HED
DOC.
NO.
014533
DATE:
April
10,
2001
SUBJECT:
DISULFOTON:
3
rd
Report
of
the
Hazard
Identification
Assessment
Review
Committee
FROM:
David
G.
Anderson,
Toxicologist
Reregistration
Branch­
2
Health
Effects
Division
(
7509C)

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

TO:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch­
2
Health
Effects
Division
(
7509C)

PC
Code:
032501
On
December
19,
2000
and
January
10,
2001
the
Health
Effects
Division'
s
Hazard
Identification
Assessment
Review
Committee
evaluated
the
toxicity
data
used
for
endpoints
in
short­
term
occupational/
residential
exposure.
The
Committee
did
not
address
other
endpoints.
The
Committee'
s
conclusions
are
presented
in
this
report.
Members
in
Attendance
Hazard
Identification
Assessment
Review
Committee
members
in
attendance:
William
Burnam,
,
Beth
Doyle,
Pamela
Hurley,
Elizabeth
Mendez,
Ayaad
Assaad,
Yung
Yang,
Jonathan
Chen,
David
Nixon,
Jess
Rowland
and
Brenda
Tarplee
(
Executive
Secretary)
.

Data
Presentation:
and
David
G
Anderson
Report
Preparation
Toxicologist
1.
INTRODUCTION
On
April
25,
1996
,
the
Health
Effects
Division'
s
RfD/
Peer
Review
Committee
evaluated
the
toxicology
data
base
of
Disulfoton
and
established
the
Reference
Dose
(
RfD)
of
0.0003
mg/
kg/
day
based
on
a
NOAEL
of
0.025mg/
kg/
day
and
an
Uncertainty
Factor
of
100
for
inter
species
extrapolation
and
intraspecies
variation
(
Memorandum
:
G.
Ghali
to
G.
LaRoca,
April
21,
1997)
.

On
May
14,
1996,
the
Toxicology
Endpoint
Selection
Committee
selected
the
doses
and
endpoints
for
acute
dietary
and
occupational
as
well
as
residential
exposure
risk
assessments
(
TES
Document
6/
5/
96)
.

On
November
20,
1997
,
the
Health
Effects
Division
 
s
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
re­
evaluated
the
toxicology
data
base,
re­
assessed
the
RfD
and
selected
the
toxicology
endpoints
for
acute
dietary
as
well
as
occupational
and
residential
exposure
risk
assessments.
In
addition,
the
HIARC
also
addressed
the
potential
enhanced
susceptibility
of
infants
and
children
from
exposure
to
disulfoton
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

On
April
9,
1998
,
the
HIARC
reviewed
the
results
of
a
two­
generation
reproduction
study
in
rats
(
MRID#
44440801)
that
was
recently
submitted
to
the
Agency
and
the
impact
of
this
study
in
the
doses
and
endpoints
selected
for
the
various
risk
assessments.

On
May
12­
14,
1998
,
the
HIARC
conducted
a
comprehensive
review
of
40
organophosphates,
including
disulfoton.
At
this
meeting
it
was
concluded
that
the
toxicology
database
is
inadequate
since
there
was
a
data
gap
for
an
acceptable
acute
delayed
neurotoxicity
study
in
the
hen.
Subsequently,
the
requirement
of
a
developmental
neurotoxicity
study
was
 
reserved
 
at
this
time.
.

On
January
19,
2000
,
the
HIARC
reviewed
the
results
of
a
new
acute
delayed
neurotoxicity
study
in
the
hen.
In
addition,
the
equivocal
results
of
a
90­
day
neurotoxicity
study
in
rats
were
reviewed
for
potential
disulfoton
induced
neuropathy.
HIARC
also
evaluated
the
toxicology
data
base
for
disulfoton
to
determine
whether
a
DNT
was
triggered
None
of
the
endpoints
for
any
of
the
RfDs
or
occupational
or
residential
exposure
were
changed
from
the
previous
HIARC.

On
December
19,
2000
and
January
11,
2001
,
the
HIARC
reviewed
the
results
from
a
3­
day
dermal
toxicity
study
in
rats
(
recently
submitted
to
the
Agency)
in
conjunction
with
the
available
21­
day
dermal
toxicity
studies
in
rabbits.
These
studies
were
evaluated
together
to
determine
their
suitability
for
use
in
short­
term
dermal
risk
assessment.

The
report
supercedes
the
previous
HIARC
reports
2.
HAZARD
IDENTIFICATION
2.1.
Acute
Reference
Dose
(
RfD)

Study
Selected:
Acute
Neurotoxicity
­
Rat
§
81­
8
MRID
No.
42755801
Executive
Summary:
In
an
acute
neurotoxicity
screening
study,
disulfoton
(
97.8%
a.
i.
)
was
administered
in
a
single
gavage
dose
to
10
male
Sprague­
Dawley
rats
at
doses
of
0,
0.25,
1.5,
or
5.0
mg/
kg
and
to
10
female
Sprague­
Dawley
rats
at
doses
of
0,
0.25,
0.75
or
1.5
mg/
kg.
These
rats
were
assessed
for
reactions
in
functional
observational
battery
(
FOB)
and
motor
activity
measurements
at
approximately
90
minutes
post­
dosing
and
on
days
7
and
14.
Cholinesterase
determinations
(
erythrocyte
and
plasma)
were
made
at
24
hours
post­
dosing.
Six
rats/
sex/
dose
were
examined
for
neuropathological
lesions.

At
0.75
mg/
kg,
4/
10
females
had
muscle
fasciculations.
At
1.5
mg/
kg,
males
had
muscle
fasciculations,
diarrhea,
and
sluggishness
and
females
also
had
tremors,
ataxia,
oral
staining,
decreased
activity/
sluggishness,
decreases
in
motor
and
locomotor
activity
(
38­
49%
of
control)
,
and
a
slightly
increased
duration
of
nasal
staining.
One
female
at
1.5
mg/
kg
died
from
cholinergic
intoxication
on
the
day
of
dosing.
At
5.0
mg/
kg,
males
also
had
symptoms
similar
to
those
observed
in
females
at
1.5
mg/
kg/
day,
including
reduced
motor/
locomotor
activity
(
36­
45%
of
control)
.
Recovery
appeared
to
be
complete
in
surviving
animals
by
Day
14.
Based
on
the
evidence
of
neurotoxicity
(
probably
associated
with
inhibition
of
cholinesterase)
in
females
at
0.75
mg/
kg,
the
study
LOAEL
is
0.75
mg/
kg
and
the
study
NOAEL
is
0.25
mg/
kg.

At
0.75
mg/
kg
in
females,
cholinesterase
activities
were
inhibited
by
53%
(
erythrocyte)
and
30%
(
plasma)
and
by
75%
(
erythrocyte)
and
52%
(
plasma)
at
1.5
mg/
kg
in
females.
At
5.0
mg/
kg
in
males,
cholinesterase
activities
were
inhibited
by
21%
(
erythrocyte)
and
25%
(
plasma)
.
The
LOAEL
for
inhibition
of
cholinesterase
activity
is
0.75
mg/
kg
and
the
NOAEL
for
inhibition
of
cholinesterase
activity
is
0.25
mg/
kg.

Dose
and
Endpoints
for
Establishing
the
Acute
RfD:
NOAEL=
0.25
mg/
kg
based
on
neurotoxicity
signs,
plasma
and
erythrocyte
cholinesterase
inhibition
in
female
rats.

Uncertainty
Factor
(
UF)
:
100
Comments
about
the
study
and/
or
Endpoint:
This
dose
and
endpoint
is
appropriate
since
the
toxicological
effects
were
observed
following
a
single
oral
dose.

