Disulfoton/
June/
2001
RED
Toxicology
Chapter
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
06/
25/
2001
PREVENTION,
PESTICIDES
AND
MEMORANDUM
:
TOXIC
SUBSTANCES
Subject:
Health
Effects
Division
Toxicity
Chapter
for
Disulfoton
for
Reregistration
Eligibility
Decision
(
RED)
(
Reformatted
and
Revised)
.

DP
Barcode:
D275193
Sub
DP
Barcode
of
D239907
Rereg
Case:
0102
From:
David
G
Anderson,
Toxicologist
Reregistration
Branch­
2
HED
(
7509C)

To:
Christina
Jarvis
Risk
Assessor
for
Disulfoton
RRB­
2,
HED
(
7509C)

Thru:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch­
2
HED
(
7509C)

INTRODUCTION:
PC
Code:
032501
Cas
Reg
No.
:
274­
04­
4
Caswell
File
No.
:
341
Betty
Shackleford/
Christina
Scheltema
Reregistration
Branch­
3
SRRD
(
7507C)

This
Toxicology
Chapter
for
the
Reregistration
Eligibility
Decision
Document
represents
the
second
revision
to
the
Toxicology
Chapter.
The
chapter
is
reformatted
according
to
the
SOP
as
of
June
21,
2000.
The
chapter
incorporates
two
new
dermal
toxicity
studies
and
a
3
rd
HIARC
report
with
revisions
to
the
Occupational/
residential
exposure
endpoints
only.

EXECUTIVE
SUMMARY:
Disulfoton
was
too
toxic
for
guideline
studies
on
primary
eye,
skin
irritation
and
dermal
sensitization
to
be
conducted,
thus
the
data
requirements
were
waived.
Disulfoton
is
classified
as
acutely
toxic,
toxicity
category
I,
by
the
oral,
dermal
and
inhalation
routes
of
exposure.
The
mode
of
action
of
disulfoton
is
inhibition
of
cholinesterase.
In
all
of
the
studies
evaluated
in
this
hazard
assessment,
the
LOAEL
and
NOAEL
were
established
through
the
inhibition
of
cholinesterase
(
the
basis
for
all
regulatory
endpoints)
.
Clinical
signs,
such
as
muscle
fasciculation
and
tremors
are
seen
either
at
higher
dose
levels
or
at
the
LOAEL
for
some
studies.
All
three
cholinesterases
(
plasma,
erythrocyte
and
brain)
are
inhibited
at
the
lowest
dose
tested
and
1
Disulfoton/
June/
2001
RED
Toxicology
Chapter
are
likely
to
occur
across
species
including
humans.
There
are
slight
species
differences,
but
the
differences
may
be
due
to
normal
variation
and
differences
in
the
duration
of
the
studies
conducted
in
different
species.
Adult
females
appear
to
be
slightly
more
sensitive,
and
in
a
6­
month
study
in
rats
(
MRID#
43058401)
,
cholinesterase
inhibition
was
seen
only
in
females.
The
cholinesterase
NOAELs
ranged
over
a
10
fold
exposure
levels
between
acute
and
chronic
studies
in
rats.
Longer
exposure
always
show
cholinesterase
inhibition
at
lower
dose
levels.
Clinical
signs
occurred
at
the
same
dose
level
as
cholinesterase
inhibition
in
the
acute
neurotoxicity
study,
whereas
in
the
90­
day
neurotoxicity
study,
cholinesterase
inhibition
occurred
at
a
lower
dose
level.
Motor
activity
was
affected
at
lower
dose
levels
in
the
90­
day
study
than
in
the
acute
study,
but
no
treatment
related
or
significant
neuropathology
occurred
either
acutely
or
in
the
90­
day
studies.
No
organophosphate
induced
neuropathy
(
OPIDN)
or
inhibition
of
the
neurotoxic
target
enzyme
(
NTE)
was
seen
in
the
acute
delayed
neurotoxicity
study.
There
is
no
increased
susceptibility
to
fetuses
or
pups
in
acceptable
developmental
and
reproductive
toxicity
studies
in
the
rabbit
or
rat.
Pup
death
occurred
at
the
highest
dose
tested.
The
deaths
were
attributed
to
an
inadequate
milk
supply
and
maternal
care
failure.
In
the
developmental
toxicity
study
in
the
rat,
developmental
toxicity
occurred
at
higher
doses
than
caused
toxicity
in
dams.
Developmental
toxicity
in
the
rat
was
seen
in
the
form
of
incomplete
ossification,
but
no
developmental
toxicity
was
seen
in
the
rabbit
at
the
dose
levels
administered.
In
the
study
on
reproduction,
cholinesterase
was
inhibited
(
plasma,
erythrocyte
and
brain)
in
parents
at
lower
dose
levels
than
in
pups.
No
obvious
endocrine
disruption
was
seen
in
any
of
the
studies.
Absolute
testes
and
ovarian
weights
were
decreased
at
the
highest
dose
level,
which
may
be
endocrine
mediated.
These
organ
weight
decreases
occurred
in
the
presence
of
relatively
severe
cholinesterase
inhibition.
However,
the
effect
on
organ
weights
could
not
be
unequivocally
attributed
to
endocrine
effects.
There
is
an
adequate
dermal
absorption
study
in
rats
and
adequate
3­
day
dermal
rat
study
and
21­
day
dermal
studies
in
rabbits
showing
cholinesterase
inhibition
(
plasma,
erythrocyte
and
brain)
.
There
are
no
carcinogenicity
concerns
in
two
acceptable
studies
in
the
rat
and
mouse.
An
adequate
dose
level
was
reached
in
the
study
in
rats
to
test
the
carcinogenic
potential
of
disulfoton,
based
on
decreased
body
weights
and
body
weight
gains.
In
mice,
the
highest
dose
tested
in
this
study
is
approximates
35%
of
the
LD50
and
higher
dietary
concentrations
would
have
resulted
in
significant
compound­
related
mortality
of
the
test
animals.
Thus,
the
dose
levels
were
considered
adequate
to
test
the
carcinogen
potential
of
disulfoton
in
mice.
Disulfoton
is
positive
in
some
mutagenicity
studies
without
activation,
but
negative
or
weakly
positive
in
most
with
activation.
With
no
carcinogenicity
concerns
and
no
reproductive
toxicity
concerns
at
relevant
dose
levels,
the
mutagenicity
concerns
are
low.
The
mutagenicity
data
base
is
complete
for
the
pre­
1990
required
three
mutagenicity
categories
and
the
in
vivo
data
base
support
a
lack
of
concern
for
the
mutagenicity
of
disulfoton.
The
metabolism
of
disulfoton
was
studied
in
the
rat.
The
toxic
metabolites
of
disulfoton
are
disulfoton
sulfoxide,
disulfoton
sulfone,
disulfoton
oxygen
analog
(
demeton­
S)
,
disulfoton
oxygen
analog
sulfoxide
and
disulfoton
oxygen
analog
sulfone.
Disulfoton
was
found
to
be
rapidly
absorbed
and
excreted
with
over
95%
of
the
administered
C
14
labeled
disulfoton
being
recovered
in
the
urine
and
approximately
90%
excretion
within
24
hours.
Less
than
2%
was
recovered
from
the
feces.
Bioaccummulation
was
not
observed
with
less
than
0.3%
being
recovered
in
tissues
and
less
than
1%
being
recovered
in
the
carcass.
A
major
metabolite
was
incompletely
identified,
but
it
co­

2
Disulfoton/
June/
2001
RED
Toxicology
Chapter
chromatographed
with
1­
(
ethylsulfonyl)
­
2­
(
methylsulfonyl)
ethane,
a
fully
oxidized
form
of
the
putative
hydrolysis
product.
The
Metabolism
Committee
determined
that
the
raw
agriculture
commodity,
meat,
diary
and
poultry
product
residues
to
be
regulated
are
disulfoton,
disulfoton
oxygenated
analog
and
their
sulfoxides
and
sulfones.

