Document ID: EPA-HQ-OPP-2002-0329-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-12-06T05:00Z

DATE:
12/
05/
2001
MEMORANDUM
SUBJECT:
ASULAM
­
2nd
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
John
J.
Liccione,
Toxicologist.
Reregistration
Branch­
3
Health
Effects
Division
(
7509C)

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

TO:
Jose
Morales,
Risk
Assessor
Reregistration
Branch­
3
Health
Effects
Division
(
7509C)

PC
Code:
106901;
106902
On
November
13,
2001,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
ASULAM
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risks
assessments.
This
is
the
first
re­
evaluation
after
a
1995
RED.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
Committee
Members
in
Attendance
Members
present
were:
Ayaad
Assaad,
William
Burnam,
Jonathan
Chen,
Paula
Deschamp,
Pamela
Hurley,
John
Liccione,
Sue
Makris,
David
Nixon,
Jess
Rowland,
and
Brenda
Tarplee.

Member(
s)
in
absentia:
Elizabeth
Doyle.

Data
evaluation
prepared
by:
John
Liccione,
Reregistration
Branch­
3
Also
in
attendance
were:
Steve
Knizner,
RRB­
3,
HED;
Cathy
Eiden,
RRB­
3,
HED;
Barry
O Keefe,
RRB­
3,
HED;
Jose
Morales,
RRB­
3,
HED
Data
Evaluation
/
Report
Presentation
John
J.
Liccione
Toxicologist
2
1.
INTRODUCTION
In
a
previous
meeting
(
March
19,
1998),
the
Health
Effects
Division s
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
met
to
evaluate
the
toxicology
data
base
for
asulam
for
risk
assessment
purposes.
The
present
HIARC
meeting
(
November
13,
2001)
is
a
revisit
of
asulam
for
toxicological
endpoint
selection
for
use
in
occupational/
residential
exposure
risk
assessments.
In
addition,
the
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
ASULAM
was
re­
evaluated.

2.
HAZARD
IDENTIFICATION
2.1
Acute
Reference
Dose
(
RfD)

Study
Selected:
None
Dose
and
Endpoint
for
Establishing
RfD:
Not
applicable.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
No
appropriate
toxicological
endpoint
clearly
attributable
to
a
single
exposure
was
identified
including
the
oral
developmental
toxicity
studies
in
rats
and
rabbits.
Although
a
slight
to
moderate
increase
(
non­
significant)
in
preimplantation
loss
was
observed
in
a
developmental
rat
study,
the
LOAEL
for
this
effect
was
1,500
mg/
kg/
day
and
the
NOAEL
was
1,000
mg/
kg/
day
(
limit
dose).

2.2
Chronic
Reference
Dose
(
RfD)

Study
Selected:
Combined
Chronic
Toxicity/
Oncogenicity
feeding­
rat;
OPPTS
870.4300
[
§
83­
5]
§
MRID
No.:
00098543
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

3
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.

This
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirement
for
a
combined
chronic
toxicity/
carcinogenicity
study
(
83­
5)
in
the
rat.
A
minor
study
deficiency
includes
the
lack
of
thyroid
weight
data.

Dose
and
Endpoint
for
Establishing
RfD:
NOAEL
of
36
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
observed
in
male
rats
at
180
mg/
kg/
day.

Uncertainty
Factor(
s):
100
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
This
endpoint
is
of
the
appropriate
route
and
duration
of
exposure
and
applies
to
the
population
of
concern
(
general
population,
including
infants
and
children).

This
study
was
selected
by
the
RfD/
Peer
Review
committee
(
1993)
for
the
chronic
RfD.

Chronic
RfD
=
36
mg/
kg/
day
(
NOAEL)
=
0.36
mg/
kg/
day
100
(
UF)

2.3
Occupational/
Residential
Exposure
2.3.1
Short­
Term
(
1
Day
­
1
Month)
Incidental
Oral
Exposure
Since
there
are
no
residential
uses,
toxic
endpoints
were
not
selected.

2.3.2
Intermediate­
Term
(
1­
6
Months)
Incidental
Oral
Exposure
4
Since
there
are
no
residential
uses,
toxic
endpoints
were
not
selected.

2.3.3
Dermal
Absorption
Dermal
Absorption
Factor:
100%

Comments
about
the
Factor:
There
are
no
dermal
absorption
studies
with
asulam.
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.

2.3.4
Short­
Term
Dermal
(
1
Day
­
1
Month)
Exposure
Study
Selected:
Two­
Generation
Reproduction
Study
Guideline
#:
870.3800
MRID
No.:
00098540
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
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
significant
decreases
in
mean
live
births
per
litter.
The
NOAEL
for
reproductive/
offspring
toxicity
is
1,000
ppm
(
50
mg/
kg/
day).

5
This
two­
generation
reproduction
study
in
the
rat
is
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirement
for
a
reproduction
study
(
83­
4)
in
rats.

Dose
and
Endpoint
for
Risk
Assessment:
Offspring
NOAEL
of
50
mg/
kg/
day,
based
on
significant
and
dose­
related
decreases
in
mean
live
births
per
litter
in
the
first
generation
at
a
LOAEL
of
250
mg/
kg/
day.

