Document ID: EPA-HQ-OPP-2004-0220-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-07-22T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
WASHINGTON,
D.
C.
20460
MEMORANDUM
DATE:
July
20,
2004
TXR:
0052745
SUBJECT:
2,4­
DB
and
2,4­
DB­
DMA.
Toxicology
Chapter
for
RED.

PC
Code:
030801
(
2,4­
DB)
and
030819
(
2,4­
DB­
DMA)
DP
Barcode:
D291214
TO:
Mika
Hunter,
Chemical
Review
Manager
Special
Review
Branch
Special
Review
and
Reregistration
Division
(
7508C)

FROM:
Kit
Farwell,
D.
V.
M.
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

THRU:
Whang
Phang,
Ph.
D.,
Senior
Scientist
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

Attached
is
the
Toxicology
Chapter
for
2,4­
DB
and
2,4­
DB­
DMA.
This
chapter
was
revised
in
response
to
error
only
comments
from
the
2,4­
DB
Task
Force.
2,4­
DB
and
2,4­
DB­
DMA
PC
Codes:
030801
and
030819
Toxicology
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:
July
11,
2003
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Prepared
by:
Kit
Farwell,
D.
V.
M.
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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1
2.0
REQUIREMENTS
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3
3.0
DATA
GAPS
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4
4.0
HAZARD
ASSESSMENT
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4
4.1
Acute
Toxicity
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4
4.2
Subchronic
Toxicity
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6
4.3
Prenatal
Developmental
Toxicity
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11
4.4
Reproductive
Toxicity
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15
4.5
Chronic
Toxicity
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17
4.6
Carcinogenicity
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20
4.7
Mutagenicity
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22
4.8
Neurotoxicity
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23
4.9
Metabolism.
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23
5.0
TOXICITY
ENDPOINT
SELECTION
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27
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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27
5.2
Dermal
Absorption
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27
5.3
Classification
of
Carcinogenic
Potential
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27
6.0
FQPA
CONSIDERATIONS
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28
6.1
Special
Sensitivity
to
Infants
and
Children
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28
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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29
7.0
REFERENCES
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30
8.0
APPENDICES
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34
8.1
Toxicity
Profile
Summary
Tables
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35
8.1.1
Acute
Toxicity
Table
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35
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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35
8.2
Toxicological
Dose
and
Endpoints
for
Use
in
Human
Risk
Assessment
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39
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
1
1.0
HAZARD
CHARACTERIZATION
2,4­
DB
and
2,4­
DB­
DMA
are
chlorophenoxy
herbicides.
This
class
of
herbicides
function
by
mimicking
the
action
of
auxins,
plant
growth
hormones.
2,4­
DB
(
2,4­
dichlorophenoxy
butyric
acid)
is
an
acid
and
2,4­
DB­
DMA
(
2,4­
dichlorophenoxy
butyric
acid,
dimethyl
amine
salt)
is
its
dimethyl
amine
salt.
They
are
broadleaf
herbicides
used
in
agriculture
with
no
current
residential
uses.

A
metabolism
study
in
rats
showed
that
2,4­
DB­
DMA
dissociates
to
2,4­
DB,
after
which
they
shared
the
same
metabolic
pathway.
Urine
was
the
major
route
of
excretion;
2,4­
D
and
conjugated
dichlorophenol
were
the
major
metabolites
for
both
chemicals.
Most
toxicity
studies
were
conducted
with
2,4­
DB;
studies
with
2,4­
DB­
DMA
included
subchronic
feeding
study
in
rats,
developmental
toxicity
in
rats,
dermal
toxicity
in
rabbits,
mutagenicity
studies,
and
metabolism.
Toxicity
and
LOAELs
for
2,4­
DB
and
2,4­
DB­
DMA
were
similar
in
the
studies
which
were
conducted
with
both
chemicals.
For
the
above
reasons,
the
same
endpoints
were
selected
for
both
2,4­
DB
and
2,4­
DB­
DMA
and
the
database
was
adequate
for
establishing
toxicity
endpoints
for
risk
assessment.

A
minor
difference
in
toxicity
between
the
acid
and
DMA
salt
was
that
2,4­
DB­
DMA
was
more
irritating
than
2,4­
DB.
2,4­
DB­
DMA
caused
inflamed
lacrimal
glands
and
gastric
mucosal
irritation
in
the
subchronic
rat
feeding
study,
dermal
irritation
in
the
subchronic
dermal
toxicity
study,
and
eye
irritation
in
the
acute
eye
irritation
study;
these
effects
were
not
noted
with
2,4­
DB.

Some
form
of
liver
toxicity
was
noted
in
all
the
subchronic
and
chronic
toxicity
studies
with
2,4­
DB
and
in
the
subchronic
rat
study
with
2,4­
DB­
DMA.
Liver
weights
were
increased
in
subchronic
rat
studies
with
2,4­
DB
and
2,4­
DB­
DMA,
the
subchronic
dog
study,
and
the
mouse
carcinogenicity
study.
Liver
enzymes
(
ALT,
AST,
and/
or
alkaline
phosphatase)
were
elevated
in
the
subchronic
and
chronic
dog
studies
with
2,4­
DB
and
in
the
subchronic
rat
study
with
2,4­
DBDMA
Hepatocyte
hypertrophy
was
noted
in
the
subchronic
rat
study
with
2,4­
DB.
In
the
subchronic
dog
study
with
2,4­
DB,
BSP
retention
was
increased,
and
icterus
and
pale
livers
were
noted.

Kidney
toxicity
was
noted
in
several
studies.
Kidney
weights
were
increased
in
the
subchronic
dog
study
and
decreased
in
the
subchronic
and
chronic
rat
studies
with
2,4­
DB.
Kidney
infarcts
were
noted
in
the
chronic
rat
study.
Kidney
tubular
degeneration
was
noted
in
the
subchronic
rat
study
with
2,4­
DB­
DMA.
BUN
was
increased
in
the
subchronic
and
chronic
dog
studies
with
2,4­
DB.

Other
toxicity
included
decreased
hematological
parameters
in
the
chronic
rat
study
and
the
subchronic
and
chronic
dog
studies
with
2,4­
DB
and
in
the
subchronic
rat
study
with
2,4­
DBDMA
Heart
weights
were
decreased
in
the
subchronic
and
chronic
rat
studies
and
increased
in
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
2
the
mouse
carcinogenicity
study
with
2,4­
DB.
Light
foci
in
the
heart
were
also
noted
in
the
mouse
carcinogenicity
study.
Inflamed
lacrimal
glands
were
noted
in
the
subchronic
rat
study
with
2,4­
DB­
DMA.

No
systemic
toxicity
was
noted
in
21­
day
dermal
studies
in
rabbits
with
either
2,4­
DB
or
2,4­
DBDMA
although
dermal
irritation
occurred
in
the
dermal
study
with
2,4­
DB­
DMA.

Although
neurotoxicity
has
been
noted
with
other
phenoxy
herbicides,
clinical
signs
suggestive
of
neurotoxicity
with
2,4­
DB
and
2,4­
DB­
DMA
only
occurred
at
lethal
doses.

No
developmental
toxicity
occurred
in
the
developmental
study
in
rabbits.
Decreased
fetal
body
weight,
increased
incidence
of
skeletal
variations/
malformations,
early
resorptions,
microphthalmia,
and
retroesophageal
aortic
arches
occurred
in
developmental
rat
toxicity
studies
with
2,4­
DB
and/
or
2,4­
DB­
DMA.
Maternal
mortality
occurred
at
the
same
dose
as
did
the
developmental
toxicity.

Offspring
toxicity
in
the
2­
generation
reproduction
study
with
2,4­
DB
included
mortality,
decreased
mean
litter
weight,
and
increased
incidence
of
necropsy
findings
(
small
thymus,
distended
bladder
with
bloody/
dark
urine
and
ocular
opacity);
parental
effects
at
the
same
dose
included
decreased
food
consumption
and
body
weight,
increased
food
conversion
ratio,
increased
water
consumption,
organ
weight
changes,
and
macroscopic
renal
findings
(
kidney
pallor
and
cortical
scarring).
There
was
no
effect
upon
reproductive
parameters.

Toxicity
endpoint
studies
were
selected
from
rat
studies,
rather
than
dog
studies,
because
of
differences
in
elimination
of
phenoxyacetic
compounds
in
dogs
compared
to
other
mammalian
species.
The
dog
is
more
sensitive
to
toxicity
from
2,4­
DB
than
is
the
rat,
as
is
the
case
for
2,4­
D
and
MCPA.
Pharmacokinetic
data
on
dogs
are
not
available
for
2,4­
DB.
However,
compounds
closely
related
structurally
to
2,4­
DB,
including
2,4­
D,
triclopyr,
MCPA,
and
other
organic
acids
have
been
shown
to
have
a
decreased
clearance
in
dogs
relative
to
humans
and
rats.
Although
absorption
and
distribution
of
chlorophenoxy
herbicides
and
other
organic
acids
is
similar
across
all
species
evaluated,
the
half­
life
of
elimination
for
dogs
is
significantly
longer
than
for
all
other
species
considered.
For
2,4­
D,
dogs
exhibited
half­
lives
of
31
to
106
hours
for
doses
of
1
to
5
mg/
kg
and
in
other
species
(
mice,
rats,
pigs,
cats
and
humans)
half­
lives
ranged
from
0.75
to
11.6
hours
for
similar
doses.
The
decreased
capacity
of
the
dog
to
eliminate
organic
acids
results
in
higher
blood
levels
and
a
longer
elimination
half­
life
for
these
compounds
in
the
dog,
relative
to
those
found
in
the
rat
and
other
species.
Consequently,
effects
are
seen
at
lower
dose
levels
in
the
dog
than
in
the
rat.
(
See
HIARC
reports
for
2,4­
D
and
MCPA
for
more
details.)
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
3
2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
uses
are
in
Table
1.

Table
1.
Toxicity
Study
Requirements
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
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.
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.
.
.
.
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.
.
.
.
.
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.
.
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
Yesb
Yesb
Yesb
Yesb
Yesb
Under
review
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
28­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
No
Yes
Yesb
Yesa
Yesb
 
No
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yesb
Yesa
Yesa
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yes
Yesa
d
Yesa
Yesa
d
Yesa
Yesa
d
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yesb
Yesb
Yesb
Yesb
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
No
No
No
No
No
­
­
No
No
No
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yesb
Yesc
a
Study
requirement
satisfied
by
2,4­
DB
study
b
Study
requirement
satisfied
by
2,4­
DB
and
2,4­
DB­
DMA
studies
c
Study
requirement
satisfied
by
2,4­
DB­
DMA
study
d
A
combined
chronic/
carcinogenicity
study
fulfilled
this
requirement
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
4
3.0
DATA
GAPS
A
28­
day
inhalation
study
is
required
because
the
use
pattern
indicates
potential
repeated
exposure
via
this
route.
This
study
should
be
conducted
with
2,4­
DB­
DMA
because
of
possible
irritancy
observed
in
the
subchronic
dermal
and
feeding
studies.

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.

Both
2,4­
DB
and
2,4­
DB­
DMA
were
shown
to
be
of
low
acute
toxicity,
with
the
exception
of
the
eye
irritation
study
with
2,4­
DB­
DMA,
which
was
toxicity
category
I
due
to
persistent
corneal
opacity,
iritis,
and
erythema.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
5
Table
2a.
Acute
Toxicity
of
2,4­
DB
Guideline
No.
Study
Type
MRID
#
s
Results
Toxicity
Category
81­
1
Acute
Oral
00128854
0092159
LD50
=
1935
mg/
kg
LD50
=
1715
mg/
kg
III
81­
2
Acute
Dermal
0128854
LD50
=
>
2000
mg/
kg
III
81­
3
Acute
Inhalation
41774001
LC50
>
2.3
mg/
L
IV
81­
4
Primary
Eye
Irritation
0128854
00092160
Eye
irritation
with
complete
clearing
by
day
7
III
81­
5
Primary
Skin
Irritation
0128854
No
irritation
IV
81­
6
Dermal
Sensitization
43593904
Under
review
 
Table
2b.
Acute
Toxicity
of
2­
4­
DB­
DMA
(
26%)

Guideline
No.
Study
Type
MRID
#
Results
Toxicity
Category
81­
1
Acute
Oral
41224401
LD50
=
3583
mg/
kg
III
81­
2
Acute
Dermal
(
rabbit)
41224402
LD50
>
2000
mg/
kg
III
81­
3
Acute
Inhalation
41370101
LC50
>
7.98
mg/
L
IV
81­
4
Primary
Eye
Irritation
41958001
Persistent
corneal
opacity,
iritis,
erythema
I
81­
5
Primary
Skin
Irritation
250871
Irritation
score
=
0.99
IV
81­
6
Dermal
Sensitization
43968911
Under
review
 
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
6
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

Liver
toxicity,
kidney
toxicity,
and
decreased
hematological
parameters
were
noted
in
the
subchronic
toxicity
studies.
Liver
weights
were
increased
in
subchronic
rat
and
dog
studies
with
2,4­
DB
and
in
rats
with
2,4­
DB­
DMA.
Liver
enzymes
(
ALT,
AST,
and/
or
alkaline
phosphatase)
were
elevated
in
the
subchronic
dog
study
with
2,4­
DB
and
in
the
subchronic
rat
study
with
2,4­
DB­
DMA.
Hepatocyte
hypertrophy
was
noted
in
the
subchronic
rat
study
with
2,4­
DB.
In
the
subchronic
dog
study
with
2,4­
DB,
BSP
retention
was
increased,
and
icterus
and
pale
livers
were
noted.