Acute
RfD
=
0.25
mg/
kg
(
NOAEL)
=
0.0025
mg/
kg
100
(
UF)

2.2
Chronic
Reference
Dose
Study
Selected:
Chronic
Feeding
Dog
§
83­
1
MRID
No.
44248002
Executive
Summary:
In
a
chronic
toxicity
study,
disulfoton
(
97%
a.
i.
)
was
administered
orally
in
the
diet
to
purebred
beagle
dogs
(
4/
sex/
dose)
at
dose
levels
of
0.5,
4
or
12
ppm
(
equivalent
to
0.015,
0.121
and
0.321
mg/
kg/
day
for
males;
and
0.013,
0.094
and
0.283
mg/
kg/
day
for
females)
for
one
year.
Potential
ocular
and
neurologic
effects
were
addressed.
Plasma
cholinesterase
was
decreased
starting
at
day
7
in
the
4.0
ppm
dose
groups
of
the
study
through
to
termination
(
males
39%
to
46%
;
females
32%
to
45%
)
.
Erythrocyte
cholinesterase
was
decreased
starting
at
day
91
in
the
4.0
ppm
dose
groups
through
to
termination
(
males
23%
to
48%
;
females
17%
to
49%
)
.
Not
all
the
values
at
4.0
ppm
were
statistically
significant,
probably
because
of
the
wide
range
in
values,
but
at
least
2
animals
per
group
showed
biologically
significant
cholinesterase
inhibition.
By
termination
cholinergic
effects
of
the
plasma,
erythrocytes,
brain,
and
ocular
tissues
were
observed
in
both
sexes
in
the
4
and
12
ppm
treatment
groups.
Plasma
and
erythrocyte
cholinesterase
depression
are
compared
to
pretreatment
values.
Brain,
cornea,
retina
and
ciliary
body
cholinesterase
depression
are
compared
with
concurrent
control
values
at
termination
only.
In
the
12
ppm
treatment
groups,
depressed
cholinesterase
was
observed
in
plasma
(
56%
­
63%
)
,
erythrocytes
(
30%
­
91%
)
,
and
brain
(
32%
­
33%
)
compared
to
their
respective
controls.
In
the
4
ppm
treatment
groups
in
males
and
females,
cholinesterase
was
depressed
in
plasma
(
38%
­
46%
)
,
erythrocytes
(
40%
­
38%
)
,
and
brain
(
females
only,
22%
)
.
Disulfoton
inhibited
cholinesterase
of
the
cornea,
retina,
and
ciliary
body,
but
did
not
appear
to
alter
the
physiologic
function
of
the
visual
system.
In
the
12
ppm
treatment
groups,
depressed
cholinesterase
was
observed
in
the
cornea
(
60­
67%
)
,
ciliary
body
(
45­
54%
)
,
and
retina
(
males
only;
67%
)
.
In
the
4
ppm
treatment
groups,
cholinesterase
was
inhibited
in
the
cornea
(
50­
60%
lower)
,
and
retina
(
females
only,
25%
)
.
No
treatment­
related
ophthalmology
findings
or
histological
or
electrophysiological
changes
in
the
retina
were
observed.
No
other
treatment­
related
effects
were
observed.
No
animals
died
during
the
study.
No
treatment­
related
effects
were
observed
in
systemic
toxicity
including
food
consumption,
body
weights,
clinical
signs,
hematology,
clinical
blood
chemistry
or
urinalysis
parameters,
electrocardiogram,
electroretinograms
or
clinical
neurological
findings,
organ
weights
or
gross
or
microscopic
post­
mortem
changes
in
any
treatment
group.
No
neoplastic
tissue
was
observed
in
dogs
in
the
treatment
and
control
groups.
The
LOAEL
is
4
ppm
(
0.094
mg/
kg/
day)
,
based
on
depressed
plasma,
erythrocyte,
and
corneal
cholinesterase
levels
in
both
sexes,
and
depressed
brain
and
retinal
cholinesterase
levels
in
females.
The
NOAEL
is
0.5
ppm
(
0.013
mg/
kg/
day)
.
These
LOAEL/
NOAEL
for
plasma
cholinesterase
inhibition
extend
from
day
7
to
termination
and
for
erythrocyte
cholinesterase
inhibition
they
extend
from
day
91
to
termination.

Dose
and
Endpoint
for
Establishing
the
Chronic
RfD:
The
NOAEL
is
0.5
ppm
(
0.013
mg/
kg/
day)
based
on
depressed
plasma,
erythrocyte
and
corneal
cholinesterase
levels
in
both
sexes
and
depressed
brain
and
retinal
cholinesterase
levels
in
females.

Uncertainty
Factors
(
UF)
:
100
Chronic
RfD
=
0.013
mg/
kg
(
NOAEL)
=
0.00013
mg/
kg/
day
100
(
UF)

2.3.
Occupational/
Residential
Exposure
2.3.1.
Dermal
Absorption;
§
85­
2
MRID
No.
:
43360201
The
test
material
was
applied
to
the
backs
of
rats
at
0.85,
8.5,
and
85
F
g/
cm
2
(
approximately
0.051,
0.51
and
5.1
mg/
kg)
.
The
percent
of
absorbed
dose
at
10
hours
post­
application
was
26,
36,
and
25%
,
respectively.

Dermal
Absorption
Factor
:
36%

Comments
about
the
Study
Endpoint
:
The
HIARC
indicated
that
dermal
absorption
of
36%
,
obtained
after
10
hours
exposure
at
a
concentration
of
8.5
F
g/
cm
2
(
0.51
mg/
kg)
,
should
be
used
for
correcting
oral
dosing
to
dermal
dosing.
The
HIARC
concurred
with
the
TES
Committee
on
this
approach
for
the
use
of
the
dermal
absorption
factor.
HIARC
deviated
from
the
standard
practice
of
using
the
10­
hour
dermal
absorption
value
from
the
lowest
application
rate
in
this
case
because
of
the
lack
of
a
coherent
pattern
of
absorption
normally
observed
in
dermal
absorption
studies.
In
most
cases,
the
lowest
application
rate
results
in
the
highest
dermal
absorption
rate,
with
declining
absorption
at
higher
applications.
This
is
assumed
to
reflect
overloading
of
the
site
of
application.
In
as
much
as
there
was
no
dose­
related
pattern
to
the
percent
of
disulfoton
absorbed,
HIARC
elected
to
use
the
36%
absorption
rate
to
reduce
the
likelihood
of
underestimation.

2.3.2
Short
Term
Dermal
­
(
1­
7
DAYS)

Study
Selected:
3­
day
dermal
study
in
rats
MRID
No.
45239602
Executive
Summary:
In
a
3­
day
dermal
rat
study
(
MRID#
45239602)
disulfoton,
granular,
1%
a.
i.
(
1%
G
Di­
Syston
®
)
was
administered
dermally
to
5
Wistar
(
Crl:
WI(
HAN)
BR)
rats/
sex/
dose
at
0,
50,
100,
200
or
500
mg/
kg/
day
(
equivalent
to
0,
0.5,
1.0,
2.0
or
5.0
mg
a.
i.
/
kg/
day)
.
Plasma
and
erythrocyte
cholinesterase
was
measured
at
24
hours
after
the
first
and
day
3
dose.
Brain
cholinesterase
was
measured
at
termination
on
day
4.
Test
material
was
ground
and
applied
to
plastic
backed
gauze,
moistened
with
water,
applied
to
the
shaved
test
site
(
about
10%
of
the
body
surface)
,
and
then
secured
with
a
bandage.
The
animals
were
exposed
dermally
for
6
hour
per
day
with
washing
at
the
end
of
the
exposure
period.

No
clinical
signs
were
noted
or
body
weight
decrement.
No
other
signs
of
toxicity
were
noted,
but
the
study
was
designed
to
determine
cholinesterase
depression
only.
After
1
day
of
dosing,
the
NOAEL
in
males
was
200
mg/
kg
and
the
LOAEL
was
500
mg/
kg
based
on
biologically
significant
31%
erythrocyte
cholinesterase
inhibition
which
was
not
statistically
significant.
After
1
day
of
dosing
the
NOAEL
in
females
was
100
mg/
kg
and
the
LOAEL
was
200
mg/
kg
based
on
biologically
significantly
increased
inhibition
of
plasma
cholinesterase
(
36%
)
.
After
3­
days
of
dermal
dosing
the
NOAEL
in
males
was
100
mg/
kg/
day
and
LOAEL
was
200
mg/
kg/
day
based
on
a
increase
in
brain
cholinesterase
inhibition
of
21%
(
statistically
significant)
.
After
3
days
of
dosing
the
NOAEL
in
females
was
50
mg/
kg/
day
and
the
LOAEL
was
100
mg/
kg/
day
based
on
statistically
significant
plasma
and
brain
cholinesterase
inhibition
of
37%
and
18%
,
respectively.