Comments
about
Study/
Endpoint:.
Although
a
21­
day
dermal
toxicity
study
(
NOAEL
=
1000
mg/
kg/
day)
in
the
rabbit
was
available,
the
study
did
not
include
examination
of
thyroid
weights
and
thyroid
pathology,
and
does
not
evaluate
offspring
toxicity.
A
number
of
toxicity
studies,
including
a
carcinogenicity
feeding
study
in
the
mouse
(
MRID#
00081183),
a
combined
chronic
toxicity/
carcinogenicity
rat
study
(
MRID#
00098543),
a
two­
generation
rat
reproduction
study
(
MRID#
00098540),
a
3­
month
oral
dog
study
(
MRID#
00081183),
a
6­
month
oral
dog
study
(
MRID
#
00098536),
and
a
combined
chronic
toxicity/
carcinogenicity
rat
study
(
MRID#
00098543),
indicate
the
thyroid
as
a
target
organ.
Offspring
toxicity
was
noted
in
the
two­
generation
reproduction
study
in
the
rat
(
discussed
above).

For
this
exposure
scenario,
the
two­
generation
reproduction
study
in
the
rat
(
MRID#
00098540)
is
selected
for
risk
assessment
because
the
decreased
mean
live
births
per
litter
occurred
during
days
0
­
30,
which
is
the
appropriate
duration
of
exposure
for
this
risk
assessment.
It
is
also
protective
of
offspring/
reproductive
effects,
and
possibly
protective
of
thyroid
effects.

A
dermal
absorption
study
was
not
available.
A
dermal
absorption
factor
of
100%
will
be
used
for
route­
to­
route
extrapolation.

2.3.5
Intermediate­
Term
Dermal
(
1­
6
Months)
Exposure
Study
Selected:
Two­
Generation
Reproduction
Study
Guideline
#:
870.3800
MRID
No.:
00098540
Executive
Summary:
See
Short­
term
Dermal
Exposure
Section.

Dose/
Endpoint
for
Risk
Assessment:
Offspring
NOAEL
of
50
mg/
kg/
day,
based
on
significant
and
dose­
related
decreases
in
mean
live
births
per
litter
in
the
first
generation
at
a
LOAEL
of
250
mg/
kg/
day.

Comments
about
Study/
Endpoint:
Refer
to
 
Comments
about
Study/
Endpoint 
for
Short­
term
Dermal
Exposure
which
provides
a
rationale
for
not
selecting
the
21­
day
dermal
toxicity
study
(
NOAEL
=
1000
mg/
kg/
day)
in
rabbits
for
risk
assessment.
The
3­
month
oral
dog
study
(
which
examined
thyroid)
was
also
considered
for
possible
selection
for
this
exposure
scenario.
Although
the
study
was
classified
as
nonacceptable
guideline,
it
6
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).
The
results
of
the
dog
studies
with
a
NOAEL
of
50
mg/
kg/
day
(
3­
month
dog
study)
or
60
mg/
kg/
day
(
6­
month
dog
study)
support
the
NOAEL
from
the
two­
generation
reproduction
study.
The
two­
generation
reproduction
study
is
selected
for
the
intermediate­
term
dermal
exposure.
An
8­
week
oral
range­
finding
study
in
mice
(
MRID#
42110002)
was
also
available,
however,
the
thyroid
was
not
examined.
A
dermal
absorption
factor
of
100%
will
be
used
for
route­
to­
route
extrapolation.

2.3.6
Long­
Term
Dermal
(
Longer
than
6
Months)
Exposure
Study
Selected:
Combined
Chronic
Toxicity/
Oncogenicity
feeding­
rat;
OPPTS
870.4300
[
§
83­
5]

MRID
No.:
00098543
Executive
Summary:
See
Section
2.2
Chronic
Reference
Dose
(
RfD)

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
of
36
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
observed
in
male
rats
at
180
mg/
kg/
day.

Comments
about
Study/
Endpoint:
A
long­
term
dermal
toxicity
study
was
not
available.
In
addition,
there
was
no
dermal
absorption
study.
The
combined
chronic
toxicity/
carcinogenicity
oral
study
in
the
rat
is
of
the
appropriate
duration
of
exposure.
A
dermal
absorption
factor
of
100%
will
be
used
for
route­
to­
route
extrapolation.

2.3.7
Short­
term
Inhalation
(
1
Day
­
1
Month)
Exposure
Study
Selected:
Two­
Generation
Reproduction
Study
Guideline
#:
870.3800
MRID:
00098540
Executive
Summary:
See
Short­
term
Dermal
Dose/
Endpoint
for
Risk
Assessment:
Offspring
NOAEL
of
50
mg/
kg/
day,
based
on
significant
and
dose­
related
decreases
in
mean
live
births
per
litter
in
the
first
generation
at
a
LOAEL
of
250
mg/
kg/
day.

Comments
about
Study/
Endpoint:
Although
a
1­
month
inhalation
toxicity
study
in
rats
was
available
(
NOAEL
=
15.3
mg/
L),
thyroid
weights
and
thyroid
pathology
were
not
7
examined.
As
discussed
previously,
a
number
of
toxicity
studies,
including
carcinogenicity
feeding
study
in
the
mouse
(
MRID#
00081183),
a
combined
chronic
toxicity/
carcinogenicity
rat
study
(
MRID#
00098543),
a
two­
generation
rat
reproduction
study
(
MRID#
00098540),
a
3­
month
oral
dog
study
(
MRID#
00081183),
a
6­
month
oral
dog
study
(
MRID
#
00098536),
and
a
combined
chronic
toxicity/
carcinogenicity
rat
study
(
MRID#
00098543),
indicate
the
thyroid
as
a
target
organ.
Offspring
toxicity
was
observed
in
the
two­
generation
reproduction
study.