3
Disulfoton/
June/
2001
RED
Toxicology
Chapter
DISULFOTON
PC
Code:
032501
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed
Prepared
for:
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Prepared
by:
David
G
Anderson
form:
FINAL
June
21,
2000
EPA
Reviewer:
David
G
Anderson,
PhD
,
Date
1
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Reregistration
Branch­
2
(
7509C)

Registration
Action
Branch­
3
(
7509C)
Secondary
EPA
Reviewer:
Stephen
Dapson,
PhD
,
Date
TABLE
OF
CONTENTS
1.
0
HAZARD
CHARACTERIZATION
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2­

2.
0
REQUIREMENTS
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3­

3.
0
DATA
GAP(
S)
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4­

4.
0
HAZARD
ASSESSMENT
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4­
4.
1
Acute
Toxicity
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4­
4.
2
Subchronic
Toxicity
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5­
4.
3
Prenatal
Developmental
Toxicity
.
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8­
4.4
Reproductive
Toxicity
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10­
4.
5
Chronic
Toxicity
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12­
4.6
Carcinogenicity
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14­
4.7
Combined
Chronic/
Carcinogenicity
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15­
4.8
Mutagenicity
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19­
4.
9
Neurotoxicity
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20­
4.10
Metabolism
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23­
4.11
Special/
other
Studies
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24­

5.0
TOXICITY
ENDPOINT
SELECTION
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­
27­
5.1
See
Section
8.2
for
Endpoint
Selection
Table.
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27­
5.
2
Dermal
Absorption
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27­
5.3
Classification
of
Carcinogenic
Potential
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28­

6.
0
FQPA
Considerations
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28­
6.1
Special
Sensitivity
to
Infants
and
Children
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29­
6.
2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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29­

7.
0
RERERENCES
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29­

8.0
APPENDICES
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32­
8.1
Toxicity
Profile
Summary
Tables
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33­
8.1.1
Acute
Toxicity
Data
Table
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­
33­
8.1.2
Subchronic,
Chronic
and
other
Toxicity
Tables
.
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­
34­
8.2
Summary
of
Toxicological
Dose
and
Endpoints
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
­
39­
1.0
HAZARD
CHARACTERIZATION
Disulfoton
was
too
toxic
for
guideline
studies
on
primary
eye,
skin
irritation
and
dermal
­
2­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
sensitization
to
be
conducted,
thus
the
data
requirements
were
waived.
Disulfoton
is
classified
as
acutely
toxic,
toxicity
category
I,
by
the
oral,
dermal
and
inhalation
routes
of
exposure.
The
mode
of
action
of
disulfoton
is
inhibition
of
cholinesterase.
In
all
of
the
studies
evaluated
in
this
hazard
assessment,
the
LOAEL
and
NOAEL
were
established
through
the
inhibition
of
cholinesterase
(
the
basis
for
all
regulatory
endpoints)
.
Clinical
signs,
such
as
muscle
fasciculation
and
tremors
are
seen
either
at
higher
dose
levels
or
at
the
LOAEL
for
some
studies.
All
three
cholinesterases
(
plasma,
erythrocyte
and
brain)
are
inhibited
at
the
lowest
dose
tested
and
are
likely
to
occur
across
species
including
humans.
There
are
slight
species
differences,
but
the
differences
may
be
due
to
normal
variation
and
differences
in
the
duration
of
the
studies
conducted
in
different
species.
Adult
females
appear
to
be
slightly
more
sensitive,
and
in
a
6­
month
study
in
rats
(
MRID#
43058401)
,
cholinesterase
inhibition
was
seen
only
in
females.
The
cholinesterase
NOAELs
ranged
over
a
10
fold
exposure
levels
between
acute
and
chronic
studies
in
rats.
Longer
exposure
always
show
cholinesterase
inhibition
at
lower
dose
levels.
Clinical
signs
occurred
at
the
same
dose
level
as
cholinesterase
inhibition
in
the
acute
neurotoxicity
study,
whereas
in
the
90­
day
neurotoxicity
study,
cholinesterase
inhibition
occurred
at
a
lower
dose
level.
Motor
activity
was
affected
at
lower
dose
levels
in
the
90­
day
study
than
in
the
acute
study,
but
no
treatment
related
or
significant
neuropathology
occurred
either
acutely
or
in
the
90­
day
studies.
No
organophosphate
induced
neuropathy
(
OPIDN)
or
inhibition
of
the
neurotoxic
target
enzyme
(
NTE)
was
seen
in
the
acute
delayed
neurotoxicity
study.
There
is
no
increased
susceptibility
to
fetuses
or
pups
in
acceptable
developmental
and
reproductive
toxicity
studies
in
the
rabbit
or
rat.
Pup
death
occurred
at
the
highest
dose
tested.
The
deaths
were
attributed
to
an
inadequate
milk
supply
and
maternal
care
failure.
In
the
developmental
toxicity
study
in
the
rat,
developmental
toxicity
occurred
at
higher
doses
than
caused
toxicity
in
dams.
Developmental
toxicity
in
the
rat
was
seen
in
the
form
of
incomplete
ossification,
but
no
developmental
toxicity
was
seen
in
the
rabbit
at
the
dose
levels
administered.
In
the
study
on
reproduction,
cholinesterase
was
inhibited
(
plasma,
erythrocyte
and
brain)
in
parents
at
lower
dose
levels
than
in
pups.
No
obvious
endocrine
disruption
was
seen
in
any
of
the
studies.
Absolute
testes
and
ovarian
weights
were
decreased
at
the
highest
dose
level,
which
may
be
endocrine
mediated.
These
organ
weight
decreases
occurred
in
the
presence
of
relatively
severe
cholinesterase
inhibition.
However,
the
effect
on
organ
weights
could
not
be
unequivocally
attributed
to
endocrine
effects.
There
is
an
adequate
dermal
absorption
study
in
rats
and
adequate
3­
day
dermal
rat
study
and
21­
day
dermal
studies
in
rabbits
showing
cholinesterase
inhibition
(
plasma,
erythrocyte
and
brain)
.
There
are
no
carcinogenicity
concerns
in
two
acceptable
studies
in
the
rat
and
mouse.
An
adequate
dose
level
was
reached
in
the
study
in
rats
to
test
the
carcinogenic
potential
of
disulfoton,
based
on
decreased
body
weights
and
body
weight
gains.
In
mice,
the
highest
dose
tested
in
this
study
is
approximates
35%
of
the
LD50
and
higher
dietary
concentrations
would
have
resulted
in
significant
compound­
related
mortality
of
the
test
animals.
Thus,
the
dose
levels
were
considered
adequate
to
test
the
carcinogen
potential
of
disulfoton
in
mice.
Disulfoton
is
positive
in
some
mutagenicity
studies
without
activation,
but
negative
or
weakly
positive
in
most
with
activation.
With
no
carcinogenicity
concerns
and
no
reproductive
toxicity
concerns
at
relevant
dose
levels,
the
mutagenicity
concerns
are
low.
The
mutagenicity
data
base
is
complete
for
the
pre­
1990
required
three
mutagenicity
categories
and
the
in
vivo
data
base
support
a
lack
of
concern
for
the
mutagenicity
of
disulfoton.

