Document ID: EPA-HQ-OPP-2002-0329-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-12-06T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
October
12,
2001
MEMORANDUM
Subject:
EPA
Id
#.
Asulam.
Toxicology
Chapter
of
the
RED.

TXR
No.:
.
PC
Code
No.:
106901;
106902
DP
Barcode
No.:
Submission
No.:

From:
John
J.
Liccione
ReRegistraion
Branch
III
Health
Effects
Division
7509C
To:
Jose
Morales
Risk
Assessor
ReRegistration
Branch
III
Health
Effects
Division
7509C
Through:
Catherine
Eiden
Branch
Senior
Scientist
ReRegistration
Branch
III
Health
Effects
Division
7509C
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
Attached
is
the
Toxicology
Chapter
for
the
RED
for
asulam.
An
electronic
copy
is
available
in
the
LAN
or
in
the
IHAD
system.

1
EPA
Reviewer:
John
J.
Liccione
,
Date
ReRegistration
Branch
III
(
7509C)
Secondary
Reviewer:
Catherine
Eiden
,
Date
ReRegistration
Branch
III
(
7509C)

2
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
...........................................
4
2.0
REQUIREMENTS
........................................................
5
3.0
DATA
GAP(
S)
...........................................................
7
4.0
HAZARD
ASSESSMENT
..................................................
7
4.1
Acute
Toxicity........................................................
7
4.2
Subchronic
Toxicity
...................................................
8
4.3
Prenatal
Developmental
Toxicity
........................................
10
4.4
Reproductive
Toxicity.................................................
11
4.5
Chronic
Toxicity
.....................................................
12
4.6
Carcinogenicity
......................................................
13
4.7
Mutagenicity
........................................................
14
4.8
Neurotoxicity
.......................................................
15
4.9
Metabolism
.........................................................
15
4.10
Special/
Other
Studies
No
special
studies
pertaining
to
asulam
have
been
identified.
............
16
5.0
TOXICITY
ENDPOINT
SELECTION........................................
16
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
..............................
16
5.2
Dermal
Absorption
...................................................
16
5.3
Classification
of
Carcinogenic
Potential...................................
16
6.0
FQPA
CONSIDERATIONS
................................................
17
6.1
Special
Sensitivity
to
Infants
and
Children.................................
17
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
...................
17
7.0
OTHER
ISSUES
No
other
special
issues
have
been
identified.
...............................
17
8.0
REFERENCES
..........................................................
18
9.0
APPENDICES...........................................................
23
9.1
Toxicity
Profile
Summary
Tables
........................................
24
9.1.1
Acute
Toxicity
Table
.........................................
24
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
....................
24
3
Asulam
(
December,
2001)
RED
Toxicology
Chapter
1.0
HAZARD
CHARACTERIZATION
The
acute
toxicity
of
asulam
is
low.
The
acute
oral
LD50
for
asulam
in
rats
exceeded
5000
mg/
kg.
The
acute
inhalation
LC50
was
greater
than
5
mg/
L
in
rats.
The
acute
dermal
LD50
for
asulam
in
rabbits
exceeded
4000
mg/
kg.
Application
of
technical
asulam
to
rabbit
eyes
produced
mild
chemosis,
irritation,
and
redness
which
cleared
by
day
seven
post­
treatment.
Asulam
was
not
an
irritant
in
a
primary
skin
irrigation
study
in
rabbits.
It
did
not
cause
dermal
sensitization
in
guinea
pigs.

Reproductive
toxicity.
The
potential
reproductive
toxicity
of
asulam
was
examined
in
a
two­
generation
reproduction
study
in
the
rat.
In
this
study,
significantly
fewer
mean
live
births
per
litter
were
observed
at
250
mg/
kg/
day
and
1250
mg/
kg/
day
in
the
first
generation;
the
LOAEL
for
offspring
toxicity
is
250
mg/
kg/
day.
A
dose­
response
relationship
was
evident.
No
effects
on
mean
live
births
per
litter
were
observed
at
50
mg/
kg/
day,
the
NOAEL
for
offspring
toxicity.
The
LOAEL
for
parental
systemic
toxicity
is
1250
mg/
kg/
day
and
was
based
on
decreased
body
weights
(
F0
males,
F1
females)
and
organ
weight
effects
(
increased
absolute
and
relative
thyroid
weights
in
F1
males
and
F2
males
and
females;
increased
absolute
and
relative
liver
weights
in
F1
females;
and
increased
ovarian
weights
in
F1
females
at
31
days
old
but
not
at
terminal
necropsy).
The
NOAEL
for
parental
systemic
toxicity
is
250
mg/
kg/
day.
This
study
provided
evidence
for
a
quantitative
increase
susceptibility
of
the
rat
fetus.

Developmental
toxicity.
Asulam
has
been
evaluated
for
potential
developmental
effects
in
the
rat
and
the
rabbit.
In
the
developmental
study
in
the
rat,
a
slight
to
moderate
increase
in
preimplantation
loss
was
observed
at
the
high
dose
level
(
1,500
mg/
kg/
day);
the
developmental
NOAEL
was
1,000
mg/
kg/
day.
Decreased
maternal
body
weight
gain
was
noted
at
1,500
mg/
kg/
day
(
maternal
LOAEL),
but
not
at
1,000
mg/
kg/
day
(
maternal
NOAEL).
There
was
no
indication
of
treatment­
related
effects
on
developmental
parameters
(
at
dose
levels
up
to
750
mg/
kg/
day)
in
a
developmental
toxicity
study
in
the
rabbit;
the
NOAEL
for
developmental
toxicity
is
750
mg/
kg/
day.
Decreased
maternal
body
weight
gain
was
observed
at
750
mg/
kg/
day
(
the
NOAEL
is
300
mg/
kg/
day).

Systemic
toxicity.
Subchronic
and
chronic
toxicity
studies
demonstrate
that
the
thyroid
gland
is
a
target
organ
for
asulam
in
the
rat
and
dog.
Thyroid
findings,
consisting
of
hyperplastic
changes
in
thyroid
follicular
cells
in
male
rats
(
LOAEL
=
180
mg/
kg/
day;
NOAEL
=
36
mg/
kg/
day),
were
reported
in
a
two­
year
combined
chronic/
oncogenicity
feeding
study.
Thyroid
weights
were
not
monitored
in
the
study.
Other
toxicological
effects
included
adrenal
medullary
hyperplastic
alterations
in
male
rats,
and
decreased
body
weight
gains
in
male
and
female
rats.
The
chronic
RfD
for
asulam
is
derived
from
the
NOAEL
of
36
mg/
kg/
day,
based
on
thyroid
follicular
hyperplasia
at
180
and
953
mg/
kg/
day.
An
uncertainty
factor
of
100
was
used
to
account
for
interspecies
extrapolation
and
intraspecies
variability.

In
a
six­
month
dog
study,
increased
thyroid
weights
(
elevated
absolute
weights
in
females
at
300
mg/
kg/
day
and
elevated
absolute
and
relative
weights
in
males
and
females
at
1500
mg/
kg/
day)
were
reported.
Similar
findings
were
noted
in
a
three­
month
gavage
study
in
the
dog.

In
a
18­
month
carcinogenicity
study
with
Carworth
CF­
1
outbred
albino
mice,
decreased
4
Asulam
(
December,
2001)
RED
Toxicology
Chapter
absolute
and
relative
thyroid
weights
were
observed
in
females
administered
225
or
750
mg/
kg/
day
in
the
diets.
However,
this
study
was
classified
as
unacceptable.
No
pathological
effects
in
the
thyroid
were
reported
in
a
repeat
two­
year
feeding
study
in
the
mouse;
the
strain
was
Charles
River
CD­
1
mice.
However,
thyroid
weights
were
not
assessed
in
this
study.

Carcinogenicity.
A
combined
chronic
toxicity/
oncogenicity
study
in
the
rat
provided
limited
evidence
for
the
carcinogenicity
of
asulam
in
this
species.
There
was
a
statistically
significant
increase
in
thyroid
gland
C­
cell
carcinomas
in
male
rats
fed
diets
containing
36
and
180
mg/
kg/
day
asulam.
There
was
also
a
statistically
significant
increase
in
adrenal
medullary
pheochromocytomas
in
males
administered
953
mg/
kg/
day
(
high
dose
tested).
In
a
two­
year
feeding
study
in
the
mouse,
no
evidence
of
carcinogenicity
was
found.
Asulam
has
been
classified
as
a
Group
C
carcinogen
(
possible
human
carcinogen)
by
the
Agency.
The
Agency
decided
not
to
quantify
the
carcinogenic
risk
for
asulam.

