMA
333­
10000

g/
plate.
No
evidence
of
bacterial
mutation
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
Cytogenetics
Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
41409805,
41870102
[
micronucleus]
classification:
Acceptable
DMA
Doses:
60,
120,
or
600
mg/
kg.
Not
clastogenic;
no
significant
increase
in
frequency
of
MPE's.
Toxic
signs
[
languidness,
prostration,
rough
hair
coat
or
death]
at
600
mg/
kg.

Other
Genotoxicity
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
41409808
classification:
Acceptable
DMA
Doses
[
2.5
to
100
µ
g/
mL].
Negative.
No
appreciable
increase
in
net
nuclear
grain
counts
of
treated
rat
hepatocytes.

ETHYLHEXYL
ESTER
[
EHE]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41409803
classification:
Acceptable
EHE
333­
10000

g/
plate.
No
evidence
of
bacterial
mutation
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
Cytogenetics
Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
41409806,
41870103
classification:
Acceptable
EHE
Doses:
60,
120,
or
600
mg/
kg.
Not
clastogenic;
no
significant
increase
in
frequency
of
MPE's.
Toxic
signs
[
languidness,
prostration,
rough
hair
coat
or
death]
at
600
mg/
kg.

Other
Genotoxicity
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
36
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
41409809
classification:
Acceptable
EHE
Doses
2.5
to
100
µ
g/
mL.
Negative.
No
appreciable
increase
in
net
nuclear
grain
counts
of
treated
rat
hepatocytes.

ISOPROPYLAMINE
[
IPA]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41388203,
41797902,
42015701
classification:
Acceptable
IPA
333­
10000

g/
plate.
Not
mutagenic
w/
and
w/
out
S9
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,

Guideline
870.5300,
HPRT
locus
(
CHO)
cells
[
in
vitro]
MRID
43327304
classification:
Acceptable
IPA
Doses:
500,
1,000,
1500,
2000,
and
3000
µ
g/
mL
with
and
without
S9
activation
[
Aroclor­
induced
rat
liver];
cytotoxic
at
dose
of
2500
µ
g/
mL
with
and
without
S9
activation.
There
was
no
evidence
of
mutagenic
effect
at
any
dose
level
with
or
without
activation.

Cytogenetics
Guideline
870.5375,
in
vitro
chromosome
aberration
[
rat
lymphocytes];
MRID
43327303
classification:
Acceptable
IPA
Doses:
96,
192,
384,
767,
1534,
3068,
and
61370
µ
g/
mL
with
or
without
metabolic
activation.
Negative;
not
clastogenic
at
dose
levels
upto
3000

g/
mL
Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
41478303,
42015701,
42015703,
42015706
classification:
Acceptable
IPA
Doses
(
oral):
75,
150,
or
750
mg/
kg;
Not
clastogenic;
no
significant
increase
in
frequency
of
micronucleated
polychromatic
erythrocytes
(
MPEs);
toxic
signs
were
languidness
with
ataxia
and/
or
rough
hair
coat.

Other
Genotoxicity
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
41498103.

classification:
Unacceptable
IPA
5
doses
[
5.0
to
500
µ
g/
mL]
did
not
induce
an
appreciable
increase
in
the
net
nuclear
grain
counts
in
two
independent
unscheduled
DNA
(
UDS)
assays,
but
technical
problems
preclude
accurate
assessment
of
results;
excessively
high
background
cytoplasmic
and
nuclear
grain
counts
in
all
groups
make
it
difficult
to
distinguish
between
a
positive
and
negative
genotoxic
response.

ISOPROPYLESTER
[
IPE]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
43935101
classification:
Acceptable
IPE
100­
5000

g/
plate
+
S9/
10­
2500

g/
plate
­
S9.
Not
mutagenic
w/
and
w/
out
S9
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,

Cytogenetics
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
37
Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
43930801
classification:
Acceptable
IPE
oral
[
gavage]
doses
of
100,
200,
and
400
mg/
kg
to
CD­
1
mice;
did
not
induce
a
significant
increase
in
micronuclei
in
bone
marrow
polychromatic
erythrocytes.

Other
Genotoxicity
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
43930501
classification:
Acceptable
IPE
5.01­
200
µ
g/
mL.
No
significant
increases
in
net
nuclear
grain
counts
at
any
concentration.

2,4­
D
TRIISOPROPANOLAMINE
[
TIPA]

Gene
Mutation
Guideline
870.5265,
Ames,
reverse
mutation;
MRID
41388202
,41797901,
42015701
classification:
Acceptable
TIPA
1000­
10000

g/
plate.
No
evidence
of
bacterial
mutation
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
Guideline
870.5300,
HPRT
locus
(
CHO)
cells
[
in
vitro]
MRID
43327302
classification:
Acceptable
TIPA
Doses:
800,
1,000,
1,250,
2,500,
and
5,000
µ
g/
mL
with
and
without
S9
activation
[
Aroclor­
induced
rat
liver];
cytotoxic
at
the
limit
dose
of
5,000
µ
g/
mL
without
S9
activation.
There
was
no
evidence
of
mutagenic
effect
at
any
dose
level
with
or
without
activation.

Cytogenetics
Guideline
870.5375,
in
vitro
chromosome
aberration
[
rat
lymphocytes];
MRID
43327301
classification:
Acceptable
TIPA
Doses:
78,
156,
313,
625,
1,250,
2,500,
and
5,000
µ
g/
mL
with
or
without
metabolic
activation.
Negative.

Guideline
870.,
in
vivo
chromosome
aberration
[
mouse
bone
marrow]
MRID
41478302.,
42015701,
42015702,
42015705
classification:
acceptable
TIPA
Doses:
75,
250,
or
750
mg/
kg;
did
not
cause
a
significant
increase
in
frequency
of
micronucleated
polychromatic
erythrocytes
(
MPEs);
2
deaths
occurred
at
750
mg/
kg
Other
Genotoxicity
Guideline
870.5450,
Unscheduled
DNA
synthesis
assay
[
rat
hepatocytes];
MRID
41498102.

classification:
Unacceptable
TIPA
5
doses
[
5.0
to
500
µ
g/
mL]
did
not
induce
an
appreciable
increase
in
the
net
nuclear
grain
counts
in
two
independent
unscheduled
DNA
(
UDS)
assays,
but
technical
problems
preclude
accurate
assessment
of
results;
excessively
high
background
cytoplasmic
and
nuclear
grain
counts
in
all
groups
make
it
difficult
to
distinguish
between
a
positive
and
negative
genotoxic
response.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
The
data
base
for
neurotoxicity
is
not
considered
complete.
A
developmental
neurotoxicity
study
is
required
and
is
considered
a
datagap.
Evidence
of
neurotoxicity
was
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
38
observed
following
both
acute
and
repeated
dose
exposure
at
dose
levels
above
saturation
of
renal
clearance.
Following
acute
exposure,
there
was
an
increased
incidence
of
incoordination,
slight
gait
abnormalities
and
decreased
motor
activity.
There
was
evidence
of
neuropathology
[
increased
incidence
of
bilateral
retinal
degeneration]
following
repeated
dosing
and
increased
fore­/
hindlimb
grip
strength.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
This
study
is
not
required
for
this
chemical.

870.6200a
Acute
Neurotoxicity
Screening
Battery
EXECUTIVE
SUMMARY:
In
an
acute
neurotoxicity
study
[
MRID
43115201],
Fischer
344
rats
(
10/
sex/
dose)
were
orally
gavaged
once
with
2,4­
D
[
96.6%
a.
i.]
at
doses
of
0
(
corn
oil),
15,
75,
or
250
mg/
kg
(
actual:
0,
13,
67
or
227
mg/
kg).
Neurobehavioral
evaluations,
consisting
of
Functional
Observational
Battery
(
FOB)
and
motor
activity,
were
conducted
at
Day
­
1
(
prestudy),
Day
1
(
approximately
5­
6
hrs
postdosing,
peak
time
of
effect)
and
Days
8
and
15.
At
terminal
sacrifice
(
Day
15),
animals
were
euthanized
and
neuropathological
examination
performed
on
control
and
treated
animals
(
5/
sex/
dose).

There
were
no
treatment­
related
mortalities,
and
no
significant
differences
were
noted
in
the
mean
body
weights
or
mean
body­
weight
gains.
Treatment­
related,
clinical
signs
[
uncoordinated
movement/
behavior]
were
observed
in
the
high­
dose
rats
only.
During
the
Day
2
and
3
clinical
examinations,
incoordination
was
noted
in
high­
dose
animals
of
both
sexes
[
Day
2,
2/
10
males
and
5/
10
females;
Day
3,
2/
10
males,
1/
10
females;
Day
4,
0/
10
males,
1/
10
females].
The
incidence
of
incoordination
decreased
to
control
levels
by
Day
4
in
males
and
Day
5
in
females.
Neurobehavioral
evaluation
revealed
treatment­
related
changes.
During
the
Day
1
FOB
evaluations,
increased
incidences
of
incoordination
(
6/
10,
males;
4/
10,
females)
and
slight
gait
abnormalities,
described
as
forepaw
flexing
or
knuckling,
were
observed
in
high­
dose
animals
(
8/
10,
males;
8/
10
females).
Slight
gait
abnormalities,
observed
in
a
single
mid­
dose
female,
were
not
judged
to
be
treatment­
related
since
no
other
signs
of
toxicity
were
evident.
Minimal
[
equivocal]
gait
abnormalities,
not
judged
to
be
treatment­
related,
were
observed
in
one
low­
dose
female
and
one
each
mid­
and
high­
dose
male.
In
high­
dose
animals,
total
motor
activity
was
significantly
lower
at
Day
1
only.
No
treatment­
related
gross
or
neuropathological
findings
were
present
at
any
dose
level
in
either
sex.

The
NOAEL
for
neurotoxicity
is
67
mg/
kg,
based
on
an
increased
incidence
of
incoordination
and
slight
gait
abnormalities
[
described
as
forepaw
flexing
or
knuckling]
and
decreased
total
motor
activity
at
the
LOAEL
of
227
mg/
kg.
The
NOAEL
for
systemic
toxicity
was
227
mg/
kg
[
the
highest
dose
tested]
in
males
and
females.

This
acute
neurotoxicity
study
in
the
rat
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
6200a;
§
81­
8]
for
an
acute
neurotoxicity
study
in
the
rat.

870.6200b
Subchronic
Neurotoxicity
Screening
Battery
In
lieu
of
the
90­
day
subchronic
neurotoxicity
study,
a
one­
year
chronic
neurotoxicity
study
was
performed.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
39
EXECUTIVE
SUMMARY:
In
this
chronic
toxicity/
carcinogenicity
study
with
a
chronic
neurotoxicity
screening
battery
substudy
[
MRID
43293901],
50
Fischer
344
rats/
sex/
group
[
main
study];
15/
sex/
group
[
substudy]
were
administered
2,4­
dichlorophenoxyacetic
acid
[
96.4%]
via
the
diet
for
up
to
24
months
at
concentrations
of
0
[
basal
diet],
5
mg/
kg/
day,
75
mg/
kg/
day,
and
150
mg/
kg/
day
[
achieved
doses
were
4.6,
71.2,
and
141.1
mg/
kg/
day
[
males]
and
4.6,
68.0,
and
138.9
mg/
kg/
day
[
females],
respectively.
Additionally,
10
rats/
sex/
group
were
sacrificed
at
12
months
[
interim
sacrifice].
NOTE:
This
DER
presents
the
results
of
the
interim
[
one­
year]
sacrifice
and
neurotoxicity
substudy.

NEUROTOXICITY
STUDY
No
treatment­
related,
hand­
held,
FOB
observations
were
noted
at
any
of
the
evaluation
periods.
Relative
forelimb
grip
strength
was
significantly
increased
in
both
sexes
at
the
high­
dose
level,
but
there
was
no
treatment­
related
change
in
absolute
grip
strength.
There
was
no
treatment­
related
effect
on
motor
activity.
In
agreement
with
the
chronic
toxicity
portion
of
the
study,
an
increased
incidence
of
bilateral
retinal
degeneration
was
observed
in
the
high­
dose
females.

The
NOAEL
for
neurotoxicity
is
75
mg/
kg/
day,
based
on
increased
relative
forelimb
grip
strength
and
increased
incidence
of
bilateral
retinal
degeneration
at
the
LOAEL
of
150
mg/
kg/
day.

CHRONIC
TOXICITY
STUDY
There
were
no
treatment­
related
deaths
or
clinical
signs
of
toxicity.
Decreased
body
weight
was
observed
throughout
the
first
year
of
the
study
at
the
high­
dose
level
in
both
sexes
[
males
91%/
females
88%
of
control
at
the
interim
sacrifice]
and
at
the
mid­
dose
level
in
females
[
94%
of
control
at
the
interim
sacrifice].
At
90
days,
the
decrease
in
body
weight
was
very
slight
in
the
high­
dose
males
[
96%
of
control]
and
somewhat
greater
in
the
mid­
[
95%
of
control]
and
high­
dose
[
90%
of
control]
females.
Body­
weight
gains
were
decreased
throughout
the
first
year
at
the
mid­
and
high­
dose
levels
in
both
sexes,
although
statistical
significance
was
not
always
attained
in
males
at
the
mid­
dose
level
[
2­
week
interval
(
males:
mid­
dose
90%/
high­
dose
84%;
females:
mid­
dose
81%/
high­
dose
63%
of
control);
3­
month
interval
(
males:
mid­
dose
98%/
high­
dose
88%;
females:
mid­
dose
87%/
high­
dose
75%
of
control);
and
1­
year
interval
(
males:
mid­
dose
95%/
high­
dose
82%;
females:
mid­
dose
89%/
high­
dose
73%
of
control).
Consistent
with
the
decreased
body­
weight
gains
was
a
slight
decrease
in
food
consumption,
which
was
observed
in
both
sexes
at
the
high­
dose
level.

Ophthalmology
findings
were
comparable
among
the
groups
at
the
interim
sacrifice.
Decreased
RBC
[
mid­
and
high­
dose
females
(
6
&
12
months)
and
high­
dose
males
(
12
months)],
HCT
[
mid­
and
high­
dose
females
and
high­
dose
males
(
6
&
12
months)],
HGB
[
high­
dose
females
(
6
months)],
WBC
high­
dose
females
(
6
months)],
and
platelet
counts
[
mid­
and
high­
dose
females
and
high­
dose
males
(
6
&
12
months)
were
observed.
A
doserelated
increase
in
aspartate
aminotransferase,
alanine
aminotransferase,
and
alkaline
phosphatase
was
observed
in
the
mid­
and
high­
dose
males
at
6
months
but
not
at
12
months.
The
mid­
and
high­
dose
females
displayed
a
dose­
related
increase
in
alkaline
phosphatase
values
at
both
the
6
and
12­
month
intervals.
Cholesterol
levels
were
decreased
in
the
mid­
(
males
at
12
months
only)
and
high­
dose
rats
of
both
sexes
at
both
time
intervals.
T4
values
were
decreased
at
both
time
points
in
both
sexes
at
the
mid­
and
high­
dose
levels,
although
the
middose
males
at
6
months
did
not
attain
statistical
significance.
The
only
urinalysis
finding
was
a
decrease
in
specific
gravity
,
which
was
observed
in
both
sexes
and
time
points
at
the
mid­
and
high­
dose
levels.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
40
Thyroid
weights
[
absolute
and
relative]
were
statistically­
significantly
increased
in
the
mid­
dose
females
[

20%
greater
than
control]
and
in
both
sexes
at
the
high­
dose
level
[

20%
greater
than
control]
at
the
12­
month
interim
sacrifice.
Decreased
testes
weights
[
absolute
and
relative
to
brain]
were
observed
at
the
high­
dose
level
at
12
months
[

15%
lower
than
control].
Kidney
weights
[
absolute
and
relative]
were
increased
at
the
12­
months
sacrifice
in
males
at
the
mid­
[
7%­
12%
greater
than
control]
and
high­
dose
[
8%­
16%
greater
than
control]
levels
[
dose­
related].

