TXR
NO.
0051956
DATE:
June
13,
2003
MEMORANDUM
SUBJECT:
2,4­
DB
and
2,4­
DB­
DMA
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

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

THROUGH:
Jess
Rowland,
Co­
Chair
and
Elizabeth
Doyle,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
Jeff
Dawson,
Risk
Assessor
Reregistration
Branch
1
Health
Effects
Division
(
7509C)

PC
Code:
030801
(
2,4­
DB)
030819
(
2,4­
DB­
DMA)

On
May
6,
2003,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
2,4­
DB
and
2,4­
DB­
DMA
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
2,4­
DB
and
2,4­
DB­
DMA
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
using
the
2002
OPP
10X
Guidance
Document.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
present
were:
Ayaad
Assaad,
William
Burnam,
Jonathan
Chen,
Elizabeth
Doyle,
Pamela
Hurley,
John
Liccione,
Elizabeth
Mendez,
PV
Shah,
Jess
Rowland,
Brenda
Tarplee
Member(
s)
in
absentia:
Donna
Davis,
Paula
Deschamp,
William
Dykstra,
Susan
Makris
Data
evaluation
prepared
by:
Kit
Farwell,
D.
V.
M.

Also
in
attendance
were:
Whang
Phang,
Michael
Metzger,
Jeff
Dawson,
and
Cecelia
Watson
(
SRRD)

Data
Evaluation
/
Report
Presentation
Kit
Farwell,
D.
V.
M.
Toxicologist
3
INTRODUCTION
On
May
6,
2003,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
2,4­
DB
and
2,4­
DBDMA
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
2,4­
DB
and
2,4­
DB­
DMA
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996
using
the
2002
OPP
10X
Guidance
Document.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.

Both
2,4­
DB
and
2,4­
DB­
DMA
are
chlorophenoxy
herbicides
which
function
by
mimicking
the
action
of
auxins,
plant
growth
hormones.
They
are
broadleaf
herbicides
used
in
agriculture
with
no
current
residential
uses.
2,4­
DB
(
PC
code
030801)
is
the
acid
form
and
has
the
chemical
name
of
2,4­
dichlorophenoxy
butyric
acid.
2,4­
DB­
DMA
(
PC
code
030801)
is
its
salt
and
has
the
chemical
name
of
2,4­
dichlorophenoxy
butyric
acid,
dimethyl
amine
salt.

The
database
for
2,4­
DB
is
complete.
The
database
for
2,4­
DB­
DMA
is
more
limited:
the
guideline
studies
available
for
this
chemical
are
subchronic
feeding
study
in
rats,
developmental
toxicity
in
rats,
dermal
toxicity
in
rabbits,
and
mutagenicity
studies.
Toxicity
and
LOAELs
for
2,4­
DB
and
2,4­
DB­
DMA
were
generally
similar
in
the
2
subchronic
rat
studies
and
in
the
2
developmental
rat
studies.

A
metabolism
study
in
rats
showed
that
2,4­
DB­
DMA
dissociates
to
2,4­
DB,
after
which
they
share
the
same
metabolic
pathway.
The
toxicity
studies
for
2,4­
DB
were
therefore
also
used
to
evaluate
toxicity
and
to
select
endpoints
for
2,4­
DB­
DMA.

I.
FQPA
HAZARD
CONSIDERATIONS
1.
Adequacy
of
the
Toxicity
Data
Base
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.

2.
Evidence
of
Neurotoxicity
No
neurotoxicity
studies
are
available
for
2,4­
DB
or
2,4­
DB­
DMA.
Clinical
signs
suggestive
of
neurotoxicity
occurred
only
at
lethal
doses.
The
HIARC
concluded
that
these
effects
were
agonal
in
nature
and
there
is
not
a
concern
for
neurotoxicity
resulting
from
exposure
to
2,4­
DB
and
2,4­
DB­
DMA.
4
3.
Developmental
Toxicity
Study
Conclusions
Rat
Developmental
Toxicity
Study
with
2,4­
DB:

In
the
range­
finding
developmental
toxicity
study
(
MRID
41382701)
,
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
postimplantation
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
post­
implantation
loss
(
10.8%
vs.
1.3%
for
controls).