For
this
exposure
scenario,
the
two­
generation
reproduction
study
in
the
rat
(
MRID#
00098540)
is
selected
for
risk
assessment
because
the
decreased
mean
live
births
per
litter
occurred
during
days
0
­
30,
which
is
the
appropriate
duration
of
exposure
for
this
risk
assessment.
It
is
also
protective
of
offspring/
reproductive
effects.

An
inhalation
absorption
factor
of
100%
(
default
value
assuming
equivalent
inhalation
and
oral
absorption)
will
be
used
for
route­
to­
route
extrapolation.

2.3.8
Intermediate­
term
Inhalation
(
1­
6
Months)
Exposure
Study
Selected:
Two­
Generation
Reproduction
Study
Guideline
#:
870.3800
MRID:
00098540
Executive
Summary:
See
Short­
term
Dermal
Dose/
Endpoint
for
Risk
Assessment:
Offspring
NOAEL
of
50
mg/
kg/
day,
based
on
significant
and
dose­
related
decreases
in
mean
live
births
per
litter
in
the
first
generation
at
a
LOAEL
of
250
mg/
kg/
day.

Comments
about
Study/
Endpoint:
Refer
to
 
Comments
about
Study/
Endpoint 
for
Short­
term
Inhalation
Exposure
which
provides
a
rationale
for
not
selecting
the
one­
month
inhalation
toxicity
study
in
rats
for
risk
assessment.
The
3­
month
oral
dog
study
(
which
examined
thyroid)
was
also
considered
for
possible
selection
for
this
exposure
scenario.
Although
the
study
was
classified
as
nonacceptable
guideline,
it
was
supported
by
the
findings
of
the
6­
month
oral
dog
study.
The
results
of
the
two
studies
were
similar
(
i.
e.,
based
on
increased
thyroid
weights,
the
LOAEL
and
NOAEL
for
the
6­
month
dog
study
were
300
mg/
kg/
day
and
60
mg/
kg/
day,
respectively,
while
the
LOAEL
and
NOAEL
for
the
3­
month
dog
study
were
500
mg/
kg/
day
and
50
mg/
kg/
day,
respectively.
The
results
of
the
dog
studies
with
a
NOAEL
of
50
mg/
kg/
day
(
3­
month
dog
study)
or
60
mg/
kg/
day
(
6­
month
dog
study)
support
the
NOAEL
from
the
two­
generation
reproduction
study.
The
two­
generation
reproduction
study
is
selected
for
the
intermediate­
term
inhalation
exposure.
An
8­
week
oral
range­
finding
study
in
mice
(
MRID#
42110002)
was
also
available,
however,
the
thyroid
was
not
examined.
An
inhalation
absorption
factor
of
100%
(
default
value
assuming
equivalent
inhalation
and
oral
absorption)
will
be
used
for
route­
to­
route
extrapolation.

8
2.3.9
Long­
term
Inhalation
(
Longer
than
6
Months)
Exposure
Study
Selected:
Combined
Chronic
Toxicity/
Oncogenicity
feeding­
rat;
OPPTS
870.4300
[
§
83­
5]

MRID:
00098543
Executive
Summary:
See
Section
2.2
Chronic
Reference
Dose
(
RfD)

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
of
36
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
observed
in
male
rats
at
180
mg/
kg/
day.

Comments
about
Study/
Endpoint:
A
long­
term
inhalation
toxicity
study
was
not
available.
The
combined
chronic
toxicity/
carcinogenicity
oral
study
in
the
rat
is
of
the
appropriate
duration
of
exposure.
An
inhalation
absorption
factor
of
100%
(
default
value
assuming
equivalent
inhalation
and
oral
aborption)
will
be
used
for
route­
to­
route
extrapolation.

2.3.10
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessments
A
margin
of
exposure
(
MOE)
of
100
is
adequate
for
dermal/
inhalation
occupational
exposure
risk
assessment.
The
acceptable
MOEs
for
non­
occupational
and
dietary
exposures
will
be
determined
by
the
FQPA
SF
Committee.

2.4
Recommendation
for
Aggregate
Exposure
Risk
Assessments
There
are
no
residential
uses
for
asulam.
The
chronic
aggregate
risk
assessment
is
therefore
limited
to
food
and
water.

CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.
00098543
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
9
3
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.

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).

This
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat
is
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirement
for
a
combined
chronic
toxicity/
carcinogenicity
study
(
83­
5)
in
the
rat.
A
minor
study
deficiency
includes
the
lack
of
thyroid
weight
data.

Discussion
of
Tumor
Data:
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.

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.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
is
considered
adequate
to
assess
the
oncogenic
potential
of
asulam
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males.

3.2
Carcinogenicity
Study
in
Mice
Selected
Study:
Oncogenicity
study
in
mice
Guideline
#:
870.4300
MRID
No.:
42338201
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
10
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.

This
carcinogenicity
study
in
the
mouse
is
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirement
for
a
carcinogenicity
study
(
83­
2b)
in
this
species.
One
limitation
of
the
study
is
the
lack
of
thyroid
weight
measurements.

Discussion
of
Tumor
Data:
Under
the
conditions
of
this
study,
there
was
no
evidence
of
carcinogenicity
of
asulam.

Adequacy
of
the
Dose
Levels
Tested:
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.