Gross
pathology
findings
included
decreased
fat
in
high­
dose
females
[
4/
10]
and
multifocal
pale
foci
in
the
lungs
[
1/
10
mid­
dose,
10/
10
high­
dose
females].
Microscopically,
there
were
increased
incidences
of
lesions
in
the
bone
marrow
[
decreased
hematopoiesis
in
high­
dose
females],
eyes
[
bilateral
retina
degeneration
in
1
male
and
10
females
at
high
dose],
kidney
[
proximal
tubule
degeneration
in
mid­
and
high­
dose
males
and
females],
liver
[
altered
tinctorial
properties
in
mid­
dose
females
and
both
sexes
at
high
dose],
lungs
[
multifocal
,
subacute
to
chronic
inflammation
(
mid­
dose
females,
both
sexes
at
high
dose),
alveolar
histiocytosis
in
females
at
high
dose],
adipose
tissue
[
atrophy
in
mid­
and
high­
dose
females],
testes
[
atrophy
at
high
dose],
and
thyroid
[
decreased
secretory
material,
epithelial
cells­
high­
dose
females].

The
NOAEL
is
5
mg/
kg/
day.
The
LOAEL
of
75
mg/
kg/
day
is
based
on
decreased
body
weight
(
females)/
body­
weight
gain
(
both
sexes),
alterations
in
hematology
[
decreased
RBC,
HCT,
and
platelets
(
females)],
clinical
chemistry
parameters
[
increased
alanine
and
aspartate
aminotransferases
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
cholesterol
(
both
sexes),
and
decreased
T4
(
both
sexes)],
and
urinalysis
[
decreased
specific
gravity
(
both
sexes)],
increased
kidney
weights
(
males),
increased
incidence
of
degeneration
of
the
descending
proximal
tubules
(
both
sexes),
hepatocellular
hypertrophy
with
altered
tinctorial
properties
(
females),
lung
inflammation
(
females),
adipose
tissue
atrophy
(
females).
At
the
high­
dose
level,
there
also
were
microscopic
lesions
in
the
eyes
(
both
sexes),
liver
(
males),
testes
(
males),
thyroid
(
females),
and
lungs
(
males).

This
chronic
toxicity/
neurotoxicity
study
in
the
rat
is
classified
ACCEPTABLE/
Guideline,
and
it
satisfies
the
guideline
requirement
[
OPPTS
870.
6200b;
§
82­
7]
for
a
subchronic
neurotoxicity
study
in
the
rat.

870.6300
Developmental
Neurotoxicity
Study
This
is
a
datagap.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
The
metabolism
and
excretion
of
2,4­
D
have
been
investigated
in
a
number
of
species
including
humans.
In
general,
2,4­
D
undergoes
limited
metabolism
primarily
involving
minor
conjugation
of
the
parent
acid
that
is
then
excreted
in
the
urine.
No
detectable
metabolites
of
2,4­
D
have
been
reported
in
the
rat;
i.
e.,
only
the
parent
acid
is
found
in
rat
urine.
In
addition
to
2,4­
D
itself,
2,4­
D
conjugates
have
been
found
in
the
urine
of
dogs,
humans,
mice,
and
hamsters
following
oral
exposure.
The
mechanisms
responsible
for
the
renal
clearance
of
2,4­
D
have
been
investigated
in
several
species
also.
This
phenoxy
herbicide
is
actively
secreted
by
the
proximal
tubules
in
a
manner
similar
to
PAH,
and
this
mechanism
of
renal
clearance
for
2,4­
D
is
consistent
with
results
seen
with
other
phenoxy
acids.
It
has
been
suggested
that
the
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
41
observed
dose­
dependent
non­
linear
pharmacokinetics
of
2,4­
D
are
primarily
due
to
the
saturation
of
this
renal
secretory
transport
system.
Data
show
that
saturation
in
the
rat
occurs
at

50
mg/
kg/
day.

870.7485
Metabolism
­
Rat
EXECUTIVE
SUMMARY:
In
a
metabolism
study
[
MRID
41737302],
Fischer
rats
[
5
rats/
sex/
group]
were
administered
single
doses
of
[
phenyl
­
U­
14C]­
2,4­
dichlorophenoxyacetic
acid
[
2,4­
D]
at
dose
levels
of
0.95­
0.97
mg/
kg
[
I.
v.],
1.04­
1.05
mg/
kg
[
oral],
97.1­
97.4
mg/
kg
[
oral],
or
1.06
mg/
kg
followed
by
a
14­
day
treatment
with
unlabeled
2,4­
d
at
1
mg/
kg/
day.

Recoveries
[
85.5%­
93.7%]
of
radiolabel
in
urine
following
oral
dosing
indicate
extensive
absorption
of
2,4­
D
from
the
gastrointestinal
tract.
Total
recovery
of
radiolabel
at
48
hours
post
dose
accounted
for
94.1%
to
99.5%
of
the
dose
following
oral
exposure
and
94.1%
to
95.7%
of
the
dose
following
I.
v.
exposure.
Among
the
orally
dose
groups,
approximately
85.5%­
93.7%
of
the
dose
was
eliminated
in
the
urine
and
3.6%­
10.5%
of
the
dose
was
eliminated
via
the
feces.

At
study
termination,
total
radiolabel
residue
was
less
than
0.52%­
0.69%
of
the
dose
at
the
low
dose
and
1.17%­
2.57%
at
the
high
dose.
The
highest
tissue
levels
were
found
in
the
kidneys.
No
differences
were
noted
between
the
sexes
as
to
the
extent
of
absorption
or
excretion
at
either
dose
level,
and
repeated
low
doses
did
not
affect
excretion.
At
the
high­
dose
level,
however,
it
appears
that
a
nonlinear
region
[
decreased
clearance]
is
being
reached
in
the
disposition
of
2,4­
D.

Parent
2,4­
D
was
the
major
metabolite
found
in
the
urine
[
72.9%­
90.5%
of
the
oral
dose],
with
small
amounts
of
uncharacterized
compounds
[
0.6%­
1.3%
and
0%­
0.7%]
being
found
in
the
urine.

This
metabolism
study
is
classified
Acceptable/
guideline,
and
it
satisfies
the
guideline
requirement
[
870.7485;
§
85­
1]
for
a
metabolism
study.

In
limited
metabolism
studies
on
BEE
[
MRID
42579701],
EHE
[
MRID
42261801],
IPA
[
MRID
42865301],
and
TIPA
[
MRID
42220301],
similar
rapid
absorption
and
excretion
of
unchanged
parent
compound,
mainly
via
the
urine,
were
observed.

870.7600
Dermal
Absorption
­
Rat
EXECUTIVE
SUMMARY:
In
a
human
study
used
to
evaluate
dermal
absorption,
14C­
labeled
2,4­
D
acid
was
applied
to
the
skin
of
the
ventral
forearm
of
6
male
volunteers
in
a
0.25%
acetone
solution
at
a
rate
of
4

g/
cm2.
The
acetone
solution
was
pipetted
onto
the
area
marked
by
a
ring
and
evaporated
by
gentle
blowing
during
application;
the
solvent
was
on
the
skin
for
only
a
few
seconds.
The
skin
sites
were
left
unprotected,
and
the
subjects
were
ask
not
to
wash
the
area
for
24
hours.
Urine
was
collected
for
5
days
for
measurement
of
excreted
radioactivity.
To
correct
for
incomplete
urinary
recovery,
prior
to
the
dermal
study,
the
volunteers
received
intravenous
injection
of
a
tracer
dose
of
the
radiolabeled
test
material
in
the
weight
range
of
the
cutaneous
exposure.
Urine
was
also
collected
for
5
days
for
measurement
of
radioactivity.
[
Reference:
Feldman.
R.
J.
and
Maibach,
H.
I.
(
1974).
Percutaneous
Penetration
of
Some
Pesticides
and
Herbicides
in
Man.
Toxicol.
Appl.
Pharmacol.
28:
126­
132].
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
42
Excretion
of
radioactivity
in
the
urine
following
dermal
application
was
5.8%
±
2.4%
and
after
i.
v.
administration
was
100%
±
2.5%.

4.10
Special/
Other
Studies
Numerous
studies
in
the
open
literature
provide
additional
rationale
for
concern
for
endocrine
disruption
and
developmental
effects
following
exposure
to
2,4­
D
at
dose
levels
above
the
threshold
of
saturation
of
renal
clearance.
Myelin
deficit
in
offspring
brain
following
exposure
through
mother's
milk
has
been
demonstrated
in
rats,
and
neurotoxicity
has
been
demonstrated
in
rat
offspring
following
pre­
and/
or
postnatal
exposure
to
2,4­
D
at
dose
levels
that
exceed
the
threshold
for
renal
clearance.
Effects
on
neurotransmitters
and
reproductive
hormones
have
also
been
demonstrated
following
exposure
to
laboratory
animals
and
humans.

Reference
Results
Duffard,
R.
,
Garcia,
G.,
Russo,
S.,
et
al.
(
1996).
Central
Nervous
System
Myelin
Deficit
in
Rats
Exposed
to
2,4­
Dichlorophenoxyacetic
Acid
Throughout
Lactation.
Neurotoxicology
and
Teratology,
18
(
6):
691­
696
(
1996).

[
100
mg/
kg
[
i.
p.]
2,4­
D
exposure
through
mother's
milk
[
administered
to
Wistar
rat
dam
I.
p.]
during
the
period
of
rapid
myelination
[
postnatal
days
15
to
25]
resulted
in
a
myelin
deficit
in
the
pup's
brain.
The
brains
of
male
and
female
rats
showed
a
significant
decrease
in
myelin
markers,
such
as
monohexosylceramide,
as
well
as
phospholipids
and
free
fatty
acids
and
an
increase
of
cholesteryl
esters.
Histological
studies
revealed
myelin
deficit
in
some
brain
regions.

Bortolozzi,
A.
A.,
Duffard,
R.
O.,
and
Evangelista
De
Duffard,
A.
M.
(
1999).
Behavioral
Alterations
Induced
in
Rats
by
a
Pre­
and
Postnatal
Exposure
to
2,4­
Dichlorophenoxyacetic
Acid.
Neurotoxicology
and
Teratology,
21
(
4):
451­
465
(
1999).

70
mg/
kg/
day
(
orally)
2,4­
D
neonatal
exposure
[
dams
dosed
orally
from
gestation
day
16
to
postnatal
day
23;
after
weaning
on
PND
23,
pups
were
either
maintained
on
untreated
diet
or
administered
2,4­
D
diets
until
PND
90]
induced
delay
of
the
ontogeny
of
righting
reflex
and
negative
geotaxis
accompanied
by
motor
abnormalities,
stereotypic
behaviors
[
excessive
grooming
and
vertical
head
movements],
and
hyperactivity
in
the
open
field.

Brusco,
B.
A.,
Saavedra,
J.
P.,
Tagliaferro,
G.
G.,
et
al.
(
1997).
2,4­
Dichlorophenoxyacetic
Acid
Through
Lactation
Induces
Astrogliosis
in
Rat
Brain.
Mol.
Chem.
Neuropathol.
30,
175­
185
70
mg/
kg/
day
Dams
were
injected
i.
p.
with
2,4­
D
from
PND
9
to
PND
25,
and
astroglial
immunoreactivity
in
the
mesencephalon,
cerebellum,
and
hippocampus
was
compared
in
the
25
day­
old
pups.
Neurotoxicity
was
observed
in
reactive
gliosis
in
all
hippocampal
layers
and
in
cerebellar
and
raphe
regions.

Faustini,
A.,
Settimi,
L.,
Pacifici,
R.,
et
al.
(
1996).
Immunological
changes
among
farmers
exposed
to
phenoxy
herbicides:
preliminary
observations.
Occupational
and
Environmental
Medicine
53,
583­
585.
Following
agricultural
exposure
to
commercial
formulations
of
chlorophenoxy
herbicides,
a
significant
reduction
was
found
1
to
12
days
after
exposure
in
the
following
variables:
(
1)
circulating
helper
(
CD4)
and
suppressor
T
cells
(
CD8),
cytotoxic
T
lymphocytes
(
CTL),
natural
killer
cells
(
NK),
and
CD8
cells
expressing
the
surface
antigens
HLADR
(
CD8­
DR),
and
lymphoproliferative
response
to
mitogen
stimulations.
All
immunological
values
found
50­
70
days
after
exposure
were
comparable
with
concentrations
before
exposure,
but
mitogenic
proliferative
responses
of
lymphocytes
were
still
significantly
decreased.
The
authors
concluded
that
the
findings
suggest
that
agricultural
exposure
to
commercial
2,4­
D
and
MCPA
formulations
may
exert
shortterm
immunosuppressive
effects.
However,
there
are
study
design
issues;
i.
e.,
no
appropriate
control
group,
that
limit
interpretation
of
the
findings.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Reference
Results
43
Garry,
V.
F.,
Tarone,
R.
E.,
Kirsch,
I.
R.,
et
al.
Biomarker
correlations
of
urinary
2,4­
D
levels
in
foresters:
genomic
instability
and
endocrine
disruption.
Environmental
Health
Perspectives
(
2001).
109
(
5):
495­
500.
In
a
published
article
on
applicators
whose
exposures
were
mostly
limited
to
chlorophenoxy
herbicides,
urinary
levels
of
2,4­
D
obtained
at
the
time
of
maximum
2,4­
D
use
were
compared
to,
among
other
parameters,
reproductive
hormone
levels.
It
was
concluded
that
herbicide
applicators
with
high
urinary
levels
of
2,4­
D
[
back
pack
and
boom
spray
application]
exhibited
elevated
LH
levels.
The
authors
acknowledge
the
fact
that
the
study
should
be
interpreted
with
caution
based
on
the
limited
sample
size.

Lee,
K.,
Johnson,
V.,
and
Blakley,
B.
(
2001).
The
Effect
of
Exposure
to
a
Commercial
2,4­
D
Formulation
During
Gestation
on
the
Immune
Response
in
CD­
1
Mice.
Toxicology
2001
Aug
13:
165
(
1):
39­
49.
In
a
published
study
in
CD­
1
mice,
pregnant
mice
were
administered
a
"
commercial
2,4­
D
formulation"
on
gestation
days
6­
16
in
drinking
water
at
concentrations
ranging
from
0
to
1.0%
of
the
formulated
product
[
equivalent
to

0­
650
mg/
kg/
day
"
expressed
as
the
amine
derivative".
The
effect
of
2,4­
D
on
immune
function
was
evaluated
in
the
offspring
7
weeks
after
birth.
It
was
reported
that
the
dams
tolerated
repeated
exposure
in
the
drinking
water
"
without
difficulty"
[
no
effects
were
reported].
The
offspring
exhibited
decreased
body
weight
with
minor
reductions
in
kidney
weights
at
0.1
and
1.0%.
A
generalized
suppression
of
lymphocyte
stimulation
by
concanavalin
A
[
Con
A]
was
observed
at
the
high
dose.
Cytometric
studies
of
the
lymphocyte
subpopulations
demonstrated
an
increased
relative
count
of
B
cells
and
reduced
T
cytotoxic
or
suppressor
cells
at
1.0%.
The
humoral
immune
response,
antibody
production
against
sheep
red
blood
cells,
and
peritoneal
macrophage
phagocytic
function
were
not
altered
by
2,4­
D.
It
was
concluded
by
the
authors
that
since
the
immune
alterations
in
the
offspring
were
observed
many
weeks
after
exposure,
it
appears
as
though
2,4­
D
exposure
during
gestation
causes
permanent
changes
in
cell
types
associated
with
immune
function.
It
is
stated
also
that
since
"
2,4­
D
is
not
considered
a
persistent
chemical,
it
is
unlikely
that
2,4­
D
residues
are
contributing
significantly
to
the
observed
immune
alterations."