In
the
main
developmental
toxicity
study
(
MRID
41382702),
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,
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
sternebrae
#
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
5
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.

Rat
Developmental
Toxicity
Study
with
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
nonsignificantly
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
non­
significantly
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
non­
significant
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).
6
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.

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.

Rabbit
Developmental
Toxicity
Study
with
2,4­
DB:

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
developmental
toxicity
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.
7
4.
Reproductive
Toxicity
Study
Conclusions
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.

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
NOAEL
is
300
ppm
(
25
mg/
kg
bw/
day
in
males
and
30
mg/
kg
bw/
day
in
8
females).
The
parental
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
offspring
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).

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
twogeneration
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
rats.

5.
Additional
Information
from
Literature
Sources
No
information
related
to
developmental
or
reproductive
susceptibility
from
2,4­
DB
or
2,4­
DBDMA
was
found
in
a
Toxline
search.

6.
Pre­
and/
or
Postnatal
Toxicity
The
HIARC
concluded
that
there
is
concern
for
postnatal
toxicity
resulting
from
exposure
to
2,4­
DB
or
2,4­
DB­
DMA.

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.
9
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.
The
results
of
the
HIARC
Degree
of
Concern
analysis
for
2,4­
DB
follow.

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
because
the
dose/
endpoint
selected
for
longterm
risk
assessments
is
considerably
lower
and
would
address
the
concerns
for
offspring
toxicity
seen
in
this
study.
Therefore,
the
Committee
concluded
that
there
are
no
residual
uncertainties
for
pre­
and/
or
postnatal
toxicity.

C.
Special
FQPA
Safety
Factor(
s):

Based
upon
the
above
data,
no
special
FQPA
Safety
Factor
is
needed
(
i.
e.
1X)
since
there
are
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.

7.
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
is
not
required
for
2,4­
DB
or
2,4­
DB­
DMA.

II.
HAZARD
IDENTIFICATION
10
1.
Acute
Reference
Dose
(
aRfD)
­
Females
13+
years
of
age
Study
Selected:
Developmental
toxicity
in
rats
(
2,4­
DB)
Developmental
toxicity
in
rats
(
2,4­
DB­
DMA)

OPPTS
870.3700a
[
§
83­
3a];
OECD
414
MRID
Nos.:
41382701
and
41382702
(
2,4­
DB)
42536101
and
42595201
(
2,4­
DB­
DMA)

Executive
Summaries:
See
developmental
toxicity
section.

Dose
and
Endpoint
for
Establishing
aRfD:
Developmental
NOAEL
=
62.5
mg/
kg/
day
and
LOAEL
=
125
mg/
kg/
day
in
both
studies.
The
developmental
LOAEL
is
based
on
skeletal
variations/
malformations,
microphthalmia,
and
post­
implantation
loss.

Uncertainty
Factor
(
UF):
100
(
10
for
interspecies
extrapolation
and
10
for
intraspecies
variability)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
endpoint
(
developmental
toxicity)
is
presumed
to
occur
after
a
single
dose.

Acute
RfD
(
Females
13+)
=
62.5
mg/
kg
(
NOAEL)
=
0.6
mg/
kg/
day
100
(
UF)

2.
Acute
Reference
Dose
(
aRfD)
­
General
Population,
Including
Infants
and
Children
Study
Selected:
None
MRID
No.:
N/
A
Executive
Summary:
N/
A
Dose
and
Endpoint
for
Establishing
aRfD:
N/
A
Comments
about
Endpoint:
Data
do
not
show
a
toxicity
endpoint
attributable
to
a
single
exposure
appropriate
for
the
general
population.

3.
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
Rat
Feeding
Study
OPPTS
870.4300
(
OPP
§
83­
5)

MRID
No.:
40257501
11
Executive
Summary:
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.
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
12
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).
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.