3.3
Classification
of
Carcinogenic
Potential
On
November
12,
1987,
the
Carcinogenicity
Peer
Review
Committee
met
to
discuss
and
evaluate
the
weight­
of­
the
evidence
on
asulam
with
particular
reference
to
its
carcinogenic
potential
(
Peer
Review
of
Asulam
­
memo
date
2/
17/
88).
The
Committee
concluded
that
the
available
data
for
asulam
provided
limited
evidence
for
the
carcinogenicity
of
the
chemical
in
rats,
and
asulam
was
classified
as
a
Category
C
Carcinogen.
The
Committee
recommended
that
the
18­
month
carcinogenicity
mouse
study
(
MRID
00081183;
unacceptable­
guideline)
be
repeated
and
agreed
to
reevaluate
the
classification
when
a
new
mouse
study
on
asulam
was
submitted
and
reviewed.

A
new
mouse
study
(
MRID
#
423382­
01;
discussed
previously)
was
submitted
by
the
registrant
and
reviewed.
The
committee
considered
the
new
mouse
study
to
be
acceptable.
The
dose
levels
tested
in
the
mouse
study
were
considered
to
be
adequate
for
carcinogenicity
testing.
The
high
dose
tested
was
higher
than
the
limit
dose
level
as
specified
under
Subpart
F
of
the
Pesticide
Assessment
Guideline
for
carcinogenicity
testing
in
mice.
The
treatment
did
not
alter
the
spontaneous
tumor
profile
for
this
strain
of
mouse.
The
Committee
concluded
that
the
new
mouse
study
did
not
impact
the
current
classification
of
asulam
as
a
 
Group
C, 
possible
human
carcinogen.

11
4
MUTAGENICITY
CONCLUSION:
The
four
mutagenicity
studies
have
been
reviewed.
With
the
exception
of
MRID
No.
00082250
(
dominant
lethal
mutations
in
mice)
all
other
assays
were
found
to
be
Acceptable.
These
studies
satisfy
the
pre­
1991
FIFRA
guideline
requirement
for
mutagenicity
studies
(
§
84­
2);
no
further
testing
is
required
at
this
time.
Presented
below
are
the
citations
and
Executive
Summaries
for
the
reviewed
studies;
the
revised
Data
Evaluation
Records
(
DERs)
are
attached.

CITATION:
Hastings,
S.
E.
and
Huffman,
K.
W.
(
1975).
Dominant
Lethal
Study
of
Asulam
in
Mice;
Hess
&
Clark,
Div
of
Rhodia,
Ashland,
OH;
Study
Report
No.
SEH­
75:
94,
Project
No.
CH­
62;
dated:
August
29,
1975.
(
Unpublished)
MRID
NUMBER:
00082250.

EXECUTIVE
SUMMARY:
In
a
dominant
lethal
mutation
assay
(
MRID
No.
00082250),
groups
of
15
male
Carworth
CF­
1
mice
received
dietary
administrations
of
1500
or
5000
ppm
Asulam
(
unspecified
purity)
for
45
days.
Fifteen
males
were
in
the
vehicle
control
group
and
10
males/
group
were
in
the
two
positive
control
groups.
After
treatment,
individual
males
were
mated
with
two
untreated
virgin
females
(
CD­
1
mice)
for
1
week
and
remated
at
the
same
mating
ratio
of
males
to
females
(
1:
2)
for
a
second
week.
Females
were
sacrificed
13
days
after
the
mid­
week
of
mating
and
uterine
contents
were
examined.

No
adverse
effects
were
seen
in
the
males
and
no
differences
in
the
percent
pregnancy,
number
of
implants
or
early
fetal
deaths
were
observed
in
the
females.
The
expected
response
was
induced
in
animals
administered
the
positive
control.
Means
and
standard
error
of
the
means
indicated
that
there
was
no
evidence
that
Asulam
induced
a
dominant
lethal
effect.

This
study
is
classified
as
Unacceptable
because
purity
information
on
the
test
material
has
not
been
provided.
It
does
not
satisfy
the
guideline
requirements
for
a
dominant
lethal
assay
(
84­
2).

CITATION:
Ingham,
R.
(
1979).
Asulam
C3H/
10T1/
2
Cell
Transformation
Assay:
EG
&
G
Mason
Research
Institute,
Rockville,
MD;
Study
No.
596­
249­
8;
RES
3701;
dated:
October
5,
1979.
(
Unpublished)
MRID
NUMBER:
00098542.

EXECUTIVE
SUMMARY:
In
an
in
vitro
cell
transformation
assay
(
MRID
No.
00098542),
C3H/
10T1/
2
cells
were
exposed
to
Asulam
(
98.0­
99.9%)
at
doses
of
256,
512,
1024
or
2048
µ
g/
mL
for
18
hours.
Surviving
cells
were
plated
for
8
days
to
determine
cloning
efficiency
(
CE);
Type
II
and
Type
III
foci
were
scored
35
days
after
treatment.
An
S9­
activated
phase
of
testing
was
not
included.
The
test
material
was
delivered
to
the
test
system
in
acetone.

Cytotoxicity,
as
indicated
by
a
50­
75%
reduction
in
the
CE,
was
apparent
at
2048
µ
g/
mL.
The
positive
control
induced
the
expected
increase
in
Type
II
transformed
foci.
There
was,
however,
no
evidence
that
Asulam
induced
morphological
transformation.