The
overall
NOAEL
of
100
mg/
kg/
day
(
equivalent
to
1.0
mg
a.
i.
/
kg/
day)
with
a
LOAEL
of
200
mg/
kg/
day
(
equivalent
to
2.0
mg
a.
i.
/
kg/
day)
was
based
on
female
plasma
cholinesterase
depression
for
1
day
of
dosing.
After
3
days
of
dosing
the
NOAEL
was
50
mg/
kg/
day
(
equivalent
to
0.50
mg
a.
i.
/
kg/
day)
with
a
LOAEL
of
100
mg/
kg/
day
(
equivalent
to
1.0
mg
a.
i.
/
kg/
day)
based
on
depressed
plasma
and
brain
cholinesterase
in
females.

The
study
is
acceptable
for
selecting
a
regulatory
endpoint
although
neither
a
1­
day
nor
a
3­
day
dermal
study
in
the
rat
is
a
guideline
study.

Dose
and
Endpoint
for
risk
assessment:
The
NOAEL
=
0.5
mg/
kg/
day
based
on
plasma
and
brain
cholinesterase
inhibition
in
females
rats
at
1.0
mg/
kg/
day
(
LOAEL)
.

Comments
about
the
study
and/
or
endpoint:
The
3­
day
dermal
study
was
the
most
appropriate
for
several
reasons.
It
was
conducted
in
the
appropriate
species.
Cholinesterase
was
seen
in
two
compartments,
plasma
and
brain.
The
LOAEL
of
1.0
mg/
kg/
day
in
the
selected
study
is
supported
by
the
LOAELs
in
the
1988
and
1986
21­
day
dermal
studies
in
the
rabbit
of
1.0
and
1.6
mg/
kg/
day,
respectively
at
day
8
to
15.
The
test
material
consisted
of
the
granular
material
to
which
the
handlers
are
exposed.

A
21­
day
dermal
toxicity
study
in
rabbits
(
1988)
with
a
NOAEL
=
0.8
mg/
kg/
day
and
a
LOAEL
=
1.0
mg/
kg/
day
(
based
upon
plasma
cholinesterase
inhibition
at
Day
8)
was
not
selected
for
this
endpoint.
The
NOAEL
for
this
study
overlapped
the
LOAEL
in
the
developmental
toxicity
study
in
rats,
suggesting
that
the
rat
is
more
sensitive
than
the
rabbit
to
the
effects
of
disulfoton.
Therefore,
the
HIARC
selected
the
NOAEL
from
the
3­
day
dermal
study
in
rats.
In
addition,
the
NOAEL
of
0.5
mg/
kg/
day
was
selected
in
preference
to
the
0.3
and
0.4
mg/
kg/
day
NOAELs
from
the
developmental
toxicity
study
in
rats
and
the
21­
day
dermal
study
in
rabbits
(
1986)
because
the
LOAELs
from
all
three
studies
were
similar
and
the
spread
between
0.3
and
0.5
mg/
kg/
day
is
likely
due
to
dose
selection
and
does
not
reflect
differential
toxicity.

2.3.3
Intermediate
Term
Dermal
Exposure
(
1
Week
to
Several
Months)
:

Study
Selected
­
Special
6­
months
cholinesterase
study
MRID
No.
:
43058401
Executive
Summary:
In
a
6­
month
study
designed
to
establish
a
NOAEL
and
LOAEL
for
cholinesterase
inhibition,
technical
grade
disulfoton
(
98­
99%
a.
i.
)
was
administered
in
the
diet
to
35
male
and
female
Fisher
344
rats
for
up
to
6
months
at
levels
of
0,
0.25,
0.5
or
1
ppm
(
approximate
doses
of
0,
0.02,
0.03
or
0.06
mg/
kg/
day
for
males
and
0,
0.02,
0.03
or
0.07
mg/
kg/
day
for
females)
.
At
the
end
of
2,
4
and
6
months,
10
rats/
sex/
dose
were
taken
for
blood
and
brain
cholinesterase
assays.
Statistically
significant
inhibition
of
cholinesterase
activity
was
observed
in
erythrocytes
in
females
at
all
doses
(
3­
14%
inhibition,
11­
17%
inhibition,
and
23­
29%
inhibition
at
0.24,
0.5,
and
1.0
ppm,
respectively.
In
addition,
at
1.0
ppm,
males
had
decreased
erythrocyte
cholinesterase
activity
(
10­
16%
inhibition)
and
females
had
decreased
plasma
(
8­
17%
inhibition)
and
brain
(
7­
13%
inhibition)
cholinesterase
activities.
However,
biologically
significant
and
statistically
significant
inhibition
of
cholinesterase
activity
was
observed
only
in
the
plasma,
erythrocytes
and
brain
of
females
at
1.0
ppm.
No
biologically
significant
inhibition
of
cholinesterase
activity
was
observed
in
males.
The
LOAEL
for
inhibition
of
cholinesterase
activity
was
1.0
ppm
is
based
on
a
23­
29%
inhibition
of
erythrocyte,
12­
17%
inhibition
of
plasma
and
13%
inhibition
of
brain
cholinesterase
in
females.
The
NOAEL
is
0.5
ppm
(
0.03
mg/
kg/
day)
.
No
biological
meaningful
cholinesterase
inhibition
was
observed
in
males
at
any
dose
level.
Body
weight,
food
consumption,
and
clinical
signs
were
also
monitored,
but
showed
no
treatment
related
effects.
Based
on
these
few
parameters,
no
systemic
effects
were
observed
at
any
dose
level
and
the
NOAEL
for
systemic
toxicity
was
1.0
ppm
(
0.06
mg/
kg/
day
for
males
and
0.07
mg/
kg/
day
for
females)
.

Dose
and
Endpoint
for
use
in
risk
assessment:
NOAEL=
0.03
mg/
kg/
day
was
based
on
plasma,
erythrocyte
and
brain
cholinesterase
inhibition
in
female
rats
at
0.07
mg/
kg/
day
(
LOAEL)
.

Comments
about
study
and/
or
endpoint:
Since
an
oral
NOAEL
was
identified,
a
dermal
absorption
factor
of
36%
should
be
used
for
this
risk
assessment.
This
endpoint
is
supported
by
similar
effects
(
plasma,
erythrocyte
and
brain
cholinesterase
inhibition)
observed
in
a
subchronic
neurotoxicity
study
in
rats
(
MRID#
42977401)
.
A
comparison
of
the
oral
developmental
studies
with
the
oral
90­
day
neurotoxicity
study
(
MRID#
42977401)
shows
a
relationship
between
increased
cholinesterase
inhibition
with
increased
duration
of
the
study.
The
dermal
equivalent
of
LOAEL
of
0.2
mg/
kg/
day
in
the
90­
day
study
(
i.
e.
,
0.07
mg/
kg/
day
÷
0.36
=
=
0.2
mg/
kg/
day)
at
4
weeks
is
lower
than
the
LOAEL
from
either
the
1986
(
LOAEL=
1.6
mg/
kg/
day)
or
the
1988
21­
day
rabbit
dermal
studies
(
LOAEL=
1.0
mg/
kg/
day)
at
the
end
of
3
weeks.
These
comparisons
support
the
generally
held
perception
that
rabbit
dermal
studies
tend
to
underestimate
toxicity
from
an
organo­
thiophosphate
pesticide.
The
new
2­
generation
study
on
reproduction
(
MRID#
44440801)
also
supports
the
6­
month
cholinesterase
study
endpoints.