Kidney
weights
were
increased
in
the
subchronic
dog
study
and
in
the
subchronic
rat
studies
with
2,4­
DB.
BUN
was
increased
in
the
subchronic
dog
study
with
2,4­
DB.

Other
toxicity
included
decreased
hematological
parameters
in
the
subchronic
dog
study
with
2,4­
DB
and
in
the
subchronic
rat
study
with
2,4­
DB­
DMA.
Heart
weights
were
decreased
in
the
subchronic
rat
study
with
2,4­
DB.
Inflamed
lacrimal
glands
and
gastric
mucosal
irritation
were
noted
in
the
subchronic
rat
study
with
2,4­
DB­
DMA,
probably
due
to
direct
irritation
of
the
salt.
No
systemic
toxicity
was
noted
in
21­
day
dermal
studies
in
rabbits
with
either
2,4­
DB
or
2,4­
DBDMA
although
dermal
irritation
occurred
in
the
dermal
study
with
2,4­
DB­
DMA.
Although
a
subchronic
neurotoxicity
study
was
not
available,
signs
suggestive
of
neurotoxicity
with
2,4­
DB
and
2,4­
DB­
DMA
only
occurred
at
lethal
doses.

870.3100
90­
Day
Oral
Toxicity
­
Rat
­
2,4­
DB
In
a
90­
day
oral
toxicity
study
(
MRID
00104739)
2,4­
DB
[
98.5%
a.
i
(
from
MRID
00092165),
batch/
lot
#
811012]
was
administered
to
10
Charles
River
albino
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
316,
1000
or
3160
ppm
(
0,
15.8,
50
or
158
mg/
kg/
day
based
on
1
ppm
equals
0.05
mg/
kg/
day)
for
three
months.
An
additional
group
of
10
rats/
sex
was
administered
100
ppm
(
5
mg/
kg/
day)
for
three
months
starting
seven
weeks
after
initiation
of
treatment
in
the
other
groups.
Clinical
pathology
measurements
were
performed
on
5
animals/
sex/
group.
Microscopic
examinations
at
necropsy
were
conducted
on
5
rats/
sex
from
the
control
and
3160
ppm
groups.
The
thyroids,
liver,
kidneys
and
any
unusual
lesions
were
examined
in
5
rats/
sex
of
the
1000
ppm
group.
The
liver,
kidneys
and
any
unusual
lesions
were
examined
in
5
rats/
sex
of
the
100
and
316
ppm
groups.
All
animals
survived
to
study
termination.
The
only
clinical
signs
of
toxicity
were
bloated
appearance
and
soft
feces
in
five
of
ten
males
in
the
3160
ppm
group.
Mean
body
weights
were
decreased
in
the
3160
ppm
males
(
80­
91%
of
control)
and
females
(
75­
92%)
and
slightly
in
the
1000
ppm
females
(
90­
93%).
Mean
body
weight
gain
over
the
course
of
the
study
was
decreased
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
7
in
the
3160
ppm
males
(
77%)
and
females
(
61%)
and
slightly
in
the
1000
ppm
females
(
89%).
There
were
slight
alterations
in
clinical
chemistry
values
(
decreased
glucose,
increased
SGPT,
alkaline
phosphatase)
in
the
3160
ppm
group
males
and
females.
At
necropsy,
the
absolute
weight
of
the
heart,
spleen
and
adrenals
was
significantly
decreased
in
the
3160
ppm
males;
the
absolute
weight
of
the
thyroids,
heart
and
adrenals
was
significantly
increased
in
the
3160
ppm
females.
The
relative
weight
(
to
body
weight)
of
the
liver
and
kidneys
was
increased
in
the
3160
ppm
males
and
females
and
in
the
1000
ppm
males.
On
microscopic
examination,
there
was
increased
activity
in
the
thyroid
glands
of
the
3160
ppm
males
and
females
as
evidenced
by
an
increased
number
of
small
follicles.
In
both
sexes
of
the
1000
and
3160
ppm
groups,
there
was
an
increased
incidence
and
severity
of
the
following
lesions:
hepatocyte
hypertrophy
and
increased
pigment
in
the
liver,
regenerative
epithelium
in
the
kidneys
and
mucosal
edema
of
the
stomach.
The
NOAEL
is
316
ppm
(
15.8
mg/
kg/
day).
The
LOAEL
is
1000
ppm
(
50
mg/
kg/
day),
based
on
slightly
decreased
body
weight
gain
(
females),
increased
relative
weight
of
the
liver
and
kidneys
(
males)
and
increased
incidence
of
microscopic
alterations
in
the
liver,
kidneys
and
stomach.
Although
microscopic
examinations
of
target
tissues
were
not
performed
on
all
dose
groups,
a
NOAEL
for
microscopic
effects
can
be
determined
in
conjunction
with
the
chronic
toxicity
study
in
rats
with
2,4­
DB
(
MRID
40257501).
This
90­
day
oral
toxicity
study
in
the
rat
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
the
rat.

870.3100
90­
Day
Oral
Toxicity
­
Rat
­
2,4­
DB­
DMA
In
a
90­
day
oral
toxicity
study
(
MRID
41775401)
2,4­
DB
dimethylamine
(
25.8%
%
a.
i.,
lot
#
50215906)]
was
administered
in
the
diet
for
90
days
at
dose
levels
of
0,
60,
600
or
1800
ppm
(
equivalent
to
0,
4.16,
41.86
and
130.37
mg/
kg/
day
for
males
and
0,
4.96,
51.36
and
153.64
mg/
kg/
day
for
females)
to
20
Crl:
CD(
SD)
BR
rats/
sex/
group.
An
additional
10/
sex/
group
in
the
controls
and
1800
ppm
groups
were
untreated
for
another
4
weeks
prior
to
sacrifice.
Dietary
concentrations
were
based
on
2,4­
DB
amine
after
correction
for
purity.
All
animals
survived
the
study,
except
for
a
male
in
the
control
group.
There
were
no
treatment­
related
clinical
signs
of
toxicity.
Mean
body
weights
were
significantly
decreased
throughout
the
study
in
the
1800
ppm
males
(
87­
98%
of
control
value)
and
females
(
84­
87%)
and
in
the
600
ppm
females
(
89­
91%).
Mean
body
weight
gain
was
significantly
decreased
in
the
1800
ppm
males
(
82­
86%)
and
females
(
72­
79%)
and
in
the
600
ppm
females
(
81­
85%).
Mean
food
consumption
was
significantly
decreased
throughout
the
study
in
the
1800
ppm
males
(
90­
95%),
at
the
beginning
of
the
study
in
the
1800
ppm
females
(
86­
93%)
and
occasionally
in
the
600
ppm
females
(
92%).
Males
in
the
600
and
1800
ppm
groups
had
a
higher
incidence
of
dacryoadenitis
(
inflammation
of
the
lacrimal
gland)
during
the
Week
13
eye
examination.
One
of
the
high
dose
animals
with
the
lesion
that
was
part
of
the
recovery
group
had
no
evidence
of
the
inflammation
at
Week
17.
No
histological
lesions
were
observed
in
the
lacrimal
gland.
The
toxicological
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
8
significance
of
this
finding
is
unknown.
Males
and
females
in
the
1800
ppm
group
had
significant
but
slight
(

92%
of
control)
decreases
in
RBC
and
HCT,
slight
(

103%)
increases
in
MCH
and
MCHC
and
decreases
(
72­
78%)
in
platelet
counts.
Slight
but
significant
decreases
in
RBC
and
platelet
counts
and
increases
in
MCH
were
also
observed
in
the
600
ppm
females.
There
were
significant
changes
in
multiple
clinical
chemistry
parameters
in
the
600
and
1800
ppm
males
and
females;
however,
most
of
the
differences
from
control
were
slight
and
not
dose­
responsive.
The
toxicological
significance
of
the
hematology
and
clinical
chemistry
findings
is
questionable.
Kidney
weights
(
absolute,
kidney:
body
and
kidney:
brain)
were
significantly
increased
in
the
600
and
1800
ppm
males
and
1800
ppm
females
at
the
Week
14
necropsy.
Only
the
kidney:
body
weights
were
significantly
increased
in
the
1800
ppm
males
(
right
kidney
only)
and
females
at
the
Week
18
necropsy.
Kidney:
body
weight
was
increased
in
the
600
ppm
females
at
Week
14.
Liver
weights
(
absolute
and
liver:
brain)
were
significantly
decreased
in
the
1800
ppm
males
and
females
at
the
Week
18
necropsy.
Liver:
body
weights
were
significantly
increased
in
the
1800
ppm
females
at
the
Week
14
and
18
necropsies.
Other
organ
weight
effects
included:
significant
increase
in
brain:
body
weight
in
the
1800
ppm
males
and
females
and
600
ppm
females
at
Week
14;
significant
increase
in
brain:
body
weight
in
600
ppm
females
at
Week
18;
significant
increase
in
absolute
testes
weight
at
Week
14
and
decrease
in
absolute
testes
weight
at
Week
18
in
the
1800
ppm
males;
and
significant
decrease
in
the
absolute
weight
of
the
left
ovary
in
the
1800
ppm
females
at
Week
18.
There
was
an
increased
incidence
of
dark
foci
in
the
stomach
on
macroscopic
examination
and
mucosal
erosion
on
microscopic
examination
in
the
1800
ppm
males
and
females
at
Week
14
and
in
the
1800
ppm
females
at
Week
18.
There
was
also
an
increased
incidence
of
kidney
tubular
cell
degeneration
in
the
1800
ppm
males
and
females
and
the
600
ppm
females
at
Week
14
and
in
the
1800
ppm
females
at
Week
18.
The
LOAEL
is
600
ppm
(
41.86
mg/
kg/
day
in
males
and
51.36
mg/
kg/
day
in
females),
based
on
decreased
body
weight
and
body
weight
gain
(
females),
increased
kidney
weights
and
increased
incidence
of
kidney
tubular
degeneration
(
females).
The
NOAEL
is
60
ppm
(
4.16
mg/
kg/
day
in
males
and
4.96
mg/
kg/
day
in
females).
This
90­
day
oral
toxicity
study
in
the
rat
is
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
the
rat.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
9
870.3100
Subchronic
Oral
Toxicity
­
Mouse
In
a
rangefinding
study
(
MRID
42387301),
2,4­
DB
(
97.74%,
lot
#
not
specified)
was
administered
to
Crl:
CD­
1
(
CR)
BR
mice
for
4­
weeks.
There
were
10
mice/
sex/
dose
group.
Dietary
doses
were
0,
30,
100,
300,
1000,
or
3000
ppm,
which
was
equivalent
to
0,
4.5,
15,
45,
150,
or
450
mg/
kg/
day,
using
a
0.15
conversion
factor.
At
300
ppm,
body
weight
gain
was
decreased
by
15%
and
18%
in
males
and
females,
respectively.
At
1000
ppm,
mean
body
weight
gains
were
decreased
17%
and
15%
in
males
and
females,
respectively
(
in
the
absence
of
any
palatability
problems)
and
liver
weights
were
increased
in
both
sexes.
At
3000
ppm,
there
was
decreased
survival
in
both
sexes,
decreased
body
weight
gain
and
food
consumption
and
increased
absolute
and
relative
liver
weights.
The
NOAEL
is
100
ppm
(
15
mg/
kg/
day)
and
the
LOAEL
is
300
ppm
(
45
mg/
kg/
day)
based
on
decreased
body
weight
gain.
This
study
is
classified
acceptable/
non­
guideline.

870.3150
90­
Day
Oral
Toxicity
­
Dog
In
a
90­
day
oral
toxicity
study
(
MRID
00092165)
2,4­
DB
(
98.5%
a.
i.,
batch/
lot
#
811012)
was
administered
to
4
beagle
dogs/
sex/
dose
in
the
diet
at
dose
levels
of
0,
316,
1000
or
3160
ppm
for
the
first
two
weeks
and
then
as
capsules
at
8,
25
or
80
mg/
kg/
day
for
the
remainder
of
the
three­
month
study;
the
latter
levels
are
equivalent
to
the
dietary
levels.
A
group
of
4
dogs/
sex
was
also
treated
with
capsules
at
2.5
mg/
kg/
day
for
three
months.
One
dog
died
and
the
remaining
seven
dogs
in
the
3160
ppm
group
were
sacrificed
in
extremis
during
the
third
week.
Two
males
and
two
females
in
the
1000
ppm
group
were
sacrificed
prior
to
termination.
Animals
in
the
1000
and
3160
ppm
groups
had
a
variety
of
clinical
signs
including
diarrhea
and/
or
soft
feces,
inactivity,
cysts
and/
or
abscesses,
depression,
lack
of
alertness,
dull
eyes,
weakness
and
lack
of
coordination.
Mean
body
weights
were
decreased
in
the
1000
ppm
males
(
63­
84%
of
control)
and
females
(
81­
86%
of
control)
at
different
intervals
throughout
the
study.
However,
all
groups,
except
the
female
controls,
had
negative
body
weight
gains
over
the
course
of
the
study.
There
was
no
apparent
treatment­
related
effect
on
food
consumption.
Mean
hematology
values
(
Hct,
Hgb,
RBC)
of
the
combined
sexes
in
the
1000
ppm
group
were
decreased,
especially
during
Week
13
of
testing.
There
were
slight
increases
in
BUN,
SGOT
and
alkaline
phosphatase
in
the
combined
sexes
of
the
1000
ppm
group.
Also,
BSP
retention
was
approximately
2.5
times
higher
than
the
Week
0
value
at
Week
4.
Glucose
and
calcium
were
decreased
in
the
1000
ppm
group.
The
organ
weight
to
terminal
body
weight
ratios
were
increased
for
liver,
kidney
and
spleen
in
the
1000
ppm
males
and
females.
On
gross
necropsy,
there
was
evidence
of
generalized
toxicity
in
the
1000
and
3160
ppm
animals,
including
icterus
or
gray
discoloration
of
the
sclera,
oral
mucosa
and
connective
tissue,
reddened
lymph
node
medullae,
distended
gallbladders,
pale
livers,
eye
discharges,
lung
froth,
discolored
kidneys,
gastric
mucosal
petechia,
subepicardial
hemorrhages
and
altered
large
intestine
mucosa.
Microscopic
examinations
showed
hemorrhage
and
edema
of
most
tissues
and
organs,
hepatocyte
necrosis,
renal
tubular
dilation,
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
10
aspermatogenesis
and
altered
ovarian,
thyroid
and
pancreatic
function
at
1000
and
3160
ppm.
The
NOAEL
is
8
mg/
kg/
day
and
the
LOAEL
is
25
mg/
kg/
day,
based
on
death
(
sacrifice
in
extremis),
clinical
signs
of
toxicity,
decreased
body
weight,
decreased
hematology
parameters,
altered
clinical
chemistry
parameters,
increased
relative
weight
of
multiple
organs
(
liver,
kidney
and
spleen)
and
gross
and
microscopic
necropsy
evidence
of
generalized
toxicity.
This
90­
day
oral
toxicity
study
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3150;
OECD
409)
in
the
dog.