Dose
and
Endpoint
for
Establishing
cRfD:
NOAEL
=
3
mg/
kg/
day
based
upon
decreased
body
weight
gain
and
food
consumption
in
females
at
the
LOAEL
of
30
mg/
kg/
day.

Uncertainty
Factor(
s):
100
(
10
for
interspecies
extrapolation
and
10
for
intraspecies
variations)

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
Consideration
was
given
to
using
an
endpoint
from
the
chronic
dog
study.
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
a
decreased
clearance
in
dogs
relative
to
that
predicted
from
the
allometric
relationship,
whereas
humans,
rats,
mice,
and
other
species
all
fit
the
relationship.
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,
and
consequently,
effects
are
seen
at
lower
dose
levels
in
the
dog
than
in
the
rat.
(
See
HIARC
reports
for
2,4­
D
[
TXR
0051866]
and
MCPA
[
TXR
0051862]
for
more
details.)
The
difference
in
the
elimination
pattern
among
dogs
and
other
mammalian
species
persuaded
HIARC
that
the
rat
was
a
better
predictor
than
the
dog
of
the
potential
toxicity
of
2,4­
DB
and
2,4­
DB­
DMA
to
humans.

Chronic
RfD
=
3
mg/
kg/
day
(
NOAEL)
=
0.03mg/
kg/
day
100
(
UF)

4.
Incidental
Oral
Exposure:
Short­
Term
(
1­
30
days)

Study
Selected:
Developmental
toxicity
in
rats
(
2,4­
DB)
Developmental
toxicity
in
rats
(
2,4­
DB­
DMA)

OPPTS
870.3700a
[
§
83­
3a];
OECD
414
MRID
No.:
41382701
and
41382702
(
2,4­
DB)
42536101
and
42595201
(
2,4­
DB­
DMA)

Executive
Summary:
See
developmental
toxicity
section.
13
Dose
and
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
=
31.25
mg/
kg
based
on
decreased
body
weight,
body
weight
gain,
and
food
consumption
and
clinical
signs
of
toxicity
(
emaciation,
few
feces)
at
the
LOAEL
of
62.5
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
study
is
appropriate
for
the
population
of
concern
(
infants
and
children)
and
for
the
route
and
duration
of
exposure.
There
was
confidence
in
the
endpoint
because
NOAEL
values
and
the
types
of
toxicity
seen
were
comparable
in
the
rat
studies
with
both
2,4­
DB
and
2,4­
DB­
DMA.

5.
Incidental
Oral
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
90­
Day
Feeding
Study
in
Rats
with
2,4­
DB
OPPTS
870.3100
[
§
82­
1a]

MRID
No.:
00104739
Executive
Summary:
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
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.
14
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.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
15.8
mg/
kg/
day
based
upon
slightly
decreased
body
weight
gain
(
females),
increased
relative
weight
of
the
liver
and
kidneys
(
males)
and
increased
incidence
of
microscopic
changes
(
hepatocyte
hypertrophy,
regenerative
kidney
epithelium,
gastric
mucosal
edema)
at
the
LOAEL
of
50
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
endpoint
is
appropriate
for
the
population
of
concern
(
infants
and
children)
and
for
the
route
and
duration
of
exposure.
Consideration
was
given
to
using
the
subchronic
rat
study
with
2,4­
DB­
DMA,
which
has
a
lower
NOAEL
(
4mg/
kg/
day
in
males
and
5
mg/
kg/
day).
However,
the
lower
NOAEL
in
the
2,4­
DB­
DMA
study
is
believed
to
be
due
to
dose
spacing
because
the
LOAEL
for
both
studies
was
the
mid­
dose
(
50
mg/
kg/
day)
and
the
low­
dose
(
NOAEL)
for
2,4­
DB
was
16
mg/
kg/
day
and
for
2,4­
DB­
DMA
was
only
5
mg/
kg/
day.

6.
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.