2.3.4.
Long­
Term
Dermal
(
Several
Months
to
Life
Time)

Study
selected:
Chronic
Toxicity
­
Dog
§
83­
1
MRID
No.
44248002
Executive
Summary:
See
summary
under
Chronic
RfD.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL=
0.013
mg/
kg/
day
based
on
depressed
plasma,
erythrocyte
and
corneal
cholinesterase
levels
in
both
sexes
and
depressed
brain
and
retinal
cholinesterase
levels
in
females.

Comments
about
study
and/
or
endpoint
:
This
dose
was
used
to
establish
the
chronic
RfD.
Since
an
oral
NOAEL
was
identified,
a
dermal
absorption
factor
of
36%
should
be
used
for
this
risk
assessment.

2.3.5.
Inhalation
Exposure
(
All
Time
Periods)

Study
Selected:
90­
Day
Inhalation
­
Rat
§
82­
4
MRID
No.
:
41224301
Executive
Summary:
Disulfoton
was
administered
by
inhalation
to
12
Fisher
344
rats
per
sex
per
group
for
air
control,
polyethylene
glycol­
400:
50%
ethanol
vehicle
control,
0.015,
0.15
or
1.5
mg/
m
3
nominal
dose
levels
for
90­
days
in
a
nose
only
chamber.
The
analytical
determined
mean
dose
levels
were
0,
0,
0.018,
0.16
and
1.4
mg/
m
3
for
male
and
female
rats.
The
rats
were
exposed
to
the
test
material
6
hours
per
day,
5
days
per
week.
The
particle
sizes
in
the
inhalation
chambers
had
a
MMAD
±
geometric
standard
deviation
of
1.3
±
1.4,
,
1.1
±
1.3,
,
1.0
±
1.3
and
1.1
±
1.4
F
m
for
the
two
controls,
0.015,
0.15
and
1.5
mg/
m
3
nominal
dose
levels,
respectively.
The
range
in
mean
daily
particle
sizes
had
a
MMAD
of
0.5
±
1.0
F
m
to
2.6
±
1.6
F
m.
At
the
highest
dose
level,
plasma
cholinesterase
was
depressed
in
males
(
19%
and
14%
from
air
controls
at
38
days
and
term,
respectively,
p
#
0.05)
and
in
females
(
27%
and
31%
from
air
controls
at
38
days
and
term,
respectively,
p
#
0.05)
.
Brain
cholinesterase
was
depressed
in
males
(
29%
)
and
females
(
28%
)
at
termination.
Erythrocyte
cholinesterase
was
depressed
in
females
at
38
days
(
11%
at
38
days,
p
#
0.05,
not
considered
biologically
relevant)
at
0.16
mg/
m
3
and
higher
in
males
and
females
at
1.4
mg/
m
3
at
38
days
and
term.
Brain
cholinesterase
was
depressed
(
10%
,
p
#
0.05)
at
0.16
mg/
m
3
,
but
this
degree
of
variation
was
not
considered
biologically
relevant
due
to
variation
noted
in
this
parameter.
Inflammation
of
the
male
nasal
turbinates
occurred
at
1.4
mg/
m
3
.
No
other
test
material
related
effects
were
noted.
The
NOAEL/
LOAEL
is
0.16/
1.4
mg/
m
3
for
plasma,
erythrocyte
and
brain
cholinesterase
depression
in
males
and/
or
females.

Dose
and
Endpoint
for
use
in
risk
assessment:
NOAEL=
0.00016
mg/
L
based
on
plasma,
erythrocyte
and
brain
cholinesterase
inhibition.
The
rat
inhalation
NOAEL
when
converted
to
mg/
kg
is
0.045
mg/
kg/
day.

Conversion
1
of
mg/
L
to
mg/
kg/
day
using
route­
to­
route
extrapolation
policy.
[
0.00016
mg/
L
(
NOAEL)
x
1(
fractional
absorption)
x
7.15
L/
hr
(
respiratory
volume
for
Fisher
344
rats)
x
6(
hours)
x
1(
activity
factor)
]
/
[
0.152
kg
(
body
weight)
]
=
=
0.045
mg/
kg.

Comments
about
the
study
and/
or
endpoint:
This
NOAEL
will
be
used
for
inhalation
exposure
risk
assessments
for
any
time
period
(
i.
e.
,
Short,
Intermediate
and
Long­
term)
.
An
inhalation
toxicity
study
with
3
to
5
day
exposure
was
available.
In
that
study,
the
LOAEL
was
<
0.0005
mg/
L
(
lowest
dose
tested)
;
a
NOAEL
was
not
established.
Although
this
study
could
have
been
used
for
the
Short­
Term
exposure
risk
assessment,
the
HIARC
did
not
use
this
study
because:
(
i)
it
demonstrated
a
LOAEL
rather
than
a
NOAEL;
(
ii)
the
use
of
a
LOAEL
would
have
required
an
additional
3
x
UF;
and
(
iii)
the
value
derived
from
the
use
of
the
LOAEL
and
3
UF
(
0.0005
÷
3=
0.00017
mg/
L)
is
comparable
to
the
NOAEL
of
0.00016
mg/
L
in
the
90­
day
study.

Memorandum
of
10/
10/
98
from
John
Whalan
to
Stasikowski,
HED.
Route­
to­
Route
Extrapolation,
page
8.
2.3.6.
Margins
of
Exposure
for
(
Occupational/
Residential)
Exposures
A
Margin
of
Exposure
(
MOE)
of
100
is
adequate
for
occupational
exposure
risk
assessments.
The
FQPA
Safety
Committee
determined
that
an
MOE
of
100
is
adequate
for
residential
exposure
risk
assessments.

2.4.
Recommendation
for
Aggregate
Exposure
Risk
Assessment
For
acute,
short,
intermediate
and
long­
term
de
aggregate
exposure
risk
assessment,
the
oral,
dermal
and
inhalation
routes
can
be
combined
since
a
common
toxicological
endpoint
(
cholinesterase)
was
observed
during
all
routes
of
exposure
(
oral,
dermal
and
inhalation)
in
the
toxicity
studies.

3.
CLASSIFICATION
OF
CANCER
POTENTIAL
The
HED
RfD/
Peer
Review
classified
disulfoton
as
a
Group
E
Chemical­
Not
Classifiable
to
Carcinogenicity
based
on
the
lack
of
evidence
of
carcinogenicity
study
in
mice
and
rats
at
dose
levels
adequate
to
test
for
carcinogenicity.

4.
MUTAGENICITY
The
following
was
taken
from
a
document
written
by
Nancy
McCarroll
for
the
Hazard
Identification
Assessment
Review
Committee
proceedings.
Combining
the
acceptable
studies
with
the
additional
EPA­
sponsored
studies
will
satisfy
the
Pre­
1991
mutagenicity
initial
testing
battery
guidelines.
No
further
mutagenicity
testing
has
been
identified
at
this
time.
In
addition,
disulfoton
is
not
genotoxic
in
vivo
or
carcinogenic
in
mice
or
rats.

In
some
of
the
mutagenicity
studies,
positive
effects
were
seen
without
activation
while
negative
effects
were
seen
with
activation.
This
may
be
due
to
microsomal
enzyme
metabolism,
since
pretreatment
of
rats
and
mice
with
phenobarbital
reduces
toxicity
from
disulfoton.

4.1
Gene
Mutation
(
84­
2)

Salmonella
typhimurium/
Escherichia
coli
reverse
gene
mutation
plate
incorporation
assay
(
Accession
No.
00028625;
Doc.
No.
003958:
As
part
of
an
Agency
sponsored
mutagenicity
screening
battery,
disulfoton
was
negative
in
all
strains
up
to
the
HTD
(
5000
F
g/
plate
+
/
­
S9)
in
three
independent
trials.

Chinese
hamster
ovary
(
CHO)
cell
HGPRT
forward
gene
mutation
assay
(
MRID#
40638401,
Doc#
008394)
:
This
unacceptable
study
is
considered
to
be
positive,
because
the
assay
was
conducted
at
partially
soluble
levels(
0.1­
1.0
F
L/
ml
­
S9;
0.7­
1.0
F
L/
ml
+
S9)
and
insoluble
doses
(
5­
10
F
L/
ml
­
S9;
3­
10
F
L/
ml
+
S9)
but
not
active
at
soluble
concentrations
(
#
0.06
F
L/
ml
+
/
­
S9)
.
The
mutagenic
response
appeared
to
be
stronger
without
metabolic
(
S9)
activation
.