Garabrant,
D.
H.
and
Philbert,
M.
A.
(
2002).
Review
of
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D)
Epidemiology
and
Toxicology.
Crit
Rev
Toxicol
32
(
4):
233­
57.
In
a
published
review
article,
it
is
stated
that
there
is
no
evidence
that
2,4­
D
in
any
of
its
forms
activates
or
transforms
the
immune
system
in
animals
at
any
dose.

R.
J.
Griffin,
V.
B.
Godfrey,
Y­
C
Kim,
and
L.
T.
Burka
(
1997).
Sex­
Dependent
Differences
in
the
Disposition
of
2,4­
Dichlorophenoxyacetic
Acid
in
Sprague­
Dawley
Rats,
B6C3F1
Mice,
and
Syrian
Hamsters.[
Drug
Metabolism
and
Disposition
(
1997).
The
American
Society
for
Pharmacology
and
Experimental
Therapeutics,
Vol.
25,
No.
9.
The
National
Toxicology
Program
is
conducting
a
multi­
species
study
into
the
mechanisms
of
peroxisomal
proliferation,
and
2,4­
D
was
selected
as
a
model
noncarcinogenic,
weak
peroxisomal
proliferator
Arbuckle,
T.
E.,
Schrader,
S.
M.,
Cole,
D.,
et
al.
(
1999)
.2,4­
Dichlorophenoxyacetic
acid
residues
in
semen
of
Ontario
farmers.
Reprod
Toxicol.
13(
6):
421­
9.
2,4­
Dichlorophenoxyacetic
acid
residues
in
semen
of
Ontario
farmers.
Reproductive
Toxicology
13:
421­
429],
measurable
levels
of
2,4­
D
were
found
in
semen
and
were
of
the
same
order
of
magnitude
as
those
measured
in
the
24­
hour
urine
samples
following
a
brief
period
of
exposure.

Blakley,
B.
R.
and
Schiefer,
B.
H.
(
1986).
The
effect
of
topically
applied
n­
butylester
of
2,4­
dichlorophenoxyacetic
acid
on
the
immune
response
in
mice.
J.
Appl.
Toxicol.
6(
4):
291­
295.
evidence
of
clinical
toxicity,
myotonia
and
depression,
and
histopathological
alterations
in
the
CNS
[
perivascular
edema
and
ganglial
cell
necrosis]
were
reported
following
acute
dermal
application
[
up
to
500
mg/
kg]
to
CD­
1
mice.
Subacute
2,4­
D
ester
exposure
[
up
to
300
mg/
kg/
day
for
3
weeks]
produced
minimal
clinical
or
pathological
alterations.
Although
no
effect
was
observed
on
antibody
production,
2,4­
D
did
enhance
the
B­
and
T­
lymphocyte
proliferative
responses.
It
was
stated
that
the
immunosuppressive
effects
of
acute
2,4­
D
ester
exposure
were
unlikely
a
direct
immunological
alteration
but
rather
a
secondary
manifestation
of
the
clinical
syndrome.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Reference
Results
44
Evangelista
de
Duffard,
A.
M.
,
N.
De
Aldrete,
M.,
and
Duffard,
R.
(
1990)].
Changes
in
brain
serotonin
and
5­
hydroxyindoleacetic
acid
levels
induced
by
2,4­
dichlorophenoxyacetic
acid
butyl
ester.
Toxicol.
64,
265­
270.


69
mg/
kg/
day
Adult
offspring
of
Wistar
dams
fed
2,4­
D
butyl
ester
during
lactation
had
increased
brain
concentrations
of
serotonin
and
5­
hydroxyindoleacetic
acid,
but
in
utero
exposure
without
exposure
via
lactation
had
no
effect
on
the
postnatal
status
of
these
neurotransmitters.

M.
F.
Cavieres,
J.
Jaeger,
and
W.
Porter
(
2002).
Developmental
Toxicity
of
a
Commercial
Herbicide
Mixture
in
Mice:
I.
Effects
on
Embryo
Implantation
and
Litter
Size.
Environmental
Hlth
Perspectives
110
(
11),
1081­
1085.
pregnant
ND4
mice
[
Harlan
Sprague­
Dawley]
were
exposed
to
a
mixture
of
2,4­
D
[
0.01,
0.1,
20,
100
mg/
kg/
day],
mecoprop
[
0.004,
0.04,
8.07,
40.39
mg/
kg/
day],
and
dicamba
[
00009,
009,
1.83,
9.166
mg/
kg/
day]
in
the
drinking
water
either
during
preimplantation
and
organogenesis
or
only
during
organogenesis.
Litter
size,
birth
weight,
and
crown­
rump
length
were
determined
at
birth,
and
the
pups
were
allowed
to
lactate
and
grow
without
additional
herbicide
exposure
so
that
they
could
be
subjected
to
additional
immune,
endocrine,
and
behavioral
studies
[
the
results
of
which
were
not
reported
in
this
paper].
At
weaning,
dams
were
sacrificed,
and
the
number
of
implantation
sites
were
determined.

The
data
were
reported
to
show
"
an
inverted
or
U­
shaped
dose­
response
pattern
for
reduced
litter
size,
with
the
low
end
of
the
dose
range
producing
the
greatest
decrease
in
the
number
of
live
pups
born",
which
the
authors
believe
was
influenced
by
season.
The
decrease
in
litter
size
was
associated
with
a
decrease
in
the
number
of
implantation
sites,
but
only
at
the
two
lowest
dose
levels.
Fetotoxicity,
as
evidenced
by
a
decrease
in
body
weight
and
crown­
rump
length
of
the
newborn
pups
or
embryo
resorptions,
was
not
significantly
different.
The
HIARC
determined
that
the
effects
reported
in
this
study
cannot
be
attributed
to
2,4­
D
since
a
mixture
of
chemicals
[
2,4­
D,
mecoprop,
dicamba]
was
tested.
The
HIARC
concluded
that
the
study
is
not
relevant
for
risk
assessment.

5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
5.8
%

The
value
is
derived
from
a
human
volunteer
study.

The
dermal
absorption
factor
is
required
for
the
short­
term,
intermediate­
term,
and
chronic
dermal
risk
assessments
since
oral
doses
were
selected
for
these
exposure
periods.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
Classification
of
Carcinogenic
Potential
In
accordance
with
the
Draft
Carcinogen
Risk
Assessment
Guidelines
[
1996],
the
HED
Carcinogenicity
Peer
Review
Committee
[
CPRC]
classified
2,4­
D
acid
as
a
Group
D
chemical
[
Not
Classifiable
as
to
Human
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
45
Carcinogenicity]
[
TXR
#
0050017].

5.3.2
Quantification
of
Carcinogenic
Potential
Not
applicable.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
There
is
qualitative
evidence
of
susceptibility
in
the
rat
developmental
toxicity
study
with
the
acid
where
fetal
effects
[
skeletal
abnormalities]
were
observed
at
a
dose
level
that
produced
less
severe
maternal
toxicity
[
decreased
body­
weight
gain
and
food
consumption].
In
the
previous
assessment
by
the
HIARC,
these
effects
were
not
considered
to
be
severe
in
nature
[
HIARC;
TXR
No.
0050426];
however,
based
on
a
reassessment
of
the
effects
observed,
it
was
determined
that
the
presence
of
7th
cervical
ribs
is
of
concern
and
is
considered
an
abnormality
and,
therefore,
evidence
of
qualitative
susceptibility.

There
is
no
evidence
of
increased
[
quantitative
or
qualitative]
susceptibility
in
the
prenatal
developmental
toxicity
study
in
rabbits
or
in
the
2­
generation
reproductive
study
in
rats
on
2,4­
D.
There
is
no
evidence
of
increased
susceptibility
[
quantitative
or
qualitative]
in
the
prenatal
developmental
toxicity
study
in
rat
and
rabbits
on
any
of
the
amine
salts
or
esters
of
2,4­
D.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
On
April
8,
2003,
based
on
the
weight
of
evidence
presented,
the
HIARC
reaffirmed
the
previous
conclusion
[
HED
Document
No.
014234]
that
a
developmental
neurotoxicity
[
DNT]
study
in
rats
is
required
for
2,4­
D.
In
addition,
the
HIARC
determined
that
a
repeat
2­
generation
reproduction
study
[
using
the
new
protocol]
is
required
to
address
concerns
for
endocrine
disruption
[
thyroid
and
immunotoxicity
measures].
The
registrant
should
consult
the
Agency
for
the
protocol.
The
scientific
evidence
is
incomplete
to
reach
a
final
conclusion
regarding
these
concerns.

The
HIARC
determined
that
a
10X
database
uncertainty
factor
(
UF
DB)
is
needed
to
account
for
the
lack
of
these
studies
since
the
available
data
provide
no
basis
to
support
reduction
or
removal
of
the
default
10X
factor.

7.0
OTHER
ISSUES
Arguments
were
provided
to
support
the
hypothesis
that
use
of
the
dog
data
on
2,4­
D
as
the
basis
for
regulation
exaggerates
the
apparent
severity
of
effects
anticipated
because
of
the
limited
capacity
of
dogs
to
excrete
organic
acids.
Points
of
consideration
included
(
1)
the
data
show
the
dog
to
have
a
decreased
clearance,
relative
to
that
predicted
from
the
allometric
relationship,
whereas
humans,
rats,
mice,
and
other
species
all
fir
the
relationship.
This
observation
is
true
for
2,4­
D,
as
well
as
for
triclopyr.
MCPA,
and
other
organic
acids.
The
decreased
capacity
of
the
dog
to
eliminate
organic
acids
results
in
higher
blood
levels
in
the
dog
relative
to
those
found
in
the
rat
and
consequently,
effects
are
observed
at
lower
dose
levels
in
the
dog
than
in
the
rat.
(
2)
Although
absorption
and
distribution
of
2,4­
D
and
other
organic
acids
are
similar
across
all
species
evaluated,
the
half­
live
of
elimination
for
dogs
is
significantly
longer
than
for
all
other
species
considered.
(
3)
Although
the
primary
means
of
elimination
of
2,4­
D
and
other
organic
acids
is
via
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
46
the
kidney,
the
difference
in
the
elimination
pattern
among
dogs
and
other
mammalian
species
persuaded
HIARC
that
the
rat
was
a
better
predictor
than
the
dog
of
the
potential
toxicity
of
2,4­
D
to
man.

EXECUTIVE
SUMMARY:
In
a
pharmacokinetics/
metabolism
study
(
MRID
45840901),
(
14C)
2,4­
D
[
98%%
a.
i.,
lot
#
227­
45B;
(
14C)
batch
#
011022,
specific
radioactivity
9.206
MBq/
mg),
ring
labeled]
was
administered
to
18
male
and
16
female
Fischer­
strain
rats
[
CDF
Crl:
BR
(
F­
344)]
and
4
per
sex
pure­
bred
beagle
dogs
once
via
gavage
at
dose
levels
of
0,
5,
and
50
mg/
kg.

There
were
no
overt
signs
of
toxicity
in
either
species
or
sex
at
either
dose
level.
Essentially
all
of
the
radiolabel
was
recovered
from
the
rats,
while
approximately
half
was
recovered
from
the
dogs
[
dog
carcasses
were
not
monitored].
Plasma
levels
of
radiolabel
reached
maximum
concentration
at
1
hour
[
low
dose]
and
2
hours
[
high
dose]
post
dose
in
rats
of
both
sexes.
Maximum
plasma
concentrations
of
radiolabel
in
the
dog
were
attained
at
5.5
hours
[
males]/
6.0
hours
[
females]
at
the
low
dose
and
8.0
hours
[
males]/
10
hours
[
females]
at
the
high­
dose.
In
both
the
rat
and
dog,
clearance
of
radiolabel
from
plasma
was
slightly
more
prolonged
in
females
than
in
males
at
both
dose
levels.
In
the
rat,
pharmacokinetic
parameters
were
not
linear
with
respect
to
dose
level.
A
10­
fold
increase
in
dose
resulted
in
an

60­
fold
increase
in
AUC
and
an

20­
fold
increase
in
C
max,
suggesting
that
a
clearance
mechanism
was
saturated
at
the
high­
dose
level
in
the
rat.
In
contrast,
the
pharmacokinetic
parameters
in
the
dog
were
essentially
proportional
with
the
10­
fold
increase
in
dose
level,
with
a
similar
increase
in
both
AUC
and
C
max.

The
majority
of
the
radiolabel
was
excreted
in
the
urine
of
both
male
[
low

77%/
high

73%]
and
female
[
low

73%/
high
57%]
rats
at
both
dose
levels
and
both
sexes
of
dogs
at
the
low­
dose
level
[
males
35%/
females
36%].
Of
the
amount
excreted
via
the
urine,
greater
than
90%
was
excreted
by
12
hours
post
dose
in
the
low­
dose
rats
[
both
sexes]
and
high­
dose
male
rats,
while
the
high­
dose
female
rats
excreted
only
79%
by
12
hours
post
dose
[
96%
by
24
hours
post
dose].
In
the
dog,
of
the
amount
excreted
via
the
urine,
less
than
15%
was
excreted
by
12
hours
post
dose.
Elimination
of

80%
of
the
dose
via
the
urine
by
the
dogs
was
not
attained
until
96
hours
post
dose
in
both
sexes
and
both
dose
levels
[
low
males
84%/
females
83%;
high
males
80%/
females
84%].
Less
than
2.5%
of
the
radiolabel
was
excreted
in
the
feces
of
male
rats
at
both
dose
levels,
and
the
low­
dose
female
rats
excreted

3.4%
via
the
feces.
High­
dose
female
rats
excreted

8.4%
via
the
feces.
Of
the
amount
of
radiolabel
excreted
via
the
feces,
the
majority
was
excreted
by
12
hours
post
dose
in
both
the
low­
[
76%]
and
high­
[
66%]
dose
male
rats.
Of
the
amount
of
radiolabel
excreted
via
the
feces
in
the
low­
dose
females,
only
9%
was
eliminated
by
12
hours
post
dose;
83%
was
eliminated
by
the
24­
hour
timepoint.
For
the
high­
dose
female
rats,
52%
was
excreted
by
the
12­
hour
time
point
and
27%
by
the
24­
hour
time
point.
In
the
dogs,
excretion
via
the
feces
occurred
throughout
the
duration
of
the
study.
Lowdose
male
[
13.03%]
and
female
[
10.08%]
dogs
excreted
about
half
the
amount
of
radiolabel
via
the
feces
as
did
the
high­
dose
male
[
25%]
and
female
[
21.27%]
dogs.
At
120
hours
post
dose,
the
amount
eliminated
via
the
feces
[
both
sexes]
was
15%
at
the
low
dose
and
11%
[
males]/
13%
[
females]
at
the
high
dose.
At
the
high­
dose
level,
the
greatest
amount
excreted
via
the
feces
occurred
at
the
48­
and
72­
hour
timepoints
post
dose
in
both
sexes
of
the
dog.
At
the
low­
dose
level,
the
greatest
amount
excreted
via
the
feces
also
occurred
at
the
48­
and
72­
hour
timepoints
post
dose
in
the
male
dogs,
while
comparable
amounts
[

20%]
were
excreted
at
the
24­,
48,
and
72
hour
timepoints
in
the
low­
dose
females.
Females
of
both
sexes
displayed
a
slower,
more
prolonged
clearance
from
the
plasma
than
the
males,
although
the
difference
between
the
sexes
was
more
pronounced
in
the
rat
than
in
the
dog.