­
3­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
The
metabolism
of
disulfoton
was
studied
in
the
rat.
The
toxic
metabolites
of
disulfoton
are
disulfoton
sulfoxide,
disulfoton
sulfone,
disulfoton
oxygen
analog
(
demeton­
S)
,
disulfoton
oxygen
analog
sulfoxide
and
disulfoton
oxygen
analog
sulfone.
Disulfoton
was
found
to
be
rapidly
absorbed
and
excreted
with
over
95%
of
the
administered
C
14
labeled
disulfoton
being
recovered
in
the
urine
and
approximately
90%
excretion
within
24
hours.
Less
than
2%
was
recovered
from
the
feces.
Bioaccummulation
was
not
observed
with
less
than
0.3%
being
recovered
in
tissues
and
less
than
1%
being
recovered
in
the
carcass.
A
major
metabolite
was
incompletely
identified,
but
it
co
­
chromatographed
with
1­
(
ethylsulfonyl)
­
2­
(
methylsulfonyl)
ethane,
a
fully
oxidized
form
of
the
putative
hydrolysis
product.
The
Metabolism
Committee
determined
that
the
raw
agriculture
commodity,
meat,
diary
and
poultry
product
residues
to
be
regulated
are
disulfoton,
disulfoton
oxygenated
analog
and
their
sulfoxides
and
sulfones.

2.0
REQUIREMENTS
The
requirement
(
CFR
158.340)
for
food
and
non
food
use
for
disulfoton
are
in
Table
1.
Use
of
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
1.
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3465
90­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
No
Yes
Yes
1
Yes
2
Yes
Yes
Yes
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yes
Yes
870.4100a
Chronic
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100b
Chronic
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200a
Oncogenicity
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200b
Oncogenicity
(
mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
.
870.5xxx
Mutagenicity
 
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
­
4­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Test
Technical
Required
Satisfied
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
No
Yes
Yes
Yes
Yes
­
3
Yes
Yes
Pending
4
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Yes
Yes
Yes
Yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Reserved
Reserved
Reserved
No
No
No
Special
Studies
(
NG)
Acute
and
3­
5
day
Inhalation
(
rat)
3­
Day
Dermal
(
rat)
6­
Month
Cholinesterase
(
rat)
No
No
Yes
Yes
5
Yes
5
Yes
6
1
Requirement
is
satisfied
by
Guideline
870.4100a;
2
Requirement
is
satisfied
by
Guideline
870.4100b;
3
Not
required
when
the
870.6200a
is
negative.
4
Currently
being
conducted
in
response
to
the
general
data­
call­
in
for
organophosphates.
5
Special
studies
used
in
the
assessment
of
occupational/
residential
exposure.
6
Requested
special
study
for
assessment
purposes.

3.0
DATA
GAP(
S)

There
are
no
data
gaps,
however,
disulfoton
is
subject
to
a
data­
call­
in
for
organophosphate
pesticides
(
a
confirmatory
developmental
neurotoxicity
study)
.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Disulfoton
is
acutely
toxic
(
Toxicity
category
I)
with
an
oral
LD50
of
1.9
mg/
kg
for
female
rats.
The
dermal
LD50
is
3.6
mg/
kg
for
female
rats.
Note
at
the
LD50,
apparently
greater
than
50%
of
dermaly
applied
disulfoton
is
absorbed,
while
at
lower
concentrations
only
36%
is
absorbed.
The
data
requirements
for
primary
eye
irritation,
dermal
irritation
and
dermal
sensitization
were
waived
because
of
the
acute
toxicity
of
disulfoton.
The
studies
on
acute
neurotoxicity
in
the
hen
and
rat
showed
cholinesterase
inhibition,
but
no
neuropathy.
The
acute
toxicity
data
on
disulfoton
technical
are
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
disulfoton
­
5­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Guideline
No.
Study
Type
MRID
#
(
S)
.
Results
Toxicity
Category
870.1100
Acute
Oral
00139595,
Doc#
003958,
p41
LD50
=
M:
6.2
mg/
kg;
F:
1.9
mg/
kg
I
870.1200
Acute
Dermal
Acc#
07793,
Doc#
03958,
p71
&
004223,
p24
LD50
=
M:
15.9
mg/
kg;
F:
3.6
mg/
kg
I
870.1300
Acute
Inhalation
00147754,
Doc#
05789
LC50
=
M:
0.06
mg/
L;
F:
0.015
mg/
L
I
870.2400
Primary
Eye
Irritation
Data
requirement
waived.
Doc#
03958,
p12;
004223,
p14
Defaults
to
most
severe
category
870.2500
Primary
Skin
Irritation
Data
requirement
waived.
Doc#
03958,
p12;
004223.
p14
Defaults
to
most
severe
category
870.2600
Dermal
Sensitization
Data
requirement
waived.
Doc#
03958,
p12
Defaults
to
most
severe
category
4.2
Subchronic
Toxicity
Chronic
feeding
toxicity
studies
in
the
dog,
rat
and
mouse
satisfy
this
requirement
for
oral
subchronic
studies.
The
toxicity
data
base
for
subchronic
toxicity
is
considered
complete.
No
additional
studies
are
require
at
this
time.
Subchronic
inhalation
studies
in
the
rat
and
dermal
studies
in
the
rabbit
show
that
cholinesterase
is
inhibited
at
the
LOAEL.
Almost
all
the
studies
showed
cholinesterase
was
inhibited
in
all
three
compartments.
In
addition,
subchronic
oral
neurotoxicity
studies
in
the
rat
(
See
Section
4.10)
and
special
3­
day
dermal
studies
in
the
rat
(
See
Section
4.7)
show
that
cholinesterase
is
inhibited
at
the
LOAEL.

870.3200
21­
Day
Dermal
Toxicity
­
Rabbits
(
82­
5)

CITATION:
Flucke,
W.
(
1986)
Study
of
Subacute
Dermal
Toxicity
to
Rabbits.
Bayer
AG,
Fachbereich
Toxikologie,
Wuppertal
­
Elberfeld,
F.
R.
Germany.
Study
No.
:
14747.
June
20,
1986.
MRID
00162338.
Unpublished.

EXECUTIVE
SUMMARY
:
In
a
study
(
MRID
00162338)
S276
Technical
disulfoton
(
97.8%
a.
i.
,
Batch
No.
79­
R­
225­
40)
,
was
applied
to
the
shaved
skin
of
5
New
Zealand
White
rabbits/
sex/
dose
at
dose
levels
of
0,
0.4,
1.6
or
6.5
mg/
kg,
6
hours
a
day,
5
days/
week
for
15
days.
Doses
were
selected
based
on
a
preliminary
range­
finding
study
in
which
clinical
signs
of
cholinergic
intoxication
and
death
at
10
mg/
kg/
day
following
1
or
2
applications.
Slight
inhibition
of
plasma
­
6­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
ChE
at
2
mg/
kg
and
no
effect
on
plasma
or
RBC
ChE
inhibition
at
0.4
mg/
kg.
Plasma
and
RBC
ChE
were
measured
at
study
initiation,
day
6,
11,
and
termination.
Brain
ChE
was
determined
at
termination.
Repeated
dermal
application
of
disulfoton
or
vehicle
(
Cremophor
EL
in
sterile
saline)
6
hours
a
day
for
15
days
had
no
effect
on
hematology,
clinical
chemistry,
urinalysis,
gross
pathology
and
absolute
and
relative
organ
weights.
There
was
no
dermal
reaction
to
repeated
dermal
application.
Systemic
Toxicity
was
observed
in
high­
dose
males
and
females
as
a
marked
reduction
in
food
consumption
and
body
weights
and
death
ensuing
within
1
to
2
weeks
of
initiation
of
treatment.
The
Systemic
Toxicity
NOAEL
=
1.6
mg/
kg/
day
and
LOAEL
=
6.5
mg/
kg/
day
,
based
on
reduced
food
consumption
and
weight
gain.
At
the
highest
dose,
all
males
and
females
died
or
were
sacrificed
following
.
6
days
of
treatment
due
to
acute
cholinergic
signs
such
as
muscle
spasms,
dyspnea
and
salivation.
In
one
high
dose
male
which
survived
6
treatments,
plasma
(
75%
)
and
RBC
(
31%
)
Cholinesterase
was
depressed.
Plasma
ChE
of
mid­
dose
males
(
17
­
24%
)
and
females
(
31
­
44%
)
depressed;
RBC
ChE
of
males
(
15
­
19%
)
and
females
(
7
­
33%
)
was
depressed,
compared
to
concurrent
controls.
Brain
ChE
of
males
and
females
was
depressed
7
­
8%
.
The
ChE
NOAEL
=
0.4
mg/
kg/
day
and
LOAEL
=
1.6
mg/
kg/
day
,
based
on
inhibition
of
plasma
and
RBC
ChE
and
marginal
inhibition
of
brain
ChE.