12
This
study
is
classified
as
Acceptable
(
Nonguideline).

CITATION:
Galloway,
S.
M.
and
Myhr,
B.
C.
(
1984).
Asulam:
Mutagenicity
Evaluation
of
Asulam
Technical
(
Dried)
in
an
In
Vitro
Cytogenetics
Assay
measuring
Chromosome
Aberration
Frequencies
in
Human
Lymphocytes;
Litton
Bionetics,
Inc.,
Kensington,
MD;
Study
No.
20990;
dated:
March
1984.
(
Unpublished)
MRID
NUMBER:
40415301.

EXECUTIVE
SUMMARY:
In
a
mammalian
cell
cytogenetic
assay
(
MRID
No.
40415301),
cultured
human
lymphocytes
were
exposed
to
Asulam
technical
(
97.5­
99.8%)
at
doses
ranging
from
125­
2500
µ
g/
mL
in
the
absence
of
metabolic
activation
or
to
S9­
activated
doses
of
250­
2500
µ
g/
mL
and
cells
were
harvested
48
hours
post­
exposure.
The
S9
homogenate
was
derived
from
Aroclor
1254­
induced
Sprague
Dawley
rat
livers
and
the
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide.

Doses
$
1000
µ
g/
mL
­
S9
were
cytotoxic.
No
cytotoxicity
was
seen
in
the
presence
of
S9
activation;
however,
results
from
the
preliminary
study
suggested
that
Asulam
was
tested
up
to
the
highest
subcytotoxic
concentration.
The
positive
controls
induced
the
expected
clastogenic
responses
with
or
without
S9
activation.
There
was,
however,
no
evidence
that
Asulam
technical
induced
a
clastogenic
response
either
in
the
presence
or
the
absence
of
S9
activation.

This
study
is
classified
as
Acceptable
(
Guideline)
and
satisfies
the
guideline
requirement
for
an
in
vitro
mammalian
cell
cytogenetic
assay
(
§
84­
2).

CITATION:
Hoorn,
A.
J.
W.
(
1983).
Asulam:
Mutagenicity
Evaluation
of
Asulam
Technical
(
Dried)
in
the
Ames
Salmonella/
Microsome
Plate
Test
Preincubation
Method;
Litton
Bionetics,
Inc.,
Veenedaal,
The
Netherlands;
Study
No.
E­
9177
dated:
October
1983.
(
Unpublished)
MRID
NUMBER:
40415302.

EXECUTIVE
SUMMARY:
In
a
microbial
reverse
gene
mutation
preincubation
assay
(
MRID
No.
40415302),
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA98
and
TA100
were
exposed
to
seven
doses
of
Asulam
technical
(
97.5­
99.87%)
ranging
from
0.9­
2000
µ
g/
plate
in
both
the
presence
and
the
absence
of
S9
activation.
The
S9
fraction
was
derived
from
Aroclor
1254­
induced
Sprague
Dawley
male
rat
livers
and
the
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide.

Cytotoxicity
was
evident
for
the
majority
of
strains
at
>
500
Fg/
plate­
S9
or
at
>
1000
Fg/
plate
+
S9.
All
strains
responded
in
the
expected
manner
to
the
appropriate
positive
control.
There
was,
however,
no
evidence
that
Asulam
technical
induced
a
mutagenic
effect
in
any
strain.

This
study
is
classified
as
Acceptable
(
Guideline)
and
satisfies
the
guideline
requirements
for
a
bacterial
gene
mutation
assay
(
84­
2).

13
5
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
The
following
acceptable
studies
are
available:

 
Developmental
toxicity
studies
in
the
rat
&
rabbit
 
Two­
Generation
Reproduction
Study
5.2
Neurotoxicity
No
acute,
subchronic,
or
developmental
neurotoxicity
studies
have
been
conducted.
However,
there
is
no
evidence
of
neurotoxicity
in
the
available
acute,
subchronic,
chronic,
and
oncogenicity
studies.
In
the
March
31,
1998
HIARC
meeting,
the
HIARC
concluded:
 
The
data
and
information
provided
by
the
Registrant
demonstrate
that
Asulam,
being
a
carbamate
herbicide
rather
than
a
carbamate
insecticide,
has
chemical
structure
and
biological
properties
considerably
different
from
those
of
the
insecticides.
Several
studies
were
cited
to
illustrate
the
lack
of
cholinesterase
inhibition
and
the
absence
of
clinical
signs
suggestive
of
neurotoxicity.
Based
on
these
factors,
the
Agency
waived
the
requirements
for
acute,
subchronic,
and
developmental
neurotoxicity
studies
(
memorandum,
L.
Taylor
to
C.
Peterson,
dated
January
29,
1992. 

5.3
Developmental
Toxicity
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
high­
dose
group
(
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.

This
prenatal
developmental
toxicity
study
in
the
rat
is
Acceptable­
Guideline,
and
does
satisfy
14
the
guideline
requirement
for
a
developmental
study
(
83­
3)
in
the
rat.
The
highest
dose
tested
was
1,500
mg/
kg/
day.

COMMENTS:

In
a
memo
dated
May
24,
1994,
a
Toxicology
Branch
review
of
supplemental
data
to
clarify
the
mating
procedures
utilized
in
the
rat
developmental
study
concluded
that
the
study
was
acceptable.

Rabbit
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%)
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
weight
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
gain
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.

This
prenatal
developmental
toxicity
study
in
the
rabbit
is
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirement
for
a
developmental
study
(
83­
3)
in
the
rabbit.
The
study
employed
an
adequate
number
of
animals,
and
the
doses
were
high
enough
to
challenge
the
animals.

5.4
Reproductive
Toxicity
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
15
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
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).