870.3200
21­
Day
Dermal
Toxicity
 
Rabbit
­
2,4­
DB
In
a
21­
day
dermal
toxicity
study
(
MRID
41551301),
10
New
Zealand
rabbits/
sex/
group
received
dermal
applications
of
2,4­
DB
acid
(
98.1%,
HLA
Sample
90300425)
at
0,
500,
1000
or
2000
mg/
kg/
day,
6
hours/
day,
5
days/
week
for
3
weeks.
There
was
no
evidence
of
a
treatment­
related
effect
on
any
of
the
study
parameters.
Statistically
significant
changes
in
some
hematology
(
lower
erythrocyte
counts
in
males
at
2000
mg/
kg/
day
and
higher
MCV
and
MCH
values
in
males
at
1000
or
2000
mg/
kg/
day)
and
clinical
chemistry
(
lower
creatinine
values
in
females
at
500
mg/
kg/
day)
parameters
were
not
considered
treatment­
related
due
to
very
small
changes
which
were
within
the
expected
ranges.
There
was
also
no
evidence
of
a
treatment­
related
effect
on
dermal
irritation.
The
LOAELs
for
systemic
toxicity
and
dermal
irritation
were
not
established.
The
NOAELs
for
systemic
toxicity
and
dermal
irritation
were
2000
mg/
kg/
day
(
HDT).
The
developmental
toxicity
study
in
the
rat
is
classified
acceptable
(
guideline);
and
satisfies
the
guideline
requirement
for
a
21­
day
dermal
toxicity
study
(
OPPTS
870.3200
;
OECD
410)
in
the
rabbit.

870.3200
21­
Day
Dermal
Toxicity
 
Rabbit
­
2,4­
DB­
DMA
In
a
21­
day
dermal
toxicity
study
(
MRID
41529901),
2,4­
DB
amine
(
25.8%
a.
i.,
HLA
sample
no.
90503004)
was
applied
to
the
shaved
skin
of
10
New
Zealand
White
rabbits/
sex/
dose
at
dose
levels
of
0,
250,
750
or
1500
mg/
kg
bw/
day,
6
hours/
day
for
5
days/
week
during
a
21­
day
period.
There
was
no
evidence
of
a
treatment­
related
effect
on
any
of
the
study
parameters
assessing
systemic
toxicity.
Dermal
irritation
was
observed
at
all
dose
levels;
however,
the
severity
was
increased
in
the
750
and
1500
mg/
kg/
day
groups.
The
vehicle
control
(
deionized
water)
and
250
mg/
kg/
day
groups
had
slight
erythema
and
desquamation.
At
750
mg/
kg/
day,
animals
had
slight
erythema,
slight
to
moderate
desquamation
and
slight
to
moderate
fissuring.
At
1500
mg/
kg/
day,
there
was
slight
to
moderate
erythema,
slight
to
moderate
fissuring,
slight
to
moderate
atonia,
slight
to
moderate
edema
and
blanching
with
subcutaneous
hemorrhages.
The
systemic
LOAEL
was
not
established.
The
systemic
NOAEL
was
1500
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
11
mg/
kg/
day,
the
highest
dose
tested.
The
dermal
irritation
LOAEL
was
750
mg/
kg/
day
based
on
erythema,
desquamation
and
fissuring
which
were
more
severe
than
control
lesions.
The
dermal
NOAEL
was
250
mg/
kg/
day.
This
21­
day
dermal
toxicity
study
in
the
rabbit
is
classified
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
21­
day
dermal
toxicity
study
(
OPPTS
870.3200
;
OECD
410)
in
the
rabbit.

870.3465
90­
Day
Inhalation
 
Rat
An
inhalation
toxicity
study
with
2,4­
DB
or
2,4­
DB­
DMA
is
not
available
and
is
a
datagap.
This
study
should
be
conducted
with
2,4­
DB­
DMA
because
of
possible
irritancy
observed
in
the
subchronic
dermal
and
feeding
studies.

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.

No
developmental
toxicity
was
found
in
the
developmental
study
in
rabbits.
Decreased
fetal
body
weight,
increased
incidence
of
skeletal
variations/
malformations,
early
resorptions,
microphthalmia,
and
retroesophageal
aortic
arches
occurred
in
developmental
rat
toxicity
studies
with
2,4­
DB
and/
or
2,4­
DB­
DMA.
Maternal
mortality
was
demonstrated
at
the
same
dose
at
which
developmental
toxicity
occurred.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
­
2,4­
DB
In
the
range­
finding
developmental
toxicity
study
(
MRID
41382702)
,
5
Crl:
CD
BR
impregnated
rats
were
dosed
by
gavage
with
0,
125,
250,
500
or
1000
mg/
kg/
day
2,4­
DB
(
98.1%
a.
i.,
HLA
Sample
90300425)
on
Days
6
through
15
of
gestation.
All
rats
in
the
500
and
1000
mg/
kg/
day
groups
died
or
were
euthanized
by
day
15
of
gestation;
only
20%
of
the
250
mg/
kg/
day
group
survived
to
day
20
of
gestation.
There
were
no
deaths
or
clinical
signs
of
toxicity
in
the
control
and
125
mg/
kg/
day
groups.
A
variety
of
clinical
signs,
including
languidness,
prostration
and
reduced
activity,
were
observed
at
250
mg/
kg/
day
and
above.
Body
weight
was
statistically
significantly
reduced
in
all
treated
groups.
There
were
no
significant
differences
in
pre­
and
post­
implantation
losses,
percent
of
live
or
resorbed
fetuses
at
125
mg/
kg/
day.
However,
3
of
4
litters
in
this
group
had
early
resorptions
and
an
increased
postimplantation
loss
(
10.8%
vs.
1.3%
for
controls).
In
the
main
developmental
toxicity
study
(
MRID
41382701),
2,
4­
DB
(
98.1%
a.
i.,
HLA
Sample
90300425)
was
administered
to
25
Crl:
CD
rats/
dose
in
by
gavage
at
dose
levels
of
0,
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
12
31.25,
62.5
or
125
mg/
kg
bw/
day
from
days
6
through15
of
gestation.
The
death
of
one
dam
in
the
125
mg/
kg/
day
group
was
attributed
to
treatment.
Clinical
signs
of
toxicity
observed
at
125
mg/
kg/
day
included
emaciation,
hunched
appearance,
languidness,
poor
muscle
tone,
cold
to
touch,
piloerection
and
urogenital
staining.
Mean
body
weight
was
statistically
significantly
reduced
in
the
125
mg/
kg/
day
group
(
18%
of
control)
and
non­
significantly
in
the
62.5
mg/
kg/
day
group
(
87%)
for
days
6­
16;
body
weight
gain
was
significantly
decreased
in
the
125
mg/
kg/
day
(
73%)
and
62.5
(
73%)
groups
for
days
0­
20.
The
pregnancy
rates
were
100%
for
the
control
and
96%
for
all
treated
groups.
In
the
125
mg/
kg/
day
group,
4
(
17%)
of
the
23
dams
that
were
pregnant
on
gestation
day
20
had
complete
litter
resorptions.
This
group
had
higher
post­
implantation
losses
and
decreased
live
fetuses
due
to
the
increase
in
early
resorptions.
The
maternal
NOAEL
is
31.25
mg/
kg/
day
and
the
maternal
LOAEL
is
62.5
mg/
kg/
day
based
on
decreased
body
weight
(
days
6­
16)
and
body
weight
gain
(
days
0­
20).
Mean
fetal
weight
was
significantly
reduced
(
83%
of
control
value)
in
the
125
mg/
kg/
day
group.
Also
in
this
group,
there
was
a
non­
significant
increase
in
undeveloped
renal
papillae
and
a
decrease
in
distended
ureters;
these
effects
were
not
considered
treatment­
related.
In
the
125
mg/
kg/
day
group,
three
fetuses
in
two
litters
had
microphthalmia.
Two
fetuses
in
two
litters
and
one
fetus
in
one
litter
in
the
125
and
32.5
mg/
kg/
groups,
respectively,
had
retro­
esophageal
aortic
arches.
Both
fetal
and
litter
incidences
of
unossified­
hyoid
body
of
the
skull
bone,
reduced
cervical
arches
and
thoracic
centra,
unossified
sternebra
#
2,
and
malformed
ribs
were
increased
on
a
litter
basis
in
the
125
mg/
kg/
day
group.
Skeletal
variations
were
not
increased
on
a
litter
basis
in
the
62.5
mg/
kg/
day
group.
The
developmental
NOAEL
is
62.5
mg/
kg/
day.
The
developmental
LOAEL
is
125
mg/
kg/
day,
based
on
decreased
fetal
body
weight,
microphthalmia,
retro­
esophageal
aortic
arches,
skeletal
malformations/
variations,
and
increased
postimplantation
loss
(
early
resorptions).
This
developmental
toxicity
study
in
the
rat
is
classified
acceptable
(
guideline);
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
the
rat.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
13
870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
­
2,4­
DB­
DMA
In
the
range­
finding
developmental
toxicity
study
(
MRID
42536101),
six
Crl:
CD
BR
VAF/
Plus
impregnated
rats
were
dosed
by
gavage
with
0,
25,
50,
100,
175
or
275
mg/
kg/
day
Butyrac
200
(
25.8%
a.
i.,
lot
#
50215006)
on
Days
6
through
15
of
gestation.
Maternal
toxicity
was
observed
at
dose
levels
of
100
mg/
kg/
day
and
above
as
evidenced
by
increased
mortality
(
275
mg/
kg/
day;
4/
6
dams),
increased
clinical
signs
(
175
and
275
mg/
kg/
day);
decreased
body
weight/
body
weight
gain
(
100,
175
and
275
mg/
kg/
day).
Developmental
toxicity
was
observed
at
175
and
275
mg/
kg/
day
as
evidenced
by
decreased
fetal
weight
in
both
dose
groups
and
increased
mortality
and
resorptions
at
175
mg/
kg/
day.
Only
two
dams
survived
in
the
275
mg/
kg/
day
group;
therefore,
the
fetal
effects
were
not
manifested
in
this
group.
In
the
main
study
(
MRID
42595201),
25
Crl:
CD
BR
VAF/
Plus
impregnated
rats
were
dosed
by
gavage
with
0,
31.25,
62.5
or
125
mg/
kg/
day
Butyrac
200,
adjusted
for
test
article
activity,
(
25.8%
a.
i.,
lot
#
50215906)
on
Days
6
through
15
of
gestation.
One
female
in
the
125
mg/
kg/
day
group
was
sacrificed
in
moribund
condition
on
gestation
day
(
GD)
13
and
two
other
females
died
on
GDs
16
and
20.
No
abortions
were
reported.
Clinical
signs
observed
at
125
mg/
kg/
day
included
decreased
activity,
hunched
posture,
ataxia,
cool
to
touch,
rales,
few
feces,
soft
stool,
no
feces,
mucoid
stools,
red
vaginal
discharge,
emaciation,
rough
coat,
fecal
stain,
urine
stain
and
pale
extremities.
At
62.5
mg/
kg/
day,
clinical
signs
were
limited
to
few
feces
and
emaciation.
Mean
body
weight
gain
was
statistically
significantly
decreased
in
the
125
mg/
kg/
day
group
during
GDs
6­
16
(
38%
of
control)
value
and
during
GDs
0­
20
(
74%).
Mean
body
weight
was
also
non­
significantly
decreased
during
GDs
6­
16
in
the
62.5
mg/
kg/
day
group
(
81%).
Corrected
body
weight
gain
was
non­
significantly
decreased
in
the
31.25
(
90%),
62.5
(
87%)
and
125
mg/
kg/
day
(
69%)
groups.
Mean
food
consumption
was
significantly
decreased
during
GDs
6­
16
(
72%
of
control)
and
during
GDs
0­
20
(
88%)
in
the
125
mg/
kg/
day
group
and
nonsignificantly
during
GDs
6­
16
(
91%)
in
the
62.5
mg/
kg/
day
group.
There
was
a
rebound
after
treatment
(
GDs
16­
20)
in
which
both
the
62.5
and
125
mg/
kg/
day
groups
had
significantly
increased
food
consumption.
Two
dams
in
the
125
mg/
kg/
day
group
had
100%
resorption
of
their
litters.
A
nonsignificant
increase
in
early
resorptions
in
this
dose
group,
principally
due
to
the
2
dams
with
total
resorptions,
resulted
in
a
statistically
significant
decrease
in
the
number
of
live
fetuses/
dam.
Fetal
weight/
litter
was
also
significantly
decreased
in
this
group.
There
was
an
increase
in
the
number
of
skeletal
malformations
in
the
125
mg/
kg/
day
group,
including
vertebral
anomalies
with/
without
rib
anomalies
(
3
fetuses/
2
litters)
and
rib
anomalies
(
4
fetuses/
2
litters)
as
compared
to
none
in
the
control
group.
Microphthalmia
was
noted
in
1
fetus
in
the
31.25
mg/
kg/
day
group
and
in
3
fetuses
in
1
litter
in
the
125
mg/
kg/
day
group;
this
malformation
was
also
noted
in
the
rat
developmental
study
with
2,4­
DB
(
MRID
41382702).
The
maternal
NOAEL
is
31.25
mg/
kg/
day.
The
maternal
LOAEL
is
62.5
mg/
kg/
day,
based
on
clinical
signs
of
toxicity
(
including
emaciation)
and
decreased
body
weight
gain
and
food
consumption.
At
125
mg/
kg/
day,
there
were
3
deaths
and
clinical
signs
including
ataxia,
decreased
activity
and
hunched
posture.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
14
The
developmental
NOAEL
is
62.5
mg/
kg/
day.
The
developmental
LOAEL
is
125
mg/
kg/
day
based
on
increased
post­
implantation
loss
(
early
resorptions)
and
decreased
number
of
live
fetuses
per
dam,
decreased
fetal
weight,
skeletal
malformations
and
microphthalmia.
This
developmental
toxicity
study
in
the
rat
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700a;
OECD
414)
in
rats.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
In
a
range­
finding
developmental
toxicity
study
(
MRID
41529903),
8
female
Hra:
(
NZW)
SPF
rabbits
were
dosed
by
gavage
with
0,
50,
100,
200
or
400
mg/
kg/
day
2,
4­
DB
(
98.1%
a.
i.,
HLA
Sample
90300425)
on
Days
7
through
19
of
gestation.
All
rabbits
in
the
200
or
400
mg/
kg/
day
groups
died
or
were
sacrificed
moribund
by
Day
13
of
gestation.
The
percent
of
animals
surviving
to
the
end
of
the
study
was
100%,
88%
and
25%
for
the
control,
50
mg/
kg/
day
and
100
mg/
kg/
day
groups.
Clinical
signs
of
toxicity,
including
ataxia,
prostration,
pale
eyes
and
emaciation,
were
observed
at
all
dose
levels.
Body
weight
and
body
weight
gain
were
significantly
decreased
at
all
dose
levels.
Gross
necropsy
lesions
(
stomach
erosions)
were
observed
at