Neurotoxicity.
No
neurotoxicity
studies
were
available
for
asulam.
There
was
no
evidence
of
neurotoxicity
(
clinical
signs,
cholinesterase
inhibition,
or
pathology)
in
subchronic
and
chronic
toxicity
studies
in
the
rat,
dog,
or
mouse.

Immunotoxicity.
None
of
the
available
data
on
asulam
suggest
an
immunotoxic
potential
for
this
chemical.

The
mutagenicity/
genetic
toxicity
data
base
is
considered
complete
and
there
is
no
concern
for
adverse
mutagenicity
effects.

Inhalation
toxicity.
Data
regarding
the
potential
inhalation
toxicity
of
asulam
are
limited
to
a
one­
month
inhalation
and
an
acute
inhalation
study
in
the
rat.
No
effects
of
apparent
toxicological
significance
were
noted
in
rats
exposed
(
nose­
only)
to
asulam
at
concentrations
up
to
15.3
mg/
L
for
4
hours
per
day,
5
days
per
week,
for
1
month.
However,
there
was
no
examination
of
thyroid
weights
or
thyroid
pathology.

Metabolism.
Metabolism
studies
in
the
rat
demonstrate
that
asulam
was
rapidly
eliminated,
primarily
in
the
urine,
following
administration
of
a
single
oral
or
intravenous
dose,
or
after
repeated
intravenous
doses
for
14
days.
No
unusual
localization
of
asulam
occurred
in
tissues.
Unchanged
parent
compound
was
identified
as
the
major
excretory
product,
with
acetylasulam
and
acetylsulphanilamide
as
minor
metabolites.

The
dermal
absorption
of
asulam
has
not
been
determined.

2.0
REQUIREMENTS
The
data
requirements
(
CFR
158.340)
for
the
several
uses
for
Asulam
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
Most
studies
were
conducted
well
before
the
1998
guidelines
and
follow
earlier
guidelines.
Note:
The
data
gaps
and
additional
data
required
are
more
simply
presented
in
the
following
section
(
3.0
below).

5
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Table
1.
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
...........................
870.1200
Acute
Dermal
Toxicity
........................
870.1300
Acute
Inhalation
Toxicity
......................
870.2400
Primary
Eye
Irritation
.........................
870.2500
Primary
Dermal
Irritation
......................
870.2600
Dermal
Sensitization
..........................
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.3100
Oral
Subchronic
(
rodent)
.......................
870.3150
Oral
Subchronic
(
nonrodent)
....................
870.3200
21­
Day
Dermal
..............................
870.3250
90­
Day
Dermal
..............................
870.3465
90­
Day
Inhalation
............................
Yes
Yes
Yes
No
(
c)
(
a)
Yes
(
b)
N/
A
No
870.3700a
Developmental
Toxicity
(
rodent)
................
870.3700b
Developmental
Toxicity
(
nonrodent)
.............
870.3800
Reproduction
................................
Yes
Yes
Yes
Yes
Yes
Yes
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
Yes
Yes
Yes
Yes
Yes
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
Yes
Yes
Yes
Yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
..................
870.6100b
90­
Day
Neurotoxicity
(
hen)
....................
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
...........
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
............
870.6300
Develop.
Neuro
..............................
No
No
(
d)
(
d)
No
­­

N/
A
N/
A
N/
A
870.7485
General
Metabolism
..........................
870.7600
Dermal
Penetration
...........................
Yes
No
Yes
N/
A
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
..............................
Subchronic
Oral
(
rat)
..........................
Six­
month
Oral
(
dog)
.........................
No
No
No
N/
A
N/
A
N/
A
(
a)
Interim
data
from
the
chronic
toxicity
satisfy
this
requirement.
(
b)
A
21­
day
dermal
toxicity
study
in
the
rat
was
available,
however,
the
study
did
not
include
an
examination
of
the
thyroid
gland,
the
target
organ
for
asulam.
The
HIARC
(
11/
13/
01)
determined
that
a
21­
day
dermal
toxicity
study,
with
examination
of
thyroid
weight
and
pathology,
is
required.
(
c)
A
one­
month
inhalation
toxicity
study
was
available;
however,
this
study
did
not
examine
the
thyroid
gland,
the
target
organ.
The
HIARC
(
11/
13/
01)
determined
that
a
28­
day
inhalation
toxicity
study,
with
examination
of
thyroid
weight
and
pathology,
is
required.
HIARC
did
not
identify
a
need
for
a
90­
day
inhalation
study.

6
Asulam
(
December,
2001)
RED
Toxicology
Chapter
(
d)
The
HIARC
determined
that
the
acute,
subchronic,
and
developmental
neurotoxicity
studies
were
not
required.
HIARC
recommended
the
requirement
for
a
comparative
thyroid
rat
assay
in
adults
and
offspring.
It
was
further
recommended
that
the
adult
study
should
include
interim
measures
(
e.
g.,
7,
14,
and
28
days).
The
HIARC
also
recommended
that
thyroid
parameters
selected
for
the
comparative
study
should
be
based
on
Agency
guidance
(
under
current
development)
for
thyroid
toxicity
testing.

3.0
DATA
GAP(
S)

On
November
13,
2001,
the
HIARC
identified
the
following
data
gaps:

 
Comparative
thyroid
rat
assay
in
adult
and
offspring.
It
was
further
recommended
that
the
adult
study
should
include
interim
measures
(
e.
g.,
7,
14,
and
28
days).
HIARC
also
recommended
that
thyroid
parameters
selected
for
the
comparative
study
should
be
based
on
Agency
guidelines
(
under
current
development)
for
thyroid
toxicity
testing.

 
21­
day
Dermal
Study
in
Rats
with
examination
of
thyroid
weight
and
pathology.

 
28­
day
Inhalation
Study
in
Rats
with
examination
of
thyroid
weight
and
pathology.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
The
acute
toxicity
data
on
asulam
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
of
asulam.

Study
Type
MRID
No.:
Result
81­
1.
Acute
Oral
Toxicity
­
rat.
Rhone­
Poulenc
Ag
Co.,
Study
No.:
51­
260,
November
7,
1988
409605­
01
LD50
>
5000
mg/
kg.
Toxicity
Category
IV
Classification:
Guideline
81­
2.
Acute
Dermal
Toxicity
­
rabbit.
Rhone­
Poulenc
Ag
Co.,
Study
No.:
51­
260,
November
8,
1988
409605­
01
LD50
>
4000
mg/
kg.
Toxicity
Category
III
Classification:
Guideline
7
Asulam
(
December,
2001)
RED
Toxicology
Chapter
81­
3.
Acute
Inhalation
Toxicity
­
rat.
Rhone­
Poulenc
Ag
Co.,
Study
No.:
51­
583,
November
7,
1988
409605­
02
413616­
01
LC50
>
5
mg/
L
Toxicity
Category
IV
Classification:
Minmum
81­
4.
Primary
Ocular
Irritation
­
rabbit.
Rhone­
Poulenc
Ag
Co.,
Study
No.:
R.
Tox.
57,
June
1981
00098534
Some
chemosis,
redness,
and
irritation
were
noted,
but
eyes
were
clear
by
day
7.
Toxicity
Category
III
Classification:
Minimum
81­
5.
Primary
Dermal
Irritation
­
rabbit.
Rhone­
Poulenc
Ag
Co.,
Study
No.:
RES
2853,
March
1977
00098535
No
dermal
irritation
was
observed.
Toxicity
Category
III
Classification:
Minimum
81­
6.
Dermal
Sensitization
­
guinea
pig.
Rhone­
Poulenc
Ag
Co.,
Study
No.:
RES
2853,
March
1977
00098535
No
evidence
of
sensitization
in
the
Guinea
Pig.
Classification:
Minimum.

Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
No
subchronic
oral
toxicity
studies
in
the
rodent
per
se
were
identified
in
the
data
base
for
asulam.
However,
the
chronic
oral
studies
in
the
rodent
provided
frequent
monitoring
of
clinical
signs
and
interim
measurements
of
body
weights,
food
consumption,
hematology,
clinical
chemistry
and
urinalysis,
and
the
results
provided
insight
into
potential
subchronic
effects.

In
a
subchronic
oral
(
90­
day)
study,
dogs
displayed
increased
thyroid
weights.
Although
the
study
was
classified
as
 
unacceptable
guideline ,
it
was
supported
by
the
findings
of
the
6­
month
oral
dog
study.
The
results
of
the
two
studies
were
similar
(
i.
e.,
the
LOAEL
and
NOAEL
(
based
on
increased
thyroid
weights)
for
the
6­
month
dog
study
were
300
mg/
kg/
day
and
60
mg/
kg/
day,
respectively,
while
the
LOAEL
and
NOAEL
(
also
based
on
increased
thyroid
weights)
for
the
3­
month
dog
study
were
500
mg/
kg/
day
and
50
mg/
kg/
day,
respectively).

A
one­
month
inhalation
toxicity
study
and
21­
day
dermal
toxicity
study
were
available;
however,
neither
study
included
assessment
of
thyroid
weights
and
pathology.
The
data
base
for
subchronic
toxicity
is
considered
complete
for
oral
and
dermal
studies.
A
28­
day
subchronic
inhalation
study
is
required,
one
that
includes
examination
of
thyroid
weights
and
thyroid
pathology.

870.3100
90­
Day
Oral
Toxicity
­
Rat
Refer
to
the
chronic
toxicity
studies
below.

870.3150
90­
Day
Oral
Toxicity
­
Dog
Executive
Summary.
In
a
subchronic
toxicity
study
(
MRID#
00056414),
asulam
(
purity
not
stated)

8
4.2
Asulam
(
December,
2001)
RED
Toxicology
Chapter
was
administered
to
beagle
dogs
(
3
dogs/
sex/
group)
by
gavage
at
dose
levels
of
0,
5,
50,
or
500
mg/
kg/
day
for
three
months.
All
but
one
dog
were
apparently
infected
with
ascarids.
An
increase
in
white
blood
cell
counts,
most
likely
reflecting
infection,
was
observed
in
all
control
and
treated
females,
and
in
the
low­
and
high­
dose
males,
toward
the
end
of
the
study.
In
addition,
diarrhea
was
present
in
all
dogs
during
the
last
3
weeks
of
the
study.
The
diarrhea
may
have
been
associated
with
ascarid
infection.
At
the
end
of
the
treatment
period,
mean
body
weights
of
treated
males
were
lower
than
those
of
controls,
while
mean
body
weights
of
treated
females
were
higher
than
controls.
Interpretation
of
the
body
weight
differences
is
complicated
by
the
differences
in
initial
body
weights
of
the
control
dogs
(
i.
e.,
control
male
body
weight
was
more
than
10%
greater,
while
control
female
body
weight
was
5­
15%
lower,
than
those
of
treated
animals).
Overall
mean
body
weight
gains
(
day
0
­
91)
in
treated
dogs
were
for
the
most
part
higher
than
those
of
control
dogs.
Absolute
and
relative
thyroid
weights
were
elevated
in
both
high­
dose
males
and
females.
There
were
no
apparent
treatment­
related
effects
on
survival
or
pathology
findings.

The
LOAEL
is
500
mg/
kg/
day
based
on
increased
absolute
and
relative
(
to
body
weight)
thyroid
weights
in
male
and
female
dogs.
The
NOAEL
is
50
mg/
kg/
day.

Classification:
This
subchronic
study
in
the
dog
is
Unacceptable­
Guideline,
and
does
not
satisfy
the
guideline
requirement
for
a
subchronic
nonrodent
study
(
82­
1)
in
this
species.
No
information
on
purity
of
the
test
material,
no
food
consumption
data,
the
lack
of
individual
pathology
sheets,
no
information
on
the
care
and
feeding
of
the
dogs,
the
failure
to
randomize
animals
to
groups
on
the
basis
of
body
weights
so
that
initial
body
weights
were
comparable
between
groups,
and
no
rationale
provided
for
dose
selection.
Although
the
sample
size
was
less
than
guideline
requirements
(
i.
e.,
3
rather
than
4
dogs),
the
thyroid
weight
effects
observed
in
this
study
are
supported
by
a
six­
month
dog
study
(
MRID
No.
00098536);
the
LOAEL
in
the
six­
month
dog
study
was
300
mg/
kg/
day,
while
the
NOAEL
was
60
mg/
kg/
day.

870.3200
21/
28­
Day
Dermal
Toxicity
 
Rat
Executive
Summary.
In
a
repeat­
dose
dermal
toxicity
study
(
MRID
#
41076901),
asulam
(
88%
a.
i.)
was
applied
to
the
clipped
skin
of
10
New
Zealand
rabbits/
sex/
dose
at
dose
levels
of
0
(
carboxymethylcellulose
vehicle
control)
or
1,000
mg/
kg/
day
(
limit
dose),
once
daily
for
7
days/
week
during
a
21­
day
period.

No
apparent
treatment­
related
systemic
effects
were
observed
when
body
weight,
food
consumption,
clinical
pathology,
organ
weights,
ophthalmology,
urinalysis,
and
histopathology
were
examined.
The
NOAEL
is
greater
than
or
equal
to
1,000
mg/
kg/
day.

Local
skin
irritation,
which
was
slight
and
transient,
was
observed
in
a
small
number
of
treated
females.

Classification:
This
21­
day
dermal
toxicity
study
is
classified
as
Acceptable­
Guideline.

870.3465
90­
Day
Inhalation
 
Rat
9
Asulam
(
December,
2001)
RED
Toxicology
Chapter
There
are
no
90­
day
inhalation
toxicity
studies
available
on
asulam.
However,
a
one­
month
inhalation
toxicity
study
(
MRID
#
00098537)
in
the
rat
was
available.
In
the
one­
month
inhalation
study,
asulam
(
purity
not
stated)
was
administered
to
15
CD
rats/
sex/
group
by
nose­
only
exposure
at
concentrations
of
0,
1.6,
3.9,
or
15.3
mg/
L
for
4
hours
per
day,
5
days
per
week,
for
4
weeks.
Control
rats
were
exposed
to
clean
air
only.
The
estimated
mass
median
diameter
of
the
particles
was
4.5
Fm.
No
effects
due
to
exposure
were
observed,
as
judged
by
survival,
clinical
signs,
body
weights,
food
consumption,
ophthalmoscopic
examinations,
hematology,
clinical
chemistry,
urinalysis,
and
pathology.
Although
several
significant
organ
weight
changes
(
i.
e.,
increased
absolute
and
relative
lung,
heart
and
adrenal
weights;
decreased
absolute
and
relative
spleen
weights;
increased
relative
pituitary
weights)
were
observed
in
high­
dose
males
immediately
following
exposure,
these
changes
were
not
seen
in
the
high­
dose
males
sacrificed
5­
7
days
after
final
dosing
(
suggesting
reversibility
of
the
effects).
In
addition,
there
were
no
corresponding
histological
lesions
in
these
organs.
Females
sacrificed
5­
7
days
after
final
dosing
displayed
increased
absolute
and
relative
liver
and
heart
weights.
However,
the
liver
and
heart
weight
alterations
were
not
accompanied
by
histological
findings.
The
organ
weight
changes
in
the
males
and
females
are
of
equivocal
toxicological
significance.
The
NOAEL
is
15.3
mg/
L.
This
study
is
limited
because
of
the
lack
of
thyroid
weight
measurements
and
pathological
examination
of
the
thyroid.

Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
prenatal
developmental
toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary.
In
a
developmental
toxicity
study
(
MRID
#
00098538),
asulam
(
98.0­
99.9
%
a.
i.)
was
administered
to
23­
27
pregnant
Charles
River
(
CD)
rats/
dose
by
oral
gavage
at
dose
levels
of
0,
500,
1,000,
or
1,500
mg/
kg/
day
from
days
5
through
17
of
gestation.