The
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
a
subchronic
dermal
toxicity
study
(
82­
2)
in
rabbits.

870.3200
21­
Day
Dermal
Toxicity
­
Rabbit
CITATION:
Flucke,
W
(
1988)
S
276
Technical
grade
Disulfoton:
Study
of
the
Subacute
Dermal
Toxicity
to
Rabbits.
Bayer
AG.
,
Germany.
Study
Number
98347.
Report
No.
116342,
January
5,
1988.
MRID
45239601.
Unpublished.

SPONSOR:
Bayer
Corporation,
Stillwell,
KS.

EXECUTIVE
SUMMARY:
In
a
21­
day
dermal
toxicity
study
in
rabbits
(
MRID
45239601)
,
disulfoton
(
97%
a.
i.
%
)
was
administered
dermally
to
New
Zealand
White
(
HC:
NZW)
rabbits
(
5/
sex/
dose)
at
dose
levels
of
0,
0.8,
1.0
or
3.0
mg/
kg/
day
for
21­
days.
Plasma,
erythrocyte
cholinesterase
was
determined
day
­
2,
8,
15
and
21.
Brain
cholinesterase
was
determined
at
termination
on
day
21.
Plasma
and
erythrocyte
cholinesterase
were
compared
with
day
­
2
values
while
brain
cholinesterase
was
compared
with
concurrent
control
values.
Clinical
observations,
chemistry
and
histological
examination
of
tissues
were
conducted.
Body
weight
was
slightly
decreased
and
statistically
significant
(
­
3%
compared
with
controls)
during
the
last
2
weeks
of
the
study
at
3.0
mg/
kg/
day
in
females.
Clinical
signs
consistent
with
cholinergic
signs
occurred
in
males
at
the
end
of
the
study.
Muscle
spasm,
tremors,
diarrhea,
and/
or
difficulty
in
breathing
in
4
animals
and
one
male
death
occurred
at
3.0
mg/
kg/
day
toward
the
end
of
the
study.
One
female
was
lethargic
and
had
difficulty
breathing
on
the
last
day
of
the
study
at
3.0
mg/
kg/
day.
No
differences
attributed
to
treatment
were
noted
in
organ
weights
or
clinical
­
7­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
chemistries
other
than
cholinesterase
activity.
Plasma
cholinesterase
was
statistically
significantly
inhibited
in
males
at
1.0
and
3.0
mg/
kg/
day
at
day
15
(
22%
)
and
21
(
24%
)
and
at
day
8
(
63%
)
,
15
(
70%
)
and
21
(
65%
)
,
respectively.
In
females,
plasma
cholinesterase
was
statistically
significantly
inhibited
only
at
3.0
mg/
kg/
day
and
only
on
day
15
(
61%
)
and
21
(
61%
)
,
but
it
was
44%
inhibited
on
day
8
(
not
statistically
significant)
.
Erythrocyte
cholinesterase
was
statistically
significantly
inhibited
in
males
days
8
(
53%
)
,
15
(
56%
)
and
21
(
62%
)
at
3.0
mg/
kg/
day
and
day
21
(
17%
)
at
1.0
mg/
kg/
day.
In
females,
erythrocyte
cholinesterase
was
statistically
significantly
inhibited
on
days
8
(
42%
)
,
15
(
55%
)
and
21
(
51%
)
at
3.0
mg/
kg/
day,
but
at
1.0
mg/
kg/
day
it
was
statistically
significantly
inhibited
on
days
15
(
28%
)
and
21
(
25%
)
only.
Although,
erythrocyte
cholinesterase
was
inhibited
in
females
30%
at
1.0
mg/
kg/
day
on
day
8,
it
was
not
statistically
significant,
possibly
due
to
the
high
standard
deviation
in
day
­
2
values
used
for
comparison.
However,
concurrent
control
females
and
the
0.8
mg/
kg/
day
dose
group
showed
21%
and
24%
erythrocyte
cholinesterase
inhibition
on
day
8,
respectively,
compared
with
the
­
2
day
values.
Thus
the
30%
erythrocyte
cholinesterase
inhibition
in
females
on
day
8
at
1.0
mg/
kg/
day
was
not
considered
biologically
significant.
At
termination,
brain
cholinesterase
was
55%
inhibited
in
males
and
27%
inhibited
in
females
only
at
3.0
mg/
kg/
day
(
neither
were
marked
as
being
statistically
significant,
but
they
were
depressed
according
to
the
report
author)
.
Due
to
the
timing
of
sample
collection
in
females,
depression
in
brain
cholinesterase
values
seen
for
females,
probably
had
time
to
partly
reverse
before
collection.
There
was
no
definitive
indication
from
these
data
that
there
was
or
was
not
accumulation
of
the
test
material,
which
caused
increased
cholinesterase
depression
with
days
on
study,
however,
frequently
the
day
15
and/
or
day
21
values
were
nominally
lower
than
the
day
8
cholinesterase
activity
values,
and
cholinergic
clinical
signs
occurred
in
animals
after
day
15.

The
overall
NOAEL
was
0.8
mg/
kg/
day
for
any
day
of
dosing.
The
overall
LOAEL
is
1.0
mg/
kg/
day
based
on
statistically
significant
inhibition
of
plasma
cholinesterase
in
males
by
day
15
and
statistically
significant
inhibition
of
erythrocyte
cholinesterase
inhibition
in
females
by
day
15.
Significant
plasma
and
erythrocyte
cholinesterase
inhibition
occurred
by
day
8
only
at
3.0
mg/
kg/
day
in
males
and
females.

This
study
is
classified
acceptable
and
satisfies
the
Subdivision
F
guideline
requirement
for
a
21­
day
dermal
study
in
rabbits
(
82­
2)
.

870.3465
Subchronic
Inhalation/
Rats
(
82­
4)

CITATION:
Shiotsuka,
RN
(
1989)
Subchronic
inhalation
study
of
technical
grade
disulfoton
(
Di­
Syston
®
)
inhalation
in
rats.
Testing
Lab:
Mobay
Corp.
Study#
88­
141­
AU/
99648.
Date:
7/
31/
89.
MRID#
41224301.
Unpublished
study.

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
(
MRID
No.
:
41224301)
.
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
­
8­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
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
were
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
mg/
m
3
/
1.4
mg/
m
3
or
0.00016/
0.0014
mg/
L
for
plasma,
erythrocyte
and
brain
cholinesterase
depression.

Core
classification:
Guideline.
The
study
(
MRID#
41224301)
is
acceptable
under
guideline
82­
4
for
a
90­
day
inhalation
study
in
rats.

Comments
about
study
and/
or
endpoint:
This
study
also
has
cholinesterase
inhibition
data
for
day
37.