7.
Dermal
Exposure:
Short­
Term
(
1­
30
days)
Exposure
Study
Selected:
None
MRID
No.:
N/
A
Executive
Summary:
N/
A
Dose
and
Endpoint
for
Establishing
aRfD:
N/
A
15
Comments
about
Endpoint:
Quantification
of
short­
term
dermal
exposure
is
not
required.
No
systemic
toxicity
developed
in
21­
day
dermal
toxicity
studies
with
2,4­
DB
and
2,4­
DB­
DMA.
There
were
no
effects
on
body
weight,
food
consumption,
clinical
signs,
hematology,
clinical
chemistry,
organ
weights,
and
gross
or
microscopic
pathology
of
organs,
including
liver
and
kidney.
Dermal
irritation
(
moderate)
occurred
with
2,4­
DB­
DMA
treatment.
The
systemic
NOAEL
and
highest
dose
tested
was
2000
mg/
kg/
day
with
2,4­
DB
and
1500
mg/
kg/
day
with
2,4­
DB­
DMA.

There
are
no
developmental
toxicity
concerns.
This
is
because
developmental
toxicity
in
rats
only
occurred
at
doses
two
fold
greater
than
those
causing
maternal
toxicity,
and
no
systemic
toxicity
occurred
in
the
dermal
studies
with
2,4­
DB
and
2,4­
DB­
DMA.
Furthermore,
developmental
toxicity
in
rats
(
skeletal
variations/
malformations,
microphthalmia,
and
post­
implantation
loss),
occurred
only
at
a
dose
that
was
lethal
to
the
dams.
In
rabbits,
no
developmental
toxicity
occurred,
even
at
a
dose
causing
maternal
mortality
and
clinical
signs.

8.
Dermal
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
90­
Day
Feeding
Study
in
Rats
with
2,4­
DB
OPPTS
870.3100
[
§
82­
1a]

MRID
No.:
00104739
Executive
Summary:
See
intermediate­
term
incidental
oral
section
of
this
report.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
15.8
mg/
kg/
day
based
upon
slightly
decreased
body
weight
gain
(
females),
increased
relative
weight
of
the
liver
and
kidneys
(
males)
and
increased
incidence
of
microscopic
changes
(
hepatocyte
hypertrophy,
regenerative
kidney
epithelium,
gastric
mucosal
edema)
at
the
LOAEL
of
50
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
duration
of
exposure
is
appropriate
for
this
endpoint.
The
21­
day
dermal
toxicity
study
in
rabbits
was
not
used
for
this
endpoint
because
the
duration
of
exposure
(
21­
days)
was
considered
too
short
for
liver
and
kidney
toxicity
to
develop.
Consideration
was
also
given
to
using
the
subchronic
rat
study
with
2,4­
DB­
DMA,
which
has
a
lower
NOAEL
(
4
mg/
kg/
day
in
males
and
5
mg/
kg/
day).
However,
the
lower
NOAEL
in
the
2,4­
DB­
DMA
study
is
believed
to
be
an
artifact
of
dose
spacing,
as
described
in
Section
II.
5
(
Incidental
oral,
intermediate­
term
exposure).
Since
an
oral
dose
was
selected,
the
23%
dermal
absorption
factor
should
be
used
for
route­
to­
route
extrapolation.

9.
Dermal
Exposure
Long­
Term
(>
6
Months)

Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
Rat
Feeding
Study
OPPTS
870.4300
(
OPP
§
83­
5
MRID
No.:
40257501
16
Executive
Summary:
See
chronic
dietary
section.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
3
mg/
kg/
day
based
upon
decreased
body
weight
gain
and
food
consumption
in
females
at
the
LOAEL
of
30
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
dose/
endpoint/
study
was
also
used
for
establishing
the
chronic
RfD.
See
Comments
section
for
the
Chronic
RfD
in
this
report
for
more
details.
Since
an
oral
dose
was
selected,
the
23%
dermal
absorption
factor
should
be
used
for
route­
to­
route
extrapolation.

10.
Inhalation
Exposure:
Short
­
Term
(
1­
30
days)

Study
Selected:
Developmental
toxicity
in
rats
(
2,4­
DB)
Developmental
toxicity
in
rats
(
2,4­
DB­
DMA)

OPPTS
870.3700a
[
§
83­
3a];
OECD
414
MRID
No.:
41382701
and
41382702
(
2,4­
DB)
42536101
and
42595201
(
2,4­
DB­
DMA)

Executive
Summary:
See
developmental
toxicity
section.