Mean
maternal
body
weight
gain
(
days
5­
18)
was
9%
lower
in
the
high­
dose
group
than
in
controls.
There
were
no
treatment­
related
effects
on
other
maternal
parameters
including
mortality,
clinical
signs,
and
food
consumption.
A
slight
to
moderate
increase
(
not
statistically
significant)
in
preimplantation
loss
was
observed
in
the
mid­
and
high­
dose
groups
(
compared
to
controls).
The
slight
increase
in
postimplantation
loss
at
the
high
dose
(
1500
mg/
kg/
day)
was
not
statistically
significantly
different
from
control
values,
and
was
not
of
any
apparent
biological
significance.
The
maternal
LOAEL
is
1,500
mg/
kg/
day
based
on
body
weight
gain
decrement.
The
maternal
NOAEL
is
1,000
mg/
kg/
day.

The
developmental
LOAEL
is
1,500
mg/
kg/
day
based
on
slight
to
moderate
increase
in
preimplantation
loss.
The
developmental
NOAEL
is
1,000
mg/
kg/
day.

Classification:
This
prenatal
developmental
toxicity
study
in
the
rat
is
Acceptable­
Guideline.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
10
4.3
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Executive
Summary.
In
a
developmental
toxicity
study
(
MRID
#
00098539),
asulam
(
98.0­
99.9
%
a.
i.)
was
administered
to
15­
23
pregnant
New
Zealand
rabbits/
dose
by
oral
gavage
at
dose
levels
of
0,
60,
300,
or
750
mg/
kg/
day
from
days
5
through
20
of
gestation.
Rabbits
were
sacrificed
on
gestation
day
29.
Originally,
the
high
dose
selected
was
1,500
mg/
kg/
day.
However,
severe
maternal
toxicity
(
greater
than
20%
weight
loss,
mortality,
and
signs
of
starvation)
occurred
after
administration
of
the
1,500
mg/
kg/
day
dose
level.
All
animals
in
this
group
died
or
were
sacrificed
for
humane
reasons.
A
new
group
was
added
to
the
study
using
a
lower
dose
of
750
mg/
kg/
day.

Mean
maternal
body
weight
gain
was
markedly
reduced
(
35%
but
not
statistically
significant)
in
the
750
mg/
kg/
day
group
than
in
controls
during
the
dosing
period
(
days
5
­
21).
In
addition,
mean
maternal
body
weight
gains
were
markedly
reduced
during
days
5­
9,
5­
13,
and
5­
17.
During
the
postdosing
period,
mean
body
weights
of
rabbits
treated
with
750
mg/
kg/
day
were
comparable
to
those
of
controls,
and
rabbits
displayed
some
improvement
in
body
weight
gain.
Rabbits
given
750
mg/
kg/
day
exhibited
a
non­
statistically
significant
decrease
in
food
consumption
at
several
intervals
during
dosing
(
days
5­
9,
9­
13,
13­
17).
There
were
no
apparent
treatment­
related
effects
on
mortality
or
clinical
signs.
The
maternal
LOAEL
is
750
mg/
kg/
day
based
on
decreased
body
weight
during
the
dosing
period.
The
maternal
NOAEL
is
300
mg/
kg/
day.

There
were
no
apparent
treatment­
related
effects
on
developmental
parameters
at
dose
levels
up
to
750
mg/
kg/
day.
The
developmental
NOAEL
is
750
mg/
kg/
day.

Classification:
This
prenatal
developmental
toxicity
study
in
the
rabbit
is
Acceptable­
Guideline.

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.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary.
In
a
two­
generation
reproduction
toxicity
study
(
MRID
00098540),
groups
of
12
male
and
24
female
Charles
River
CD
rats
were
administered
asulam
(
98.0­
100.6
%
a.
i.)
in
the
diet
at
concentrations
of
0
(
control),
1,000,
5,000,
or
25,000
ppm
(
equivalent
to
approximately
50,
250,
and
1250
mg/
kg/
day,
respectively).
F0
animals
were
mated
after
being
on
diet
for
100
days.
Following
weaning,
F1
animals
(
16
males
and
32
females)
continued
treatment
for
a
further
120
days
prior
to
mating.

Systemic
effects
observed
at
the
high
dose
(
25,000
ppm)
included
decreased
body
weights
in
F0
males
and
F1
females,
increased
absolute
and/
or
relative
thyroid
weights
in
F1
males
and
F2
males
and
females,
increased
absolute
and
relative
liver
weights
in
F1
females,
and
increased
ovarian
weights
in
F1
females
(
at
age
31
but
not
at
terminal
necropsy).
The
LOAEL
for
11
4.4
Asulam
(
December,
2001)
RED
Toxicology
Chapter
systemic
toxicity
is
25,000
ppm
(
1250
mg/
kg/
day)
based
on
decreased
body
weights
(
F0
males,
F1
females)
and
organ
weight
effects
(
increased
absolute
and
relative
thyroid
weights
F1
males
and
F2
males
and
females,
increased
absolute
and
relative
liver
weights
in
F1
females,
and
increased
ovarian
weights
in
F1
females
at
31
days
old
but
not
at
terminal
necropsy).
The
NOAEL
is
5,000
ppm
(
250
mg/
kg/
day).

Significantly
fewer
mean
live
births
per
litter
were
observed
at
5,000
and
25,000
ppm
in
the
first
generation.
Also,
a
dose­
response
relationship
was
evident.
Fertility
index
was
slightly
lower
in
F1
parents
at
5,000
and
25,000
ppm;
however,
the
decreases
were
not
statistically
significant
when
compared
to
controls
and
did
not
display
a
dose
response.
The
LOAEL
for
reproductive/
offspring
toxicity
is
5,000
ppm
(
250
mg/
kg/
day)
based
on
decreased
mean
live
births
per
litter.
The
NOAEL
is
1,000
ppm
(
50
mg/
kg/
day).

Classification:
This
two­
generation
reproduction
study
in
the
rat
is
Acceptable­
Guideline
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.

870.4100a
(
870.4300)
Chronic
Toxicity
 
Rat
Refer
to
the
Combined
Chronic
Feeding/
Carcinogenicity
study
below.

870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary.
In
a
six­
month
toxicity
study
(
MRID
#
40977601),
asulam
(
98.0­
100.6%
a.
i.)
was
administered
to
6
beagle
dogs/
sex/
dose
by
oral
gavage
at
dose
levels
of
0,
60,
300,
or
1,500
mg/
kg/
day.
Doses
were
selected
on
the
basis
of
the
results
of
preliminary
acute,
subacute,
and
subchronic
studies.
There
was
no
apparent
relationship
between
test
material
administration
and
mortality.
Treatment­
related
findings
included
reductions
in
body
weight
gains
and
food
consumption
in
the
high­
dose
males
and
females;
increased
frequency
of
emesis
and
diarrhea
in
the
high­
dose
males
and
females;
increased
absolute
thyroid
weights
in
the
mid­
and
high­
dose
females
and
in
the
high­
dose
males;
increased
relative
(
to
body
weight)
thyroid
weights
in
the
high­
dose
males
and
females;
decreased
absolute
testes
and
lung
weights
in
the
high­
dose
males;
decreased
relative
testes
weights
in
the
high­
dose
males;
and
increased
relative
kidney
weights
in
the
high­
dose
males.
No
histopathological
effects
of
toxicological
significance
were
observed.
There
were
no
apparent
effects
on
prothrombin
time,
kaolin
partial
thromboplastin
time
or
platelet
counts
in
males.
Platelet
counts
were
slightly
decreased
in
treated
females;
however,
the
decreases
were
not
dose­
related
at
most
intervals
and
control
values
appeared
to
be
slightly
elevated.
Platelet
count
in
the
high­
dose
females
was
significantly
lower
at
the
26­
week
interval
only.
Plasma
and
brain
cholinesterase
activities
were
not
affected
by
treatment
in
either
sex.

The
LOAEL
is
300
mg/
kg/
day,
based
on
significant
(
p
<
0.05)
increases
in
absolute
thyroid
weights
in
females.
Absolute
and
relative
thyroid
weights
were
elevated
at
the
high­
dose
(
1500
mg/
kg/
day)
in
both
males
and
females.
The
increased
absolute
thyroid
weights
in
the
mid­
and
high­
dose
females
appeared
dose
related.
Although
histological
effects
in
the
12
4.5
Asulam
(
December,
2001)
RED
Toxicology
Chapter
thyroid
were
not
observed
in
the
dog
study,
the
duration
of
the
study
was
6
months,
which
is
less
than
recommended
by
guidelines
(
i.
e.,
12
months).
The
NOAEL
is
60
mg/
kg/
day.