4.3
Prenatal
Developmental
Toxicity
There
is
no
increased
susceptibility
to
fetuses
in
acceptable
developmental
toxicity
studies
in
the
rabbit
or
rat.
In
the
developmental
toxicity
study
in
the
rat,
developmental
toxicity
occurred
at
higher
doses
than
caused
toxicity
in
dams.
Developmental
toxicity
in
the
rat
was
seen
in
the
form
of
incomplete
ossification,
but
no
developmental
toxicity
was
seen
in
the
rabbit
at
the
dose
levels
administered.

870.3700
Prenatal
Developmental
Toxicity
Study
in
Rats
(
83­
3)

CITATION:
Lamb­
DW
and
Hixson­
EJ
(
1983)
Embyrotoxic
and
teratogenic
effects
of
Disulfoton.
Study#
81­
611­
02
submitted
by
Mobay
Chem.
Corp.
May
13,
1983.
MRID#
:
00129458.
Unpublished
Report.

EXECUTIVE
SUMMARY:
Disulfoton,
technical
(
98.2%
)
was
administered
in
a
carbowax
(
polyethylene
glycol
400)
vehicle
by
gavage
to
25
pregnant
Sprague
Dawley
rats/
group
at
0,
0.1,
0.3
or
1.0
mg/
kg/
day
from
day
6
through
day
15
of
gestation
(
MRID#
00129458)
.
On
day
21,
the
rats
were
killed
and
50%
of
each
litter
was
examined
for
skeletal
anomalies
and
the
remainder
for
visceral
anomalies.
Cholinesterase
inhibition
studies
on
the
dams
at
21
days
(
2
weeks
dosing)
indicated
an
NOAEL/
LOAEL
of
0.1/
0.3
mg/
kg/
day
based
on
41%
inhibition
of
both
plasma
and
erythrocyte
cholinesterase.
Fetuses
showed
incomplete
ossification
of
the
intraparietals
and
sternebrae
at
1.0
mg/
kg/
day.
The
NOAEL/
LOAEL
for
maternal
toxicity
were
0.1/
0.3
mg/
kg/
day
based
on
41%
inhibition
of
both
plasma
and
erythrocyte
cholinesterase.
The
NOAEL/
LOAEL
for
­
9­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
developmental
toxicity
were
0.3/
1.0
mg/
kg/
day
based
on
incomplete
ossification
of
the
intraparietals
and
sternebrae.

The
study
is
acceptable
under
Guideline
83­
3
for
a
developmental
toxicity
study
in
rats.

­
10­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
870.3700
Prenatal
Developmental
Toxicity
in
Rabbits
(
83­
3)

CITATION:
Tesh­
JM
et
al.
(
1982)
S276:
Effects
of
oral
administration
upon
pregnancy
in
the
rabbit.
An
unpublished
report
(
Bayer
No.
R
2351)
prepared
by
Life
Science
Research,
Essex,
England
and
submitted
to
Bayer
AG,
Wuppertal,
Germany.
Dated
December
22,
1982.
MRID#
00147886.
Unpublished
Report.

EXECUTIVE
SUMMARY:
Disulfoton,
technical
was
administered
by
gavage
in
a
corn
oil
vehicle
(
5ml/
kg)
to
15,
14,
14
or
22
pregnant
New
Zealand
White
rabbits
per
group
at
0,
0.3,
1.0
or
3.0
mg/
kg/
day,
respectively
from
day
6
to
18
of
gestation
(
MRID#
00147886)
.
Since
mortality
and
clinical
signs
were
observed
at
3.0
mg/
kg/
day,
this
dose
level
was
reduced
to
2.0
mg/
kg/
day
and
finally
to
1.5
mg/
kg/
day.
Analysis
showed
that
the
dosing
solutions
were
17,
14
and
10%
below
the
target
concentrations
for
the
low
to
highest
doe
tested
(
HDT)
,
respectively.
Females
were
artificially
inseminated.
Maternal
signs
such
as
muscle
tremors,
unsteadiness/
in
coordination
and
increased
respiratory
rate
were
seen
4
hours
after
dosing
and
in
some
cases
persisted
for
more
than
24
hours
at
the
HDT.
No
toxic
signs
were
noted
at
the
MDT
and
LDT.
At
the
MDT
one
low
and
3
control
females
were
found
dead
or
moribund
from
a
mid­
ear
disease
or
respiratory
infection.
Test
material
related
mortalities
at
the
HDT
occurred
mostly
prior
to
dosage
reduction
to
1.5
mg/
kg.
Nine
of
22
animals
survived
to
termination
at
the
HDT.
Two
animals
aborted
at
the
MDT.
No
test
material
related
body
weight
changes
were
noted.
No
dose
related
soft
tissue
or
skeletal
anomalies
were
noted
at
any
dose
levels.
The
NOAEL/
LOAEL
for
dams
were
1.0/
1.5
based
on
tremors,
unsteadiness/
in
coordination
and
increased
respiration.
The
NOAEL/
LOAEL
for
developmental
toxicity
were
>
3.0/
>
3.0
mg/
kg/
day.

The
study
is
acceptable
for
Guideline
83­
3
for
a
developmental
toxicity
study
in
rabbits
and
was
upgraded
from
supplementary
to
fully
acceptable
in
HED
Doc#
004698
and
by
the
RfD/
QA
Peer
Review
Committee.

4.4
Reproductive
Toxicity
There
is
no
increased
susceptibility
to
pups
in
two
acceptable
reproductive
toxicity
studies
in
the
rat.
Pup
death
occurred
in
the
newer
study
at
the
highest
dose
tested.
The
deaths
were
attributed
to
an
inadequate
milk
supply
and
maternal
care
failure.
In
the
newer
study
on
reproduction,
cholinesterase
was
inhibited
(
plasma,
erythrocyte
and
brain)
in
parents
at
lower
dose
levels
than
in
pups.
The
newer
study
measured
more
endpoints
than
the
older
study,
but
the
results
of
the
two
studies
were
not
inconsistent.

870.3800
Two­
Generation
Reproductive
Toxicity
Study/
Rats
(
83­
4)

CITATION:
Astroff,
A
Barry
(
1997)
A
Two
Generation
Reproductive
Toxicity
study
with
Disulfoton
Technical
(
Disyston
®
)
in
the
Sprague
Dawley
Rat.
Laboratory
name
Bayer
Corp.
,

­
11­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Stilwell,
KA.
Laboratory
report
number:
95­
672­
FZ,
report#
108002,
File
8368.
November
19,
1997.
MRID#
44440801.
Unpublished
EXECUTIVE
SUMMARY:
In
a
2­
generation
reproduction
study
(
MRID#
44440801)
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
reproductive
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
the
2
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
(
1
P0
female)
,
tremors
(
15
P0
females,
10
F1
females)
and
dams
(
7
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
(
2
dams)
pups
cold
to
the
touch
and
3
F1
(
2
dams)
not
being
cared
for
and
63
F2
pups
(
7
dams)
with
no
milk
in
their
stomachs
and
93
F2
weak
pups
(
10
dams)
from
the
affected
dams.
In
addition,
1
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
­
12­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
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
day
and
21
day
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.

The
reproductive
study
in
the
rat
is
classified
acceptable
and
does
satisfy
the
guideline
requirement
for
a
2­
generation
reproductive
study
(
OPPTS
870.3800,
§
83­
4)
in
rat.

870.3800
Two­
Generation
Reproductive
Toxicity/
Rats
(
83­
4)

CITATION:
Hixson,
EJ
and
Hathaway,
TR
(
1986)
Effect
of
disulfoton
(
Di­
Syston
®
)
on
reproduction
in
the
rat.
Conducting
laboratory:
Mobay
Chem.
Date:
2/
12/
86.
Study#
82­
671­
02.
MRID#
00157511.
Unpublished
Study.