100
mg/
kg/
day.
There
were
no
effects
on
developmental
toxicity
parameters.
In
the
main
study
(
MRID
41529902),
2,
4­
DB
(
98.1%
a.
i.,
HLA
Sample
90300425)
was
administered
to
16
impregnated
Hra:(
NZW)
SPF
rabbits/
group
by
gavage
at
dose
levels
of
0,
15,
30
or
60
mg/
kg
bw/
day
from
days
7
through
19
of
gestation.
There
were
two
control
does
and
one
30
mg/
kg/
day
doe
that
aborted
and
were
sacrificed.
At
30
mg/
kg/
day,
one
doe
died,
apparently
from
dosing
trauma.
At
60
mg/
kg/
day,
two
does
aborted
and
were
sacrificed
and
two
does
were
sacrificed
in
extremis
due
to
treatment­
related
effects.
Clinical
signs
of
toxicity,
including
loss
of
coordination,
reduced
activity,
ataxia,
prostration
and/
or
yellow
discharge
from
the
eyes
were
observed
at
60
mg/
kg/
day.
At
this
dose,
body
weight
gain
was
also
decreased
(
54%
of
control
for
days
7­
20)
.
There
were
no
treatment­
related
effects
on
pregnancy
rates,
which
were
69%,
81%,
75%
and
56%
at
the
0,
15,
30
and
60
mg/
kg/
day
groups,
respectively.
No
maternal
toxicity
was
observed
at
15
or
30
mg/
kg/
day.
The
maternal
LOAEL
was
60
mg/
kg
bw/
day,
based
on
death
(
sacrifice
in
extremis)
clinical
signs
of
toxicity
and
decreased
body
weight
gains.
The
maternal
NOAEL
was
30
mg/
kg
bw/
day.
There
were
no
treatment­
related
effects
on
fetal
body
weight,
viability
or
external,
visceral
or
skeletal
variations
and
malformations.
The
developmental
LOAEL
was
not
determined.
The
developmental
NOAEL
was
60
mg/
kg/
day
(
HDT).
The
developmental
toxicity
study
in
the
rabbit
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
rabbits.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
15
4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

Offspring
toxicity
in
the
2­
generation
reproduction
study
with
2,4­
DB
included
mortality,
decreased
mean
litter
weight,
and
increased
incidence
of
necropsy
findings
(
small
thymus,
distended
bladder
with
bloody/
dark
urine
and
ocular
opacity);
parental
effects
at
the
same
dose
included
decreased
food
consumption
and
body
weight,
increased
food
conversion
ratio,
increased
water
consumption,
organ
weight
changes,
and
macroscopic
renal
findings
(
kidney
pallor
and
cortical
scarring).
There
was
no
effect
upon
reproductive
parameters
870.3800
Reproduction
and
Fertility
Effects
­
Rat
In
a
two­
generation
reproduction
study
(
MRID
40257503)
2,4­
DB
(
97.7%
a.
i.,
batch
#
853686)]
was
administered
to
28
Crl:
COBS
CD(
SD)
BR
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,60,
300
or
1500
ppm
(
equivalent
to
approximately
0,
5,
25
or
112
mg/
kg
bw/
day
for
males
and
0,
6,
30
and
133
mg/
kg/
day
for
females).
After
weaning
of
the
F
1
A
generation
at
21
days,
males
and
females
were
remated
using
alternative
pairings
to
produce
the
F
1
B
generation.
Weanlings
from
the
F
1
B
generation
were
selected
as
parental
animals
for
the
F
2
generation.
Due
to
the
loss
of
almost
all
litters
in
the
two
matings
of
the
F
0
generation
at
1500
ppm,
it
was
impossible
to
rear
a
second
generation
at
this
concentration.
The
only
treatment­
related
clinical
sign
was
diffuse
or
patchy
alopecia
on
the
back
of
F
0
generation
females
at
1500
ppm.
Ten
adults
died
during
the
study
but
there
was
no
evidence
of
a
treatment­
related
effect.
Females
in
the
F
0
generation
treated
at
1500
ppm
had
a
higher
water
intake
(
8­
20%
increase)
than
the
control
group.
Overall
(
10
weeks)
premating
food
consumption
in
the
F
0
generation
was
decreased
in
males
(
8%)
and
females
(
7%)
at
1500
ppm
at
the
first
mating.
No
effect
on
food
consumption
was
reported
for
other
parental
animals.
Food
conversion
(
food
consumption/
body
weight
gain)
was
increased
only
in
the
F
0
generation
females
at
1500
ppm.
During
gestation
and
lactation
of
the
F
0
generation,
body
weight
was
decreased
approximately
10%
in
females
at
1500
ppm.
There
was
no
evidence
of
a
treatment­
related
effect
on
reproduction
parameters,
except
for
a
slightly
longer
mean
gestational
period
with
the
1500
ppm
group
(
22.9
days
vs
22.3
days
for
controls
during
the
first
mating;
22.7
days
vs
22.2
days
for
controls
for
the
second
mating).
The
toxicological
significance
of
the
finding
is
questionable
due
to
the
minimal
non­
significant
effect.
On
necropsy
of
the
parental
animals
from
the
F
0
generation,
there
were
several
statistically
significant
organ
weight
changes.
The
weight
(
adjusted
for
body
weight
as
a
covariate)
of
the
liver
was
decreased
and
the
kidneys
increased
in
males
at
1500
ppm.
In
females
at
1500
ppm,
there
was
a
decrease
in
the
weight
of
the
heart
and
spleen
(
using
body
weight
as
a
covariate)
along
with
decreases
in
adrenal
and
ovarian
weights.
On
macroscopic
examination
of
F
0
generation
adults
at
termination,
there
was
a
higher
incidence
of
pallor
of
the
kidneys
in
females
and
irregular
renal
cortical
scarring
in
males
at
1500
ppm.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
16
The
mean
litter
size
and
mean
litter
weight
were
lower
at
birth
for
offspring
in
the
1500
ppm
group
at
both
matings
of
the
F
0
generation.
From
birth
to
Day
21,
all
litters
in
this
group
were
lost,
except
for
one
from
the
first
mating
and
three
from
the
second
mating.
The
percentage
of
males
in
all
treated
groups
of
the
first
mating
of
the
F
0
generation
and
in
the
300
ppm
group
of
the
first
mating
of
the
F
1
generation
was
statistically
significantly
decreased
in
comparison
to
the
controls.
The
toxicological
significance
of
this
change
is
questionable
since
it
was
not
a
consistent
finding
at
all
matings.
On
necropsy
of
offspring
from
the
F
0
generation
females,
there
was
an
increased
incidence
of
animals
with
a
small
thymus,
distended
bladder
with
bloody/
dark
urine
and
ocular
opacity
in
the
1500
ppm
group.
There
was
a
dose­
related
increase
in
the
renal
pelvic
dilatation
in
the
60
and
300
ppm
groups
in
both
generations.
The
toxicological
significance
of
this
finding
is
questionable
as
there
was
no
increase
at
1500
ppm
in
the
F
0
generation.
The
parental
systemic
LOAEL
is
1500
ppm
(
approximately
112
mg/
kg
bw/
day
in
males
and
133
mg/
kg
bw/
day
in
females),
based
on
increased
water
consumption
(
females),
decreased
food
consumption
and
body
weight,
increased
food
conversion
ratio
(
females),
organ
weight
changes
and
macroscopic
renal
findings.
The
parental
systemic
NOAEL
is
300
ppm
(
25
mg/
kg
bw/
day
in
males
and
30
mg/
kg
bw/
day
in
females).
The
offspring
LOAEL
is
1500
ppm
(
approximately
112
mg/
kg
bw/
day
in
males
and
133
mg/
kg
bw/
day
in
females),
based
on
increased
mortality,
decreased
mean
litter
weight
and
increased
incidence
of
necropsy
findings
(
small
thymus,
distended
bladder
with
bloody/
dark
urine
and
ocular
opacity).
The
offspring
NOAEL
is
300
ppm
(
25
mg/
kg
bw/
day
in
males
and
30
mg/
kg
bw/
day
in
females).
As
there
was
no
treatment­
related
effect
on
reproduction
parameters,
the
reproductive
LOAEL
is
not
established.
The
reproductive
NOAEL
is
1500
ppm
(
HDT)
(
approximately
112
mg/
kg
bw/
day
in
males
and
133
mg/
kg
bw/
day
in
females).
This
study
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
two­
generation
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
rats.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
17
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.

Liver
weights
were
increased
in
the
rat
and
mouse
carcinogenicity
studies.
Liver
enzymes
(
ALT
and
AST)
were
elevated
in
the
chronic
rat
and
dog
studies
with
2,4­
DB.
Kidney
weights
were
decreased,
and
kidney
infarcts
were
noted
in
the
chronic
rat
study
with
2,4­
DB.
BUN
was
increased
in
the
chronic
dog
study
with
2,4­
DB.

Other
toxicity
included
decreased
hematological
parameters
in
the
chronic
rat
and
dog
studies
with
2,4­
DB.
Heart
weights
were
decreased
in
the
chronic
rat
study
and
increased
in
the
mouse
carcinogenicity
study
with
2,4­
DB.
Light
foci
in
the
heart
were
also
noted
in
the
mouse
carcinogenicity
study.