Classification:
This
chronic
oral
study
in
the
dog
is
Acceptable­
Nonguideline.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
carcinogenicity
data
base
for
asulam
is
considered
complete.
There
is
one
acceptable
combined
chronic
toxicity/
oncogenicity
dietary
study
in
the
rat,
and
one
acceptable
oncogenicity
dietary
study
in
the
mouse.

870.4200a
Carcinogenicity
Study
­
rat
Executive
Summary.
In
a
two­
year
combined
chronic
feeding/
carcinogenicity
study
(
MRID#
00098543),
CD
rats
(
50/
sex/
dose)
were
administered
asulam
(
97.5­
99.9%)
at
dose
levels
of
0,
1,000
(
low­
dose),
5,000
(
mid­
dose)
or
25,000
ppm
(
high­
dose).
These
dietary
levels
were
equivalent
to
0,
36,
180
and
953
mg/
kg/
day
in
males
and
0,
47,
243
and
1,280
mg/
kg/
day
in
females,
respectively.
An
additional
group
(
15/
sex/
dose)
was
administered
asulam
for
78
weeks.
Bodyweight
change
in
the
high­
dose
animals
for
various
intervals
was
more
than
10%
lower
than
controls.
Mean
bodyweight
change
was
significantly
lower
than
controls
in
high­
dose
females
from
week
0­
52
and
in
the
mid­
and
high­
dose
females
from
weeks
6­
52.
Mean
bodyweight
change
was
significantly
lower
in
the
high­
dose
males
(
p<
0.01)
from
weeks
6­
52.
Hyperplastic
changes
were
observed
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males
at
the
mid­
and
high­
dose
levels.

There
was
a
statistically
significant
increase
in
thyroid
gland
C­
cell
carcinomas
in
both
the
low­
and
mid­
dose
males.
There
was
also
a
statistically­
significant
increase
in
adrenal
medullary
pheochromocytomas
at
the
high
dose
in
males.
With
the
exception
of
a
non­
dose­
related
enlargement
of
the
pituitary
gland
in
female
rats
(
3/
15
controls;
7/
15
low­
dose;
8/
15
mid­
dose;
7/
15
high­
dose),
no
unusual
toxicological
findings
occurred
in
the
animals
sacrificed
at
78
weeks.

The
LOAEL
is
5,000
ppm
(
180
mg/
kg/
day)
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males.
The
NOAEL
is
1,000
ppm
(
36
mg/
kg/
day).

Under
the
conditions
of
this
study,
there
was
evidence
of
an
increase
in
tumor
incidence
in
males
when
compared
to
controls.
Therefore,
asulam
is
a
potential
oncogen
in
this
study.
Dosing
is
considered
adequate
to
assess
the
oncogenic
potential
of
asulam.

Classification:
This
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
Acceptable­
Guideline.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
13
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Executive
Summary.
In
a
two­
year
carcinogenicity
study
with
Charles
River
CD­
1
mice
(
MRID#
42338201),
asulam
(
88%
a.
i.)
was
administered
in
the
diet
at
0,
500,
5,000
or
50,000
ppm.
Concentrations
were
corrected
for
88%
a.
i.
These
dietary
levels
were
equivalent
to
0,
74,
730
and
8,040
mg/
kg/
day
in
males
and
0,
95,
938
and
10,353
mg/
kg/
day
in
females,
respectively.
Mean
body
weights
of
the
high­
dose
males
were
generally
less
than
6%
lower
than
control
values
during
the
first
24
weeks
of
treatment,
while
body
weights
of
females
were
less
than
6%
lower
than
control
values
throughout
the
study.
The
high­
dose
males
displayed
a
reduction
(
greater
than
10%)
in
mean
body
weight
gain
when
compared
to
the
control
group
at
various
intervals.
Increased
mortality
was
observed
in
the
high­
dose
females;
however,
the
number
of
high­
dose
females
was
adequate
to
assess
the
carcinogenic
potential
of
asulam.
There
was
no
treatment­
related
effect
on
food
consumption.
Hematologic
findings
in
the
high­
dose
males
and
females
consisted
of
increased
leukocyte
counts,
decreased
erythrocyte
counts,
and
decreased
hematocrit
levels.
Organ
weight
changes
included
decreased
brain
weight
in
the
high­
dose
females,
and
increased
spleen
weight
in
the
high­
dose
males.
There
was
an
increased
incidence
of
brown
granular
pigment
deposits
in
the
livers
of
males
of
all
treatment
groups
and
high­
dose
females.
Increased
incidences
of
brown
granular
pigment
deposits
were
also
noted
in
the
spleens
of
the
high­
dose
rats
of
both
sexes.
The
brown
granular
pigment
deposit
was
not
identified,
and
is
therefore
of
uncertain
toxicological
significance.
There
was
no
increase
in
the
incidence
of
any
tumors.

The
LOAEL
is
50,000
ppm,
based
on
increased
spleen
weight
and
decreased
body
weight
gain
in
males,
and
decreased
brain
weight
and
survival
in
females.
The
NOAEL
was
5,000
ppm.

Under
the
conditions
of
this
study,
there
was
no
evidence
of
carcinogenicity
of
asulam.
Dosing
is
considered
adequate
to
assess
the
carcinogenic
potential
of
asulam
based
on
decreased
body
weight
gain,
spleen
and
brain
weight
changes,
and
decreased
survival.

Classification:
This
carcinogenicity
study
in
the
mouse
is
Acceptable­
Guideline
4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
With
the
exception
of
the
dominant
lethal
mutation
assay
in
mice,
all
other
mutagenicity
assays
were
found
to
be
acceptable.
These
studies
satistfy
the
pre­
1991
guideline
requirements
for
mutagenicity
studies;
no
further
testing
is
required
at
this
time.
The
data
indicate
that
there
is
no
mutagenicity/
genetic
toxicity
concern.
The
following
table
summarizes
the
mutagenicity/
genetic
toxicity
data
base.

Study
Results
Bacterial
mutagenicity
(
Ames
test)
­
Salmonella
typhimurium.
Litton
Bionetics,
Inc.,
Study
No.:
E­
9177,
1983.
MRID
No.:
40415302
Not
mutagenic
with
and
without
metabolic
activation
at
doses
up
to
2000
Fg/
plate.
Classification:
Acceptable­
Guideline
14
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Study
Results
Dominant
lethal
­
Mouse
­
Hess
&
Clark
(
Div.
of
Rhodia),
Study
No.:
SEH­
75,
1975
MRID
No.:
00082250
No
evidence
of
induction
of
dominant
lethal
effect
at
dietary
concentrations
of
1500
or
5000
ppm.
Classification:
Unacceptable
because
purity
information
on
the
test
material
was
not
provided.

In
vitro
cell
transformation
assay
in
C3H/
10T1/
2
cells.
Mason
Research
Institute.
Study
No.:
596­
249­
8,
October
1979.
MRID
No.:
00098542
No
evidence
of
induction
of
morphological
transformation
at
dose
levels
of
256,
512,
1024,
or
2048
Fg/
mL
for
18
hours
exposure.
Cytotoxicity
was
apparent
at
2048
Fg/
mL.
Classification:
Acceptable
(
Nonguideline).

In
vitro
cytogenetics
in
human
lymphocytes.
Litton
Bionetics,
Inc.
Study
No.:
20990,
March
1984.
MRID
No.:
40415301
Cabinet
d Etudes
et
de
Recherches
en
Tox.
Study
No.:
658,
May
10,
1982.
MRID
No.:
00144051
No
evidence
of
induction
of
a
clastogenic
response
at
doses
of
125­
2500
Fg/
mL
(
absence
of
metabolic
activation)
or
250­
2500
Fg/
mL.
Classification:
Acceptable.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
There
are
no
series
81­
8,
82­
7
or
83­
6
acute,
subchronic
or
developmental
neurotoxicity
studies
available.
The
HIARC
(
November
13,
2001)
determined
that
these
neurotoxicity
studies
are
not
required.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
Asulam
is
not
an
organophosphate
insecticide
and
this
type
of
study
is
not
required.