Dose
and
Endpoint
for
Risk
Assessment:
Maternal
NOAEL
=
31.25
mg/
kg
based
on
decreased
body
weight,
body
weight
gain,
and
food
consumption
and
clinical
signs
of
toxicity
(
emaciation,
few
feces)
at
the
LOAEL
of
62.5
mg/
kg/
day.

Comments
about
Study/
Endpoint:
In
the
absence
of
a
repeated­
exposure
inhalation
study,
an
oral
dose
was
selected.
There
was
confidence
in
the
endpoint
because
NOAEL
values
and
the
types
of
toxicity
seen
were
comparable
in
the
rat
studies
with
both
2,4­
DB
and
2,4­
DB­
DMA.
Absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
oral
absorption.

11.
Inhalation
Exposure:
Intermediate­
Term
(
1­
6Months)

Study
Selected:
90­
Day
Feeding
Study
in
Rats
with
2,4­
DB
OPPTS
870.3100
[
§
82­
1a]

MRID
No.:
00104739
Executive
Summary:
See
intermediate­
term
incidental
oral
section
of
this
report.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
15.8
mg/
kg/
day
based
upon
slightly
decreased
body
weight
gain
(
females),
increased
relative
weight
of
the
liver
and
kidneys
(
males)
and
increased
incidence
of
microscopic
changes
(
hepatocyte
hypertrophy,
regenerative
kidney
epithelium,
gastric
mucosal
edema)
at
the
LOAEL
of
50
mg/
kg/
day.
17
Comments
about
Study/
Endpoint:
In
the
absence
of
a
repeated­
exposure
inhalation
study,
an
oral
dose
was
selected.
Absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
oral
absorption.

12.
Inhalation
Exposure:
Long­
Term
(>
6
Months)

Study
Selected:
Combined
Chronic
Toxicity/
Carcinogenicity
Rat
Feeding
Study
OPPTS
870.4300
(
OPP
§
83­
5
MRID
No.:
40257501
Executive
Summary:
See
chronic
dietary
section.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
3
mg/
kg/
day
based
upon
decreased
body
weight
gain
and
food
consumption
in
females
at
the
LOAEL
of
30
mg/
kg/
day.

Comments
about
Study/
Endpoint:
This
dose/
endpoint/
study
was
also
selected
for
establishing
the
chronic
RfD
and
long­
term
dermal
risk
assessments.
See
Comments
section
for
the
Chronic
RfD
in
this
report
for
more
details.
Absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
oral
absorption.

13.
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.

Route
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Dermal
N/
A
100
100
Inhalation
100
100
100
Residential
(
Non­
Dietary)
Exposure
Oral
100
100
N/
A
Dermal
N/
A
100
100
Inhalation
100
100
100
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100
(
10
for
intraspecies
extrapolation
and
10
for
interspecies
variation)
For
Residential
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100
(
10
for
intraspecies
extrapolation
and
10
for
interspecies
variation).
18
14.
Recommendation
for
Aggregate
Exposure
Risk
Assessments
As
per
FQPA,
1996,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
For
intermediate­
term
and
long­
term
aggregate
exposure
risk
assessments,
the
oral,
dermal,
and
inhalation
routes
can
be
combined
because
a
common
toxicity
endpoint
(
using
oral
equivalents)
was
identified
for
all
3
routes
of
exposure.
For
short­
term
aggregate
exposure
risk
assessments,
the
oral
and
inhalation
routes
can
be
combined
because
a
common
toxicity
endpoint
(
using
oral
equivalents)
was
identified;
quantification
of
short­
term
dermal
exposure
is
not
required
(
see
short­
term
dermal
exposure
section
of
this
document).

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.
40257501
Executive
Summary:
See
chronic
dietary
section
of
this
document.