870.4100a
(
870.4300)
Chronic
Toxicity
 
Rat
In
a
combined
chronic/
carcinogenicity
study
(
MRID
40257501)
2,4­
DB
(
97.74%
a.
i.,
batch/
lot
#
not
provided)
was
administered
to
50
Crl:
CD
®
(
SD)
BR
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
60,
600
or
1800
ppm
(
equivalent
to
0,
3,
30
or
90
mg/
kg
bw/
day
based
on
1
ppm
equals
0.05
mg/
kg)
for
24
months
to
test
the
carcinogenic
potential
of
the
chemical.
An
additional
20
rats/
sex/
group
were
administered
2,4­
DB
in
the
diet
at
the
same
concentrations
for
24
months
to
test
the
chronic
toxicity
of
the
chemical.
Ten
(
10)
rats/
sex/
group
were
treated
for
12
months
at
the
same
concentrations
and
then
sacrificed.
Ten
(
10)
were
treated
at
0
or
1800
ppm
for
12
months
and
then
untreated
for
another
4
weeks
before
sacrifice
to
test
the
reversibility
of
toxicity.
There
was
no
treatment­
related
effect
on
the
survival
or
clinical
signs
of
toxicity.
Mean
body
weight
was
statistically
significantly
decreased
in
1800
males
(
87­
97%
of
control
value)
and
females
(
77­
93%
of
control)
and
in
600
ppm
females
(
91­
97%
of
control).
Mean
body
weight
gain
was
significantly
decreased
in
1800
ppm
males
(
82­
90%
control)
and
females
(
69­
76%
of
control)
and
in
600
ppm
females
(
88­
91%
of
control).
Mean
weekly
food
consumption
was
significantly
decreased
in
the
1800
ppm
males
during
the
first
50
weeks
of
the
study.
Females
in
the
1800
and
600
ppm
groups
had
significantly
decreased
food
consumption
during
the
first
13
weeks
and
first
10
weeks,
respectively.
Hematology
parameters
(
RBC,
hemoglobin,
hematocrit)
were
significantly
decreased
and
MCHC
increased
in
the
1800
ppm
females
at
various
periods
(
6
and
12
months
most
frequently).
Platelet
counts
were
significantly
decreased
in
the
1800
ppm
males
(
3
and
6
months)
and
females
(
6
months).
Multiple
clinical
chemistry
parameters
were
significantly
changed
in
the
1800
ppm
males
and
females
at
several
testing
periods;
a
few
parameters
were
altered
in
the
600
ppm
males
and
females.
The
following
clinical
chemistry
parameters
were
altered
in
the
1800
ppm
males
and
females:
decreased
total
protein,
globulin,
total
bilirubin,
cholesterol,
LDH,
CK,
K,
glucose
(
females),
Ca
(
females)
and
P
(
females);
increased
A/
G
ratio,
AST
(
males),
ALT
(
males)
and
AP.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
18
The
following
parameters
were
altered
in
the
600
ppm
males
and
females:
increased
A/
G
ratio,
decreased
total
protein
(
females),
decreased
cholesterol,
decreased
CK
(
males).
The
toxicological
significance
of
the
clinical
pathology
changes
in
the
600
ppm
groups
is
questionable
as
there
were
no
gross
or
microscopic
alterations.
Absolute
weight
of
the
spleen
was
significantly
decreased
in
the
1800
ppm
males
(
12
and
24
month
sacrifices)
and
females
(
12
and
13
month
sacrifices).
The
weights
of
the
heart
and
liver
were
significantly
decreased
in
1800
ppm
males
and
females.
Absolute
and
relative
(
to
body
weight)
weights
of
one
or
both
kidneys
were
decreased
at
the
12
and
24
month
(
females)
sacrifices.
At
gross
necropsy,
there
was
an
increased
incidence
of
depressed
focus
in
the
kidneys
in
males
at
1800
ppm.
On
microscopic
examination,
there
was
a
significant
increased
incidence
of
kidney
infarcts
in
both
sexes
at
1800
ppm
and
an
increase
in
mononuclear
cell
infiltration
and
spongy
degeneration
of
the
liver
in
the
1800
ppm
males.
The
LOAEL
in
males
is
1800
ppm
(
90
mg/
kg/
day)
based
on
decreased
body
weight,
body
weight
gain
and
food
consumption,
clinical
pathology
changes
and
necropsy
alterations
(
decreased
kidney
weights,
increased
incidence
of
kidney
foci
and
infarcts
and
liver
mononuclear
infiltration
and
spongy
degeneration).
The
LOAEL
in
females
is
600
ppm
(
30
mg/
kg/
day),
based
on
decreased
body
weight
gain
and
food
consumption.
The
NOAEL
in
males
is
600
pp
(
30
mg/
kg/
day).
The
NOAEL
in
females
is
60
ppm
(
3
mg/
kg/
day)
.
At
the
doses
tested,
there
was
no
treatment
related
increase
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate
based
on
based
on
the
effects
on
body
weight,
body
weight
gain,
food
consumption,
clinical
pathology
and
necropsy
findings.
This
chronic/
carcinogenicity
study
in
the
rat
is
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
rat.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
19
870.4100b
Chronic
Toxicity
­
Dog
In
a
1­
year
chronic
toxicity
study
(
MRIDs
42006301,
42384001),
6
beagle
dogs/
sex/
group
were
fed
diets
containing
0,
75,
225
or
450
(
reduced
from
675
ppm
after
week
6)
(
0,
2.39,
6.07
and
12.94
mg/
kg/
day
for
males;
2.15,
7.06
and
14.16
mg/
kg/
day
for
females)
2,4­
DB
acid
(
97.7%,
lot
no.
RT
#
853686)
for
52
weeks.
At
that
time,
4
dogs/
sex/
group
were
sacrificed;
the
remaining
2
dogs/
sex/
group
were
sacrificed
after
a
4­
week
recovery
period
during
which
they
were
fed
the
basal
diet
without
2,4­
DB.
Due
to
decreased
appetites
and
weight
loss
in
animals
dosed
at
675
ppm
during
the
first
six
weeks
of
the
study,
the
dose
level
was
reduced
to
450
ppm.
Mean
body
weight
was
decreased
throughout
the
study
in
the
450
ppm
males
(
68­
94%
of
control)
and
females
(
69­
76%
of
control)
in
comparison
to
control
values.
Mean
body
weight
gain
was
also
decreased
in
the
450
ppm
males
(
32­
86%
of
control)
and
females
(
34­
40%
of
control)
during
most
of
the
study.
Body
weight
gain
was
also
decreased
in
the
225
ppm
males
(
83­
89%
of
control)
and
females
(
69­
77%
of
control).
Mean
food
consumption
was
statistically
significantly
decreased
in
the
450
ppm
males
(
53%
of
control)
and
females
(
63%
of
control)
during
weeks
1­
6.
During
the
week
13
testing,
there
were
statistically
significant
decreases
in
hematology
parameters
in
males
(
RBC,
hemoglobin,
hematocrit)
and
females
(
hemoglobin)
at
450
ppm.
At
26
weeks,
only
hemoglobin
and
hematocrit
were
decreased
in
males
at
450
ppm.
There
were
no
statistically
significant
changes
at
week
52.
There
was
evidence
of
a
dose­
related
effect
on
kidney
and
liver
function
at
weeks
13,
26
and
52,
which
was
reversible
by
week
56.
BUN
and
creatinine
were
statistically
significantly
elevated
in
males
and
females
of
all
dose
levels.
ALT
was
increased
significantly
in
all
treated
females
at
weeks
13,
26
and
52
in
a
dose­
related
manner;
it
was
also
elevated
in
all
treated
males,
although
the
changes
from
control
were
not
always
significant.
AST
was
elevated
in
treated
males
and
females,
although
most
of
the
changes
were
not
significant
or
dose­
related.
On
necropsy
at
week
53,
distended
gallbladders
were
observed
in
1/
8
low­
dose,
3/
8
middose
and
6/
8
high­
dose
animals;
dark
areas
of
the
colon
were
observed
in
2/
8
high­
dose
dogs.
No
gross
abnormalities
were
observed
at
week
57.
At
the
week
53
necropsy,
absolute
adrenal
weights
were
decreased
non­
significantly
in
all
treated
groups.
Absolute
and
relative
testes
and
ovarian
weights
were
non­
significantly
decreased
in
the
225
and
450
ppm
males
and
all
treated
females,
respectively.
The
toxicological
significance
of
these
organ
weight
changes
is
questionable
since
there
were
no
microscopic
findings
in
these
organs.
Absolute
liver
and
kidney
weights
were
non­
significantly
decreased
in
treated
females,
although
there
was
no
dose­
response
effect.
There
was
an
increase
in
the
number
and
severity
of
Kupffer
cell/
macrophage
pigment,
sinusoid
ectasia
and
hepatocyte
pigment
in
males
and
females
at
225
and
450
ppm.
Kidney
tubule
cell
pigment
was
increased
in
number
and
severity
in
all
treated
males
and
females.
The
LOAEL
is
75
ppm
(
2.39
and
2.15
mg/
kg/
day
in
males
and
females,
respectively),
the
lowest
dose
tested,
based
on
clinical
pathology
changes
(
increased
BUN,
ALT
and
AST),
decreased
liver
and
kidney
weights
(
females)
and
microscopic
changes
in
the
kidney.
The
NOAEL
has
not
been
established.
This
chronic
study
in
the
dog
is
classified
acceptable/
guideline
and
satisfies
the
guideline
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
20
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
dog.
Although
a
NOAEL
was
not
established,
a
new
study
is
not
recommended.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
At
the
doses
tested,
there
were
no
treatment
related
increases
in
tumor
incidence
in
rats
or
mice.
Dose
levels
were
considered
adequate
for
carcinogenicity
testing.

870.4200a
Carcinogenicity
Study
­
rat
In
a
combined
chronic/
carcinogenicity
study
(
MRID
40257501)
2,4­
DB
(
97.74%
a.
i.,
batch/
lot
#
not
provided)
was
administered
to
50
Crl:
CD
®
(
SD)
BR
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
60,
600
or
1800
ppm
(
equivalent
to
0,
3,
30
or
90
mg/
kg
bw/
day
based
on
1
ppm
equals
0.05
mg/
kg)
for
24
months
to
test
the
carcinogenic
potential
of
the
chemical.
An
additional
20
rats/
sex/
group
were
administered
2,4­
DB
in
the
diet
at
the
same
concentrations
for
24
months
to
test
the
chronic
toxicity
of
the
chemical.
Ten
(
10)
rats/
sex/
group
were
treated
for
12
months
at
the
same
concentrations
and
then
sacrificed.
Ten
(
10)
were
treated
at
0
or
1800
ppm
for
12
months
and
then
untreated
for
another
4
weeks
before
sacrifice
to
test
the
reversibility
of
toxicity.
At
the
doses
tested,
there
was
no
treatment
related
increase
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate
based
on
the
effects
on
body
weight,
body
weight
gain,
food
consumption,
clinical
pathology
and
necropsy
findings.

This
chronic/
carcinogenicity
study
in
the
rat
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
rat.
Note:
See
the
chronic
toxicity
section
of
this
document
for
details
of
chronic
toxicity
in
this
study.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
21
870.4200b
Carcinogenicity
(
feeding)
­
Mouse
In
a
carcinogenicity
study
(
MRIDs
40257502,
41936201
and
42387301)
2,4­
DB
(
97.4%
a.
i.,
no
batch/
lot
#
provided)
was
administered
to
50
Crl:
CD1
(
CR)
BR
mice/
sex/
dose
in
the
diet
at
dose
levels
of
0,
25,
250
or
750
ppm
(
equivalent
to
0,
3.75,
37.5
and
112.5
mg/
kg
bw/
day
based
on
7
ppm
in
the
diet
equals
1
mg/
kg/
day)
for
78
weeks,
except
males
at
750
ppm
were
terminated
at
66
weeks.
An
additional
20
animals/
sex/
group
were
terminated
after
receiving
the
same
doses
for
52
weeks.
Males
dosed
at
750
ppm
had
a
dramatic
increase
in
mortality
beginning
about
weeks
58­
61;
therefore,
all
males
in
this
group
were
terminated
at
week
66.
There
were
no
treatmentrelated
effects
on
body
weight,
body
weight
gain,
food
consumption,
ophthalmological
examinations
or
clinical
pathology
parameters.
At
the
12­
month
and
terminal
sacrifices,
the
absolute
and
relative
(
to
body
weight)
weights
of
the
left
and
right
kidneys
were
increased
in
the
750
ppm
males
(
6­
19%)
and
females
(
8­
20%),
although
not
always
statistically
significantly
and
not
always
in
a
dose­
related
manner.
Liver
absolute
and
relative
weights
at
the
12­
month
sacrifice
were
also
increased
in
the
750
ppm
males
(
7­
10%)
and
females
(
22­
24%),
although
not
significantly,
and
in
750
ppm
males
(
14%)
at
the
terminal
sacrifice.
The
absolute
weight
of
the
heart
was
significantly
increased
in
the
750
ppm
males
at
the
terminal
sacrifice.
On
gross
pathological
examination
at
the
terminal
necropsy,
there
was
a
statistically
significant
increased
incidence
of
irregularly­
shaped
kidneys,
diffusely
dark
livers
and
light
foci
in
the
heart
of
males
at
750
ppm.
On
microscopic
examination,
males
at
750
ppm
had
an
increased
incidence
of
amyloidosis
in
a
number
of
organs
and
a
significant
increase
in
hepatocellular
enlargement
at
the
terminal
sacrifice.
The
LOAEL
is
750
ppm
(
112.5
mg/
kg/
day),
based
on
increased
mortality
in
males
and
increased
absolute
and
relative
organ
weights
(
liver
and
kidney
in
both
sexes,
heart
in
males),
gross
pathological
changes
in
liver
and
kidney
(
males)
and
increased
amyloidosis
and
hepatocellular
enlargement
(
males).
The
NOAEL
is
250
ppm
(
37.5
mg/
kg/
day).
At
the
doses
tested,
there
was
no
treatment­
related
increase
in
tumor
incidence.
Dosing
was
considered
adequate
based
on
the
findings
of
the
4­
week
range­
finding
study
(
MRID
42387301).
In
this
study,
10
Crl:
CD1
(
CR)
BR
mice/
sex/
dose
were
dosed
with
0,
30,
100,
300,
1000
or
3000
ppm
2,4­
DB
in
the
diet
for
4
weeks.
At
300
ppm,
body
weight
gain
was
decreased
by
15%
and
18%
in
males
and
females,
respectively.
At
1000
ppm,
mean
body
weight
gains
were
17%
and
15%
decreased
in
males
and
females,
respectively
(
in
the
absence
of
any
palatability
problems)
and
liver
weights
were
increased
in
both
sexes.
At
3000
ppm,
there
was
decreased
survival
in
both
sexes,
decreased
body
weight
gain
and
food
consumption
and
increased
absolute
and
relative
liver
weights.
This
carcinogenicity
study
in
the
mice
is
acceptable
(
guideline)
and
satisfies
guideline
requirements
for
a
carcinogenicity
study
[
OPPTS
870.4200;
OECD
451]
in
mice.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
22
4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate.
The
data
showed
that
2,4­
DB
and
2,4­
DB­
DMA
did
not
cause
mutagenic
effects
in
most
studies.
Although
2,4­
DB­
DMA
was
shown
to
be
positive
in
a
UDS
assay,
effects
were
not
manifested
as
either
gene
mutations
or
chromosomal
aberrations.
The
HIARC
concluded
that
there
is
not
a
concern
for
mutagenicity
resulting
from
exposure
to
2,4­
DB
or
2,4­
DB­
DMA.