870.6200
Acute
Neurotoxicity
Screening
Battery
As
per
the
November
13,
2001
HIARC
recommendations,
this
study
is
not
required.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
As
per
the
November
13,
2001
HIARC
recommendations,
this
study
is
not
required.

870.6300
Developmental
Neurotoxicity
Study
As
per
the
November
13,
2001
HIARC
recommendations,
this
study
is
not
required.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
The
urinary
route
is
the
predominant
route
of
elimination
in
the
rat.

870.7485
Metabolism
­
Rat
15
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Executive
Summary:
Metabolism
studies
were
conducted
in
male
and
female
Sprague­
Dawley
rats
(
MRID
41345601).
The
tests
used
a
single
oral
or
i.
v.
dose,
or
repeated
oral
doses
for
14
days.
The
pharmacokinetics
of
asulam
were
similar
after
all
dose
regimens
in
both
sexes.
Peak
blood
levels
were
attained
at
0.5
hours.
No
unusual
localization
of
asulam
occurred
in
tissues
and
all
tissue
levels
were
low
at
72
hours.
Asulam
was
rapidly
eliminated,
mostly
within
24
hours.
Most
of
the
administered
dose
(
76.5%
to
101.5%)
was
eliminated
in
the
urine,
and
1.4%
to
25.3%
of
the
dose
in
feces.
The
major
excretory
product
was
unchanged
parent
compound
(
70%
to
80­%),
with
acetylasulam
(
3%
to
8%)
and
acetylsulphanilamide
(<
3%)
being
the
two
major
metabolites.

Overall
Conclusion.
The
metabolism
of
asulam
in
rats
is
considered
to
be
demonstrated
and
no
additional
data
are
required
at
this
time.

Classification.

4.10
Special/
Other
Studies
No
special
studies
pertaining
to
asulam
have
been
identified.

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

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
100%.
There
are
no
dermal
absorption
studies
with
asulam.
HIARC
(
11/
13/
01)
concluded
that
a
comparison
of
the
developmental
oral
rabbit
study
to
the
dermal
rabbit
study
is
not
appropriate.
The
dermal
rabbit
study
did
not
include
examination
of
the
thyroid,
the
target
organ.

870.7600
Dermal
Absorption
­
Rat
No
dermal
absorption
studies
with
asulam
are
available.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
On
November
12,
1987
the
HED
Carcinogenicity
Peer
Review
Committee
classified
asulam
as
Group
C,
a
possible
human
carcinogen,
based
on
thyroid
and
adrenal
tumors
in
the
rat
sutdy
(
MRID
00098543).
They
also
recommended
that
the
mouse
study
be
repeated
and
agreed
to
reconsider
the
cancer
classification
upon
receipt
and
evaluation
of
the
new
mouse
study.
On
September
22,
1994
the
HED
RfD
peer
Review
committee
met
to
review
the
new
mouse
study
(
MRID
42338201).
The
committee
concluded
that
the
findings
of
the
new
mouse
study
have
no
impact
on
the
current
classification
of
the
chemical
as
a
 
Group
C, 
possible
human
carcinogen,
They
determined
that
a
low
dose
linear
extrapolation
risk
model
was
not
appropriate
for
asulam.

5.3.2
Classification
of
Carcinogenic
Potential
16
Asulam
(
December,
2001)
RED
Toxicology
Chapter
The
Agency
has
classified
asulam
as
Group
C,
possible
human
carcinogen.

5.3.3
Quantification
of
Carcinogenic
Potential
Not
applicable.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
The
HIARC
concluded
that
there
is
no
quantitative/
qualitative
evidence
of
increased
susceptibility
of
rat
or
rabbit
fetuses
following
in
utero
exposure
to
asulam
in
the
developmental
toxicity
studies
in
these
species.
However,
there
was
evidence
of
quantitative
susceptibility
in
a
two­
generation
reproduction
study
in
the
rat.
In
this
study,
the
decreased
mean
live
births
per
litter
(
offspring
NOAEL
=
50
mg/
kg/
day)
was
observed
at
lower
dose
levels
than
that
associated
with
parental/
systemic
toxicity
(
NOAEL
=
250
mg/
kg/
day).

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
a
developmental
neurotoxicity
study
was
not
needed.
However,
HIARC
recommended
the
requirement
for
a
comparative
thyroid
rat
assay
in
adults
and
offspring.
It
was
further
recommended
that
the
adult
study
should
include
interim
measures
(
e.
g.,
7,
14,
and
28
days).
HIARC
also
recommended
that
thyroid
parameters
selected
for
the
comparative
study
should
be
based
on
Agency
guidelines
(
under
current
development)
for
thyroid
toxicity
testing.

7.0
OTHER
ISSUES
No
other
special
issues
have
been
identified.

17
Asulam
(
December,
2001)
RED
Toxicology
Chapter
8.0
REFERENCES
in
MRID
order
00056414
Farr,
M.
J.;
Heath,
S.
A.
B.;
Rivett,
K.
F.;
et
al.
(
1968)
Herbicides:
Asulam:
Chronic
Oral
Toxicity
in
the
Dog:
PRG/
180.
(
Unpublished
study
received
Jun
11,
1972
under
2G1200;
prepared
by
May
&
Baker,
Ltd.,
submitted
by
Rhodia,
Inc.,
New
Brunswick,
N.
J.;
CDL:
091017­
Q).

00081183
Hastings,
S.
E.;
Winbigler,
J.
C.;
Page,
J.
G.;
et
al.
(
1978)
Eighteen
Month
Carcinogenicity
Study
of
Asulam
Technical
in
Mice:
Report
No.
SEH
77:
1.
(
Unpublished
study
received
Apr
12,
1979
under
359­
662;
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
238026­
A;
238027;
238028).

00082250
Hastings,
S.
E.;
Huffman,
K.
W.
(
1975)
Dominant
Lethal
Study
of
Asulam
in
Mice:
Report
No.
SEH
75:
94.
(
Unpublished
study
re­
ceived
Dec
17,
1975
under
6F1717;
submitted
by
Rhodia,
Inc.,
New
Brunswick,
N.
J.;
CDL:
098085­
E).

00083453
Hastings,
S.
E.;
Huffman,
K.
W.
(
1975)
Dominant
Lethal
Study
of
Asulam
in
Mice:
Report
No.
SEH
75:
94.
(
Unpublished
study
re­
ceived
on
unknown
date
under
6F1716;
submitted
by
Rhodia,
Inc.,
New
Brunswick,
N.
J.;
CDL:
097998­
J).

00098533
Brentnall,
D.
W.
(
1977)
Asulam:
Acute
Inhalation
Toxicity
of
the
Dry
Powder
in
Rats:
RES.
No.
2938.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
Eng­
land,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junc­
tion,
N.
J.;
CDL:
070776­
C)

00098534
Ward,
R.
J.
(
1981)
Asulam
(
Technical
Grade):
Primary
Eye
Irrita­
tion
Study
in
the
Rabbit:
Report
Ref.
R.
Tox.
57.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070776­
D)

00098535
Dale,
E.
A.;
Grimmett,
J.
E.
(
1977)
Asulam:
Tests
for
Primary
Skin
Irritation
in
Rabbits
and
Skin
Sensitization
in
Guinea
Pigs:
RES/
2853.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070776­
E)

00098536
Dale,
E.
A.;
Ingham,
B.;
Woolf,
N.;
et
al.
(
1979)
Asulam:
Six
Month
Oral
Toxicity
Study
in
Beagles:
Report
Ref.
RES
3699.
(
Unpub­
lished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
18
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070776­
F)

00098537
Brentnall,
D.
W.;
Farr,
M.
J.;
Woolf,
N.
(
1977)
Asulam:
1
Month
Inhalation
Toxicity
of
the
Dry
Powder
in
Rats:
RES/
3014.
(
Un­
published
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070776­
G)

00098538
Copping,
G.
P.
(
1981)
Asulam:
Teratogenicity
Study
by
the
Oral
Route
in
the
Rat:
Report
Ref.
R.
Tox.
11.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Mon­
mouth
Junction,
N.
J.;
CDL:
070776­
H)

00098539
Copping,
G.
P.
(
1981)
Asulam:
Teratogenicity
Study
by
the
Oral
Route
in
the
Rabbit:
Report
Ref.
R.
Tox.
37.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Mon­
mouth
Junction,
N.
J.;
CDL:
070776­
I)

00098540
Brentnall,
D.
W.;
Woolf,
N.
(
1981)
Asulam:
Two
Generation
Repro­
duction
Study
in
the
Rat:
Report
Ref.
R.
Tox.
34.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
May
&
Baker,
Ltd.,
England,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070776­
J)

00098541
McGregor,
D.
B.;
Crichton,
C.
(
1977)
Mutagenicity
Testing
of
Asulam,
M
&
B
9057:
Report
No.
807.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
Inveresk
Research
International,
Scotland,
submitted
by
Rhone­
Poulenc
Chemical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070776­
K).