EXECUTIVE
SUMMARY:
In
an
acceptable
2­
generation
reproductive
toxicity
study
(
MRID#
00157511;
HED
Doc#
011959
&
005796)
,
disulfoton,
technical
(
97.8%
)
was
administered
at
0,
1,
3
or
9.0
ppm
(
0,
0.04,
0.12
or
0.36
mg/
kg/
day)
.
In
this
first
and
older
reproduction
study
cholinesterase
activity
was
measured
in
pups,
but
not
in
adults.
In
this
first
study
of
reproductive
toxicity,
the
parental
toxicity
NOAEL/
LOAEL
were
3/
9
ppm
or
0.12/
0.36
mg/
kg/
day
based
on
nominally
reduced
incidence
of
females
with
sperm
and
reduced
body
weight
in
gestating
and
lactating
P0
females
with
cholinesterase
being
probably
inhibited
with
a
NOAEL/
LOAEL
of
1/
3
ppm
or
0.04/
0.12
mg/
kg/
day.
These
latter
cholinesterase
results
were
supported
by
results
from
the
chronic/
oncogenicity
rat
study.
Toxicity
on
reproduction
showed
a
NOAEL/
LOAEL
of
1/
3
ppm
or
0.04/
0.12
mg/
kg/
day
based
on
F1a
weanling
pup
brain
cholinesterase
inhibition
and
F2b
pup
survival.
The
study
is
acceptable
for
a
guideline
(
83­
4)
study
on
reproduction
in
the
rat.

4.5
Chronic
Toxicity
Two
chronic
feeding
studies
were
conducted
in
dogs,
both
showing
cholinesterase
inhibition
at
the
LOAEL.
The
newer
study
in
dogs
included
cholinesterase
inhibition
in
eye
tissue
and
studied
more
parameters
and
showed
a
slightly
lower
NOAEL
than
the
older
study,
but
the
studies
were
­
13­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
consistent
with
the
each
other.
The
newer
study
was
used
for
risk
assessment.
The
chronic
feeding
toxicity
study
in
the
rodent
is
satisfied
by
the
combinded
chronic/
carcinogenicity
study
in
rats
(
See
Section
4.7)
.

870.4100b
Chronic
Toxicity
­
Dogs
(
83­
1b)

CITATION:
Jones,
R.
D.
and
T.
F.
Hastings
(
1997)
Technical
grade
Disulfoton:
A
chronic
toxicity
feeding
study
in
the
Beagle
dog.
Bayer
Corporation,
Stillwell,
KS.
Study
Number
94­
276­
XZ.
Report
No.
107499.
February
5,
1997.
MRID
44248002.
Unpublished.

EXECUTIVE
SUMMARY:
In
a
chronic
toxicity
study
(
MRID
44248002)
,
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,
electroretinograms,
electrocardiogram
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
­
14­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
termination.

This
study
is
classified
acceptable
and
satisfies
the
Subdivision
F
guideline
requirement
for
a
chronic
oral
study
in
non­
rodents
(
83­
1b)
.

870.4100b
Chronic
Toxicity
­
Dogs
(
83­
1b)

CITATION:
Hoffman,
K.
;
Weischer,
C.
H.
;
Luchaus,
G.
;
et
al.
(
1975)
S
276
(
Disulfoton)
Chronic
Toxicity
Study
in
Dogs
(
Two­
year
Feeding
Experiment)
.
Bayer,
AG,
W.
Germany.
Report
No.
45287.
December
15,
1976.
MRID
00073348.
Unpublished.

EXECUTIVE
SUMMARY:
In
a
chronic
feeding
study
(
MRID
00073348)
Technical
Di­
Syston
(
95.7%
a.
i.
)
was
administered
in
diet
to
4
Beagles/
sex/
dose
in
the
diet
at
dose
levels
of
0,
0.5,
1
or
2/
5/
8
ppm
(
0,
0.0125,
0.025
or
0.05/
0.125/
0.2
mg/
kg/
day,
converted)
for
104
weeks.
In
the
high­
dose
group,
2
ppm
was
given
for
first
69
weeks,
5
ppm
from
70
­
72
weeks,
and
8
ppm
from
week
73
­
termination.
Body
weights
were
determined
weekly
for
52
weeks,
then
biweekly
until
termination.
Clinical
evaluations
to
detect
cholinergic
signs,
ophthalmological
evaluations,
hematology,
clinical
chemistries,
urinalysis
were
performed
on
all
animals
pre­
treatment,
on
weeks
13,
26,
39,
52,
65,
78,
91,
and
at
termination.
Plasma,
and
RBC
cholinesterase
was
determined
at
2­
week
intervals
during
the
first
13
weeks
and
at
about
3
month
intervals
thereafter.
Brain
cholinesterase
was
determined
immediately
after
necropsy.
Treatment
had
no
effects
on
general
appearance
and
behavior,
and
toxic
signs,
ophthalmoscopy
examinations,
food
consumption,
body
weight,
hematology,
clinical
chemistry,
organ
weight
and/
or
histopathology.
At
2
ppm,
plasma
and
RBC
cholinesterase
(
ChE)
was
inhibited
50
and
33%
in
males
and
22
and
36%
in
females,
respectively,
during
week
40.
Large
fluctuations
in
plasma
and
RBC
ChE
inhibitions
occurred
until
the
dose
was
raised
to
8
ppm.
By
the
termination
(
104
weeks)
of
study,
the
plasma,
RBC
and
brain
ChE
was
inhibited
65,
58,
and
34%
in
males
and
49,
48
and
18%
in
females,
respectively,
compared
to
pre­
treatment
values.
Based
on
the
above,
the
Systemic
Toxicity
NOAEL
=
2
ppm
(
0.05
mg/
kg/
day)
and
LOAEL
>
2
ppm
.
The
cholinesterase
NOAEL
=
1
ppm
(
0.025
mg/
kg/
day)
and
LOAEL
=
2
ppm
(
0.05
mg/
kg/
day)
,
based
on
plasma
and
RBC
ChE
inhibition.

The
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
a
chronic
toxicity
study
(
83­
1b)
in
the
dog.

4.6
Carcinogenicity
The
two
carcinogenicity
studies
in
mice
and
rats
were
adequately
conducted
and
showed
no
treatment
related
carcinogenicity.
The
study
in
mice
showed
only
cholinesterase
inhibition,
but
the
rat
study
showed
body
weight
decrement,
Harderian
gland
degeneration,
and
lesions
of
the
eye
and
optical
nerve,
all
at
higher
dose
levels
than
the
cholinesterase
inhibition.

870.4200b
Carcinogenicity/
Mice
(
83­
2b)

­
15­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
CITATION:
Hayes,
R.
H
(
1983)
Oncogenicity
study
of
disulfoton
technical
on
mice.
Corporate
Toxicology
Department,
Mobay
Chemical
Corporation,
Stilwell,
KS.
Study
No.
80­
271­
04.
August
10,
1983.
MRID
00129456.
Unpublished
study.