Discussion
of
Tumor
Data:
There
was
no
treatment
related
increase
in
tumor
incidence
when
compared
to
controls.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
based
on
the
effects
on
body
weight,
body
weight
gain,
food
consumption,
clinical
pathology
and
necropsy
findings.

2.
Carcinogenicity
Study
in
Mice
MRID
No.:
42387301
Executive
Summary:
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
treatment­
related
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
19
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).
This
carcinogenicity
study
in
the
mice
is
acceptable
(
guideline)
and
satisfies
guideline
requirements
for
a
carcinogenicity
study
[
OPPTS
870.4200;
OECD
451]
in
mice.

Discussion
of
Tumor
Data:
There
was
no
treatment­
related
increase
in
tumor
incidence.

Adequacy
of
the
Dose
Levels
Tested:
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
rangefinding
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.

3.
Classification
of
Carcinogenic
Potential
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.

IV.
MUTAGENICITY
The
HIARC
concluded
that
there
is
not
a
concern
for
mutagenicity
resulting
from
exposure
to
2,4­
DB
or
2,4­
DB­
DMA.
20
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).

V.
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.

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.

The
database
for
2,4­
DB
and
2,4­
DB­
DMA
is
adequate
for
establishing
toxicity
endpoints
for
risk
assessment.
Most
studies
were
conducted
with
2,4­
DB.
Studies
with
2,4­
DB­
DMA
include
subchronic
feeding
study
in
rats,
developmental
toxicity
in
rats,
dermal
toxicity
in
rabbits,
and
mutagenicity
studies.
Toxicity
and
LOAELs
for
2,4­
DB
and
2,4­
DB­
DMA
were
generally
similar
in
the
2
subchronic
rat
21
studies
and
in
the
2
developmental
rat
studies.
The
DMA
salt
form
appears
more
irritating
than
the
acid
form,
based
on
skin
irritation
in
the
dermal
toxicity
study
and
inflamed
lacrimal
glands
in
the
subchronic
rat
study.
Toxicity
in
the
following
section
generally
refers
to
studies
with
2,4­
DB,
unless
otherwise
specified.

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
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
toxicity
was
noted
in
several
studies.
Kidney
weights
were
increased
in
the
subchronic
dog
study
and
in
the
subchronic
rat
study
with
2,4­
DB.
In
the
chronic
rat
study
with
2,4­
DB,
kidney
weights
were
decreased
and
kidney
infarcts
were
noted.
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
DB­
DMA.
Heart
weights
were
increased
in
the
subchronic
and
chronic
rat
studies
and
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
DB­
DMA,
although
dermal
irritation
occurred
in
the
dermal
study
with
2,4­
DB­
DMA.

Although
neurotoxicity
has
been
noted
with
other
phenoxy
herbicides,
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.
Developmental
toxicity
in
rat
studies
occurred
at
the
same
dose
as
maternal
mortality
and
there
were
no
concerns
for
increased
susceptibility
of
offspring
from
the
developmental
toxicity
studies.

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.

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
a
decreased
clearance
in
dogs
relative
to
that
predicted
from
the
allometric
relationship,
whereas
humans,
rats,
mice,
22
and
other
species
all
fit
the
relationship.
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)
halflives
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,
and
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.)
The
difference
in
the
elimination
pattern
among
dogs
and
other
mammalian
species
persuaded
HIARC
that
the
rat
was
a
better
predictor
than
the
dog
of
the
potential
toxicity
of
2,4­
DB
and
2,4­
DB­
DMA
to
humans.

VI.
DATA
GAPS
/
REQUIREMENTS
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.
23
VII.
ACUTE
TOXICITY
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
­­­
Under
review
 
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
4195801
Persistent
corneal
opacity,
iritis,
erythema
I
81­
5
Primary
Skin
Irritation
250871
Irritation
score
=
0.99
IV
81­
6
Dermal
Sensitization
­­­
Under
review
 
24
VIII.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
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
Exposure
Scenario
Dose
for
Risk
Assessment
and
Uncertainty
Factor
Special
FQPA
Safety
Factor
and
Level
of
Concern
Study
and
Toxicological
Effects
25
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".

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.