00098543
Hunter,
B.;
Barnard,
A.
V.;
Street,
A.
E.;
et
al.
(
1981)
Asulam:
Tox­
icity
and
Tumorigenicity
in
Prolonged
Dietary
Administration
to
Rats:
HRC
Report
No.
M
&
B
95/
80554.
Final
rept.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
prepared
by
Hunting­
don
Research
Centre,
England,
submitted
by
Rhone­
Poulenc
Chem­
ical
Co.,
Monmouth
Junction,
N.
J.;
CDL:
070777­
A).

00108811
Rhone­
Poulenc
Chemical
Company
(
1981?)
Animal:
Metabolism
Studies
with
Asulam|.
(
Unpublished
study
received
Apr
16,
1982
under
359­
662;
CDL:
070778­
C).

40415301
Galloway,
S.;
Myhr,
B.
(
1984)
Asulum:
Mutagenicity
Evaluation
of
Asulum
Technical
(
Dried)
in
an
in
vitro
Cytogenetic
Assay
Meas­
uring
Chromosome
Aberration
Frequencies
in
Human
Lymphocytes:
LBI
Proj.
No.
20990.
Unpublished
study
prepared
by
Litton
Bio­
netics,
Inc.
24
p.

19
Asulam
(
December,
2001)
RED
Toxicology
Chapter
40415302
Hoorn,
A.
(
1983)
Asulum:
Mutagenicity
Evaluation
of
Asulam
Techni­
cal
in
the
Ames
Salmonella/
Microsome
Plate
Test
Preincubation
Method:
Genetics
Assay
No.
E­
9177.
Unpublished
study
prepared
by
Litton
Bionetics,
Inc.
22
p.

40960501
Myers,
R.;
Christopher,
S.
(
1988)
Asulam
Sodium
Salt:
Acute
Peroral
(
Rat)
and
Percutaneous
(
Rabbit)
Toxicity
Studies:
Laboratory
Project
ID
51­
620.
Unpublished
study
prepared
by
Union
Carbide
Bushy
Run
Research
Center.
16
p.

40960502
Nachreiner,
D.;
Klonne,
D.
(
1988)
Asulam
(
Sodium
Salt):
Acute
Dust
Aerosol
Inhalation
Toxicity
Test
in
Rats:
Laboratory
Project
ID
51­
583.
Unpublished
study
prepared
by
Union
Carbide
Bushy
Run
Research
Center.
28
p.

40977601
Dale,
E.;
Ingham,
B.;
Woolf,
N.;
et
al
(
1980)
Asulum:
Six
Month
Oral
Toxicity
Study
in
Beagles:
Supplemental
Raw
Data:
Proj.
ID
RES/
3699.
Unpublished
study
prepared
by
Rhone­
Poulenc
Ag
Co.
207
p.

41361601
Nachreiner,
D.;
Klonne,
D.
(
1988)
Asulam
(
Sodium
Salt):
Acute
Dust
Aerosol
Inhalation
Toxicity
Test
in
Rats:
Lab
Project
Number:
51­
583.
Unpublished
study
prepared
by
Bushy
Run
Research
Cent­
er.
28
p.

42110001
Cummins,
H.
(
1987)
FR
1398/
1:
Acute
Oral
Toxicity
Study
in
the
Rat:
Lab
Project
Number:
87/
MBL071/
011.
Unpublished
study
prepared
by
Life
Science
Research
Ltd.
20
p.

42110002
Blair,
M.
(
1989)
Eight­
Week
Range­
Finding
Dietary
Toxicity
Study
in
Mice:
Lab
Project
Number:
347­
033.
Unpublished
study
prepared
by
International
Research
and
Development
Corp.
182
p.

42338201
Blair,
M.
(
1992)
Two
Year
Dietary
Oncogenicity
Study
in
Mice:
Asulam
Sodium
Salt:
Lab
Project
Number:
347­
036.
Unpublished
study
prepared
by
International
Research
and
Development
Corp.
2959
p.

43185701
Godward,
P.
(
1980)
Asulam
Content
of
Fortified
Rat
Diets
Used
in
a
Reproduction
Study:
Lab
Project
Number:
AR/
1715.
Unpublished
study
prepared
by
May
&
Baker
Ltd.
28
p.

20
Asulam
(
December,
2001)
RED
Toxicology
Chapter
43185702
Copping,
G.
(
1981)
Mating
Records
and
Randomization
Procedures
for
the
Asulam:
Teratogenicity
Study
by
the
Oral
Route
in
the
Rat
(
MRID
00098538):
Supplement:
Lab
Project
Number:
R/
TOX/
11:
39361.
Unpublished
study
prepared
by
May
&
Baker
Ltd.
8
p.

44052001
Brentnall,
D.;
Woolf,
N.
(
1981)
Asulam:
Two
Generation
Reproduction
Study
in
the
Rat:
Replacement
of
MRID
98540:
Lab
Project
Number:
R.
TOX.
34.
Unpublished
study
prepared
by
May
&
Baker,
Ltd.
and
Middlesex
Hospital
Medical
School.
206
p.

21
Asulam
(
December,
2001)
RED
Toxicology
Chapter
22
Asulam
(
December,
2001)
RED
Toxicology
Chapter
9.0APPENDICES
Tables
for
Use
in
Risk
Assessment
23
Asulam
(
December,
2001)
RED
Toxicology
Chapter
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
in
rodents
See
combined
chronic
feeding
and
carcinogenicity
study.
See
combined
chronic
feeding
and
carcinogenicity
study.

870.3150
90­
Day
oral
toxicity
in
nonrodents
00056414
(
1968)/
Unacceptable/
Guideline/
0,
5,
50
or
500
mg/
kg/
day.
LOAEL
=
500
mg/
kg/
day,
based
on
increased
absolute
and
relative
thyroid
weights
in
male
and
female
dogs.

NOAEL
=
50
g/
kg/
day
870.3200
21­
Day
dermal
toxicity
in
rabbits
41076901
(
1989)
Acceptable/
Guideline/
0
or
1000
mg/
kg/
day.
NOAEL
=
1000
g/
kg/
day
870.3250
90­
Day
dermal
toxicity
No
study.
No
study.

870.3465
90­
Day
inhalation
toxicity
No
study.
No
study
870.3700a
Prenatal
developmental
in
rodents
00098538/(
1981)/
Accept
­
able/
guideline/
0,
500,
1,000,
or
1,500
mg/
kg/
day
Maternal
l
LOAEL
=
1,500
mg/
kg/
day
based
on
body
weight
gain
decrement.
aternal
Maternal
NOAEL
=
1,000
mg/
kg/
day.

Developmental
LOAEL
=
1,500
mg/
kg/
day
based
on
slight
to
moderate
increase
in
preimplantation
loss.
Developmental
NOAEL
=
1,000
mg/
kg/
day.

870.3700b
Prenatal
developmental
in
rabbits
00098539/
1981/
Acceptable/
Guideline/
0,
60,
300,
or
750
mg/
kg/
day
Maternal
LOAEL
=
750
mg/
kg/
day
based
on
decreased
body
weight
during
the
dosing
period.

Maternal
NOAEL
=
300
mg/
kg/
day.