This
two­
generation
reproduction
study
in
the
rat
is
Acceptable­
Guideline,
and
does
satisfy
the
guideline
requirement
for
a
reproduction
study
(
83­
4)
in
rats.

COMMENTS:

The
original
DER
identified
a
reproductive
NOEL
of
1000
ppm
based
on
fewer
live
births/
litter
at
5,000
and
25,000
ppm,
and
a
slightly
lower
fertility
index
in
F1
parents
at
5,000
and
25,000
ppm.
However,
a
previous
HIARC
committee
review
(
HED
DOC.
NO.
012556;
March
31,
1998)
disagreed
with
this
NOEL,
and
concluded
that
the
reproductive
NOEL
should
be
set
at
25000
ppm
(
1250
mg/
kg/
day)
based
on
the
following
reasons
regarding
fewer
live
births
per
litter
and
lower
fertility
index:
(
1)
The
observation
was
not
statistically
significant
between
treated
and
control
groups;
(
2)
There
was
no
dose
relationship;
(
3)
The
observations
were
not
seen
in
the
next
generation;
and
(
4)
There
was
no
developmental
effects
in
the
developmental
toxicity
study
in
rats
at
1000
mg/
kg/
day.
Also,
fewer
live
births
per
litter
was
not
seen
in
the
developmental
studies.
The
reviewer
notes
however
that
the
decreases
in
mean
numbers
of
live
pups
per
litter
from
birth
until
day
30
at
5,000
ppm
and
25,000
ppm
in
the
first
generation
were
statistically
significant
and
displayed
a
dose
response
relationship.
The
mean
numbers
of
live
pups
per
litter
from
birth
until
day
30
were
also
lower
in
the
5,000
ppm
and
25,000
ppm
groups
(
compared
to
control
group)
in
the
second
generation;
however,
statistical
significance
was
only
observed
for
the
5,000
ppm
group
at
day
0.
The
reviewer
considers
the
offspring
LOAEL
to
be
5,000
ppm.

In
a
memo
dated
May
24,
1994,
a
Toxicology
Branch
review
of
supplemental
information
on
the
dietary
concentrations,
stability,
and
homogeneity
of
the
test
material
utilized
in
the
study
concluded
that
the
supplemental
information
was
adequate
and
that
the
reproduction
study
was
16
acceptable.
Another
memo
(
7/
7/
87)
discusses
the
results
of
a
T­
test
of
controls
vs.
low
dose
in
the
reproduction
study.
The
memo
concluded
that
there
was
no
significant
difference
in
the
average
litter
size
between
the
controls
and
low
dose
group
(
1000
ppm)
for
the
F0
and
F1
females
when
tested
by
the
one
sided
t­
test.

5.5
Additional
Information
from
Literature
Sources
(
if
available)

No
relevant
literature
was
found.

5.6
Determination
of
Susceptibility
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).

5.7
Recommendation
for
a
Developmental
Neurotoxicity
Study
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.

5.7.1
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:

 
Asulam
is
listed
as
a
potential
endocrine
disruptor
on
EPA s
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC)
list.
Increased
thyroid
weights
have
been
observed
in
rats,
mice
and
dogs
following
subchronic
and
chronic
exposures.
In
addition,
hyperplastic
changes
in
the
thyroid
follicular
cells
and
thyroid
gland
C­
cell
carcinomas
were
observed
in
male
rats.
None
of
the
available
toxicity
studies
examined
potential
changes
in
thyroid
hormone
levels.
During
development,
thyroid
hormone
is
essential
for
growth,
brain
development
and
nervous
system
maturation.
Based
on
structure
activity
relationships
(
discussed
in
detail
below),
there
is
some
support
for
a
potential
hormonal
mechanism
of
thyroid
toxicity
associated
with
asulam.

No
chemical­
specific
information
pertaining
to
the
potential
mechanism
by
which
asulam
causes
endocrine
effects
was
identified
in
the
available
database
(
pesticide
study
submissions
and
recent
literature
search).
However,
the
Toxicology
Branch
Peer
Review
Committee
on
November
12,
1987
identified
three
compounds
with
some
structural
similarity
to
asulam,
and
which
have
been
tested
for
oncogenic
effects
in
rodents.
These
compounds
included:
1)
oryzalin,
a
sulfanilamide
compound
that
was
17
classified
as
a
category
C
carcinogen
on
the
basis
of
producing
benign
thyroid,
skin
and
mammary
tumors
in
male
and
female
F344
rats;
2)
sulfamethoxazole,
a
sulfonamide
that
produced
thyroid
gland
hyperplasia,
nodules
and
adenomas
in
rats;
and
3)
sulphisoxazole,
another
sulfonamide
which
was
negative
for
oncogenicty
in
rats
and
mice.
In
the
case
of
oryzalin
and
sulfamethoxazole,
the
induction
of
thyroid
tumors
was
considered
to
be
due
to
indirect
anti­
thyroid
effects
(
Oryzalin
Peer
Review
memorandum
of
3/
12/
86).
The
Committee
also
recognized
that
a
minor
sulfanilamide
metabolite
of
asulam,
4­
acetylsulfanilamide,
was
detected
in
rat
urine.
There
was
no
toxicity
information
on
this
metabolite.