4.2
Chromosome
Aberrations
(
84­
2)

Mouse
micronucleus
test
(
MRID
No.
43615701)
No
increase
over
background
in
micronucleated
polychromatic
erythrocytes
(
evidence
of
cytogenetic
damage)
of
mice
treated
intra­
peritoneally
up
to
MTD
levels
(
8
mg/
kg)
.
Lethality
and
other
signs
of
toxicity,
but
no
bone
marrow
cytotoxicity
was
seen.

4.3
Other
Gene
Mutations
:
(
84­
2)

Bacterial
DNA
Damage/
Repair:
E.
Coli
DNA
damage/
repair
test
(
Accession#
072293;
Doc#
004698)
:
The
test
is
negative
up
to
the
HDT
(
10,000
F
g/
plate
+
/
­
S9.

Mitotic
Recombination:
Saccharomyces
cerevisiae
D3
mitotic
recombination
assay
(
Accession#
00028625;
Doc#
003958)
:
Disulfoton
(
up
to
5%
+
/
­
S9)
was
negative
at
this
endpoint
in
the
Agency­
sponsored
mutagenicity
screening
battery.
The
study
is
currently
listed
as
unacceptable,
but
should
be
upgraded
to
acceptable.
Upon
further
review
of
the
data,
it
was
decided
that
the
reason
for
rejecting
the
study
(
number
of
replicates/
dose
not
provided)
did
not
interfere
with
the
interpretation
of
the
findings.

Sister
Chromatid
Exchange:
Sister
chromatid
exchange
in
CHO
cells
(
MRID#
4095001;
Doc#
008394)
:
Positive,
dose
related
effects
at
0.013­
0.1
F
L/
ml
without
S9,
but
not
active
in
the
S9
activated
phase
of
testing
up
to
a
level
(
0.20
F
L/
ml)
causing
cell
cycle
delay.

Sister
Chromatid
Exchange:
Sister
chromatid
exchange
in
Chinese
hamster
V79
cells
(
Accession#
072293;
Doc#
0044223)
:
The
test
is
negative
without
activation
up
to
the
HTD
(
80
F
g/
ml)
.
Subsequently
tested
by
the
same
investigators
(
Chen
et
al.
,
1982;
Environ.
Mutagen.
4:
621­
624)
in
the
presence
of
exogenous
metabolic
activation
and
found
to
be
negative
up
to
the
HDT
(
80
F
g/
ml)
.

Unscheduled
DNA
Synthesis
(
UDS)
:
UDS
in
WI­
38
human
fibroblasts
(
Accession#
000028625;
Doc#
003958)
:
The
test
is
positive
in
the
absence
of
S9
activation
at
precipitating
doses
(
1000­
4000
F
g/
ml)
.
With
S9
activation,
the
study
was
negative
at
comparable
percipitating
concentrations.
4.4
Other
EPA
Sponsored
Studies:

Disulfoton
was
also
included
in
second
tier
mutagenicity
test
battery
performed
at
the
EPA
(
EPA­
600/
1­
84­
003)
in
1984.
Although
DERs
have
not
been
prepared
for
these
additional
assays,
we
assess
that
they
are
acceptable
for
regulatory
purposes.

Mouse
Lymphoma
L5178Y
TK+
/
­
forward
gene
mutation
assay:
The
test
was
positive
in
the
absence
of
S9
activation
with
concentration
dependent
and
reproducible
increases
in
mutation
frequency
at
40­
90
F
g/
ml;
higher
dose
levels
were
cytotoxic.
No
mutagenic
activity
was
seen
in
the
presence
of
S9
activation
up
to
a
cytotoxic
dose
(
150
F
g/
ml)
.

Mouse
Micronucleus
Assay:
The
test
is
negative
in
Swiss
Webster
mice
up
to
a
lethal
dose
(
8
mg/
kg)
administered
once
daily
for
2
consecutive
days
by
intra­
peritoneal
injection.
No
bone
marrow
cytotoxicity
was
seen.

Sister
Chromatid
Exchange
in
CHO
cell
assay:
The
non­
activated
test
was
negative
up
to
levels
(
$
0.02%
)
that
caused
cell
cycle
delay,
but
the
test
material
was
weakly
positive
at
a
single
dose
(
0.04%
)
with
metabolic
activation.

5.
FQPA
CONSIDERATIONS
5.1.
Adequacy
of
the
Data
Base
The
toxicity
data
base
is
adequate
to
determine
the
neurotoxic
potential
from
disulfoton
exposure,
except
for
developmental
neurotoxic
potential.
A
developmental
neurotoxicity
study
for
organophosphates,
including
disulfoton
is
required.

5.2.
Neurotoxicity
Another
acute
delayed
neurotoxicity
study
(
81­
7)
was
submitted
and
reviewed
and
is
acceptable.
The
study
is
negative
for
organophosphate
induced
delayed
neuropathy
(
OPIDN)
.
Absolute
brain
weight
was
not
affected
by
treatment
in
the
guideline
chronic
studies
in
rodents.
(
The
subchronic
studies,
which
were
graded
unacceptable,
were
not
provided
for
review.
)
In
the
rat
study,
treatment­
related
eye
lesions
were
seen
(
optic
nerve
degeneration
and
corneal
vascularization)
and
skeletal
muscle
atrophy
were
observed.
The
optic
nerve
degeneration
was
related
to
orbital
sinus
bleeding
injury,
so
results
were
not
considered
treatment
related.
These
neuropathological
findings
were
not
repeated
in
the
1997
1­
year
dog
study,
but
cholinesterase
levels
in
the
cornea,
retina,
and
ciliary
body
were
depressed
with
treatment.
No
treatment
related
neuropathy
was
seen
in
acute
or
in
90­
day
neurotoxicity
studies
in
rats.
The
marginal
elevation
in
lesions
seen
the
optical
nerve
and
thoracic
spinal
cord
at
the
highest
dose
tested
were
not
considered
to
be
sufficiently
different
from
control
lesions
to
indicate
a
treatment­
related
effect
had
occurred.

The
repeat
?
acute
delayed
neurotoxicity
study
in
hens
?
requested
by
the
HIARC
of
April
23,
1998
is
summarized
below.

In
an
acute
delayed
neurotoxicity
study
in
hens
(
MRID#
44996401,
1999)
,
disulfoton
was
acutely
administered
orally
to
18
LSL
laying
hens
at
40
mg/
kg
bird
in
a
single
dose.
Fifteen
hens
were
used
as
controls.
Doses
were
administered
in
aqueous
2%
Cremophor
at
5
ml/
kg
bird.
Five
to
18
minutes
before
administration
of
the
disulfoton,
atropine
was
administered
s.
c.
(
0.5
ml/
kg
of
4%
atropine
sulfate)
.
Directly
prior
to
the
administration
of
the
disulfoton,
0.5
ml/
kg
of
10%
atropine
sulfate
and
10%
2­
PAM
chloride
was
injected
s.
c.
The
afternoon
of
day
0,
0.5
ml/
kg
of
5%
atropine
sulfate
and
5%
2­
PAM
chloride
was
injected
s.
c.
and
again
the
morning
and
afternoon
of
day
1.
Clinical
observations
were
made
at
least
daily.
Forced
motor
activity
tests
were
conducted
by
forcing
the
hens
to
run
around
a
12­
13
m
2
area
and
rated
for
coordination,
ataxia,
and
paresis.
NTE
studies
were
conducted
at
24
and
48
hours
on
the
spinal
cords,
sciatic
nerves
and
½
of
the
brain
in
each
of
3
hens
per
group.
.
Cholinesterase
activity
studies
were
conducted
on
the
other
½
of
the
brain
from
each
bird
in
the
NTE
study
at
24
and
48
hours
post
treatment.
The
study
was
conducted
at
1.4
times
the
LD50
for
hens.