At
the
50
mg/
kg
dose
level,
clearance
was
clearly
reduced
[
males
41

g/
g/
females
21

g/
g]
compared
to
the
5
mg/
kg
dose
level
[
males
238

g/
g;
females
88

g/
g]
in
both
sexes
of
rat,
suggesting
that
a
clearance
mechanism
was
saturated
at
the
higher
dose
level
in
the
rat.
The
dogs
displayed
comparable
clearance
at
both
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
47
dose
levels,
indicating
that
both
dose
levels
saturated
a
clearance
mechanism
[
males
1.0

g/
g
at
low;
1.5

g/
g
at
high
dose].

Metabolism
was
minimal
in
the
rat,
with
2,4­
D
being
excreted
in
the
urine
basically
unchanged.
In
the
dog,
numerous,
minor,
metabolites
of
2,4­
D
were
excreted
in
the
urine,
with
the
main
metabolic
route
being
by
conjugation.
In
dog
urine,
the
major
component
was
parent
compound,
but
there
were
seven
identified
metabolites
[
conjugates].
The
identified
dog
urine
metabolites
were
the
glutamic
acid,
serine,
glycine,
and
taurine
conjugates
of
2,4­
D,
the
sulphate
and
glucuronide
conjugates
of
the
de­
acetylated
parent
compound,
and
the
cysteine
conjugate
of
the
de­
chlorinated
and
de­
acetylated
parent.

This
metabolism/
pharmacokinetics
study
in
the
rat
and
dog
is
classified
ACCEPTABLE/
non­
guideline.
This
study
was
designed
specifically
to
compare
the
rat
and
dog
with
respect
to
the
excretion
of
2,4­
D
and
the
relevancy
of
the
dog
data
for
risk
assessment.
It
does
not
satisfy
the
guideline
requirement
for
a
metabolism/
pharmacokinetics
study
[
OPPTS
870.7485,
OECD
417]
in
rats
[
and
dogs].
It
is
classified
nonguideline
because
no
tissues
were
monitored,
other
than
plasma/
blood
and
the
carcass
of
the
dogs
was
not
monitored.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
48
8.0
REFERENCES
in
MRID
order
00031050
Feldman.
R.
J.
and
Maibach,
H.
I.
(
1974).
Percutaneous
Penetration
of
Some
Pesticides
and
Herbicides
in
Man.
Toxicol.
Appl.
Pharmacol.
28:
126­
132];
unpublished
submission
received
Apr
23,
1980
under
10279­
7;
submitted
by
Purdue
Freder­
ick
Co.,
Norwalk,
Conn.

00101596
Mayhew,
D.;
Johnson,
Y.;
Kingery,
A.
(
1981)
Acute
Dermal
Toxicity
Study
in
Albino
Rabbits
with
ITF­
5;
2,
4­
Dichlorophenoxyacetic
Acid,
Sodium
Salt:
Project
No.
WIL­
81233.
(
Unpublished
study
received
Jul
23,
1981
under
unknown
admin.
no.;
prepared
by
WIL
Research
Laboratories,
Inc.,
submitted
by
Dow
Chemical
U.
S.
A.,
Midland,
MI;
CDL:
247496­
F)
Accession
#:
247496
00101602
Johnson,
D.;
Myer,
J.;
Marroquin,
F.;
et
al.
(
1981)
Determination
of
Acute
Dermal
LD50
in
Rabbits:
IRDC
Study
No.
490­
006.
(
Un­
published
study
received
Dec
21,
1981
under
unknown
admin.
no.;
prepared
by
International
Research
and
Development
Corp.,
submitted
by
Dow
Chemical
U.
S.
A.,
Midland,
MI;

00101603
Johnson,
D.;
Myer,
J.;
Moxon,
P.;
et
al.
(
1981)
Determination
of
Acute
Oral
LD50
in
Fischer
344
Rats:
2,4­
Dichlorophenoxyacetic
acid,
dimethylamine
salt:
490­
003.
Rev.
(
Unpublished
study
received
Dec
21,
1981
under
unknown
admin.
no.;
prepared
by
International
Research
and
Development
Corp.,
submitted
by
Dow
Chemical
U.
S.
A.,
Midland,
MI
00101605
Johnson,
D.;
Myer,
J.;
Moxon,
P.;
et
al.
(
1981)
Determination
of
Acute
Oral
LD50
in
Fischer
344
Rats:
2,4­
Dichlorophenoxyacetic
Acid,
Technical:
490­
001.
Rev.
(
Unpublished
study
received
Dec
21,
1981
under
unknown
admin.
no.;
prepared
by
International
Research
and
Development
Corp.,
submitted
by
Dow
Chemical
U.
S.
A.,
Midland,
MI;
CDL:
247499­
C)

00130407
Rodwell,
D.;
Werchowski,
K.;
Mercieca,
M.;
et
al.
(
1983)
A
Teratology
Study
in
Fischer
344
Rats
with
2,4­
Dichlorophenoxyacetic
Acid:
Project
No.
WIL­
81135.
Final
rept.
(
Unpublished
study
received
Jun
1,
1983
under
unknown
admin.
no.;
prepared
by
WIL
Research
Laboratories,
Inc.,
submitted
by
2­
4
D
Task
Force,
Washington,
DC;
CDL:
251031­
A)
Accession
#:
251031
A
00130408
Nemec,
M.;
Kopp,
S.;
Leist,
P.;
et
al.
(
1983)
A
Range­
finding
Teratology
Study
in
Fischer
344
Rats
with
2,4­
Dichlorophenoxyacetic
Acid:
Project
No.
WIL­
22002.
Final
rept.
(
Unpublished
study
received
Jun
1,
1983
under
unknown
admin.
no.;
prepared
by
WIL
Research
Laboratories,
Inc.,
submitted
by
2­
4
D
Task
Force,
Washington,
DC;
CDL:
251032­
A)
Accession
#:
251032
A
00131303
Serota,
D.;
Colpean,
B.;
Burdock,
G.;
et
al.
(
1983)
Subchronic
Toxicity
Study
in
Mice:
2,4­
Dichlorophenoxy
Acetic
Acid
(
2,4­
D):
Project
No.
2184­
100.
Final
rept.
(
Unpublished
study
received
Oct
14,
1983
under
unknown
admin.
no.;
prepared
by
Hazleton
Laboratories
America,
Inc.,
submitted
by
2,4­
D
Task
Force,
Washington,
DC;
CDL:
251473­
A)
Accession
#:
251473
A
00131304
Serota,
D.;
Burns,
C.;
Burdock,
G.;
et
al.
(
1983)
Subchronic
Toxicity
Study
in
Rats­­
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D):
Project
No.
2184­
102.
Final
rept.
(
Unpublished
study
received
Oct
14,
1983
under
unknown
admin.
no.;
prepared
by
Hazleton
Laboratories
America,
Inc.,
submitted
by
2,4­
D
Task
Force,
Washington,
DC;
CDL:
251474­
A)
Accession
#:
251474
A
00138868
Streeter,
C.;
Young,
J.
(
1983)
XRM­
4725:
An
Acute
Aerosol
Inhalation
Study
with
Rats.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
49
(
Unpublished
study
received
Jan
18,
1984
under
464­
596;
submitted
by
Dow
Chemical
U.
S.
A.,
Midland,
MI;
CDL:
252291­
C)

00149377
Eiseman,
J.
(
1984)
The
Pharmacokinetic
Evaluation
of
[
Carbon
14]­
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D)
in
the
Mouse:
Final
Re­
port:
Project
No.
2184­
104.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
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148
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00150557
Tasker,
E.
(
1985)
A
Dietary
Two­
Generation
Reproduction
Study
in
Fischer
344
Rats
with
2,4­
Dichlorophenoxyacetic
Acid:
Final
Report:
Project
No.
WIL­
81137.
Unpublished
study
prepared
by
WIL
Research
Laboratories,
Inc.
1402
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Eisenbrandt,
D.
(
1986)
DMA
6
Weed
Killer:
Acute
Oral
Toxicity
Study
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344
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Unpublished
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15
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00157513
Carreon,
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Schuetz,
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Lomax,
L.
(
1986)
DMA
6:
Acute
Dermal
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Study
in
New
Zealand
White
Rabbits:
Study
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M­
003637­
001.
Unpublished
study
prepared
by
Dow
Chemical
U.
S.
A.
20
p.

00157514
Streeter,
C.;
Battjes,
J.;
Lomax,
L.
(
1985)
DMA­
6
Sequestered
Weed
Killer:
Acute
Aerosol
Inhalation
Study
with
Rats.
Unpublished
study
prepared
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Dow
Chemical
U.
S.
A.
13
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00157515
Carreon,
R.
(
1986)
DMA
6:
Primary
Eye
Irritation
Study
in
New
Zea­
land
White
Rabbits.
Unpublished
study
prepared
by
Dow
Chemical
U.
S.
A.
9
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00157516
Jeffrey,
M.
(
1986)
DMA
6
Weed
Killer:
Primary
Dermal
Irritation
Study
in
New
Zealand
White
Rabbits.
Unpublished
study
prepared
by
Dow
Chemical
U.
S.
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9
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00157517
Carreon,
R.
(
1985)
DMA
6:
Dermal
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Potential
in
the
Guinea
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Unpublished
study
prepared
by
Dow
Chemical
U.
S.
A.
9
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00160876
Serota,
D.
(
1986)
Combined
Toxicity
and
Oncogenicity
Study
in
Rats:
2,4­
Dichlorophenoxy
acetic
Acid:
Final
Report:
Project
No.
2184­
103.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
2049
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00161659
Gargus,
J.
(
1986)
Dermal
Sensitization
Study
in
Guinea
Pigs:
2,4­
Dichlorophenoxyacetic
Acid:
Final
Report:
Project
No.
2184­
105.
Unpublished
study
prepared
by
Hazleton
Laboratories,
Inc.
10
p.

00161660
Auletta,
C.;
Daly,
I.
(
1986)
An
Acute
Inhalation
Toxicity
Study
of
2,4­
Dichlorophenoxyacetic
Acid
in
the
Rat:
Final
Report:
Project
No.
86­
7893.
Unpublished
study
prepared
by
Bio/
dynamics
Inc.
39
p.

00163996
Brown,
R.
(
1986)
A
Dietary
Two­
Generation
Reproduction
Study
in
Fischer
344
Rats
with
2,4­
Dichlorophenoxyacetic
Acid:
Addendum
to
the
Final
Report:
[
Microscopic
Evaluation
of
the
Kidneys
of
the
FO,
F1
and
F1b
Male
Rats]:
Project
No.
WIL­
81137.
Unpublished
study
prepared
by
WIL
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
50
Research
Laboratories,
Inc.
19
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40061801
Serota,
D.
(
1986)
Oncogenicity
Study
in
Mice
with
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D):
Final
Report:
HLA
Project
No.
2184­
101.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
1797
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40085501
Heydens,
W.
(
1986)
Acute
Toxicity
of
Landmaster
II
Administered
by
Inhalation
to
Male
and
Female
Sprage­
Dawley
Rats:
Monsanto
Reference
No.
EHL
86125.
Unpublished
study
prepared
by
Monsanto
Co.,
Environmental
Health
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45
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40352701
Maedgen,
J.
(
1986)
Rat
Acute
Inhalation
Toxicity:
Tech.
Isopropyl
Ester
of
2,4­
D:
Proj.
No.
4377­
86.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
15
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40352702
Maedgen,
J.
(
1986)
Rabbit
Eye
Irritation:
Tech.
Isopropyl
Ester
of
2,4­
D:
Proj.
No.
4374­
86.
Unpublished
study
prepared
by
Still­
meadow,
Inc.
16
p.

40352703
Maedgen,
J.
(
1986)
Rabbit
Skin
Irritation:
Tech.
Isopropyl
Ester
of
2,4­
D:
Proj.
No.
4375­
86.
Unpublished
study
prepared
by
Still­
meadow,
Inc.
11
p.

40352704
Maedgen,
J.
(
1986)
Guinea
Pig
Skin
Sensitization:
Tech.
Isopropyl
Ester
of
2,4­
D:
Proj.
No.
4376­
86.
Unpublished
study
prepared
by
Stillmeadow,
Inc.
15
p.

40629801
Jeffrey,
M.;
Battjes,
J.;
Lomax.
L.
(
1987)
2,4­
D
Butoxyethyl
Ester,
Technical:
Acute
Oral
Toxicity
Study
in
Fischer
344
Rats:
Lab.
Proj.
ID
K­
007722­
006A.
Unpublished
study
prepared
by
Dow
Chemical
Co.
30
p.
Accession
#:
406298
01
40629802
Jeffrey,
M.;
Battjes,
J.;
Zimmer,
M.
(
1987)
2,4­
D
Butoxyethyl
Ester
Technical:
Acute
Dermal
Toxicity
Study
in
New
Zealand
White
Rab­
bits:
Lab.
Proj.
ID
K­
007722­
006D.
Unpublished
study
prepared
by
Dow
Chemical
Co.
27
p.

40629803
Streeter,
C.;
Battjes,
J.;
Yano,
B.
(
1987)
2,4­
D
Butoxyethyl
Ester,
Technical:
An
Acute
Aerosol
Inhalation
Study
in
Fischer
344
Rats:
Lab.
Proj.
ID
K­
007722­
007.
Unpublished
study
prepared
by
Dow
Chemical
Co.
22
p.

40629804
Jeffrey,
M.
(
1987)
2,4­
D
Butoxyethyl
Ester,
Technical:
Primary
Eye
Irritation
Study
in
New
Zealand
White
Rabbits:
Lab.
Proj.
ID
K­
007722­
006C.
Unpublished
study
prepared
by
Dow
Chemical
Co.
11
p.

40629805
Jeffrey,
M.
(
1987)
2,4­
D
Butoxyethyl
Ester,
Technical:
Primary
Dermal
Irritation
Study
in
New
Zealand
White
Rabbits:
Lab.
Proj.
ID
K­
007722­
006B.
Unpublished
study
prepared
by
Dow
Chemical
Co.
10
p.

40629806
Jeffrey,
M.
(
1986)
Butoxy
Ethyl
2,4­
Dichlorophenoxyacetate:
Dermal
Sensitization
Potential
in
the
Hartley
Albino
Guinea
Pig:
Lab.
Proj.
ID
K­
007722­
005.
Unpublished
study
prepared
by
Dow
Chemical
Co.
10
p.

41125302
Kirsch,
P.
(
1983)
Report
on
the
Study
of
the
Irritation
to
the
Eye
of
the
White
Rabbit
Based
on
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
51
Draize
of
2,4­
D:
Doc.
No.
BASF:
83/
0192.
Unpublished
study
prepared
by
BASF
Aktiengesellschaft.
10
p.

41209001
Mahlburg,
W.
(
1988)
Acute
Oral
Toxicity
Study
of
DPD
Ester
in
Sprague­
Dawley
Rats:
Project
ID:
88.3505.002;
Study
No.
89­
19A.
Unpublished
study
prepared
by
Food
&
Drug
Research
Laboratories.
95
p.