In
the
weight­
of­
evidence
evaluation
of
asulam,
the
Committee
noted
that
asulam
produced
two
types
of
endocrine
gland
tumors
in
male
Sprague
Dawley
CR­
CD
rats.
These
included
thyroid
gland
C­
cell
carcinomas
and
combined
C­
cell
adenomas/
carcinomas,
and
benign
adrenal
gland
pheochromocytomas.
In
addition,
hyperplasia
was
observed
in
the
thyroids
and
adrenals
of
asulam­
treated
male
rats.

The
Oryzalin
Peer
Review
memorandum
of
3/
12/
86
presented
a
discussion
of
structure
activity
considerations
for
oryzalin.
Oryzalin
is
a
parasubstituted
aniline
derivative
and
also
a
sulfanilamide
compound.
The
Peer
Review
Committee
considered
data
indicating
that
dietary
administration
of
another
para­
substituted
aniline
derivative,
2,4­
diaminoanisole
sulfate,
to
rats
increased
the
incidences
of
malignant
tumors
of
the
thyroid
gland
and
the
skin
in
both
sexes
at
5000
ppm.
In
B6C3F1
mice,
dietary
administration
of
2,4­
diaminoanisole
sulfate
at
2400
ppm
induced
thyroid
tumors
in
each
sex.
In
addition,
data
on
two
sulfonamides,
sulfamethoxazole
and
sulphisoxazole,
were
considered.
Orally
administered
sulfamethoxazole
produced
thyroid
gland
hyperplasia
and
neoplasia
(
nodules
and
adenomas)
in
rats,
whereas
sulphisoxazole
was
negative
for
oncogenicity
in
rats
and
mice.

The
Oryzalin
Peer
Review
Committee
concluded
that
 
there
is
presumptive
evidence
to
believe
that
the
thyroid
gland
tumors
produced
by
oryzalin
in
male
and
female
rats
were
due
to
an
anti­
thyroid
effect
of
the
compound. 
In
addition,
the
Committee
noted
that
 
anti­
thyroid
effects
have
previously
been
reported
for
para­
substituted
aniline
derivatives
(
of
which
the
sulfonamides
make
up
the
greatest
number)
in
rats,
mice,
and
dogs. 
The
Committee
further
stated
­
 
Although
no
biochemical
tests
were
performed
to
evaluate
an
effect
of
oryzalin
on
thyroid
function
in
the
data
available
for
review,
several
morphological
changes
were
observed
in
the
thyroid
gland
in
the
chronic
rat
bioassays
in
addition
to
the
tumors.
These
included:
(
a)
increased
thyroid
gland
weights
in
high­
dose
(
2700
ppm)
males
in
one
of
the
two
chronic
studies;
(
b)
a
dose­
related
increase
in
cystic
follicles
of
the
thyroid
in
males
(
controls,
3/
59,
low­
dose,
5/
59,
mid­
dose,
12/
57,
high­
dose,
19/
56)
and
females
(
controls,
2/
55,
low­
dose,
8/
59,
mid­
dose,
13/
57,
high­
dose,
15/
55),
and
(
c)
focal
follicular
hyperplasia,
particularly
at
the
high­
dose
level,
in
males
and
females.
Furthermore,
on
the
basis
of
this
information,
the
panel
considered
that
oryzalin
might
act
to
cause
thyroid
tumors
by
inhibiting
the
formation
of
thyroxin,
resulting
in
positive
feedback
stimulation
of
the
pituitary
gland
to
18
release
TSH,
thereby
causing
thyroid
gland
hypertrophy
(
goiter)
and
the
ensuing
hyperplasia
and
tumor
formation. 

Recent
data
further
support
the
anti­
thyroidal
effects
of
sulfonamides.
Sulfamethazine,
the
most
widely
used
sulfonamide,
has
been
reported
to
cause
thyroid
follicular
adenomas
in
rats
and
mice.
Residues
of
this
sulfonamide
have
been
detected
in
milk
and
meat
products.
Sulfamethazine
has
also
been
reported
to
result
in
hypersensitivity
reactions,
including
hypothyroidism,
in
humans.
Doerge
and
Decker
(
1994)
provided
evidence
that
the
primary
mechanism
for
sulfamethazine­
induced
hypothyroidism
is
via
the
reversible
inhibition
of
thyroid
peroxidase­
mediated
thyroid
hormone
synthesis,
rather
than
the
formation
and
covalent
binding
of
reactive
N­
oxygenated
metabolites.
The
subsequent
alterations
in
thyroid
hormone
levels
can
influence
the
pituitary­
thyroid
feedback
system
that
regulates
thyroid
homeostasis.
The
feedback
system
responds
to
the
decreased
thyroid
hormone
levels
by
releasing
thyroid­
stimulating
hormone.
Thyroid­
stimulating
hormone
produces
a
generalized
growth
stimulus
to
the
thyroid
causing
an
increasing
nuclear
expression
of
genes
coding
for
proteins
associated
with
thyroid
hormone
synthesis.
Moreover,
thyroid­
stimulating
hormone
is
thought
to
select
proliferative
cells,
resulting
in
clonal
expansion
of
a
transformed
phenotype.
The
postulated
mechanism
of
action
for
sulfamethazine
is
consistent
with
a
hormonal
mechanism
for
thyroid
carcinogenesis
mediated
by
thyroid­
stimulating
hormone
(
Doerge
and
Decker
1994).
This
mechanism
is
considered
not
to
be
a
genotoxic
one.