Table
3.
Mutagenicity
Testing
with
2,4­
DB
and
2,4­
DB­
DMA
Gene
Mutation
2,4­
DB
Negative
for
reverse
gene
mutations
in
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
up
to
a
concentration
exceeding
the
limit
dose.
(
MRID
40257504)

2,4­
DB­
DMA
(
26%)
Negative
for
reverse
gene
mutations
in
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
up
to
a
concentration
that
exceeded
the
limit
dose.
(
MRID
41256101).

2,4­
DB
Negative
for
forward
gene
mutations
at
the
HGPRT
locus
in
Chinese
hamster
ovary
(
CHO)
cells
­
S9
at
1000

g/
mL;
cytotoxicity
was
not
seen
at
this
level.
Equivocal
increases
in
mutation
frequency
+
S9
(
2
of
3
trials),
but
not
dose
related;
mostly
in
only
1
replicate
of
the
2
cultures
at
each
concentration.
All
increased
MF
were
within
historical
spontaneous
range
for
this
cell
line
and
below
the
MF
considered
necessary
by
the
International
Standardization
of
Genotoxicity
Workgroup
to
be
declared
a
positive
response
in
this
test
system
(
MRID
40257505).

2,4­
DB­
DMA
(
26%)
Negative
up
to
a
cytotoxic
concentration
(
MRID
41810701).

Structural
Chromosomal
Aberrations
2,4­
DB
There
were
no
significant
increases
in
chromosome
aberrations
+
S9,
up
to
solubility
limits.
Chromosomal
aberrations
were
noted
­
S9,
but
only
at
cytotoxic
doses
(
MRID
40257506).

2,4­
DB­
DMA
(
26%)
Not
clastogenic
in
CHO
cells
up
to
the
limit
dose
(
MRID
41224403).

Other
Mutagenic
Mechanisms
2,4­
DB
No
evidence
of
unscheduled
DNA
synthesis
(
UDS)
in
primary
rat
hepatocytes
up
to
a
lethal
dose
(
MRID
40257507).

2,4­
DB­
DMA
(
26%)
Positive
at
the
2
highest
concentrations
(
101
and
252

g/
mL)
for
induction
of
UDS
in
primary
rat
hepatocytes.
Increases
in
both
the
mean
net
nuclear
grains/
nucleus
and
percentage
of
the
cells
with

6
net
nuclear
grains
were
scored
at
these
levels
(
MRID
41358901).
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
23
4.8
Neurotoxicity
Neurotoxicity
studies
with
2,4­
DB
and
2,4­
DB­
DMA
are
not
available.
Clinical
signs
suggestive
of
neurotoxicity
occurred
only
at
lethal
doses.
The
HIARC
concluded
that
these
effects
were
agonal
in
nature
and
that
the
data
did
not
indicate
a
concern
for
neurotoxicity
resulting
from
exposure
to
2,4­
DB
and
2,4­
DB­
DMA.
At
this
time,
acute
and
subchronic
neurotoxicity
studies
are
not
recommended
for
2,4­
DB
and
2,4­
DB­
DMA.

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.

A
metabolism
study
in
rats
showed
that
2,4­
DB­
DMA
dissociates
to
2,4­
DB,
after
which
they
share
the
same
metabolic
pathway.
Urine
is
the
major
route
of
excretion;
2,4­
D
and
conjugated
dichlorophenol
are
the
major
metabolites
for
both
chemicals.
2,4­
DB
had
significant
biliary
excretion
and
enterohepatic
recirculation.
There
were
no
significant
differences
in
metabolism
between
males
and
females.
The
results
indicated
that
tissue
accumulation
did
not
occur.

870.7485
Metabolism
­
Rat
­
Study
#
1
(
2,4­
DB)

In
a
metabolism
study
(
MRID
41981601)
[
14C]
2,4­
DB
(%
a.
i.
not
provided,
lot
#
2376­
160),
was
administered
to
five
CD
(
Crl:
CDBR)
rats/
sex/
dose
in
the
following
groups:
A)
single
intravenous
dose
of
0.3
mg/
kg;
B)
single
oral
dose
of
5
mg/
kg;
C)
single
oral
dose
of
approximately
550
mg/
kg;
D)
5
mg/
kg
orally
following
administration
of
14
daily
oral
doses
of
5
mg
unlabeled
2,4­
DB/
kg/
day.
Three
rats/
sex
served
as
controls
and
received
the
vehicle
(
2%
methylcellulose)
by
oral
intubation.
The
position
of
the
[
14C]
was
not
stated
but
it
is
assumed
from
data
to
be
on
phenol
ring.
The
recovery
of
radioactivity
was
greater
than
90%
for
all
groups.
In
groups
A,
B
and
D,
86.2­
97.6%
of
the
total
amount
of
[
14C]
administered
was
recovered
in
the
urine
(
including
cage
wash);
3.5­
5.8%
was
recovered
in
the
feces.
In
group
C,
71.5­
76.3%
was
recovered
in
the
urine
and
13.7­
13.8%
in
the
feces.
In
groups
A,
B
and
D,
22.3­
44.4%
of
the
total
administered
dose
was
associated
with
glucuronide
and
sulfate
conjugates
of
the
metabolite
2,4­
dichlorophenol
(
DCP).
In
group
C,
these
conjugates
represented
12.5%
(
females)
and
18.1%
(
males)
of
the
total
administered
dose.
The
excretion
of
proportionally
less
conjugated
label
in
the
urine
by
the
Group
C
(
high
dose)
animals
may
be
an
indication
of
metabolic
saturation.
The
other
major
metabolites
included
2,4­
D
(
dichlorophenoxyacetic
acid),
which
accounted
for
21.6­
47.2%
of
the
radiolabeled
dose.
Metabolite
G
accounted
for
6.0­
16.7%
of
radiolabel
and
was
identified
as
4­(
2,4­
dichlorophenoxy)­
3­
hydroxybutyric
acid
in
a
subsequent
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
24
study
(
MRID
44774101).
There
were
also
10
unidentified
metabolites.
There
were
no
significant
differences
between
males
and
females
in
the
same
dose
group
with
respect
to
patterns
of
excretion
and/
or
metabolites.
This
metabolism
study
in
the
rat
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
metabolism
study
[
OPPTS
870.7485,
OECD
417]
in
the
rat.

870.7485
Metabolism
­
Rat
­
Study
#
2
(
2,4­
DB)

In
this
rat
metabolism
study
(
MRID
44774101),
[
14C­
aromatic]
or
[
12,13,14C­
aromatic]
2,4­
DB
(

98.7%
radiochemical
purity)
was
administered
to
Crl:
CD:
BR
rats
(
2
males/
dose)
as
a
single
oral
(
gavage)
dose
at
100
mg/
kg.
In
addition,
2
bile­
duct
cannulated
males
were
administered
a
single
oral
dose
of
[
12,13,14C]
2,4­
DB
at
100
mg/
kg.
Detailed
characterization
of
the
test
compounds,
[
14C]
2,4­
DB
and
[
12,13,14C]
2,4­
DB,
was
provided
in
MRIDs
44774102
and
44774103,
respectively.
The
current
study
was
submitted
as
a
supplementary
investigation
of
the
identity
of
Metabolite
G
from
an
earlier
rat
metabolism
study
(
MRID
41981601).
In
the
previous
study,
[
14C]
2,4­
DB
was
administered
to
four
groups
of
5
rats/
sex/
dose
group
as
follows:
i)
intravenously
at
0.3
mg/
kg;
ii)
orally
at
5
mg/
kg;
iii)
orally
at
approximately
550
mg/
kg;
and
iv)
orally
at
5
mg/
kg
following
14
days
of
pretreatment
with
5
mg/
kg/
day
unlabeled
2,4­
DB.
Total
recovery
in
urine,
feces,
exhaled
CO
2,
and
carcass
was
>
90%,
with
the
majority
of
the
radioactivity
associated
with
the
urinary
fraction.
Metabolite
G
was
tentatively
identified
in
the
initial
study
as
4­(
2­
chloro­
4­
hydroxyphenoxy)­
butyric
acid,
also
known
as
2­
Cl­
4­
OH­
DB,
and
accounted
for
6.0­
16.7%
of
the
dose.
Absorption
of
[
14C]
2,4­
DB
and
[
12,13,14C]
2,4­
DB
from
the
G.
I.
tract
of
rats
was
evident
based
on
the
high
level
of
urinary
excretion.
As
in
the
previous
study
(
MRID
41981601),
the
majority
of
the
radioactivity
in
the
current
study
was
associated
with
the
urinary
fraction.
In
normal
rats,
overall
renal
and
fecal
excretion
accounted
for
45.3­
54.4%
of
the
dose
within
24
hours
of
dosing,
equivalent
to
75­
80%
of
the
total
excretion.
For
the
bile­
cannulated
rats,
biliary
excretion
accounted
for
16.5%
of
the
dose
by
24
hours
post­
dose
and
represented
up
to
66%
of
the
total
biliary
excretion;
excretion
in
the
urine
was
rapid
with
20.4%
of
the
dose
being
excreted
in
the
urine
within
24
hours
of
dosing,
equivalent
to
81%
of
the
total
urinary
excretion.
Overall
excretion,
in
urine,
bile,
and
feces,
was
essentially
complete
within
24
hours
and
accounted
for
37.3%
of
the
dose,
equivalent
to
73%
of
the
total
amount
of
the
radioactivity
excreted.
Metabolite
G
was
tentatively
identified
in
the
initial
study
as
2­
Cl,
4­
OH­
DB;
however,
LC/
MS
and
NMR
data
from
the
current
study
showed
that
the
structure
of
Metabolite
G
is
4­(
2,4­
dichlorophenoxy)­
3­
hydroxybutyric
acid,
which
is
consistent
with
the
beta­
oxidation
pathway
of
2,4­
DB
to
the
principle
metabolite,
2,4­
D.
The
majority
of
radioactivity
in
the
urine
extract
was
accounted
for
by
2,4­
D
(
64.0%),
conjugates
of
2,4­
DCP
(
2,4­
D
phenol;
21.1%),
and
Metabolite
G
(
10.7%);
the
majority
of
the
radioactivity
in
the
fecal
extract
was
accounted
for
by
Metabolite
G
(
51.7%),
2,4­
DB
(
36.3%),
and
2,4­
D
(
7.2%).
The
distribution
of
metabolites
in
the
present
study
was
comparable
to
the
distribution
observed
in
the
previous
[
14C]
2,4­
DB
rat
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
25
metabolism
study.
In
the
earlier
study,
the
principal
metabolites
detected
in
urine
and
feces
were
2,4­
D
(
21.6­
47.9%
dose),
the
glucuronide
and
sulfate
conjugates
of
2,4­
DCP
(
3.8­
44.4%
dose),
Metabolite
G
(
6.0­
16.7%
dose),
and
2,4­
DCP
(<
0.1­
7.5%
dose).
This
study
is
classified
acceptable/
non­
guideline
and
when
considered
in
conjunction
with
an
earlier
2,4­
DB
metabolism
study
in
the
rat
(
MRID
41981601)
satisfies
the
guideline
(
§
85­
1;
OPPTS
870.7485)
requirement
for
a
metabolism
study
in
the
rat.

870.7485
Metabolism
­
Rat
­
Study
#
3
(
2,4­
DB
and
2,4­
DB­
DMA)

In
this
rat
metabolism
study
(
MRID
43830101),
two
adult
CD
(
Crl:
CD
®
(
SB)
BR)
rats/
sex/
group
were
administered
a
single
oral
(
gavage)
dose
of
[
14C]
2,4­
DB
acid
or
[
14C]
2,4­
DB
DMA
at
target
doses
of
5.0
mg/
kg
or
6.0
mg/
kg,
respectively.
Actual
doses
were
5.3
and
6.7
mg/
kg.
Three
rats/
sex/
group
served
as
a
vehicle
control
(
2%
aqueous
methylcellulose).
With
both
treated
groups,
the
majority
of
the
radioactivity
(
96­
97%
of
the
dose)
was
excreted
in
the
urine,
most
within
24
hours
post­
treatment.
Fecal
excretion
accounted
for

6%
of
the
dose.
Levels
of
expired
14CO
2
accounted
for

0.1%
of
the
dose.
Material
balances
between
treated
groups
were
comparable,
accounting
for
102­
104%
of
the
dose.
HPLC
analysis
of
whole
urine
showed
that
ten
metabolites
were
chromatographically
resolved.
Of
these,
five
metabolites
each
accounted
for