No
typical
signs
of
organophosphate
induced
delayed
neuropathy
was
seen
during
the
study
or
on
microscopic
examination
of
the
treated
birds
at
termination
at
3
weeks.
No
inhibition
was
seen
in
the
NTE
study
at
24
hours
or
48
hours.
Inhibition
was
low
between
4%
and
8%
and
was
not
considered
to
be
indicative
of
OPIDN.
Cholinesterase
activity
in
the
brain
was
inhibited
83%
and
59%
at
24
and
48
hours,
respectively.

No
hens
died,
but
by
day
7
there
was
a
decrease
in
body
weight
of
over
5%
.
The
hens
slowly
recovered
and
by
the
end
of
3
weeks,
body
weight
of
the
treatment
group
and
of
the
controls
did
not
differ.

Severely
uncoordinated
gait
was
observed
in
all
treated
birds
within
5
minutes
of
being
dosed
with
atropine
and
before
disulfoton
treatment.
The
report
authors
attributed
this
abnormal
gait
to
atropine
since
it
lasted
only
for
the
duration
of
the
atropine
treatment
(
2
days)
.
However,
the
report
authors
also
noted
reduced
motility
in
1­
3
birds
for
0­
1
day,
which
they
attributed
to
disulfoton
treatment.
Neither
statements
are
completely
supportable
because
the
hens
were
dosed
with
atropine
and
disulfoton
during
most
of
this
period.
However,
the
temporary
uncoordinated
gait
was
followed
by
no
microscopic
findings
in
nerve
tissue
and
no
other
signs,
which
supports
a
conclusion
of
no
demonstrated
OPIDN
in
hens
dosed
with
disulfoton.

Microscopic
examination
of
the
test
birds
showed
3
brain
(
25%
­
8%
in
each
region,
grade
1)
lesions
in
treated
birds
and
1
(
11%
,
grade
1)
in
the
same
control
brain
regions.
Since
these
lesions
were
similar
to
those
found
in
controls
from
previous
studies,
they
were
considered
incidental.

The
study
supports
a
conclusion
the
disulfoton
does
not
cause
acute
delayed
neuropathy
(
OPIDN)
in
hens.
The
study
is
acceptable
for
an
acute
delayed
neurotoxicity
study
(
OPPTS#
870.6100)
in
hens.

In
an
acute
neurotoxicity
study
in
Sprague­
Dawley
rats
(
10/
sex/
group)
,
97.8%
disulfoton
was
administered
by
a
single
gavage
dose
of
0.25,
1.5,
or
5.0
mg/
kg
in
males
and
0.25,
0.75,
or
1.5
mg/
kg
in
females.
The
NOAEL
for
neurotoxicity
and
cholinesterase
inhibition
was
0.25
mg/
kg,
based
on
muscle
fasciculations
in
4/
10
females
and
plasma
and
RBC
cholinesterase
inhibition
at
the
LOAELs
of
0.75
mg/
kg
in
females
and
1.5
mg/
kg
in
males.
The
incidence
and
type
of
clinical,
behavioral,
and
neuromotor
signs
increased
with
dose.
Females
were
clearly
more
sensitive.
Neither
brain
weight
nor
neuropathology
was
affected
by
treatment
(
MRID
42755801)
.
In
a
90­
day
subchronic
neurotoxicity
study,
98.7­
99.0%
disulfoton
was
administered
to
Fisher
344
rats
(
1
2/
sex/
group)
at
dietary
levels
of
1,
4,
or
16
ppm
(
0.063,
0.270,
or
1.08
mg/
kg/
day
in
males
and
0.071,
0.315,
or
1.31
mg/
kg/
day
in
females)
.
The
systemic
NOAEL
was
1
ppm
(
0.063/
0.071
mg/
kg/
day
for
M/
F)
,
based
upon
clinical
signs
consistent
with
cholinesterase
inhibition
(
muscle
fasciculations,
urine
staining,
increased
food
consumption)
in
females
at
the
LOAEL
of
4
ppm
(
0.270/
0.315
mg/
kg/
day
in
M/
F)
.
At
16
ppm
(
1.08/
1.31
mg/
kg/
day
in
M/
F)
,
treatment­
related
findings
in
both
sexes
also
included
increased
reactivity,
perianal
staining,
tremors,
increased
defecation,
decreased
forelimb
grip
strength,
decreased
motor
and
locomotor
activity,
decreased
body
weight
gain,
and
corneal
opacities.
Cholinesterase
inhibition
(
plasma,
erythrocyte,
and
brain)
was
observed
at
all
treatment
levels
(
ChE
NOAEL<
1
ppm;
0.063/
0.071
mg/
kg/
day
for
M/
F)
.
Clearly
females
were
again
shown
to
be
more
sensitive.
It
was
noted
that
clinical
signs
were
persistent
throughout
this
study.
There
were
no
treatment­
related
effects
on
brain
weight.
At
the
high­
dose
level,
neuropathological
lesions
(
nerve
fiber
degeneration)
were
observed
in
the
optic
nerve,
and
nerve
fiber
degeneration
was
also
observed
in
the
thoracic
spinal
cord.
These
findings,
however,
with
similar
neuropathy
in
control
rats,
the
marginal
increase
in
these
lesions
at
the
highest
dose
tested
were
not
sufficiently
different
control
lesions
to
indicate
that
treatment­
related
effect
had
occurred
(
MRID
42977401)
.

2.
Developmental
Toxicity
In
a
prenatal
developmental
toxicity
study
in
Sprague­
Dawley
rats
(
25/
group)
,
98.2%
disulfoton
was
administered
on
gestation
days
6­
15
by
gavage
in
polyethylene
glycol
400
at
dose
levels
of
0.1,
0.3,
or
1.0
mg/
kg/
day.
Cholinesterase
activity
was
measured
in
dams
(
5/
group)
on
gestation
day
15.
The
maternal
NOAEL
was
0.1
mg/
kg/
day,
and
the
maternal
LOAEL
was
0.3
mg/
kg/
day,
based
on
41%
inhibition
of
plasma
and
RBC
cholinesterase.
There
was
no
other
evidence
of
maternal
toxicity
at
any
treatment
level.
The
developmental
NOAEL
and
LOAEL
were
established
at
0.3
and
1.0
mg/
kg/
day,
based
on
incomplete
ossification
of
the
intraparietals
and
sternebrae
(
MRID
00129458)

In
a
prenatal
developmental
toxicity
study
conducted
in
New
Zealand
white
rabbits
(
15­
22/
group)
,
97.3%
disulfoton
was
administered
by
gavage
in
corn
oil
(
5
ml/
kg)
at
doses
of
0.3,
1.0,
or
3.0
(
reduced
to
2.0,
then
1.5)
mg/
kg/
day
on
gestation
days
6­
18.
The
maternal
NOAEL
was
1.0
mg/
kg/
day;
the
maternal
LOAEL
(
1.5
mg/
kg/
day)
was
based
upon
clinical
signs
of
cholinesterase
depression
(
tremors,
unsteadiness/
incoordination,
and
increased
respiration,
occurring
within
4
hours
of
dosing)
.
In
addition,
there
were
a
large
number
of
mortalities
at
the
high­
dose
level.
There
was
no
evidence
of
developmental
toxicity
(
developmental
NOAEL
>
1.5
mg/
kg/
day)
.
Neither
maternal
nor
fetal
cholinesterase
levels
were
measured
(
MRID
00147886)
.