 
In
the
two­
generation
reproduction
rat
study,
increased
absolute
brain
weight
in
F1
males,
and
increased
relative
brain
weight
in
F1
females,
were
observed.
However,
no
brain
weight
changes
were
observed
in
the
F2
parents.
Decreased
brain
weight
was
observed
in
high­
dose
females
in
a
2­
year
carcinogenicity
study
(
MRID
42338201).

5.7.2
Evidence
that
do
not
support
a
need
for
a
Developmental
Neurotoxicity
study:

 
No
developmental
CNS
malformations
were
observed
in
the
developmental
toxicity
studies
with
asulam.

 
There
was
no
evidence
of
neurotoxicity
(
clinical
signs
or
pathology)
in
subchronic
and
chronic
toxicity
studies
in
the
rat,
dog,
or
mouse.
Note:
the
Agency
waived
the
requirements
for
acute,
subchronic,
and
developmental
neurotoxicity
studies
(
memorandum,
L.
Taylor
to
c.
Peterson,
dated
January
29,
1992).

19
6.0
HAZARD
CHARACTERIZATION
Asulam
is
a
post­
emergent
systemic
herbicide
used
for
weed
control
on
sugarcane,
Christmas
tree
plantations,
ornamentals,
turf,
and
noncropland
uses.
Potential
residential
exposures
are
not
anticipated
as
a
result
of
applications
of
asulam.

Asulam
is
classified
as
Category
IV
for
acute
oral
toxicity,
acute
inhalation
toxicity
and
primary
dermal
irritation;
Category
III
for
acute
dermal
toxicity
and
primary
eye
irritation.
Asulam
is
a
nonsensitizer.

Several
studies
in
rodents
and
dogs
demonstrate
that
asulam
affects
the
endocrine
system,
in
particular,
the
thyroid.
The
Reference
Dose
(
RfD)
is
0.36
mg/
kg/
day
based
on
a
chronic
dietary
feeding
study
in
rats.
The
No­
observed­
Adverse­
Effect­
Level
(
NOAEL)
in
this
study
was
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.

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
significant
decreases
in
mean
live
births
per
litter
(
offspring
NOAEL
=
50
mg/
kg/
day)
was
observed
at
lower
dose
levels
associated
with
parental/
systemic
toxicity
(
NOAEL
=
250
mg/
kg/
day).

Asulam
was
not
mutagenic
in
the
studies
that
have
been
performed.
The
Agency
classified
asulam
as
a
Group
C,
possible
human
carcinogen,
based
on
thyroid
and
adrenal
tumors
in
the
rat
study.
The
Agency
has
decided
not
to
quantify
the
carcinogenic
risk
by
low
dose
extrapolation.

 
DATA
GAPS
 
Comparative
thyroid
rat
assay
in
adult
and
offspring
(
see
Section
5.7).

 
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.

20
 
ACUTE
TOXICITY
Acute
Toxicity
of
Asulam.

Guideline
No.
Study
Type
MRID
#(
S).
Results
Toxicity
Category
81­
1
Acute
Oral
409605­
01
LD50
=>
5000
mg/
kg
IV
81­
2
Acute
Dermal
409605­
01
LD50
=
>
4000
mg/
kg
III
81­
3
Acute
Inhalation
409605­
02
413616­
01
LC50
=>
5
mg/
L
IV
81­
4
Primary
Eye
Irritation
00098534
Mild
Irritation
III
81­
5
Primary
Skin
Irritation
00098535
Not
an
Irritant
IV
81­
6
Dermal
Sensitization
00098535
No
sensitization
NA
21
 
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
An
appropriate
endpoint
attributable
to
a
single
dose
was
not
identified.

Acute
RfD
=
not
established
Chronic
Dietary
NOAEL
=
36
mg/
kg/
day
UF
=
100
The
LOAEL
was
180
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males.
Combined
Chronic
Toxicity/
Oncogenicity
in
the
rat
Chronic
RfD
=
0.36
mg/
kg/
day
Incidental
Oral,
Short­
Term
Incidental
Oral,
Intermediate­
Term
A
toxicity
endpoint
was
not
selected
because
there
are
no
residential
uses.

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

Dermal,
Short­
Term
Dermal,
Intermediate­
Term
Oral
NOAELa
=
50
mg/
kg/
day
Oral
NOAELa
=
50
mg/
kg/
day
The
LOAEL
was
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.

The
LOAEL
was
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.
Two
Generation
Reproduction
Study
Two
Generation
Reproduction
Study
22
Dermal,
Long­
Term
Oral
NOAELa
=
36
mg/
kg/
day
The
LOAEL
was
180
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males.
Combined
Chronic
Toxicity/
Oncogenicity
in
the
rat
Inhalation,
Short­
Term
Inhalation,
Intermediate­
Term
Oral
NOAELb
=
50
mg/
kg/
day
Oral
NOAELb
=
50
mg/
kg/
day
The
LOAEL
was
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.

The
LOAEL
was
250
mg/
kg/
day
based
on
significant
decreases
in
mean
live
births
per
litter.
Two
Generation
Reproduction
Study
Two
Generation
Reproduction
Study
Inhalation,
Long­
Term
Oral
NOAELb
=
36
mg/
kg/
day
The
LOAEL
was
180
mg/
kg/
day
based
on
hyperplastic
changes
in
the
adrenal
medulla
and
in
thyroid
follicular
cells
of
males.
Combined
Chronic
Toxicity/
Oncogenicity
in
the
rat
aApply
100%
dermal
absorption
factor
for
route­
to­
route
extrapolation.
bAssume
100%
inhalation
absorption
factor
for
route­
to­
route
extrapolation.

23