EXECUTIVE
SUMMARY:
In
a
carcinogenicity
toxicity
study
(
MRID
00129456
&
00139598)
,
disulfoton
(
98.2%
a.
i.
)
was
administered
to
50
Crl:
CD­
1
mice/
sex/
dose
in
the
diet
at
dose
levels
of
0,
1,
4,
or
16
ppm
(
0.15,
0.6,
or
2.4
mg/
kg/
day,
converted)
for
108
weeks.
In
addition,
10
mice/
sex/
group
were
used
as
replacement
animals.
Cholinesterase
activity
in
the
plasma,
RBC,
and
brain
was
determined
at
final
sacrifice
for
10
mice/
sex
randomly
selected
from
the
control
and
16
ppm
groups.
Treatment
had
no
effect
on
bodyweights,
food
consumption,
hematology,
and
mortality.
Eight
mice
i.
e.
,
1
male
and
3
females
from
the
1
ppm
group,
3
males
from
the
4
ppm
group,
and
one
male
from
the
16
ppm
group,
died
during
the
first
month
and
were
replaced.
Survival
at
18
months
ranged
from
76
­
86%
in
all
males,
and
68
­
82%
in
all
females.
At
termination
survival
ranged
from
56
­
66%
and
38
­
54%
,
in
males
and
females,
respectively.
Cholinesterase
(
ChE)
was
markedly
inhibited
at
the
high­
dose.
In
males,
the
plasma,
RBC
and
brain
ChE
was
inhibited
79,
56,
and
44%
;
and
in
females
it
was
inhibited
82,
50,
and
46%
,
respectively,
compared
to
controls.
Enlarged
spleen,
liver,
and
lymph
nodes
were
observed
with
greater
frequency
in
females
than
males,
;
histologically
diagnosed
as
lymphomas.
The
number
of
animals
with
malignant
lymphoma,
of
all
histologic
cell
types,
were
10,
9,
12,
and
15
in
males
and
27,
22,
26,
and
34
in
females,
at
0,
1,
4,
and
16
ppm,
respectively.
Tumor
incidence
lacked
statistical
significance
by
either
the
Chi­
square
or
Fisher
exact
test.
In
high­
dose
females,
absolute
and
relative
kidney
weights
increased
22%
and
11%
,
respectively,
probably
related
to
increased
incidence
of
lymphomas
in
this
organ.
None
of
the
increased
organ
weights/
histopathological
findings
were
considered
treatment­
related.
Based
the
above
findings,
the
Systemic
Toxicity
LOAEL
>
2.4
mg/
kg/
day
and
LOAEL
=
2.4
mg/
kg/
day
,
based
on
plasma,
RBC
and
brain
ChE
inhibition
in
males
and
females.
The
NOAEL
=
0.6
mg/
kg/
day
.
At
the
doses
tested,
there
was
not
a
treatment
related
increase
in
tumor
incidence
when
compared
to
controls.
Dosing
was
considered
adequate
for
testing
the
carcinogenic
potential
of
disulfoton,
even
though,
there
was
no
clear
indications
of
systemic
toxicity
such
as
body
weight
gains
and
liver
specific
enzymes.
The
highest
dose
tested
in
this
study
is
approximates
35%
of
the
LD50
and
higher
dietary
concentrations
would
have
resulted
in
significant
compound­
related
mortality
of
the
test
animals.

The
study
is
classified
as
Acceptable
,
and
satisfies
the
guideline
requirement
for
a
oncogenicity
study
(
83­
2b)
in
mice.

4.7
Combined
Chronic/
Carcinogenicity
870.4300
Combined
Chronic/
Carcinogenicity
­
Rats
CITATION
:
Hayes,
R.
H
(
1985)
Chronic
feeding/
oncogenicity
study
of
technical
disulfoton
(
Di­
SYSTON)
with
rats.
Mobay
Chemical
Corporation,
Stilwell,
KS.
Study
No.
82­
271­
01.
June
25,
1985.
MRID
#
s
00146873.
Unpublished.
and
­
16­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Supplementary
data
upgrading
MRID#
00146873
from
supplementary
to
acceptable
on
the
Harderian
gland
(
MRID#
41850001)
and
optical
and
optic
nerve
lesions
(
MRID#
41850002)
.

EXECUTIVE
SUMMARY:
In
a
chronic
feeding/
carcinogenicity
study
(
MRID
#
00146873,
41850001,
41850002)
Disulfoton
(
98.1%
a.
i.
,
Batch
No.
79­
R­
255­
40)
was
administered
to
60
Fischer
344
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
0.8,
3.3,
or
13
ppm
(
0,
0.04,
0.165,
or
0.650
mg/
kg/
day,
converted
by
std.
tables)
for
105
weeks.
Hematological
determinations
were
done
on
20/
sex/
dose
and
urine
and
blood
chemistry
on
10/
sex/
dose,
randomly
selected,
at
0,
3,
6,
12,
18,
and
24
months.
Plasma
and
red
cell
cholinesterase
(
ChE)
was
determined
on
10
rats/
sex/
dose
at
pre­
treatment,
4,
14,
27,
53,
79
and
105
weeks
and
brain
ChE
at
termination.
Administration
of
disulfoton
in
the
diet
up
to
13
ppm
had
no
effect
on
mortality,
hematology,
clinical
chemistry
and
urine
analysis.
Mean
body
weights
of
high­
dose
rats
were
significantly
depressed
throughout
the
study.
Body
weight
gains
of
high­
dose
males
and
females
were
depressed
29%
and
48%
,
respectively,
by
termination
when
compared
to
the
controls.
At
the
mid
and
low
dose,
mean
body
weights
of
males
were
sporadically
depressed,
however,
by
the
end
of
study
the
mean
body
weights
were
similar
to
controls.
Females
body
weights
were
not
effected
at
these
dose
levels.
At
13
ppm,
in
females
the
absolute
heart
(
9%
)
,
liver
(
17%
)
,
and
testes
(
24%
)
were
decreased;
in
females
the
heart
(
13%
)
,
kidneys
(
13%
)
,
liver
(
27%
)
and
ovaries
(
57%
)
decreased.
Absolute
brain
weight
was
unchanged
in
males
and
females.
In
high­
dose
females
the
relative
brain
(
59%
)
,
heart
(
33%
)
,
and
kidneys
(
34%
)
increased,
compared
to
the
controls.
Also,
the
relative
lung
(
72%
)
and
liver
(
9%
)
and
brain
(
58%
)
weights
were
increased.
At
this
dose
the
male
relative
brain
weights
were
increased
by
17%
.
None
of
the
aforementioned
organ
weights
were
associated
with
any
histopathology
corroborative
of
toxicity.
In
high­
dose
males
Harderian
gland
degenerative
changes
increased
to
460%
of
controls
and
in
females
the
elevation
was
dose­
related
(
800,
1100
and
1633%
of
control
values,
respectively,
all
p
#
0.05)
.
Since
there
is
no
Harderian
gland
in
the
humans,
the
significance
of
pathological
changes
seen
in
the
rat
are
uncertain.
In
addition,
corneal
vascularity
(
693%
of
control)
,
corneal
epithelial
hyperplasia
(
1633%
of
control)
and
optic
nerve
degeneration
(
145%
of
control)
were
elevated
in
high­
dose
females
and
corneal
vascularity
(
329%
of
control)
in
males.
The
eye
histopathology
was
not
affected
in
the
mid
and
low
doses.
Based
on
the
above,
the
Systemic
Toxicity
NOAEL
=
0.8
ppm
(
0.04
mg/
kg/
day)
and
LOAEL
=
3.3
ppm
(
0.165
mg/
kg/
day)
,
based
on
Harderian
gland
degeneration.
At
termination,
a
dose­
related
inhibition
in
plasma,
red
cell
and
brain
ChE
was
observed
at
all
doses
in
both
sexes.
In
males
the
plasma,
red
cell
and
brain
ChE
was
inhibited
11%
­
94%
,
19%
­
80%
,
and
16%
­
79%
;
and
in
females,
it
was
25%
­
95%
,
12%
­
76%
,
and
21%
­
82%
,
respectively,
compared
to
the
controls.
The
Cholinesterase
NOAEL
<
0.8
ppm
(
0.04
mg/
kg/
day)
and
LOAEL
=
0.8
ppm
(
0.04
mg/
kg/
day)
,
based
on
plasma,
red
cell
and
brain
ChE
inhibition
in
males
and
females.
Starting
at
week
4
the
LOAEL
in
plasma
ChE
inhibition
was
4
ppm
(
0.165
mg/
kg/
day)
in
males
(
27%
)
and
females
(
64%
)
with
a
NOAEL
of
1
ppm
(
0.04
mg/
kg/
day)
.
Starting
at
week
4
the
LOAEL
in
erythrocyte
ChE
inhibition
was
increased
at
1
ppm
(
0.04
mg/
kg/
day)
(
LDT)
in
males
(
16%
)
and
females
(
30%
)
with
no
NOAEL.
The
maximum
tolerated
dose
(
MTD)
was
reached,
based
on
decreased
body
weights
and
body
weight
gains
and
is
considered
adequate
to
test
the
carcinogenic
potential
of
Disulfoton.
Disulfoton
treatment
did
not
alter
the
spontaneous
oncogenicity
profile
in
both
males
and
female
Fischer
344
rats
under
the
test
conditions.
In
males
and
females,
leukemia,
adrenal
cortex
adenoma,
adrenal
pheochromocytoma,
pituitary
adenoma
and
carcinoma
and
thyroid­
C
cell
adenoma
was
­
17­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
most
frequently
observed.
Mammary
gland
fibroadenoma
in
both
sexes,
but
most
frequently
in
females.
Testicular
interstitial
adenoma
in
males
and
stromal
polyp
of
the
uterus
in
females
was
observed.
All
these
neoplasms
were
similar
in
type,
time
of
onset,
and
incidence
in
both
controls
and
disulfoton
treated
animals.