41209002
Mahlburg,
W.
(
1988)
Acute
Dermal
Toxicity
Study
of
DPD
Ester
in
New
Zealand
White
Rabbits:
Project
ID:
88.3505.003;
Study
No.
89­
19A.
Unpublished
study
prepared
by
Food
&
Drug
Research
Laboratories.
39
p.

41209003
Mahlburg,
W.
(
1988)
Acute
Inhalation
Limit
Test
of
DPD
Ester
in
Sprague­
Dawley
Rats:
Project
ID:
88.3505.013;
Study
No.
89­
19A.
Unpublished
study
prepared
by
Food
&
Drug
Research
Laboratories.
90
p.

41209005
Mahlburg,
W.
(
1988)
Primary
Dermal
Irritation
Study
of
DPD
Ester
in
New
Zealand
White
Rabbits:
Project
ID:
88.3505.005;
Study
No.
89­
19A.
Unpublished
study
prepared
by
Food
&
Drug
Research
Laboratories.
34
p.

41209006
Mahlburg,
W.
(
1988)
Dermal
Sensitization
Study
in
Guinea
Pigs
with
DPD
Ester:
Project
ID:
88.3505.006;
Study
No.
89­
19A.
Unpublished
study
prepared
by
Food
&
Drug
Research
Laboratories.
38
p.

41232304
Lilja,
H.
(
1988)
Primary
Dermal
Irritation
Study:
Isopropyl:
Pro­
ject
ID:
88G­
0273.
Unpublished
study
prepared
by
Toxikon
Corp.
14
p.

41232305
Lilja,
H.
(
1989)
Epicutaneous
skin
Sensitization
Test
(
Buehler
Topical
Closed
Patch
Technique):
HIVOL­
44.
Unpublished
study
prepared
by
Toxikon
Corp.
23
p.

41388202
Samson,
Y.;
Gollapudi,
B.
(
1989)
Evaluation
of
2,4­
D
Triisopropanolamine
Salt
in
the
Ames
Salmonella/
Mammalian­
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
TXT:
M­
008866­
007.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
26
p.

41388203
Samson,
Y.;
Gollapudi,
B.
(
1989)
Evaluation
of
2,4­
D
Isopropylamine
Salt
in
the
Ames
Salmonella/
Mammalian­
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
TXT:
M­
004725­
007.
Unpublished
study
prepared
by
the
Dow
Chemical
Co.
26
p.

41388204
Samson,
Y.;
Gollapudi,
B.
(
1989)
Evaluation
of
2,4­
D
Butoxyethyl
Ester
in
the
Ames
Salmonella/
Mammalian­
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
TXT:
K­
007722­
011.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
27
p.

41407901
Mizell,
M.;
Atkin,
L.;
Crissman,
J.
(
1990)
2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
Ester:
21­
Day
Dermal
Toxicity
Study
in
New
Zealand
White
Rabbits:
Final
Report:
Study
ID:
HET
K­
007722­
008.
Unpublished
study
prepared
by
Dow
Chemical
Co.,
Toxicology
Research
Laboratory.
167
p.

41407902
Mizell,
M.;
Atkin,
L.;
Haut,
K.;
et
al.
(
1990)
2,4­
D
Triisopropanolamine
Salt:
21­
Day
Dermal
Toxicity
Study
in
New
Zealand
White
Rabbits:
Final
Report:
Study
ID:
K­
008866­
004.
Unpublished
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
52
study
prepared
by
Dow
Chemical
Co.,
Toxicology
Research
Laboratory.
168
p.

41407903
Mizell,
M.;
Atkin,
L.;
Haut,
K.;
et
al.
(
1990)
2,4­
D
Isopropylamine
Salt:
21­
Day
Dermal
Toxicity
Study
in
New
Zealand
White
Rabbits:
Lab
Project
Number:
M­
004725­
004.
Unpublished
study
prepared
by
Dow
Chemical
Co.,
Toxicology
Research
Laboratory.
166
p.

41409801
Lawlor,
T.;
Valentine,
D.
(
1990)
Mutagenicity
Test
on
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D)
in
the
Salmonella­
Microsome
Reverse
Mutation
Assay
(
Ames
Test):
Rev.
Final
Rept.:
Lab
Study
No.
10979­
0­
401.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
34
p.

41409802
Lawlor,
T.;
Valentine,
D.
(
1990)
Mutagenicity
Test
on
2,4­
D­
Dimethylamine
Salt
in
the
Salmonella/
Mammalian­
Microsome
Reverse
Mutation
Assay
(
Ames
Test):
Revised
Final
Report:
Lab
Project
No.
10981­
0­
401.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
34
p.

41409803
Lawlor,
T.;
Valentine,
D.
(
1990)
Mutagenicity
Test
on
2,4­
D­
2­
Ethylhexyl
Ester
in
the
Salmonella/
Mammalian­
Microsome
Reverse
Mutation
Assay
(
Ames
Test):
Revised
Final
Report:
Lab
Project
No.
10980­
0­
401.
Unpublished
study
prepared
by
Hazleton
Labora­
tories
America,
Inc.
34
p.

41409804
Ivett,
J.
(
1990)
Mutagenicity
Test
on
2,4­
D­
2­
Dichlorophenoxyacetic
Acid
in
vivo
Mouse
Micronucleus
Assay:
Revised
Final
Report:
Lab
Project
No.
10979­
0­
455.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
39
p.

41409805
Ivett,
J.
(
1990)
Mutagenicity
Test
on
2,4­
D
Dimethylamine
Salt
in
vivo
Mouse
Micronucleus
Assay:
Revised
Final
Report:
Lab
Project
Number:
10981­
0­
455.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
40
p.

41409806
Ivett,
J.
(
1990)
Mutagenicity
Test
on
2,4­
D­
2­
Ethylhexyl
Ester
in
vivo
Mouse
Micronucleus
Assay:
Revised
Final
Report:
Lab
Project
No.
10980­
0­
455.
Unpublished
study
prepared
by
Hazleton
Labora­
tories,
Inc.
39
p.

41409807
Cifone,
M.
(
1990)
Mutagenicity
Test
on
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D)
in
the
in
vitro
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay:
Revised
Final
Report:
Lab
Project
No.
10979­
0­
447.
Unpublished
study
prepared
by
Hazleton
Labora­
tories
America,
Inc.
43
p.

41409808
Cifone,
M.
(
1990)
Mutagenicity
Test
on
2,4­
D
Dimethylamine
Salt
in
the
in
vitro
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay:
Revised
Final
Report:
Lab
Project
Number:
10981­
0­
447.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
44
p.

41409809
Cifone,
M.
(
1990)
Mutagenicity
Test
on
2,4­
D­
2­
Ethylhexyl
Ester
in
the
in
vitro
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay:
Revised
Final
Report:
Lab
Project
Number:
10980­
0­
447.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
44
p.

41413501
Berdasco,
N.;
Schuetz,
D.;
Jersey,
G.
et
al.
(
1989)
2,4­
Dichlorophenoxyacetic
Acid
Triisopropanolamine
Salt:
Acute
Oral
Toxicity
Study
in
Fischer
344
Rats:
Lab
Project
Number:
K­
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
53
008866­
002A.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
33
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41413502
Berdasco,
N.;
Schuetz,
B.;
Yano,
B.
et
al.
(
1989)
2,4­
Dichlorophenoxyacetic
Acid
Triisopropanolamine
Salt:
Acute
Dermal
Toxicity
Study
in
New
Zealand
White
Rabbits:
Lab
Project
Number:
K­
008866
­
002D.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
19
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41413503
Nitschke,
K.;
Lomax,
L.
(
1990)
2,4­
D
Triisopropanolamine:
Acute
Aerosol
LC50
Study
in
Fischer
344
Rats:
Lab
Project
Number:
HET
K­
008866­
010.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
30
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41413504
Berdasco,
N.;
Mizell,
M.
(
1989)
2,4­
Dichorophenoxyacetic
Acid
Tri­
isopropanolamine
Salt:
Primary
Eye
Irritation
Study
in
New
Zealand
White
Rabbits:
Lab
Project
Number:
K­
008866­
002C.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
14
p.

41413505
Mizell,
M.
(
1989)
2,4­
Dichlorophenoxyacetic
Acid,
Triisopropanolamine
Salt:
Primary
Dermal
Irritation
Study
in
New
Zealand
White
Rabbits:
Lab
Project
Number:
K­
008866­
002B.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
13
p.

41413506
Berdasco,
N.
(
1989)
2,4­
Dichlorophenoxyacetic
Acid
Triisopropanolamine
Salt:
Dermal
Sensitization
Potential
in
the
Hartley
Albino
Guinea
Pig:
Lab
Project
Number:
K­
008866­
002E.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
14
p.

41420004
Ivett,
J.
(
1989)
Single
Acute
Exposure
Dose
Selection
Study
on
2,4­
D
Dimethylamine
Salt:
Lab
Project
Number:
10981­
0­
459­
PO.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
15
p.

41420005
Ivett,
J.
(
1989)
Single
Acute
Exposure
Dose
Selection
Study
on
2,4­
D­
2­
Ethylhexyl
Ester:
Lab
Project
Number:
10980­
0­
459­
PO.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
15
p.

41478301
Gollapudi,
B.
;
Samson,
Y.
;
McClintock,
M.
(
1990)
Evaluation
of
2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
Ester
(
2,4­
D
BEE)
in
the
Mouse
Bone
Marrow
Micronucleus
Test:
Lab
Project
Number:
K­
O07722­
012.
Unpublished
study
prepared
by
Dow
Chemical
Co.,
Lake
Jackson
Research
Ctr.
29
p.

41478302
Gollapudi,
B.;
Samson,
Y.;
McClintock,
M.
(
1990)
Evaluation
of
a
Formulation
Containing
2,4­
Dichlorophenoxyacetic
Acid
Triisopropanolamine
Salt
(
2,4­
D
TIPA)
in
the
Mouse
Bone
Marrow
Micronucleus
Test:
Lab
Project
Number:
K­
008866­
009.
Unpublished
study
prepared
by
Dow
Chemical
Co.,
Lake
Jackson
Research
Center.
30
p.

41478303
Gollapudi,
B.;
Samson,
Y.;
McClintock,
M.
(
1990)
Evaluation
of
a
Formulation
Containing
2,4­
Dichlorophenoxyacetic
Acid
Isopropylamine
Salt
(
2,4­
D
IPA)
in
the
Mouse
Bone
Marrow
Micronucleus
Test:
Lab
Project
Number:
M­
004725­
009.
Unpublished
study
pre­
pared
by
Dow
Chemical
Co.,
Lake
Jackson
Research
Ctr.
30
p.

41498101
McClintock,
M.;
Gollapudi,
B.
(
1990)
Evaluation
of
2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
Ester
(
2,4­
D
BEE)
in
the
Rat
Hepatocyte:
Unscheduled
DNA
Synthesis
(
UDS)
Assay:
Lab
Project
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
54
Number:
TXT:
K­
007722­
013.
Unpublished
study
prepared
by
The
Dow
Chem­
ical
Co.
46
p.

41498102
McClintock,
M.;
Gollapudi,
B.
(
1990)
Evaluation
of
a
Formulation
Containing
2,4­
Dichlorophenoxyacetic
Acid
Triisopropylamine
Salt
(
2,4­
D
TIPA)
in
the
Rat
Hepatocyte
Unscheduled
DNA
Synthesis
(
UDS)
Assay:
Lab
Project
Number:
TXT:
K­
008866­
008.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
46
p.

41498103
McClintock,
M.;
Gollapudi,
B.
(
1990)
Evaluation
of
a
Formulation
Containing
2,4­
Dichlorophenoxyacetic
Acid
Isopropylamine
Salt
(
2,4­
D
IPA)
in
the
Rat
Hepatocyte:
Unscheduled
DNA
Synthesis
(
UDS)
Assay:
Lab
Project
Number:
TXT:
M­
004725­
008.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
46
p.

41527101
Schroeder,
R.
(
1990)
A
Teratogenicity
Study
in
Rats
with
2­
Butoxyethyl
Ester
of
2,4­
D:
Lab
Project
No.:
HET
K­
007722­
017:
89­
34677.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
452
p.

41527102
Schroeder,
R.
(
1990)
A
Teratogenicity
Study
in
Rats
with
2,4­
D
Trisopropylamine:
Lab
Project
Number:
HET
K0008866­
012:
89­
3463.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
478
p.

41527103
Schroeder,
R.
(
1990)
A
Teratogenicity
Study
in
Rats
with
2,4­
D
Isopropylamine
Salt:
Lab
Project
Number:
HET
K­
004725­
011:
89­
3465.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
441
p.

41527104
Schroeder,
R.
(
1990)
A
Range­
Finding
Study
to
Evaluate
the
Toxicity
of
2­
Butoxyethyl
Ester
of
2,4­
D
in
the
Pregnant
Rat:
Lab
Project
Number:
HET
K­
007722­
016:
89­
3468.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
154
p.

41527105
Schroeder,
R.
(
1990)
A
Range­
Finding
Study
to
Evaluate
the
Toxicity
of
2,4­
D
Triisopropylamine
Salt
in
the
Pregnant
Rat:
Lab
Project
Number:
HET
K­
008866­
011:
89­
3464.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
246
p.

41527106
Schroeder,
R.
(
1990)
A
Range­
Finding
Study
to
Evaluate
the
Toxicity
of
2,4­
D
Isopropylamine
Salt
in
the
Pregnant
Rat:
Lab
Project
Number:
HET
K­
004725­
010:
89­
3466.
Unpublished
study
prepared
by
Bio/
dynamics,
Inc.
141
p.

41642803
Robbins,
G.
(
1989)
Primary
Eye
Irritation
Study
in
Rabbits:
Dri­
D
Amine:
Lab
Project
Number:
D2013.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
19
p.

41642804
Robbins,
G.
(
1989)
Primary
Dermal
Irritation
Study
in
Rabbits:
Dri­
D
Amine:
Lab
Project
Number:
E2013.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
14
p.

41642805
Robbins,
G.
(
1989)
Guinea
Pig
Sensitization
Study
(
Buehler):
Dri­
D
Amine:
Lab
Project
Number:
F2013.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
17
p.

41709901
Lilja,
H.
(
1990)
Acute
Oral
Toxicity
Study
(
LD50):
Hivol­
44:
Amended
Report:
Lab
Project
Number:
88G­
0274.
Unpublished
study
prepared
by
Toxikon
Corp.
17
p.

41709902
Lilja,
H.
(
1990)
Single
Dose
Dermal
Toxicity:
Hivol­
44:
Amended
Report:
Project
Number:
88G­
0272.
Unpublished
study
prepared
by
Toxikon
Corp.
14
p.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
55
41735201
Lochry,
E.
(
1990)
Developmental
Toxicity
(
Embryo­
Fetal
Toxicity
and
Teratogenic
Potential)
Study
of
2,4­
Dimethylamine
Salt
(
2,4­
D­
DMA
Administered
Orally
via
Gavage
to
CRL:
CD
BR
VAF/
Plus
Presumed
Pregnant
Rats:
Final
Report:
Lab
Project
Number:
320­
001.
Unpublished
study
prepared
by
Argus
Research
Labs.
436
p.

41735304
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Dermal
Toxicity
Study
in
Rabbits
with
2,4
Dichlorophenoxyacetic
Acid:
Lab
Project
Number:
2184­
109.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
186
p.