3.
Reproductive
Toxicity:

In
a
two­
generation
reproduction
study
in
Sprague­
Dawley
rats
(
25/
sex/
group)
,
97.8%
disulfoton
was
administered
at
dietary
concentrations
of
1,
3,
or
9
ppm
(
calculated
effective
doses
of
0.81,
2.4,
or
76.3
ppm;
equivalent
to
0.04,
0.12,
or
0.36
mg/
kg/
day
by
test
material
consumption)
.
The
parental
systemic
NOAEL
was
3
ppm
(
0.12
mg/
kg/
day)
.
The
parental
systemic
LOAEL
was
9
ppm
(
0.36
mg/
kg/
day)
,
based
on
decreased
females
mated
and
reduced
body
weight
during
gestation
and
lactation
in
P
females.
The
offspring
NOAEL
was
1
ppm
(
0.04
mg/
kg/
day)
,
and
the
offspring
LOAEL
was
3
ppm
(
0.12
mg/
kg/
day)
,
based
on
decreased
brain
cholinesterase
activity
in
F1a
weanling
pups
and
on
decreased
F2b
pup
survival.
Although
adult
cholinesterase
was
not
measured,
the
2­
year
chronic
study
indicates
that
cholinesterase
inhibition
was
most
likely
occurring
at
3
ppm
with
a
NOAEL
of
1
ppm;
this
was
a
conclusion
of
the
4/
25/
96
RfD
PRC
meeting
(
MRID
00157511)
.

In
a
another
2­
generation
reproduction
study,
disulfoton,
technical
(
99%
a.
i.
)
was
administered
to
30
Sprague­
Dawley
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
0.5,
2.0
or
9.0
ppm
(
0,
0.025,
0.10
or
0.45
mg/
kg/
day
by
std.
tables)
.
Dosing
was
continuous
for
the
P0
and
F1
generation.
Only
one
littering/
animal/
group
was
conducted.
In
this
second
2­
generation
reproduction
toxicity
study
with
disulfoton,
cholinesterase
activity
was
measured
in
adults
during
pre­
mating
(
at
8
weeks)
and
at
termination
and
in
pups
at
postnatal
day
4
and
day
21
in
both
generations.
The
major
effects
noted
were
cholinesterase
inhibition
and
dams
with
no
milk.
In
P0
males,
plasma
cholinesterase
(
PCHE)
was
significantly
depressed
and
dose
related
pre­
mating
at
9.0
ppm
(
$
­
34%
)
and
at
termination
at
2.0
(
$
11
)
and
9.0
ppm
(
­
46%
)
.
In
P0
females,
plasma
cholinesterase
(
PCHE)
was
significantly
depressed
pre­
mating
(
$
­
29%
)
and
at
termination
(
$
­
52%
)
at
$
2.0
ppm.
In
P0
males
and
females
erythrocyte
cholinesterase
(
ECHE)
was
significantly
depressed
and
dose
related
at
$
2.0
ppm
(
$
­
38%
&
$
­
35%
males
and
$
­
46%
&
$
­
80%
females)
a
pre­
mating
and
termination,
respectively,
but
only
in
females
at
termination
(
$
­
14%
)
at
$
0.5
ppm.
In
P0
males
and
females
brain
cholinesterase
(
BCHE)
was
significantly
depressed
and
dose
related
at
$
2.0
ppm
in
males
(
$
­
11%
)
and
$
­
14%
in
females
at
$
0.5
ppm.
PCHE
and
ECHE
depression
in
F1
males
and
females
followed
a
similar
nominal
pattern
to
that
in
P0
males
and
females,
except
that
the
statistical
significance
varied
within
the
F1
between
two
dose
levels;
sometimes
the
dose
level
showing
statistical
significance
was
higher
and
sometime
lower
of
the
two.
In
F1
males
and
females,
BCHE
was
significantly
depressed
and
dose
related
at
$
2.0
ppm
in
males
(
$
­
14%
)
and
in
females
(
$
­
50%
)
.
In
F1
and
F2
male
and
female
pups
at
day
4
and/
or
day
21
of
lactation,
PCHE
and
ECHE
were
significantly
depressed
at
9.0
ppm.
Values
for
PCHE
and
ECHE,
respectively
were
at
day
4
or
day
21
in
F1
male
pups
were
(
­
24%
&
­
47%
)
and
for
F1
female
pups
(
­
31%
&
­
43%
)
.
Values
for
PCHE
and
ECHE,
respectively,
were
at
day
4
or
day
21
in
F2
male
pups
were
(
­
46%
&
­
53%
)
and
for
F2
female
pups
(
­
48%
&
­
51%
)
.
In
F1
and
F2
male
and
female
pups
BCHE
was
significantly
depressed
at
day
4
and
day
21
at
9.0
ppm
only
(
day
4
=
­
14%
F1
males
and
­
17%
F1
females)
(
day
21
=
­
19%
F1
males
and
­
23%
F1
females)
(
day
4
=
­
11%
F2
males
and
­
13%
F2
females)
(
day
21
=
­
35%
F2
males
and
­
37%
F2
females)
.
Muscle
fasciculation
(
one
P0
female)
,
tremors
(
15
P0
females,
ten
F1
females)
and
dams
(
seven
F1
dams)
with
no
milk
were
noted
at
9.0
ppm.
No
treatment
related
organ
weight
changes
or
histopathology
were
noted
in
P0
or
F1
males
or
females
at
any
dose
level.
Clinical
observations
indicate
that
dams
were
not
caring
for
their
pups.
Observed
affects
in
pups
in
the
9.0
ppm
group
included
12
F1
(
two
dams)
pups
cold
to
the
touch
and
three
F1
(
two
dams)
not
being
cared
for
and
63
F2
pups
(
seven
dams)
with
no
milk
in
their
stomachs
and
93
F2
weak
pups
(
ten
dams)
from
the
affected
dams.
In
addition,
one
P0
dam
was
salivating
and
gasping
and
did
care
for
the
litter
and
the
litter
died
at
2.0
ppm.
This
effect
at
2.0
ppm
was
considered
test
material
related
by
the
summary
author
of
the
6(
a)
(
2)
submission
(
See
summary
6(
a)
(
2)
report,
MRID#
44440801;
memorandum
from
David
Anderson
to
PM
53,
dated
March
24,
1998,
D242573)
,
but
ignored
in
the
final
report
summary.
Findings
at
necropsy
were
noted
in
F2
pups
at
9.0
ppm
that
were
expected
in
view
of
the
maternal
toxicity
at
this
dose
level.
The
report
reasonably
considered
the
pup
deaths
due
to
failure
of
maternal
care,
because
of
the
weak
and
cold
to
the
touch
pups
and
failure
of
the
pups
to
show
milk
in
their
stomachs.
On
careful
examination
of
the
report,
this
reviewer
agrees
with
this
conclusion.
Thus,
under
these
conditions,
the
effects
in
pups
were
caused
by
maternal
toxicity
and
not
the
direct
toxicity
of
disulfoton
on
pups.
Body
weight
change
was
lower
than
control
values
during
gestation
in
P0
(
­
9%
)
and
F1
(
­
15%
)
females.
Body
weights
were
significantly
reduced
at
termination
from
control
values
in
P0
(
­
6%
)
and
F1
females
(
­
13%
)
and
in
F1
males
(
­
8%
)
.
No
other
significant
body
weights
or
changes
were
noted.
The
P0
parental
LOAELs
were
0.5
ppm
(
0.025
mg/
kg/
day)
based
on
brain
cholinesterase
activity
depression
in
P0
females
with
tremors
and
muscle
fasciculation
at
9
ppm
in
females
during
gestation
and
lactation
from
both
generations
and
with
body
weight
decrements
at
9.0
ppm,
especially
at
termination.
A
NOAEL
of
0.5
ppm
(
0.025
mg/
kg/
day)
was
seen
in
F1
parents.
F1
and
F2
pup
(
4
days
and
21
days
old)
cholinesterase
activity,
including
brain
cholinesterase
activity
was
depressed
only
at
9.0
ppm
(
0.45
mg/
kg/
day)
with
2.0
ppm
(
0.10
mg/
kg/
day)
being
the
NOAEL.
The
F1
pup
NOAEL/
LOAEL
were
2.0/
9.0
ppm
(
0.10/
0.45
mg/
kg/
day)
based
on
treatment
related
pup
deaths
and
pup
weight
decrements
at
9.0
ppm,
probably
from
inadequate
maternal
care
(
MRID#
44440801)
.