Developmental
NOAEL
=
750
mg/
kg/
day.
m
m
The
m
24
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3800
Reproduction
and
fertility
effects
00098540/
1981/
Acceptable/
0,
50,
250
or
1250
mg/
kg/
day.
Parental/
Systemic
LOAEL
=
1250
g/
kg/
day
(
HDT)
based
on
decreased
body
weights
(
F0
males,
F1
females)
and
organ
weight
effects
(
increased
absolute
and
relative
thyroid
weights
in
F1
males
and
F2
males
and
females,
increased
absolute
and
relative
liver
weights
in
F1
females,
and
increased
ovarian
weights
in
F1
females
at
31
days
old
but
not
at
terminal
necropsy).

Parental/
Systemic
NOAEL
=
250
mg/
kg/
day.

Reproductive/
Offspring
LOAEL
=
250
mg/
kg/
day
based
on
decreased
mean
live
births
per
litter.

Reproductive/
Offspring
NOAEL
=
50
mg/
kg/
day.

870.4100a
Chronic
toxicity
rodents
See
combined
chronic
feeding
and
carcinogenicity
study.
See
combined
chronic
feeding
and
carcinogenicity
study.

870.4100b
Chronic
toxicity
dogs
00098536/
1979/
Acceptable/
Nonguideline
/
0,
60,
300,
or
1,500
mg/
kg/
day.
LOAEL
=
g/
kg/
day,
based
on
significant
(
p
<
0.05)
increases
in
absolute
thyroid
weights
in
females.
roid
weights
were
elevated
at
the
high­
dose
(
1500
mg/
kg/
day)
in
both
males
and
females.
roid
weights
in
the
mid­
and
high­
dose
females
appeared
dose
related.

NOAEL
=
60
mg/
kg/
day.

870.4200
Combined
Chronic
Feeding
and
Carcinogenicity
rats
00098543/
1981/
Acceptab
le­
Guideline/
0,
36,
180
and
953
mg/
kg/
day
in
males
and
0,
47,
243
and
1,280
mg/
kg/
day
in
females.
LOAEL
=
180
mg/
kg/
day,
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males.

NOAEL
=
36
mg/
kg/
day.
Under
the
conditions
of
this
study,
there
was
evidence
of
an
increase
in
tumor
incidence
in
males
when
compared
to
controls.
Therefore,
asulam
is
a
potential
oncogen
in
this
study.

870.4300
Carcinogenicity
mice
42338201/
1982/
Acceptable/
Guideline/
0,
74,
730
and
8,040
mg/
kg/
day
in
males
and
0,
95,
938
and
10,353
mg/
kg/
day
in
females
LOAEL
=
8,040
mg/
kg/
day
in
males,
and
10,353
mg/
kg/
day
in
females,
based
on
increased
spleen
weight
and
decreased
body
weight
gain
in
males,
and
decreased
brain
weight
and
survival
in
females.

NOAEL
=
730
mg/
kg/
day
in
males
and
938
mg/
kg/
day
in
females.

Under
the
conditions
of
this
study,
there
was
no
evidence
of
carcinogenicity
of
asulam.
m
300
m
Absolute
and
relative
thy
The
increased
absolute
thy
25
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.4300
Carcinogenicity
mice
00081183/
1978/
Unacceptable/
Guideline/
0,
225,
and
750
mg/
kg/
day.
LOAEL
=
225
mg/
kg/
day,
based
on
enlargement
of
the
spleen
in
females,
decreased
absolute
and
relative
thyroid
weights
in
females,
intestinal
calcification
in
males
and
females,
and
a
dose­
related
increase
in
the
incidence
of
mild
skin/
subcutis
hyperkeratosis
in
males.

NOAEL
was
not
achieved.

Under
the
conditions
of
this
study,
there
was
no
definitive
evidence
of
carcinogenicity
of
asulam.

One­
Month
Inhalation
study
in
the
rat
00098537/
1977/
Accept­
able
Nonguideline/
nose­
only
exposure
at
concentrations
of
0,
1.6,
3.9,
or
15.3
mg/
L
for
4
hours
per
day,
5
days
per
week,
for
4
weeks.
NOAEL
=
15.3
mg/
L
(
HDT).

Oral
Range­
Finding
in
mice
42110002/
1989/
Accept­
able
Nonguideline/
0,
512,
1,673,
5,103,
and
9,022
mg/
kg/
day
for
males,
and
0,
675,
2,263,
6,835,
and
10,828
mg/
kg/
day
for
females
LOAEL
=
9,022
mg/
kg/
day
based
on
decreased
body
weight
and
body
weight
gain
in
males.

NOAEL
is
5,103
mg/
kg/
day.

Gene
Mutation
870.
A
table
presenting
the
mutagenicity
data
base
is
already
included
under
section
4.7.

870.6200a
Acute
neurotoxicity
screening
battery
No
study.
No
study
870.6200b
Subchronic
neurotoxicity
screening
battery
No
study.
No
study.

870.6300
Developmental
neurotoxicity
Not
required.

26
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.7485
Metabolism
and
pharmaco­
kinetics
41345601
(
1989)
Metabolism
studies
in
the
rat
demonstrate
that
asulam
was
rapidly
eliminated,
primarily
in
the
urine,
following
administration
of
a
single
oral
or
intravenous
dose,
or
after
repeated
intravenous
doses
for
14
days.
No
unusual
localization
of
asulam
occurred
in
tissues.
Unchanged
parent
compound
was
identified
as
the
major
excretory
product,
with
acetylasulam
and
acetylsulphanilamide
as
minor
metabolites.

870.7600
Dermal
absorpt­
ion
No
Study.
No
Study.

27
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Asulam
for
Use
in
Human
Risk
Assessment1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
No
appropriate
study
for
a
single
dose
risk
assessment.

Chronic
Dietary
all
populations
NOAEL=
36
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.36
mg/
kg/
day
FQPA
SF
=
cPAD
=
chr
RfD
FQPA
SF
=
mg/
kg/
day
Combined
Chronic
Toxicity/
Oncogenicity
study
(
MRID
No.:
00098543).
LOAEL
=
180
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
the
thyroid
follicular
cells
of
males.

Short­
Term
Oral
(
1­
30
days)

(
Residential)
A
toxicity
endpoint
was
not
selected
because
there
are
no
residential
uses.

Intermediate­
Term
Oral
(
30
days
to
six
months)

(
Residential)
A
toxicity
endpoint
was
not
selected
because
there
are
no
residential
uses.

Short­
Term
Dermal
(
1­
30
days)

(
Occupational)
Oral
study
NOAEL=
50
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)
Two­
Generation
Reproduction
Study
(
MRID
No.:
00098540).
LOAEL
=
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.

Intermediate­
Term
Dermal
(
30
days
to
six
months)

(
Occupational)
Oral
study
NOAEL=
50
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)
Two­
Generation
Reproduction
Study
(
MRID
No.:
00098540).
LOAEL
=
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.

Long­
Term
Dermal
(
several
months
­
lifetime)

(
Occupational)
NOAEL=
36
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)
Combined
Chronic
Toxicity/
Oncogenicity
study
(
MRID
No.:
00098543).
LOAEL
=
180
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
the
thyroid
follicular
cells
of
males.
Asulam
(
December,
2001)
RED
Toxicology
Chapter
28
Asulam
(
December,
2001)
RED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Short­
Term
Inhalation
(
1­
30
days)

(
Occupational)
Oral
study
NOAEL=
50
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
LOC
for
MOE
=
100
(
Occupational)
Two­
Generation
Reproduction
Study
(
MRID
No.:
00098540).
LOAEL
=
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.

Intermediate­
Term
Inhalation
(
30
days
to
six
months)

(
Occupational)
Oral
study
NOAEL=
50
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)
Two­
Generation
Reproduction
Study
(
MRID
No.:
00098540).
LOAEL
=
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.

Long­
Term
Inhalation
(
several
months
­
lifetime)

(
Occupational)
NOAEL=
36
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)
Combined
Chronic
Toxicity/
Oncogenicity
study
(
MRID
No.:
00098543).
LOAEL
=
180
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
the
thyroid
follicular
cells
of
males.

Cancer
Classified
as
a
Group
C
carcinogen
(
possible
human
carcinogen).
No
quantification
of
carcinogenic
risk.
Not
Applicable
Not
Applicable
1
UF
=
uncertainty
factor,
FQPA
SF
=
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,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
29