41735301
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Range­
finding
Study
in
Rabbits
with
2,4­
Dichlorophenoxyacetic
Acid:
Final
Report:
Lab
Project
Number:
2184­
106.
Unpublished
study
prepared
by
Hazle­
ton
Labs
America,
Inc.
39
p.

41735302
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Dermal
Range­
finding
Study
in
Rabbits
with
2,4­
Dichlorophenoxyacetic
Acid­
2­
Ethylhexyl
Ester:
Lab
Project
Number:
2184­
107.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
44
p.

41735303
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Dermal
Range­
finding
Study
in
Rabbits
with
Dimethylamine
Salt
of
2,4­
Dichlorophenoxyacetic
Acid:
Lab
Project
Number:
2184­
108.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
46
p.

41735304
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Dermal
Toxicity
Study
in
Rabbits
with
2,4
Dichlorophenoxyacetic
Acid:
Lab
Project
Number:
2184­
109.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
186
p.

41735305
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Dermal
Toxicity
Study
in
Rabbits
with
2,4­
Dichlorophenoxyacetic
Acid­
2­
ethylhexyl
Ester:
Lab
Project
Number:
2182­
110.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
200
p.

41735306
Schulze,
G.
(
1990)
21­
Day
Dermal
Irritation
and
Dermal
Toxicity
Study
in
Rabbits
with
the
Dimethylamine
Salt
of
2,4­
Dichlorophenoxyacetic
Acid:
Lab
Project
Number:
2184­
111.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
212
p.

41737301
Schulze,
G.
(
1990)
Subchronic
Toxicity
Study
in
Dogs
with
2,4­
Dichlorophenoxyacetic
Acid:
Final
Report:
Lab
Project
Number:
2184­
115.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
332
p.

41737302
Timchalk,
C.;
Dryzga,
M.;
Brzak,
K.
(
1990)
2,4­
Dichlorophenoxyacetic,
Tissue
Distribution
and
Metabolism
of
(
Carbon
14)­
Labeled,
2,4­
Dichlorophenoxyacetic
Acid
in
Fischer
344
Rats:
Final
Report:
Lab
Project
No.:
K­
2372­
47.
Unpublished
study
prepared
by
the
Dow
Chemical
Co.
70
p.

41747601
Hoberman,
A.
(
1990)
Development
Toxicity
(
Embryo­
Fetal
Toxicity
and
Teratogenic
Potential)
Study
of
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D
Acid)
Administered
Orally
via
Stomach
Tube
to
New
Zealand
White
Rabbits:
Lab
Project
Number:
320­
003.
Unpublished
study
prepared
by
Argus
Research
Laboratories,
Inc.
478
p.

41797901
Samson,
Y.;
Gollapudi,
B.
(
1990)
Response
to
the
Comments
by
the
U.
S.
EPA
on
the
Study
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
56
Entitled:
Evaluation
of
2,4­
D
Triisopropanolamine
Salt
in
the
Ames
Salmonella/
Mammalian­
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
TXT:
K­
008866­
007.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
12
p.

41797902
Samson,
Y.;
Gollapudi,
B.
(
1990)
Response
to
the
Comments
by
the
U.
S.
EPA
on
the
Study
Entitled:
Evaluation
of
2,4­
D
Isopropylamine
Salt
in
the
Ames
Salmonella/
Mammalian­
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
TXT:
K­
004725­
007.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
12
p.

41797903
Samson,
Y.;
Gollapudi,
B.
(
1990)
Response
to
the
Comments
by
the
U.
S.
EPA
on
the
Study
Entitled:
Evaluation
of
2,4­
D
Butoxyethyl
Ester
in
the
Ames
Salmonella/
Mammalian­
Microsome
Bacterial
Mutagenicity
Assay:
Lab
Project
Number:
TXT:
K­
007722­
011.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
11
p.

41870101
Ivett,
J.
(
1990)
Mutagenicity
Test
on
2,4­
Dichlorophenoxyacetic
Acid
in
vivo
Mouse
Assay:
Lab
Project
Number:
10979­
0­
455.
Un­
published
study
prepared
by
Hazleton
Laboratories
America,
Inc.
6
p.
Author:
Ivett,
J.
Content
Category:
Incomplete
or
summarized
­­
experimental
research
Receipt
Date:
08­
May­
1991
Laboratory
Project
#:
10979/
0/
455
41870102
Ivett,
J.
(
1990)
Mutagenicity
Test
on
2,4­
Dimethylamine
Salt
in
vivo
Mouse
Micronucleus
Assay:
Supplement
to
41409805:
Proj.
No.
10981­
0­
455.
Rev.
Final
Report.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
6
p.

41870103
Ivett,
J.
(
1990)
Mutagenicity
Test
on
2,4­
D­
2­
Ethylhexyl
Ester
in
vivo
Mouse
Micronucleus
Assay:
Lab
Project
Number:
10980/
0/
455.
Supplement
to
41409806.
Rev.
Final
Report.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
6
p.

41896701
Schulze,
G.
(
1991)
Subchronic
Toxicity
Study
in
Rats
with
2,4­
Di­
chlorophenoxyacetate
Acid­
2­
Ethylhexyl
Ester:
Final
Report:
Lab
Project
Number:
2184­
112.
Unpublished
study
prepared
by
Hazle­
ton
Laboratories
America,
Inc.
484
p.

41896702
Schulze,
G.
(
1991)
Subchronic
Toxicity
Study
in
Rats
with
the
Dimethylamine
Salt
of
2,4­
Dichlorophenoxyacetic
Acid:
Final
Report:
Lab
Project
Number:
2184/
113.
Unpublished
study
prepared
by
Hazleton
Laboratories
America,
Inc.
481
p.

41920901
Shults,
S.;
Brock,
A.;
Killeen,
J.
(
1990)
Acute
Oral
Toxicity
(
LD50)
Study
in
Rats
with
Diethanolamine
Salt
of
2,4­
D:
Lab
Project
Number:
90­
0161:
3592­
90­
0161­
TX­
001.
Unpublished
study
prepared
by
Ricerca,
Inc.
37
p.

41920902
Shults,
S.;
Brock,
A.;
Killeen,
J.
(
1990)
Primary
Eye
Irritation
Study
in
Albino
Rabbits
with
Diethanolamine
Salt
of
2,4­
D:
Lab
Project
Number
90­
0164:
3592­
90­
0164­
TX­
001.
Unpublished
study
prepared
by
Ricerca,
Inc.
30
p.

41920903
Shults,
S.;
Brock,
A.;
Killeen,
J.
(
1990)
Primary
Dermal
Irritation
Study
in
Albino
Rabbits
with
Diethanolamine
Salt
of
2,4­
D:
Lab
Project
Number:
90­
0165:
3592­
90­
0165­
TX­
001.
Unpublished
study
prepared
by
Ricerca,
Inc.
18
p.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
57
41920904
Shults,
S.;
Brock,
A.;
Killeen,
J.
(
1990)
Dermal
Sensitization
Study
(
Closed
Patch
Repeated
Insult)
in
Guinea
Pigs
with
Diethanolamine
Salt
of
2,4­
D:
Lab
Project
Number:
90­
0166:
3592­
90­
0166­
TX­
001.
Unpublished
study
prepared
by
Ricerca,
Inc.
37
p.

41920905
Siglin,
J.
(
1991)
21­
DAy
Dermal
Toxicity
Study
in
Rabbits
with
Diethanolamine
Salt
of
2,4­
D
DEA:
Final
Report:
Lab
Project
Num­
ber:
3229.1.
Unpublished
study
prepared
by
Springborn
Labs,
Inc.
412
p.

41920906
Siglin,
J.
(
1990)
Teratology
Study
in
Rats
with
Diethanolamine
Salt
of
2,4­
D:
Final
Report:
Lab
Project
Number:
3229.3.
Unpublished
study
prepared
by
Springborn
Labs,
Inc.
257
p.

41920907
Ivett,
J.
(
1990)
Single
Acute
Exposure
Dose
Selection
Study
on
Diethanolamine
Salt
of
2,4­
D:
Final
Report:
Lab
Project
Number:
12216­
0­
459­
PO.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
15
p.

41920908
Ivett,
J.
(
1990)
Mutagenicity
Test
on
Diethanolamine
Salt
of
2,4­
D
Acid
in
vivo
Mouse
Micronucleus
Assay:
Final
Report:
Lab
Project
Number
12216­
0­
455.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
38
p.

41920909
McKeon,
M.
(
1990)
Mutagenicity
Test
on
Diethanolamine
Salt
of
2,4­
D
in
the
In
vitro
Rat
Primary
Hepatocyte
Unscheduled
DNA
Synthesis
Assay:
Final
Report:
Lab
Project
Number:
HLA
12216­
0­
447.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
45
p.

41920910
Lawlor,
T.;
Holloway,
P.
(
1990)
Mutagenicity
Test
on
Diethanolamine
Salt
of
2,4­
D
in
the
Salmonella
Mammalian­
Microsome
Reverse
Mutation
Assay
(
Ames
Test):
Final
Report:
Lab
Project
Number:
HLA
12216­
0­
401.
Unpublished
study
prepared
by
Hazleton
Labs
America,
Inc.
51
p.

41920911
Shults,
S.;
Brock,
A.;
Killeen,
J.
(
1991)
Acute
Dermal
Toxicity
Study
in
Albino
Rabbits
with
Diethanolamine
Salt
of
2,4­
D:
Lab
Project
Number:
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Diethanolamine
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2,4­
Dichlorophenoxyacetic
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Lab
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90­
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Response
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D
BEE,
2,4­
D
IPA
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2,4­
D
TIPA
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Salmonella/
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Gollapudi,
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Response
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U.
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EPA:
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Triisopropanolamine
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2,4­
D
TIPA)
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Bone
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Gollapudi,
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Response
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Comments
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U.
S.
EPA:
Evaluation
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2,4­
Dichlorophenoxyacetic
Acid
Isopropylamine
Salt
(
2,4­
D
IPA)
in
the
Mouse
Bone
Marrow
Micronuleus
Test:
Lab
Project
Num­
ber:
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M­
004725­
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Unpublished
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prepared
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Dow
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9
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Gollapudi,
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Response
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U.
S.
EPA:
Evaluation
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2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
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2,4­
D
BEE)
in
the
Mouse
Bone
Marrow
Micronuleus
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Lab
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Dow
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Gollapudi,
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Response
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Comments
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U.
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EPA:
Evaluation
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2,4­
Dichlorophenoxyacetic
Acid
Triisopropanolamine
Salt
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2,4­
D
TIPA)
in
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Mouse
Bone
Marrow
Micronuleus
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The
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Gollapudi,
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Response
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U.
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EPA:
Evaluation
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2,4­
Dichlorophenoxyacetic
Acid
Isopropylamine
Salt
(
2,4­
D
IPA)
in
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Mouse
Bone
Marrow
Micronuleus
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Lab
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Gollapudi,
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Response
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Comments
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U.
S.
EPA:
Evaluation
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2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
Ester
(
2,4­
D
BEE)
in
the
Mouse
Bone
Marrow
Micronuleus
Test:
Lab
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Yano,
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2,4­
D
Isopropylamine
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2,4­
D
IPA):
A
13­
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Toxicity
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Fischer
344
Rats:
Lab
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M­
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Yano,
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2,4­
D
Triisopropylamine
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2,4­
D
TIPA):
A
13­
Week
Dietary
Toxicity
Study
in
Fischer
344
Rats:
Lab
Project
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K­
008866­
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Rodwell,
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Teratology
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Liberacki,
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Triisopropanolam­
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D:
Oral
Gavage
Teratology
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Isopropylamine
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Gavage
Teratology
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White
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Lab
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2­
Butoxyethyl
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Isopropylamine
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D:
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Gavage
Teratology
Probe
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White
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Triisopropanolamine
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2,4­
D:
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Gavage
Teratology
Probe
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White
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2,4­
D
2­
Butoxyethyl
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Gavage
Teratology
Probe
Study
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New
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White
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Dryzga,
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2,4­
Dichlorophenoxyacetate,
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Male
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344
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Developmental
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D
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2,4­
Dichlorophenoxyacetic
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2,4­
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47
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Developmental
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Study
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2,4­
D
2­
Ethylhexyl
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2,4­
D
Isooctyl
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Administered
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CD
BR
VAF/
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Dosage­
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Developmental
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Embryo­
Fetal
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Teratogenic
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Study
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2,4­
D
2­
Ethylhexyl
Ester
(
2,4­
D
Isooctyl
Ester)
Administered
Orally
Via
Gavage
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Crl:
CD
BR
VAF/
Plus
Presumed
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Research
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111
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update
RED
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Martin,
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1992)
Developmental
Toxicity
(
Embryo­
Fetal
Toxicity
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Teratogenic
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Study
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2,4­
D
2­
Ethylhexyl
Ester
(
2,4­
D
Isooctyl
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Administered
Orally
(
Stomach
Tube)
to
New
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White
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study
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Argus
Research
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503
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Martin,
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Dose­
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Developmental
Toxicity
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Embryo­
Fetal
Toxicity
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Teratogenic
Potential)
Study
of
2,4­
D
2­
Ethylhexyl
Ester
(
2,4­
D
Isooctyl
Ester)
Administered
Orally
(
Stomach
Tube)
to
New
Zealand
White
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Lab
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320­
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2,4­
Dichlorophenoxyacetate,
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344
Rats:
Lab
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007722­
018.
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study
prepared
by
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Dow
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59
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Cieszlak,
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2,4­
Dichlorophenoxyacetic
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Ethylhexyl
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344
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Chemical
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Dalgard,
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13­
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2184­
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2184­
126,
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by
Hazleton
Washington,
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267
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Dalgard,
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2­
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in
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2184­
127,
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study
prepared
by
Hazleton
Washington,
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VA
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Dalgard,
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4­
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Lab
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2184­
121.
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Hazleton
Washington,
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85
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Dalgard,
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4­
Week
Exploratory
Rangefinding
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in
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2­
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2,4­
D:
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Lab
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2184­
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prepared
by
Hazleton
Washington,
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99
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Dalgard,
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4­
Week
Exploratory
Rangefinding
Study
in
Dogs
with
the
Dimethylamine
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2,4­
D:
Final
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Lab
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HWA
2184­
123.
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study
prepared
by
Hazleton
Washington,
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98
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Dryzga,
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1993)
2,4­
Dichlorophenoxyacetate,
Isopropylamine
Salt:
Dissociation
and
Metabolism
in
Male
Fischer
344
Rats:
Lab
Project
Number:
M­
004725­
014.
Unpublished
study
prepared
by
The
Toxicology
Research
Lab.,
Dow
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64
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43049001
Dalgard,
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1993)
52­
Week
Dietary
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2,4­
D
in
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Lab
Project
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HWA
2184­
124:
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Hazleton
Washington,
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RED
(
or
Registration)
Toxicology
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1994)
2,4­
Dichlorophenoxyacetic
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D):
Acute
Neurotoxicity
Study
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Fischer
344
Rats:
Lab
Project
Number:
K­
002372­
066.
Unpublished
study
prepared
by
The
Dow
Chemical
Co.
451
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Mattsson,
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1994)
2,4­
Dichlorophenoxyacetic
Acid:
Chronic
Neurotoxicity
Study
in
Fischer
344
Rats:
Lab
Project
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K­
002372­
064N:
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002372­
064.
Unpublished
study
prepared
by
The
Dow
Chemical
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Linscombe,
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Evaluation
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2,4­
D
Triisopropanolamine
Salt
in
an
In
vitro
Chromosomal
Aberration
Assay
Utilizing
Rat
Lymphocytes:
Amended
Final
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Lab
Project
Number:
K­
008866­
017:
10233.
Unpublished
study
prepared
by
Dow
Chemical
Co.
46
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43327302
Linscombe,
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(
1994)
Evaluation
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2,4­
D
Triisopropanolamine
Salt
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the
Chinese
Hamster
Ovary
Cell/
Hypoxanthine­
Guanine­
Phosphoribosyl
Transferase
(
CHO/
HGPRT)
Forward
Mutation
Assay:
Amended
Final
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Lab
Project
Number:
K­
008866­
018:
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Unpublished
study
prepared
by
Dow
Chemical
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43
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Linscombe,
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Lick,
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1994)
Evaluation
of
2,4­
Dichlorophenoxyacetic
Acid
Isopropylamine
Salt
in
an
In
vitro
Chromosomal
Aberration
Assay
Utilizing
Rat
Lymphocytes:
Lab
Project
Number:
M­
004725­
016:
10233.
Unpublished
study
prepared
by
Dow
Chemical
Co.
45
p.