4.
Additional
Information
from
the
Literature
This
summary
is
provided
to
develop
a
comprehensive
picture
of
disulfoton
toxicity.
The
data
have
not
been
reviewed
in
depth,
and
no
statement
is
made
regarding
the
accuracy
or
quality
of
the
data
or
reports.

In
a
1988
study
by
McDonald
et
al.
,
disulfoton
was
administered
by
daily
i.
p.
injection
at
2
mg/
kg/
day
to
male
Long­
Evans
rats
for
14
days.
In
treated
rats,
muscarinic
receptor
binding
was
decreased
and
spacial
memory
was
decreased
in
a
T­
maze
alternation
task.

5.
Determination
of
Suseptibility
There
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
fetuses
following
in
utero
exposure
to
rats
and
rabbits
and
during
pre/
post
natal
exposure
to
rats.
In
these
studies,
toxicity
to
the
fetus
or
pups
occurred
only
at
higher
dose
levels
than
to
the
dams
(
mothers)
or
parents.

6.
Recommendation
for
Developmental
Neurotoxicity
Study
A
developmental
neurotoxicity
study
with
disulfoton
is
required
by
the
Data
Call­
In
Notice
(
September
10,
1999)
for
select
organophosphates.

7.
Determination
of
the
FQPA
Safety
Factor:

The
FQPA
Safety
Factor
Committee
met
on
January
24,
2000
to
re­
evaluate
the
hazard
and
exposure
data
for
disulfoton,
and
recommended
that
the
FQPA
Safety
Factor
(
as
required
by
Food
Quality
Protection
Act
of
August
3,
1996)
be
removed
(
1x)
in
assessing
the
risk
posed
by
this
chemical.
The
FQPA
safety
factor
recommendation
in
this
report
supercedes
that
previously
reported
for
disulfoton
in
the
FQPA
SAFETY
FACTOR
RECOMMENDATIONS
FOR
THE
ORGANOPHOSPHATES
dated
August
6,
1998.

6.
DATA
GAPS
Developmental
neurotoxicity
study
as
required
by
the
Data
Call­
In
Notice
(
September
10,
1999)
7.
HAZARD
CHARACTERIZATION
Cholinesterase
inhibition
(
plasma,
erythrocyte
and/
or
brain)
is
seen
at
the
lowest
dose
levels
tested
in
rats,
mice,
rabbits
and
dogs.
All
of
the
endpoints
are
based
on
good
dose
related
responses
in
cholinesterase
inhibition.
Many
of
the
studies
show
clinical
signs
at
higher
dose
levels.
Females
appear
to
be
more
sensitive
to
cholinesterase
inhibition
in
most
studies.

The
organophosphates
have
a
common
mode
of
action
in
that
they
decrease
erythrocyte
and/
or
brain
cholinesterase
in
animals
and
humans.
Plasma
cholinesterase
inhibition
is
a
surrogate
for
possible
muscle
and
brain
cholinesterase
inhibition.
Neuropathy
may
result
from
higher
exposures
to
these
inhibitors.
The
rabbit
21­
day
dermal
studies
did
not
show
as
consistent
cholinesterase
inhibition
with
time
as
other
studies
showed,
although
the
3­
day
dermal
rat
study
showed
a
time
dependence
between
day
2
and
day
4.
The
results
were
somewhat
dependent
on
whether
concurrent
controls
were
used
or
the
values
for
the
individual
animals
at
the
beginning
of
the
study
were
used
for
comparison.

Cholinesterase
inhibition
occurred
at
the
LOAEL
in
rats,
mice,
rabbits
and
dogs.
Therefore
the
effects
are
very
uniform
across
species.
The
female
of
the
species
appears
to
be
more
sensitive
than
the
male
and
the
cholinesterase
inhibition
occurs
at
slightly
different
dose
levels
across
the
species.
The
cholinesterase
inhibition
appears
to
be
slightly
greater
in
the
female
than
the
male
in
most
studies.

Adequate
developmental
toxicity
and
reproductive
toxicity
studies
show
adult
toxicity
occurs
at
lower
dose
levels
than
toxicity
to
the
fetus
or
offspring.
There
is
no
evidence
to
support
increased
susceptibility
following
pre
natal
exposure
to
rat
or
rabbit
fetuses
or
pre/
post
natal
exposure
to
rats.
In
these
studies,
toxicity
to
the
fetus
or
pups
occurred
only
at
higher
dose
levels
than
to
the
adults
(
dams
or
parents)
.
Thus,
there
is
no
evidence
of
increased
susceptibility
to
the
fetus
or
to
offspring.

The
following
literature
summary
is
provided
to
develop
a
comprehensive
picture
of
disulfoton
toxicity.
The
data
have
not
been
reviewed
in
depth,
and
no
statement
is
made
regarding
the
accuracy
or
quality
of
the
data
or
reports.
In
a
1988
study
by
McDonald
et
al.
,
disulfoton
was
administered
by
daily
i.
p.
injection
at
2
mg/
kg/
day
to
male
Long­
Evans
rats
for
14
days.
In
treated
rats,
muscarinic
receptor
binding
was
decreased
and
spacial
memory
was
decreased
in
a
T­
maze
alternation
task.
These
effects
occurred
in
the
presence
of
­
75%
brain
ChEI
therefore
the
effects
may
not
be
relevant
at
the
NOAEL
for
brain
ChEI.
8.
ACUTE
TOXICITY
ENDPOINTS
:

Acute
Toxicity
of
disulfoton,
technical
Guideline
No.
Study
Type
MRID
#
(
S)
.
Results
Toxicity
Category
81­
1
Acute
Oral
Acc#
072293
LD50
=
M:
6.2
mg/
kg;
F:
1.9
mg/
kg
I
81­
2
Acute
Dermal
Acc#
07793
LD50
=
M:
15.9
mg/
kg;
F:
3.6
mg/
kg
I
81­
3
Acute
Inhalation
Acc#
258569
LC50
=
M:
0.06
mg/
L;
F:
0.89
mg/
L
I
81­
4
Primary
Eye
Irritation
None
Data
requirement
waived.
N/
A
81­
5
Primary
Skin
Irritation
None
Data
requirement
waived.
N/
A
81­
6
Dermal
Sensitization
None
Data
requirement
waived.
N/
A
81­
7
Acute
Delayed
Neurotoxicity
00129384
Equivocal
81­
8
Acute
Neurotoxicity
42755801
Reversible
neurotoxic
signs
consistent
with
the
cholinesterase
inhibition
1.5
mg/
kg
in
females
and
5.0
mg/
kg
in
males
N/
A
9.
SUMMARY
OF
TOXICOLOGY
ENDPOINTS
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
in
the
table
below.

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
NOAEL
=
025
Plasma
and
RBC
cholinesterase
inhibition
and
clinical
signs
of
toxicity.
Acute
Neurotoxicity­
Rat
UF=
100
Acute
RfD
=
0.0025
mg/
kg
Chronic
Dietary
NOAEL
=
0.013
Plasma,
RBC,
brain
and
ocular
cholinesterase
inhibition
Chronic
Toxicity­
Dog
UF=
100
Chronic
RfD
=
0.00013
mg/
kg/
day
Dermal,
Short­
Term
Dermal
NOAEL
=
0.5
Plasma
and
brain
cholinesterase
inhibition
3­
Dermal
Toxicity­
Rat
Dermal,
Intermediate­
Term
Oral
NOAEL=
0.03
a
Plasma,
RBC
and
brain
cholinesterase
inhibition
6­
Month
Cholinesterase­
Rat
Dermal,
Long­
Term
Oral
NOAEL=
0.013
a
Plasma,
RBC,
brain
and
ocular
cholinesterase
inhibition
Chronic
Toxicity­
Dog
Inhalation,
Short,
Intermediate
and
Long­
Term
Inhalation
NOAEL=
0.00016
mg/
L
or
0.045
mg/
kg/
day
Plasma,
RBC
and
brain
cholinesterase
inhibition
90­
Day
Inhalation
Toxicity­
Rat
a
Use
36%
dermal
absorption
factor
for
route­
to­
route
extrapolation.