5%
of
the
dose.
The
major
urinary
metabolite
was
identified
as
2,4­
dichlorophenoxy)
acetic
acid
(
2,4­
D),
accounting
for
31­
44%
and
47­
53%
of
the
dose
in
males
and
females,
respectively.
Three
other
major
urinary
metabolites
(
U2,
U3
and
U6)
were
identified
as
conjugated
forms
of
2,4­
D,
2,4­
dichlorophenol
(
2,4­
DCP)
and
2,4­
DB,
respectively.
HPLC
analysis
of
urine
from
female
rats
treated
with
2,4­
DB
DMA
showed
that
metabolites
U2,
U3
and
U5/
U6
accounted
for
9,
23
and
6%
of
the
urinary
radiocarbon,
respectively.
An
unknown
urinary
metabolite
(
U8),
which
accounted
for
8­
12%
of
the
dose,
was
identified
by
mass
spectrometry
as
4­(
2,4­
dichlorophenoxy)­
3­
hydroxybutyric
acid
(
2,4­
DB­
OH).
HPLC
analysis
of
fecal
extracts
identified
metabolites
as
2,4­
D,
2,4­
DB­
OH
and
2,4­
DCP,
accounting
for
1.1­
2.6,
0.3­
0.7
and
0.6­
0.9%
of
the
dose,
respectively.
Trace
amounts
of
unmetabolized
2,4­
DB
accounted
for
0.7­
1.1%
of
the
dose.
Based
on
the
analyses,
a
metabolic
pathway
was
proposed.
It
appears
that
2,4­
DB
DMA
dissociates
to
the
2,4­
DB
(
free
acid)
and
then
shares
the
same
metabolic
pathway
as
the
2,4­
DB
acid,
which
includes
oxidation,
hydrolysis
and
conjugation.
This
metabolism
study
in
the
rat
is
classified
acceptable
(
non­
guideline)
and
does
not
satisfy
the
guideline
requirement
for
a
metabolism
study
[
OPPTS
870.7485,
OECD
417]
in
rat.
The
study
was
originally
intended
as
a
pilot
metabolism
study
and
as
such,
does
not
meet
the
guideline
requirements.
However,
the
individual
animal
data
did
not
show
large
variations
in
the
results,
and
the
data
were
informative
in
demonstrating
that
the
metabolism
of
2,4­
DB
and
2,4­
DB
DMA
is
similar.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
26
870.7600
Dermal
Absorption
­
Rat
In
a
dermal
penetration
study
(
MRID
44729501)
(
14C)­
2,4­
DB­
DMA
~
98%
a.
i.(
2,4­
DB)
was
administered
to
four
Male
Crl(
WI)
BR
Rats
per
dose/
duration
group.
Test
chemical
was
applied
to
a
10
cm2
area
on
the
rat's
back.
In
addition
total
urine
was
collected
from
the
1.2
mg/
rat
10
and
24
hour
exposure
groups
and
the
24
mg/
rat
24
hour
exposure
group
for
metabolite
analysis.
The
majority
of
the
recovered
(
14C)­
2,4­
DB­
DMA
was
found
in
the
skin
wash
at
all
doses
(
40­
90%).
The
majority
of
the
absorbed
dose
was
found
in
the
urine
and
carcass.
In
general
the
percent
of
dose
absorbed
increases
with
duration
of
exposure
and
decreases
with
increasing
dose
indicating
that
saturation
of
absorption
is
being
approached.
The
percent
of
the
applied
dose
that
was
retained
at
the
application
site
(
in/
on
the
skin)
decreases
with
increasing
doses
above
120
ug/
cm2
indicating
partial
saturation
at
the
skin
entry
process.
In
the
96
hour
exposure
groups
that
were
washed
at
10
hours,
continued
absorption
from
the
skin
was
minimal
at
60
ug/
cm2
but
was
significant
at
120,
1200
and
2400
ug/
cm2
indicating
that
material
remaining
on
the
skin
after
the
10­
hour
wash
has
the
potential
of
contributing
to
the
toxicity
of
the
chemical.
The
highest
dermal
absorption
value
at
96
hours
following
the
10
hour
wash,
was
23%
in
the
120ug/
cm2
group.
Peak
plasma
concentration
increased
with
increasing
dose
and
reached
a
maximum
at
4
and
10
hours
of
exposure
(
Figure
2).
After
10
hours,
excretion
became
a
major
portion
of
the
absorbed
dose
resulting
in
a
fall
of
plasma
concentration.
Urinary
metabolite
profiles
showed
that
2,4­
DB
was
completely
metabolized
following
dermal
absorption.
Seven
radiolabeled
peaks
were
observed.
Five
of
these
metabolites
were
identified
by
LC­
MS.
Proposed
metabolites
include:
2,4­
dichlorophenol
sulphate,
2,4­
dichlorophenol­
glucuronide,
2,4­
dichlorophenoxy
hydroxy
butyric
acid,
a
glycine
conjugate
of
2,4­
dichlorophenoxy
hydroxy
butyric
acid,
and
the
major
metabolite
2,4­
dichlorophenoxy
acetic
acid.
The
proposed
metabolic
pathway
for
2,4­
dichlorophenoxy
butyric
acid
is
considered
reasonable
This
study
in
the
rat
is
classified
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
dermal
penetration
study
(
870.7600)
in
rats.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
27
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
23%

This
value
is
from
a
dermal
absorption
study
with
2,4­
DB­
DMA
(
MRID
44729501)
and
is
the
value
from
a
120
ug/
cm2
exposure
determined
at
96
hours
after
a
wash
at
10
hours.

Although
this
value
is
from
a
dermal
absorption
study
with
2,4­
DB­
DMA,
it
should
also
be
used
for
2,4­
DB
because
there
is
no
dermal
absorption
study
with
2,4­
DB.
This
dermal
absorption
value
is
quite
protective
because
the
NOAELs
for
systemic
toxicity
from
21­
day
dermal
toxicity
studies
in
rabbits
were
2000
mg/
kg/
day
for
2,4­
DB
and
1500
mg/
kg/
day
for
2,4­
DB­
DMA,
the
highest
doses
tested.

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

5.3
Classification
of
Carcinogenic
Potential
There
were
no
treatment­
related
increases
in
tumor
incidences
in
the
rat
combined
toxicity/
carcinogenicity
study.
Dosing
in
the
rat
study
was
considered
adequate
based
on
effects
on
body
weight,
body
weight
gain,
food
consumption,
clinical
pathology
and
necropsy
findings.

There
were
no
treatment­
related
increases
in
tumor
incidences
in
the
mouse
carcinogenicity
study.
The
high­
dose
male
group
(
750
ppm)
was
sacrificed
at
week
66
due
to
high
mortality.
This
left
2
dose
groups
for
males
(
25
and
250
ppm).
However,
dosing
was
considered
adequate
in
males
and
females
based
on
the
findings
of
the
4­
week
range­
finding
study
(
MRID
42387301).
In
this
study,
10
Crl:
CD1
(
CR)
BR
mice/
sex/
dose
were
dosed
with
0,
30,
100,
300,
1000
or
3000
ppm
2,4­
DB
in
the
diet
for
4
weeks.
At
300
ppm,
body
weight
gain
was
decreased
by
15%
and
18%
in
males
and
females,
respectively.
At
1000
ppm,
mean
body
weight
gains
were
decreased
17%
and
15%
in
males
and
females,
respectively
(
in
the
absence
of
any
palatability
problems)
and
liver
weights
were
increased
in
both
sexes.
At
3000
ppm,
there
was
decreased
survival
in
both
sexes,
decreased
body
weight
gain
and
food
consumption
and
increased
absolute
and
relative
liver
weights.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
28
In
accordance
with
the
1999
Draft
Guidelines
for
Cancer
Risk
Assessment
(
July,
1999),
the
HIARC
classified
2,4­
DB
as
"
not
likely
to
be
carcinogenic
to
humans".
This
classification
was
based
on
the
lack
of
evidence
of
carcinogenicity
in
mice
and
rats.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
There
are
acceptable
developmental
toxicity
studies
in
rats
with
2,4­
DB
and
2,4­
DB­
DMA
and
an
acceptable
developmental
study
in
rabbits
and
a
2­
generation
reproduction
study
in
rats
with
2,4­
DB.
The
HIARC
concluded
that
the
toxicology
database
for
2,4­
DB
and
2,4­
DB­
DMA
is
complete
for
evaluation
of
residual
concerns
under
FQPA.

A.
Determination
of
Susceptibility
There
was
no
prenatal
susceptibility
in
the
developmental
rat
study
with
2,4­
DB;
developmental
effects
occurred
at
doses
two­
fold
higher
than
the
doses
that
caused
maternal
toxicity.
There
was
no
prenatal
susceptibility
in
the
developmental
rat
study
with
2,4­
DB­
DMA,
either;
developmental
effects
occurred
at
doses
two­
fold
higher
than
the
doses
that
caused
maternal
toxicity.
There
was
no
prenatal
susceptibility
in
the
rabbit
developmental
toxicity
study
with
2,4­
DB
because
no
developmental
toxicity
occurred.

There
was
qualitative,
but
not
quantitative
susceptibility
in
the
2­
generation
reproduction
study
with
2,4­
DB
because
offspring
mortality
occurred
at
a
dose
where
parental
toxicity
was
less
severe.
The
parental
NOAEL
was
30
mg/
kg/
day
and
the
parental
LOAEL
was
133
mg/
kg/
day
based
on
decreased
food
consumption
and
body
weight,
increased
food
conversion
ratio,
increased
water
consumption,
organ
weight
changes,
and
macroscopic
renal
findings
(
kidney
pallor
and
cortical
scarring).
The
offspring
NOAEL
was
30
mg/
kg/
day
and
the
offspring
LOAEL
was
133
mg/
kg/
day
based
on
mortality,
decreased
mean
litter
weight,
and
increased
incidence
of
necropsy
findings
(
small
thymus,
distended
bladder
with
bloody/
dark
urine
and
ocular
opacity).
There
was
no
effect
upon
reproductive
parameters.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
Since
there
was
evidence
of
increased
susceptibility
of
offspring
following
exposure
to
2,4­
DB
in
the
reproduction
study,
HIARC
performed
a
Degree
of
Concern
Analysis
to:
1)
determine
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identify
any
residual
uncertainties
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
for
this
chemical.
If
residual
uncertainties
are
identified,
HIARC
examines
whether
these
residual
uncertainties
can
be
addressed
by
a
special
FQPA
safety
factor
and,
if
so,
the
size
of
the
factor
needed.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
29
The
HIARC
concluded
that
there
is
low
concern
for
the
qualitative
susceptibility
because:
the
offspring
toxicity
was
well
characterized
and
was
accompanied
by
maternal
toxicity;
there
was
a
clear
NOAEL/
LOAEL
for
offspring
toxicity;
and
the
dose/
endpoint
selected
for
long­
term
risk
assessments
was
considerably
lower
and
would
address
the
concerns
for
offspring
toxicity
seen
in
this
study.
Therefore,
there
were
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

C.
Special
FQPA
Safety
Factor(
s):

Based
upon
the
above
analysis,
the
HIARC
determined
that
no
special
FQPA
Safety
Factor
was
needed
(
i.
e.
1X)
since
there
were
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

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.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
not
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
2,4­
DB
or
2,4­
DB­
DMA.
Clinical
signs
suggestive
of
neurotoxicity
in
the
developmental
toxicity
studies
only
occurred
at
lethal
doses
and
were
agonal
in
nature.
There
was
no
indication
of
toxicity
to
the
central
nervous
system
in
developmental
and/
or
reproductive
studies
with
2,4­
DB
and
2,4­
DB­
DMA.

Based
on
the
weight
of
evidence
presented,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
was
not
required
for
2,4­
DB
or
2,4­
DB­
DMA.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
30
7.0
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Laboratories
America,
Inc.,
Vienna,
VA.
Study
Number
HWA
400­
724,
June
11,
1992.
Unpublished.

MRID
42387301.
Tisdel,
M.
(
1985).
Four
Week
Range­
finding
Study
in
Mice
with
2,4­
DB
Technical.
Hazleton
Laboratories
America,
Inc.,
Madison,
WI.
Study
Number
HLA
6158­
102,
February
27,
1985.
Unpublished
MRID
42536101.
Rodwell,
D.
E.
(
1991).
Range­
Finding
Teratology
Study
in
Rats
with
Butyrac
200.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Study
Number
3147.53,
January
3,
1991.
Unpublished
MRID
42595201.
Rodwell,
D.
E.
(
1991).
Teratology
Study
in
Rats
with
Butyrac
200.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Study
Number
3147.54,
January
3,
1991.
Unpublished
MRID
43830101.
Kraut,
G.
R.,
Gibson,
N.
A.
and
Marsh,
J.
D.
(
1995)
The
Disposition
and
Metabolism
of
[
14C]
2,4­
DB
Dimethylamine
Salt
in
the
Rat.
PTRL
East,
Inc.,
Richmond,
KY.
Laboratory
Report
No.
1840,
October
13,
1995.
Unpublished.

MRID
44729501.
Thornley,
K.
(
1998)
(
Carbon­
14)­
2,4
DB­
DMA:
Dermal
Absorption
in
the
Rat:
Final
Report:
Lab
Project
Number:
1149/
22­
D1141.
Covance
Laboratories
Limited.
306
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
33
MRID
44774101.
Gibson,
N.
A.,
Marsh,
J.
D.,
Johnson,
T.
L.,
Lawrence,
L.
J.
(
1999)
Absorption,
Distribution
and
Elimination
of
[
14C]
2,4­
DB
in
the
Rat:
Addendum
1:
Structural
Confirmation
of
a
2,4­
DB
Rat
Metabolite.
PTRL
East,
Inc.,
Richmond,
KY.
Laboratory
Project/
Report
No.
325/
2014,
January
27,
1999.
Unpublished.

MRID
44774102.
King,
D.
(
1998)
Characterization
of
[
14C]
2,4­
Dichlorophenoxybutyric
Acid
(
2,4­
DB).
PTRL
East,
Inc.,
Richmond,
KY.
Laboratory
Project/
Report
No.
1170/
2023,
November
4,
1998.
Unpublished.

MRID
44774103.
King,
D.
(
1998)
Characterization
of
[
12,13,14C]
2,4­
Dichlorophenoxybutyric
Acid
(
2,4­
DB).
PTRL
East,
Inc.,
Richmond,
KY.
Laboratory
Project/
Report
No.
1167/
2024,
November
4,
1998.
Unpublished.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
34
8.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
35
8.1
Toxicity
Profile
Summary
Tables
8.1.1
Acute
Toxicity
Table
­
See
Section
4.1
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Table
4.
Toxicology
Profile
of
2,4­
DB
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rats
00104739
(
1969)
acceptable/
guideline
0,
316,
1000
or
3160
ppm
(
0,
15.8,
50
or
158
mg/
kg/
day
LOAEL
=
1000
ppm
(
50
mg/
kg/
day).,
based
on
decreased
body
weight
gain,
increased
relative
liver
and
kidney
weight,
microscopic
alterations
in
the
liver,
kidneys
and
stomach.