43327304
Linscombe,
V.;
Lick,
S.
(
1994)
Evaluation
of
2,4­
Dichlorophenoxyacetic
Acid
Isopropylamine
Salt
in
the
Chinese
Hamster
Ovary
Cell/
Hypoxanthine­
Guanine­
Phosphoribosyl
Transferase
(
CHO/
HGPRT)
Forward
Mutation
Assay:
Lab
Project
Number:
M­
004725­
017:
10233.
Unpublished
study
prepared
by
Dow
Chemical
Co.
43
p.

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Linscombe,
V.;
Lick,
S.
(
1994)
Evaluation
of
the
2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
Ester
in
an
In
vitro
Chromosomal
Aberration
Assay
Utilizing
Rat
Lymphocytes:
Lab
Project
Number:
K­
007722­
022:
10233.
Unpublished
study
prepared
by
Dow
Chemical
Co.
45
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43394201
Linscombe,
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Lick,
S.
(
1994)
Evaluation
of
2,4­
Dichlorophenoxyacetic
Acid
Butoxyethyl
Ester
in
the
Chinese
Hamster
Ovary
Cell/
Hypoxanthine­
Guanine­
Phosphoribosyl
Transferase
(
CHO/
HGPRT)
Forward
Mutation
Assay:
Lab
Project
Number:
K­
007722­
023.
Unpublished
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prepared
by
Dow
Chemical
Co.
44
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Tompkins,
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A
90­
Day
Oral
(
Capsule)
Toxicity
Study
of
2,4­
D
Isopropyl
Ester
in
Dogs:
Final
Report:
Lab
Project
Number:
WIL­
233001.
Unpublished
study
prepared
by
WIL
Research
Labs,
Inc.
572
p.
Author:
Tompkins,
E.
Content
Category:
Complete
primary
report
­­
experimental
research
Receipt
Date:
20­
Jan­
1995
Laboratory
Project
#:
WIL/
233001
43515901
Tompkins,
E.
(
1995)
A
90­
Day
Dietary
Subchronic
Toxicity
Study
of
2,4­
D
Isopropyl
Ester
in
Rats:
Final
Report:
Lab
Project
Numbers:
WIL­
233002.
Unpublished
study
prepared
by
WIL
Research
Labs,
Inc.
597
p.

43523001
Nemec,
M.
(
1994)
A
Dose
Range­
finding
Developmental
Toxicity
Study
of
2,4­
D
Isopropyl
Ester
in
Rats:
Final
Report:
Lab
Project
Number:
WIL­
233003.
Unpublished
study
prepared
by
WIL
Research
Labs,
Inc.
279
p.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
62
43523101
Nemec,
M.
(
1995)
A
Developmental
Toxicity
Study
of
2,4­
D
Isopropyl
Ester
in
Rats:
Final
Report:
Lab
Project
No.:
WIL­
233004.
Unpublished
study
prepared
by
WIL
Research
Labs,
Inc.
321
p.

43597201
Stott,
W.;
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K.;
et
al.
(
1995)
2,4­
Dichlorophenoxyacetic
Acid:
Dietary
Oncogenicity
Study
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Two
Year
Final
Report:
Lab
Project
No.
K­
002372­
063F.
Unpublished
study
prepared
by
the
Dow
Chemical
Co.
724
p.

43612001
Jeffries,
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Yano,
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al.
(
1995)
2,4­
Dichlorophenoxyacetic
Acid:
Chronic
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Oncogenicity
Study
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344
Rats:
Final
Report:
Lab
Project
No.:
K/
002372/
064.
Unpublished
study
prepared
by
Dow
Chemical
Co.,
Health
&
Environmental
Sciences.
2020
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43879801
Stott,
W.;
Johnson,
K.;
Gilbert,
K.;
et
al.
(
1995)
2,4­
Dichlorophenoxyacetic
Acid:
Dietary
Oncogenicity
Study
in
Male
B6C3F1
Mice­­
Two
Year
Final
Report:
Lab
Project
Number:
K­
002372­
063M:
33475:
913.
Unpublished
study
prepared
by
Dow
Chemical
Co.
704
p
43930501
Ham,
A.
(
1996)
Genotoxicity
Test
on
Isopropyl
Ester
of
2,4­
Dichlorophenoxyacetic
Acid
in
the
Assay
for
Unscheduled
DNA
Synthesis
in
Rat
Liver
Primary
Cell
Cultures:
Lab
Project
Number:
16692­
0­
447:
2731­
100:
615.
Unpublished
study
prepared
by
Corning
Hazleton
(
CHV).
39
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43930801
Murli,
H.
(
1996)
Mutagenicity
Test
on
Isopropyl
Ester
of
2,4­
Dichlorophenoxy
Acetic
Acid
in
an
in
vivo
Mouse
Micronucleus
Assay:
Lab
Project
Number:
16692­
0­
455:
616.
Unpublished
study
prepared
by
Hazleton
Washington,
Inc.
40
p.

43935101
Lawlor,
T.
(
1996)
Mutagenicity
Test
on
Isopropyl
Ester
of
2,4­
Dichlorophenoxy
Acetic
Acid
in
the
Salmonella/
Mammalian­
Microsome
Reverse
Mutation
Assay:
(
Ames
Test):
Final
Report:
Lab
Project
Number:
16692­
0­
401.
Unpublished
study
prepared
by
Corning
Hazleton
Inc.
46
p.

44284501
Yano,
B.
(
1997)
2,4­
Dichlorophenoxyacetic
Acid:
Chronic
Toxicity/
Oncogenicity
Study
in
Fischer
344
Rats:
Supplemental
Histopathology­­
Brains
from
Low­
and
Mid­
Dose
Level
Rats
Sacrificed
for
the
2­
Year
Necropsy:
Revised
(
Final
Report):
Lab
Project
Number:
K­
002372­
064FR:
K­
002372­
064.
Unpublished
study
prepared
by
Dow
Chemical
Co.
14
p.

44725303
Cieszlak,
F.;
Brooks,
K.
(
1998)
Esteron
6E:
Acute
Primary
Eye
Irritation
Study
in
New
Zealand
White
Rabbits:
Lab
Project
Number:
971165.
Unpublished
study
prepared
by
Dow
Chemical
Company.
16
p.

45761201
Garabrant,
D.;
Philbert,
M.
(
2002)
Review
of
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D)
Epidemiology
and
Toxicology.
Critical
Reviews
in
Toxicology
32(
4):
233­
257.

45761204
Charles,
J.;
Hanley,
T.;
Wilson,
R.;
et
al.
(
2001)
Developmental
Toxicity
Studies
in
Rats
and
Rabbits
on
2,4­
Dichlorophenoxyacetic
Acid
and
Its
Forms.
Toxicological
Sciences
60:
121­
131.

45761208
Charles,
J.;
Cunny,
H.;
Wilson,
R.;
et
al.
(
1999)
Ames
Assays
and
Unscheduled
DNA
Synthesis
Assays
on
2,4­
Dichlorophenoxyacetic
Acid
and
Its
Derivatives.
Mutation
Research
444:
207­
216.

45761209
Charles,
J.;
Cunny,
H.;
Wilson,
R.;
et
al.
(
1999)
In
Vivo
Micronucleus
Assays
on
2,4­
Dichlorophenoxyacetic
Acid
and
Its
Derivatives.
Mutation
Research
444:
227­
234.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
63
45761210
Gollapudi,
B.;
Charles,
J.;
Linscombe,
V.;
et
al.
(
1999)
Evaluation
of
the
Genotoxicity
of
2,4­
Dichlorophenoxyacetic
Acid
And
Its
Derivatives
in
Mammalian
Cell
Cultures.
Mutation
Research
444:
217­
225.

45761211
Mattsson,
J.;
Charles,
J.;
Yano,
B.;
et
al.(
1997)
Single­
Dose
and
Chronic
Dietary
Neurotoxicity
Screening
Studies
on
2,4­
Dichlorophenoxyacetic
acid
in
Rats.
Fundamental
and
Applied
Toxicology
40:
111­
119.

45761213
Charles,
J.;
Cunny,
H.;
Wilson,
R.;
et
al.
(
1996)
Comparative
Subchronic
Studies
on
2,4­
Dichlorophenoxyacetic
Acid,
Amine
and
Ester
in
Rats.
Fundamental
and
Applied
Toxicology
33:
161­
165.

45761214
Charles,
J.;
Bond,
D.;
Jeffries,
T.;
et
al.
(
1996)
Chronic
Dietary
Toxicity/
Oncogenicity
Studies
on
2,4­
Dichlorophenoxyacetic
Acid
in
Rodents.
Fundamental
and
Applied
Toxicology
33:
166­
172.

45761215
Charles,
J.;
Dalgard,
D.;
Cunny,
H.;
et
al.
(
1996)
Comparative
Subchronic
and
Chronic
Dietary
Toxicity
Studies
on
2,4­
Dichlorophenoxyacetic
Acid,
Amine
and
Ester
in
the
Dog.
Fundamental
and
Applied
Toxicology
29:
78­
85.

45840901
Hardwick,
T.
(
2002)
The
Pharmacokinetics
of
(
14C)­
2,4­
D
in
the
Rat
and
Dog.
Covance
Laboratories
Ltd.
England.
Laboratory
Study
Number
1149/
40,
Report
Number
1149/
40­
D1145,
October
11,
2002.
MRID
45840901.
Unpublished.

45897102
Hardwick,
T.
(
2003)
(
14C)­
2,4­
D:
Metabolite
Identification
in
the
Rat
and
Dog.
Covance
Laboratories
Ltd.
England.
Laboratory
Study
Number
1149/
042,
Report
Number
1149/
042­
D1145,
February,
2003.
MRID
45897102.
Unpublished.

OPEN
LITERATURE
Arbuckle,
T.
E.,
Schrader,
S.
M.,
Cole,
D.,
et
al.
(
1999).
2,4­
Dichlorophenoxyacetic
Acid
Residues
in
Semen
of
Ontario
Farmers.
Reproductive
Toxicology
13:
421­
429].

Bortolozzi,
A.
A.;
Duffard,
R.
O.;
and
Evangelista
De
Duffard,
A.
M.
(
1999).
Behavioral
Alterations
Induced
in
Rats
by
a
Pre­
and
Postnatal
Exposure
to
2,4­
Dichlorophenoxyacetic
Acid.
Neurotoxicology
and
Teratology,
21
(
4):
451­
465
Brusco,
A.;
Saavedra,
J.
P.;
Garcia,
G;
et
al.
(
1997).
2,4­
Dichlorophenoxyacetic
Acid
Through
Lactation
Induces
Astrogliosis
in
Rat
Brain.
Mol.
Chem.
Neuropathol.
30,
175­
185
Cavieres,
M.
F.
Jaeger,
J.
and
Porter,
W.
(
2002).
Developmental
Toxicity
of
a
Commercial
Herbicide
Mixture
in
Mice:
I.
Effects
on
Embryo
Implantation
and
Litter
Size.
Environmental
Hlth
Perspectives
110
(
11),
1081­
1085.

Duffard,
R.;
Garcia,
G.;
Rosso,
S.;
et
al.
(
1996).
Central
Nervous
System
Myelin
Deficit
in
Rats
Exposed
to
2,4­
Dichlorophenoxyacetic
Acid
Throughout
Lactation.
Neurotoxicology
and
Teratology,
18
(
6):
691­
696
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
64
Evangelista
de
Duffard,
A.
M.
,
N.
De
Aldrete,
M.,
and
Duffard,
R.
(
1990)].
Changes
in
brain
serotonin
and
5­
hydroxyindoleacetic
acid
levels
induced
by
2,4­
dichlorophenoxyacetic
acid
butyl
ester.
Toxicol.
64,
265­
270.

Faustini,
A.,
Settimi,
L.,
Pacifici,
R.,
et
al.
(
1996).
Immunological
changes
among
farmers
exposed
to
phenoxy
herbicides:
preliminary
observations.
Occupational
and
Environmental
Medicine
53,
583­
585.

Garabrant,
D.
H.
and
Philbert,
M.
A.
(
2002).
Review
of
2,4­
Dichlorophenoxyacetic
Acid
(
2,4­
D)
Epidemiology
and
Toxicology.
Crit
Rev
Toxicol
32
(
4):
233­
57.

Garry,
V.
F.;
Tarone,
R.
E.;
Kirsch,
I.
R.;
et
al.
(
2001).
Biomarker
Correlations
of
Urinary
2,4­
D
Levels
in
Foresters:
Genomic
Instability
and
Endocrine
Disruption.
Environmental
Health
Perspectives
(
2001).
109
(
5):
495­
500.

Griffin,
R.
J.
;
Godfrey,
V.
B.;
Kim,
Y­
C
;
et
al.
(
1997).
Sex­
Dependent
Differences
in
the
Disposition
of
2,4­
Dichlorophenoxyacetic
Acid
in
Sprague­
Dawley
Rats,
B6C3F1
Mice,
and
Syrian
Hamsters.
Drug
Metabolism
and
Disposition.
The
American
Society
for
Pharmacology
and
Experimental
Therapeutics,
Vol.
25,
No.
9.

Lee,
K.,
Johnson,
V.,
and
Blakley,
B.
(
2001).
The
Effect
of
Exposure
to
a
Commercial
2,4­
D
Formulation
During
Gestation
on
the
Immune
Response
in
CD­
1
Mice.
Toxicology:
165
(
1):
39­
49.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
65
9.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
66
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
MRID:
41991501
[
1991]
Acceptable/
Guideline
Fischer
344
1,
15,
100,
300
mg/
kg/
day
NOAEL
=
15
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day
based
on
decreases
in
body
weight/
gain,
alterations
in
hematology
and
clinical
chemistry
[
decreased
T3
and
T4]
parameters,
and
cataract
formation
in
females.

870.3150
90­
Day
oral
toxicity
in
nonrodents
MRID:
41737301
[
1990]

Acceptable/
Guideline
0,
0.3,
1.0,
3.0,
and
10
mg/
kg/
day
NOAEL
=
1
mg/
kg/
day
LOAEL
=
3
mg/
kg/
day
based
on
decreased
body
weight/
body­
weight
gain
and
food
consumption
(
males),
alterations
in
clinical
chemistry
parameters
[
increased
BUN
(
both
sexes),
creatinine
(
males)],
and
decreased
testis
weight
in
males.

870.3150
90­
Day
oral
toxicity
in
nonrodents
MRID:
42780001
[
1993]

Acceptable/
Guideline
0,
0.5,
1.0,
3.75,
and
7.5
mg/
kg/
day
NOAEL
=
1
mg/
kg/
day
LOAEL
=
3.75
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
both
sexes)
and
food
consumption
(
males),
as
well
as
alterations
in
clinical
chemistry
parameters
[
increased
BUN,
creatinine,
and
alanine
aminotransferase]
in
both
sexes,
and
decreased
testes
weight
and
slightly
higher
incidence
of
hypospermatogenesis/
juvenile
testis
and
inactive/
juvenile
prostate
were
observed.

870.3200
21­
Day
dermal
toxicity
MRID:
41735304
[
1990]
rabbits
Acceptable/
Guideline
10,
100,
1000
mg/
kg/
day
NOAEL
=
1000
mg/
kg/
day
LOAEL
=
>
1000
mg/
kg/
day
based
on
no
adverse
effects
at
the
limit
dose.

870.3250
90­
Day
dermal
toxicity
not
required
NOAEL
=
[
]
mg/
kg/
day
LOAEL
=
[
]
mg/
kg/
day
based
on
[
].

870.3465
90­
Day
inhalation
toxicity
datagap
NOAEL
=
[
]
mg/
kg/
day
LOAEL
=
[
]
mg/
kg/
day
based
on
[
].

870.3700a
Prenatal
developmental
in
rodents
MRID
00130407,
00130408
[
1983]
Fischer
344
Acceptable/
Guideline
0,
8,
25,
and
75
mg/
kg/
day
Maternal
NOAEL
=
25
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body­
weight
gains.
Survival
was
not
affected
by
treatment.

Developmental
NOAEL
=
25
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
skeletal
abnormalities.

870.3700b
Prenatal
developmental
in
nonrodents
MRID
41747601
[
1990]

Acceptable/
Guideline
0,
10,
30,
and
90
mg/
kg/
day
Maternal
NOAEL
=
30
mg/
kg/
day
LOAEL
=
90
mg/
kg/
day
based
on
clinical
signs
[
ataxia,
decreased
motor
activity,
loss
of
righting
reflex,
cold
extremities],
abortion
(
2),
decreased
body­
weight
gains.
Survival
was
not
affected
by
treatment.

Developmental
NOAEL
=
30
mg/
kg/
day
LOAEL
=
90
mg/
kg/
day,
based
on
abortions.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
67
870.3800
Reproduction
and
fertility
effects
MRID
00150557;
00163996
[
1985]

Acceptable/
Guideline
0,
5,
20,
and
80
mg/
kg/
day
Parental/
Systemic
NOAEL
=
5
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day.
based
on
decreased
female
body
weight/
bodyweight
gain
[
F1]
and
renal
tubule
alteration
in
males
[
F0
and
F!].
Reproductive
NOAEL
=
20
mg/
kg/
day
LOAEL
=
80
mg/
kg/
day,
based
on
an
increase
in
gestation
length
[
F0
females
producing
F1b
pups]

Offspring
NOAEL
=
5
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day
based
on
decreased
pup
body
weight
[
F1b].
At
80
mg/
kg/
day,
there
was
an
increase
in
dead
pups.

870.4100a
Chronic
toxicity
rodents
MRID
43612001
[
1995]

Acceptable/
Guideline
0,
5,
75,
and
150
mg/
kg/
day
NOAEL
=
5
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
females)
and
food
consumption
(
females),
alterations
in
hematology
[
decreased
RBC,
HCT,
and
HGB
(
females),
platelets
(
both
sexes)]
and
clinical
chemistry
parameters
[
increased
creatinine
(
both
sexes),
alanine
and
aspartate
aminotransferases
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
T4
(
both
sexes),
glucose
(
females),
cholesterol
(
both
sexes),
and
triglycerides
(
females)],
increased
thyroid
weights
(
both
sexes
at
study
termination),
and
decreased
testes
and
ovarian
weights
.
At
HDT,
there
were
microscopic
lesions
in
the
eyes,
liver,
adipose
tissue,
and
lungs.

870.4100b
Chronic
toxicity
dogs
MRID:
430490001
[
1993]

Acceptable/
Guideline
0,
1,
5,
and
7.5
mg/
kg/
day
NOAEL
=
1
mg/
kg/
day
LOAEL
=
5
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
both
sexes)
and
food
consumption
(
females),
as
well
as
alterations
in
clinical
chemistry
parameters
[
increased
BUN,
creatinine,
and
alanine
aminotransferase,
decreased
glucose]
in
both
sexes,
and
decreased
brain
weight
in
females,
and
histopathological
lesions
in
liver
and
kidneys.

870.4200
Carcinogenicity
rats
MRID
43612001
[
1995]

Acceptable/
Guideline
0,
5,
75,
and
150
mg/
kg/
day
NOAEL
=
5
mg/
kg/
day
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
females)
and
food
consumption
(
females),
alterations
in
hematology
[
decreased
RBC,
HCT,
and
HGB
(
females),
platelets
(
both
sexes)]
and
clinical
chemistry
parameters
[
increased
creatinine
(
both
sexes),
alanine
and
aspartate
aminotransferases
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
T4
(
both
sexes),
glucose
(
females),
cholesterol
(
both
sexes),
and
triglycerides
(
females)],
increased
thyroid
weights
(
both
sexes
at
study
termination),
and
decreased
testes
and
ovarian
weights
.
At
HDT,
there
were
microscopic
lesions
in
the
eyes,
liver,
adipose
tissue,
and
lungs.
There
was
no
evidence
of
carcinogenicity
870.4300
Carcinogenicity
mice
MRID
43879801
and
43597201
[
1995]

Acceptable/
Guideline
0,
5,
62/
150,
120/
300
mg/
kg/
day]
NOAEL
=
5
mg/
kg/
day
LOAEL
=
62/
150
mg/
kg/
day
based
on
an
increased
absolute
and/
or
relative
kidney
weights
and
an
increased
incidence
of
renal
microscopic
lesions.

There
was
no
evidence
of
carcinogenicity
Gene
Mutation
870.5265
Ames,
reverse
mutation
MRID
41409801
[
1990]
Acceptable
100­
1000

g/
plate
w/
S9;
66.7­
6670

g/
plate
w/
out
S9.
No
evidence
of
bacterial
mutation
in
S.
Typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
TA100,
w/
and
w/
out
S9
Cytogenetics
870.5385
in
vitro
chromosome
aberration
[
human
lymphocytes]
Mustonen,
et
al.
1986
classification:
N/
A
0.125­
0.35
mM;
0.125­
1.250
mM.
No
evidence
of
increased
chromosome
aberrations
in
human
lymphocytes.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
68
Cytogenetics
870.
in
vivo
chromosome
aberration
[
Wistar
rat
bone
marrow]
Adhikari
&
Grover,
1988
classification:
N/
A
0,
17.5,
35,
70
mg/
kg/
day
ip
2X.
Equivocal
[+
at
top
2
doses,
but
results
were
similar
to
DMSO
control].

Other
Effects
Unscheduled
DNA
synthesis
assay
870.5450
MRID
41409807
[
1990]

classification:
Acceptable
0.969­
2890

g/
mL
Fisher
344
primary
rat
hepatocytes.
No
evidence
of
induction
of
unscheduled
DNA
synthesis.

870.6200a
Acute
neurotoxicity
screening
battery
Fischer
344
rat
MRID:
43115201
[
1994]

Acceptable/
Guideline
0,
13,
67,
and
227
mg/
kg/
day
NOAEL
=
67
mg/
kg/
day
LOAEL
=
227
mg/
kg/
day
based
on
an
increased
incidence
of
incoordination
and
slight
gait
abnormalities
[
described
as
forepaw
flexing
or
knuckling]
and
decreased
total
motor
activity.

870.6200b
Subchronic
neurotoxicity
screening
battery
Fischer
344
rat
MRID:
43293901
[
1995]

Acceptable/
Guideline
5,
75,
150
mg/
kg/
day
NOAEL
=
75
mg/
kg/
day
LOAEL
=
150
mg/
kg/
day
based
on
increased
forelimb
grip
strength.

870.6300
Developmental
neurotoxicity
DATAGAP
Maternal
NOAEL
=
[
]
mg/
kg/
day
LOAEL
=
[
]
mg/
kg/
day
based
on
[
].
Offspring
NOAEL
=
[
]
mg/
kg/
day
LOAEL
=
[
]
mg/
kg/
day
based
on
[
].

870.7485
Metabolism
and
pharmacokinetics
MRID
41737302
[
1990
]

Acceptable/
Fischer
rats
single
doses
of
[
phenyl
­
U­
14C]­
2,4­
dichlorophenoxyacetic
acid
[
2,4­
D]
at
dose
levels
of
0.95­
0.97
mg/
kg
[
I.
v.],
1.04­
1.05
mg/
kg
[
oral],
97.1­
97.4
mg/
kg
[
oral],
or
1.06
mg/
kg
followed
by
a
14­
day
treatment
with
unlabeled
2,4­
d
at
1
mg/
kg/
day.

85.5%­
93.7%
of
dose
eliminated
in
urine;
3.6%­
10.5%
of
dose
eliminated
via
the
feces;
no
differences
noted
between
the
sexes;
at
the
high­
dose
level,
it
appears
that
a
nonlinear
region
[
decreased
clearance]
is
being
reached
in
the
disposition
of
2,4­
D.

Parent
2,4­
D
was
the
major
metabolite
found
in
urine
[
72.9%­
90.5%
of
the
oral
dose],
with
small
amounts
of
uncharacterized
compounds
[
0.6%­
1.3%
and
0%­
0.7%]
being
found
in
the
urine.

870.7600
Dermal
penetration
published
paper
Feldman.
R.
J.
And
Maibach,
H.
I.
(
1974).
Percutaneous
Penetration
of
Some
Pesticides
and
Herbicides
in
Man.
Toxicol.
Appl.
Pharmacol.
28:
126­
132.
5.8%

Special
studies
pharmacokinetics/
metabolism
study
[
single
exposure]
MRID
45840901
[
2002]
MRID
45897102
[
2003]

Acceptable/
nonguideline
Fischer­
strain
rats
[
CDF
Crl:
BR
(
F­
344)]
and
pure­
bred
beagle
dogs
0,
5,
and
50
mg/
kg.
study
designed
specifically
to
compare
the
rat
and
dog
with
respect
to
the
excretion
of
2,4­
D
and
the
relevancy
of
the
dog
data
for
risk
assessment.
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
69
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
2,4­
D
for
Use
in
Human
Risk
Assessment
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
50
years
of
age)
NOAEL
=
25
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.025
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD(
0.025)
FQPA
SF
(
1)

=
0.025
mg/
kg/
day
rat
developmental
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
skeletal
abnormalities.

Acute
Dietary
(
General
population
including
infants
and
children)
NOAEL
=
67
mg/
kg/
day
UF
=
1000
Acute
RfD
=
0.067
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
(
0.067)
FQPA
SF
(
1)

=
0.067
mg/
kg/
day
acute
neurotoxicity
study
in
rats
LOAEL
=
227
mg/
kg/
day
based
on
gait
abnormalities
Chronic
Dietary
(
All
populations)
NOAEL=
5
mg/
kg/
day
UF
=
1000
Chronic
RfD
=
0.005
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
(
0.005)
FQPA
SF
(
1)

=
0.005
mg/
kg/
day
rat
chronic
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
females)
and
food
consumption
(
females),
alterations
in
hematology
[
decreased
RBC,
HCT,
and
HGB
(
females),
platelets
(
both
sexes)]
and
clinical
chemistry
parameters
[
increased
creatinine
(
both
sexes),
alanine
and
aspartate
aminotransferases
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
T4
(
both
sexes),
glucose
(
females),
cholesterol
(
both
sexes),
and
triglycerides
(
females)],
increased
thyroid
weights
(
both
sexes
at
study
termination),
and
decreased
testes
and
ovarian
weights
.

Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
25
mg/
kg/
day
Residential
LOC
for
MOE
=
1000
Occupational
=
NA
rat
developmental
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
decreased
maternal
body­
weight
gain
and
skeletal
abnormalities
Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL
=
15
mg/
kg/
day
Residential
LOC
for
MOE
=
1000
Occupational
=
NA
subchronic
oral
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
body
weight/
body­
weight
gain,
alterations
in
some
hematology
[
decreased
platelets
(
both
sexes)]
and
clinical
chemistry
[
decreased
T3
(
females)
and
T4
(
both
sexes)]
parameters,
and
cataract
formation.

Short­
Term
Dermal
(
1
to
30
days)
Oral
study
NOAEL=
25
mg/
kg/
day
(
dermal
absorption
rate
=
5.8%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
rat
developmental
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
decreased
maternal
body­
weight
gain
and
skeletal
abnormalities
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
70
Intermediate­
Term
Dermal
(
1
to
6
months)
Oral
study
NOAEL
=
15
mg/
kg/
day
(
dermal
absorption
rate
=
5.8%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
subchronic
oral
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
body
weight/
body­
weight
gain,
alterations
in
some
hematology
[
decreased
platelets
(
both
sexes)]
and
clinical
chemistry
[
decreased
T3
(
females)
and
T4
(
both
sexes)]
parameters,
and
cataract
formation.

Long­
Term
Dermal
(>
6
months)
Oral
study
NOAEL=
5
mg/
kg/
day
(
dermal
absorption
rate
=
5.8%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
rat
chronic
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
females)
and
food
consumption
(
females),
alterations
in
hematology
[
decreased
RBC,
HCT,
and
HGB
(
females),
platelets
(
both
sexes)]
and
clinical
chemistry
parameters
[
increased
creatinine
(
both
sexes),
alanine
and
aspartate
aminotransferases
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
T4
(
both
sexes),
glucose
(
females),
cholesterol
(
both
sexes),
and
triglycerides
(
females)],
increased
thyroid
weights
(
both
sexes
at
study
termination),
and
decreased
testes
and
ovarian
weights
.

Short­
Term
Inhalation
(
1
to
30
days)
Oral
study
NOAEL=
25
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
rat
developmental
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
decreased
maternal
body­
weight
gain
and
skeletal
abnormalities
Intermediate­
Term
Inhalation
(
1
to
6
months)
Oral
study
NOAEL
=
15
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
subchronic
oral
toxicity
­
rat
LOAEL
=
100
mg/
kg/
day
based
on
decreased
body
weight/
body­
weight
gain,
alterations
in
some
hematology
[
decreased
platelets
(
both
sexes)]
and
clinical
chemistry
[
decreased
T3
(
females)
and
T4
(
both
sexes)]
parameters,
and
cataract
formation.

Long­
Term
Inhalation
(>
6
months)
Oral
study
NOAEL=
5
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
1000
Occupational
LOC
for
MOE
=
100
rat
chronic
toxicity
study
LOAEL
=
75
mg/
kg/
day
based
on
decreased
body­
weight
gain
(
females)
and
food
consumption
(
females),
alterations
in
hematology
[
decreased
RBC,
HCT,
and
HGB
(
females),
platelets
(
both
sexes)]
and
clinical
chemistry
parameters
[
increased
creatinine
(
both
sexes),
alanine
and
aspartate
aminotransferases
(
males),
alkaline
phosphatase
(
both
sexes),
decreased
T4
(
both
sexes),
glucose
(
females),
cholesterol
(
both
sexes),
and
triglycerides
(
females)],
increased
thyroid
weights
(
both
sexes
at
study
termination),
and
decreased
testes
and
ovarian
weights
.

Cancer
(
oral,
dermal,
inhalation)
Classification:
Group
D
[
not
classifiable
as
to
human
carcinogenicity]

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic),
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
CHEMICAL
NAME/
MONTH/
YEAR
of
update
RED
(
or
Registration)
Toxicology
Chapter
71
NOTE:
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.