NOAEL
=
316
ppm
(
15.8
mg/
kg/
day)

870.3150
90­
Day
oral
toxicity
dogs
00092165
(
1969)
acceptable/
guideline
capsules
at
8,
25
or
80
mg/
kg/
day;
group
of
4
dogs/
sex
was
also
treated
with
capsules
at
2.5
mg/
kg/
day
for
three
months.
LOAEL
=
25
mg/
kg/
day,
based
on
death
(
sacrifice
in
extremis),
clinical
signs
of
toxicity,
decreased
body
weight,
decreased
hematology
parameters,
altered
clinical
chemistry
parameters,
increased
relative
weight
of
liver,
kidney
and
spleen,
and
gross
and
microscopic
necropsy
evidence
of
generalized
toxicity.

NOAEL
=
8
mg/
kg/
day
870.3200
21­
day
dermal
­
rabbit
41551301
(
1989)
acceptable/
guideline
0,
500,
1000,
2000
mg/
kg/
day
The
LOAELs
for
systemic
toxicity
and
dermal
irritation
were
not
established.
The
NOAELs
for
systemic
toxicity
and
dermal
irritation
were
2000
mg/
kg/
day
(
HDT).
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
Table
4.
Toxicology
Profile
of
2,4­
DB
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
36
870.3700a
Prenatal
developmental
in
rats
MRID
41382701
(
1990)
acceptable/
guideline
0,
31.25,
62.5
or
125
mg/
kg/
day
Maternal
LOAEL
=
62.5
mg/
kg
bw/
day,
based
on
decreased
body
weight
(
days
6­
16)
and
body
weight
gain
(
days
0­
20).
One
maternal
death
was
attributed
to
treatment
at
125
mg/
kg/
day.
Maternal
NOAEL
=
31.25
mg/
kg
bw/
day.

Developmental
LOAEL
=
125
mg/
kg
bw/
day,
based
on
decreased
fetal
body
weight,
skeletal
malformations/
variations,
microphthalmia,
retroesophageal
aortic
arches.
Developmental
NOAEL
=
62.5
mg/
kg
bw/
day.

870.3700b
Prenatal
developmental
in
rabbits
MRID
41529902
(
1990)
acceptable/
guideline
0,
15,
30
or
60
mg/
kg/
day
Maternal
LOAEL
=
60
mg/
kg
bw/
day,
based
on
mortality,
clinical
signs
of
toxicity
and
decreased
body
weight
gains.
Maternal
NOAEL
=
30
mg/
kg
bw/
day.

Developmental
LOAEL
was
not
determined.
Developmental
NOAEL
=
60
mg/
kg/
day
(
HDT).

870.3800
Reproduction
and
fertility
effects
MRID
40257503
(
1986)
acceptable/
guideline
0,60,
300
or
1500
ppm
(
Males:
0,
5,
25
or
112
mg/
kg/
day
and
Females:
0,
6,
30
and
133
mg/
kg/
day)
Parental
LOAEL
=
1500
ppm
(
112
mg/
kg/
day
in
males
and
133
mg/
kg/
day
in
females),
based
on
increased
water
consumption,
decreased
food
consumption
and
body
weight,
increased
food
conversion
ratio,
organ
weight
changes
and
macroscopic
renal
findings.
Parental
NOAEL
=
300
ppm
(
25
mg/
kg/
day
in
males
and
30
mg/
kg/
day
in
females).

Offspring
LOAEL
=
1500
ppm
(
112
mg/
kg/
day
in
males
and
133
mg/
kg/
day
in
females),
based
on
increased
mortality,
decreased
mean
litter
weight
and
increased
incidence
of
necropsy
findings
(
small
thymus,
distended
bladder
with
bloody/
dark
urine
and
ocular
opacity).
Offspring
NOAEL
=
300
ppm
(
25
mg/
kg/
day
in
males
and
30
mg/
kg/
day
in
females).

No
effect
upon
reproductive
parameters.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
Table
4.
Toxicology
Profile
of
2,4­
DB
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
37
870.4100b
Chronic
toxicity
in
dogs
MRID
42006301
(
1990)
acceptable/
guideline
0,
75,
225
or
450
(
reduced
from
675
ppm
after
week
6)
(
0,
2.39,
6.07
and
12.94
mg/
kg/
day
for
males;
2.15,
7.06
and
14.16
mg/
kg/
day
for
females)
LOAEL
=
75
ppm
(
2.39
and
2.15
mg/
kg/
day
in
males
and
females,
respectively)
based
on
clinical
pathology
changes
(
increased
BUN,
ALT
and
AST),
decreased
liver
and
kidney
weights
(
females)
and
microscopic
changes
in
the
kidney.
NOAEL
has
not
been
established.

870.4200
Carcinogenicity
in
mice
40257502
(
1987)
acceptable/
guideline
0,
25,
250
or
750
ppm
(
equivalent
to
0,
3.75,
37.5
and
112.5
mg/
kg
bw/
day
based
on
7
ppm
in
the
diet
equals
1
mg/
kg/
day)
LOAEL
=
750
ppm
(
112.5
mg/
kg/
day),
based
on
increased
mortality
in
males
and
increased
absolute
and
relative
organ
weights
(
liver
and
kidney
in
both
sexes,
heart
in
males),
gross
pathological
changes
in
liver
and
kidney
(
males)
and
increased
amyloidosis
and
hepatocellular
enlargement
(
males).

NOAEL
=
250
ppm
(
37.5
mg/
kg/
day)

870.4300
Chronic
Toxicity/
Carcinogenicity
in
rats
MRID
40257501(
1987)
acceptable/
guideline
0,
60,
600
or
1800
ppm
(
equivalent
to
0,
3,
30
or
90
mg/
kg
bw/
day
based
on
1
ppm
equals
0.05
mg/
kg)
LOAEL
in
males
=
1800
ppm
(
90
mg/
kg/
day)
based
on
decreased
body
weight,
body
weight
gain
and
food
consumption,
clinical
pathology
changes
and
necropsy
alterations
(
decreased
kidney
weights,
increased
incidence
of
kidney
foci
and
infarcts
and
liver
mononuclear
infiltration
and
spongy
degeneration).
LOAEL
in
females
=
600
ppm
(
30
mg/
kg/
day),
based
on
decreased
body
weight
gain
and
food
consumption.
NOAEL
in
males
=
600
ppm
(
30
mg/
kg/
day)
NOAEL
in
females
=
60
ppm
(
3
mg/
kg/
day)
.

870.7485
Metabolism
and
pharmacokinetics
in
rats
41981601
(
1991)
acceptable/
guideline
Single
i.
v.
and
oral
doses
and
multiple
oral
dosing.
Radioactivity
recovery
in
urine
was
71.5­
97.6%
of
dose
and
3.5­
13.8%
in
feces.
Major
metabolites
were
2,4­
D
and
conjugated
2,4­
DCP.

870.7485
Metabolism
and
pharmacokinetics
in
rats
MRID
44774101(
1999)
acceptable/
guideline
Single
oral
dose
and
2
bile­
duct
cannulated
males.
Biliary
excretion
and
enterohepatic
recirculation
occurred.
Metabolite
G
was
identified
4­(
2,4­
dichlorophenoxy)­
3­
hydroxybutyric
acid.
The
distribution
of
metabolites
in
the
present
study
was
comparable
to
the
distribution
observed
in
the
previous
rat
metabolism
study.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
38
Table
5.
Toxicology
Profile
of
2,4­
DB­
DMA
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3200
21­
day
dermal
­
rabbit
41529901
(
1990)
acceptable/
guideline
0,
250,
750
or
1500
mg/
kg
bw/
day
The
systemic
LOAEL
was
not
established.
The
systemic
NOAEL
was
1500
mg/
kg/
day.
The
dermal
irritation
LOAEL
was
750
mg/
kg/
day
based
on
erythema,
desquamation
and
fissuring
which
were
more
severe
than
control
lesions.
The
dermal
NOAEL
was
250
mg/
kg/
day.

870.3100
90­
Day
oral
toxicity
rodents
41775401
(
1990)
acceptable/
guideline
0,
60,
600
or
1800
ppm
(
0,
4.16,
41.86
and
130.37
mg/
kg/
day
for
males
and
0,
4.96,
51.36
and
153.64
mg/
kg/
day
for
females)
The
LOAEL
is
600
ppm
(
41.86
mg/
kg/
day
in
males
and
51.36
mg/
kg/
day
in
females),
based
on
decreased
body
weight
and
body
weight
gain
(
females),
increased
kidney
weights
and
increased
incidence
of
tubular
degeneration
(
females).
The
NOAEL
is
60
ppm
(
4.16
mg/
kg/
day
in
males
and
4.96
mg/
kg/
day
in
females).

870.3700a
Prenatal
developmental
in
rats
42536101,
42595201
(
1991)
acceptable/
guideline
0,
31.25,
62.5
or
125
mg/
kg/
day
The
maternal
LOAEL
was
62.5
mg/
kg
bw/
day,
based
on
emaciation
and
decreased
body
weight
gain
and
food
consumption.
There
were
3
maternal
deaths
attributed
to
treatment
at
125
mg/
kg/
day.
The
maternal
NOAEL
was
31.25
mg/
kg
bw/
day.

The
developmental
LOAEL
was
125
mg/
kg/
day
based
on
an
increase
in
early
resorptions
per
dam,
skeletal
malformations,
microphthalmia,
and
a
decrease
in
fetal
weight.
The
developmental
NOAEL
was
62.5
mg/
kg/
day.
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
39
8.2
Toxicological
Dose
and
Endpoints
for
Use
in
Human
Risk
Assessment1
Table
6.
Summary
of
Toxicological
Dose
and
Endpoints
for
2,4­
DB
and
2,4­
DB­
DMA
Exposure
Scenario
Dose
for
Risk
Assessment
and
Uncertainty
Factor
Special
FQPA
Safety
Factor
and
Level
of
Concern
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
50
years
of
age)
NOAEL
=
62.5
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.6
mg/
kg/
day
FQPA
SF
=
1X
aPAD
=
acute
RfD
FQPA
SF
=
0.6
mg/
kg/
day
Rat
developmental
toxicity.
LOAEL
=
125
mg/
kg/
day
based
on
skeletal
variations/
malformations,
microphthalmia,
post­
implantation
loss
Acute
Dietary
(
General
population
including
infants
and
children)
None
N/
A
No
appropriate
endpoint
attributable
to
a
single
dose
from
oral
toxicity
studies.

Chronic
Dietary
(
All
populations)
NOAEL=
3
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.03
mg/
kg/
day
FQPA
SF
=
1X
cPAD
=
chronic
RfD
FQPA
SF
=
0.03
mg/
kg/
day
Chronic/
carcinogenicity
study
in
rats.
LOAEL
=
30
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
in
females.

Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL
=
31.25
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
Rat
developmental
toxicity.
LOAEL
=
62.5
mg/
kg/
day
based
on
decreased
maternal
body
weight,
body
weight
gain,
and
food
consumption,
and
clinical
signs
(
emaciation,
few
feces)

Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL
=
15.8
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
Subchronic
rat
toxicity
(
2,4­
DB
study).
LOAEL
=
50
mg/
kg/
day
based
on
decreased
body
weight
gain
(
females),
increased
relative
liver/
kidney
weight,
and
microscopic
changes
Short­
Term
Dermal
(
1
to
30
days)
None
N/
A
Quantitation
not
required.
No
systemic
toxicity
via
the
dermal
route
and
there
are
no
developmental
concerns.

Intermediate­
Term
Dermal
(
1
to
6
months)
Oral
NOAEL
=
15.8
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
100
Subchronic
rat
toxicity
(
2,4­
DB
study)
LOAEL
=
50
mg/
kg/
day
based
on
decreased
body
weight
gain,
increased
relative
liver/
kidney
weight,
and
microscopic
changes
2,4­
DB
and
2,4­
DB­
DMA
Toxicology
Chapter
July
20,
2004
Exposure
Scenario
Dose
for
Risk
Assessment
and
Uncertainty
Factor
Special
FQPA
Safety
Factor
and
Level
of
Concern
Study
and
Toxicological
Effects
40
Long­
Term
Dermal
(>
6
months)
Oral
NOAEL
=
3
mg/
kg/
day
(
dermal
absorption
=
23%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Chronic/
carcinogenicity
study
in
rats.
LOAEL
=
30
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
in
females.

Short­
Term
Inhalation
(
1
to
30
days)
Oral
NOAEL
=
31
mg/
kg/
day
(
inhalation
absorption
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Rat
developmental
toxicity.
LOAEL
=
62.5
mg/
kg/
day
based
on
decreased
maternal
body
weight,
body
weight
gain,
and
food
consumption,
and
clinical
signs
(
emaciation,
few
feces)

Intermediate­
Term
Inhalation
(
1
to
6
months)
Oral
NOAEL
=
15.8
mg/
kg/
day
(
inhalation
absorption
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Subchronic
rat
toxicity
(
2,4­
DB
study).
LOAEL
=
50
mg/
kg/
day
based
on
decreased
body
weight
gain,
increased
relative
liver/
kidney
weight,
and
microscopic
changes
Long­
Term
Inhalation
(>
6
months)
Oral
NOAEL
=
3
mg/
kg/
day
(
inhalation
absorption
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
Chronic/
carcinogenicity
study
in
rats.
LOAEL
=
30
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
in
females.

Cancer
None
N/
A
Classified
"
not
likely
to
be
a
human
carcinogen".

1
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
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.