The
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
a
chronic
feeding/
carcinogenicity
study
(
83­
5)
in
the
rat.

870.4300
Chronic
Feeding/
Oncogenicity
Study/
Rats
(
83­
5)

CITATION:
Carpy,
S.
;
Klotzsche,
C.
;
Cerioli,
A.
(
1975)
Disulfoton:
2­
Year
Feeding
Study
in
Rats.
Sandoz,
Ltd.
,
Switzerland.
Report
No.
47069.
December
15,
1976.
MRID
00069966.
Unpublished.

EXECUTIVE
SUMMARY:
In
a
chronic
feeding/
carcinogenicity
study
(
MRID
00069966)
Technical
Di­
Syston
®
(
(
95.7%
a.
i.
)
was
administered
to
60
SPF
Sprague­
Dawley
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
0.5/
5.0,
1.0
or
2.0
ppm
(
0,
0.0215/
0.1900,
0.0456,
or
0.0893
mg/
kg/
day
in
males
and
0,
0.0267/
0.1960,
0.0419
or
0.1033,
mg/
kg/
day
in
females,
respectively;
calculated)
for
104
weeks.
The
0.5
ppm
dose
was
fed
for
81
weeks,
then
increased
to
2
ppm
because
of
no
effects
seen
at
the
1
ppm
dose
level.
The
rats
in
the
2
ppm
group
were
initially
maintained
at
1.5
ppm
for
4
­
5
weeks,
then
increased
to
full
dose.
Body
weight,
food
consumption,
food
efficiency,
hematology,
clinical
chemistries,
and
urinalysis
were
determined.
Plasma,
red
cell
and
brain
cholinesterase
was
determined
from
5
overnight
fasted
animals/
sex/
group
at
termination.
Necropsy
was
done
on
10
animals/
sex/
dose;
all
others
were
examined
for
tumors.
Histopathology
was
done
on
5
animals/
sex
from
the
control
and
the
5
ppm
group.
Treatment
with
Di­
Syston
did
not
effect,
food
consumption,
body
weight
gain,
hematology,
clinical
chemistry,
and
urinalysis.
Mortality
was
high
(
20
­
37%
)
in
females
but
lacked
the
dose
response
and
no
clear
explanation
was
offered
for
cause
of
death;
more
than
1/
3
of
the
dead
animals
autolyzed.
At
0.5/
5
ppm,
in
males
the
absolute/
relative
liver,
spleen
and
kidney
weights
increased
12%
/
8%
,
21%
/
17%
and
23%
/
19%
,
respectively
(
P
#
0.05)
;
however,
the
histopathology
of
the
organs
were
unremarkable.
There
was
a
trend
for
decreased
absolute
and
relative
brain
weights
in
males
and
increased
trend
in
females.
The
Systemic
Toxicity
LOAEL
>
1
ppm
.
Cholinesterase
levels
in
plasma,
red
cells
and
brain
was
inhibited
in
males
and
females
at
two
higher
doses
and
it
was
dose­
related.
At
2
ppm,
the
plasma,
red
cell
and
brain
ChE
of
males
was
inhibited
14,
9.3,
9%
,
and
in
females
22,
13.3
and
17%
,
respectively,
compared
to
the
controls.
At
the
0.5/
5
ppm
dose,
plasma,
red
cell
and
brain
ChE
of
males
and
females
was
inhibited
20
­
39.6,
18.3
­
27.1
and
25
­
36%
,
respectively.
ChE
levels
in
the
1
ppm
group
males
and
females
was
not
effects.
The
ChE
NOAEL
=
1
ppm
and
the
LOAEL
=
2
ppm
,
based
on
decreased
plasma,
red
cell
and
brain
cholinesterase
levels.

The
study
is
classified
as
Unacceptable
and
can
not
upgraded
because
multiple
deficiencies
in
the
conduct
of
the
study
and
does
not
satisfy
the
guideline
requirement
for
chronic
toxicity/
oncogenicity
study
(
83­
5)
in
the
rat.

­
18­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
4.8
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.

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
.

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.

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#
40945001;
Doc#

­
19­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
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.

Other
EPA
Sponsored
Mutagenicity
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.

4.9
Neurotoxicity
The
neurotoxicity
studies
conducted
on
disulfoton
showed
cholinesterase
inhibition
and
effects
associated
with
cholinesterase
inhibition,
but
no
neuropathy
in
the
hen
or
the
rat
studies.

870.6100
Acute
Delayed
Neurotoxicity
­
Hen
CITATION:
Andrews,
P
and
Popp,
A
(
1999)
S
S276(
c.
n.
:
Disulfoton)
Study
for
Delayed
neurotoxicity
following
Acute
Oral
Administration
to
Hens,
EPA
Guideline
81­
7,
Bayer
Report
No.
109423.
75
pages.
November
5,
1999.
MRID
44996401.
Unpublished.

SPONSOR:
Bayer
Corp.
,
Agriculture
Division,
8400
Hawthorn
Road,
Kansas
City,
MO
64120­

­
20­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
0013.
Telephone:
816­
242­
2000.
Dr.
Premjit
Halarnkar
(
816­
242­
2331)
contact.

EXECUTIVE
SUMMARY:
In
an
acute
delayed
neurotoxicity
study
in
hens
(
MRID#
44996401)
,
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
OPIDP.
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
OPIDP
in
hens
dosed
with
disulfoton.
Microscopic
examination
of
the
test
birds
showed
3
(
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
(
OPIDP)
in
hens.

The
study
is
acceptable
for
an
acute
delayed
neurotoxicity
study
(
OPPTS#
870.6100)
in
hens.

870.6200
Acute
Neurotoxicity
­
Rat
CITATION:
Sheets,
LP
and
Lake,
SG
(
1993)
An
acute
oral
neurotoxicity
screening
study
with
technical
grade
disulfoton
(
Di­
Syston
®
)
in
rats
Study
number
92­
412­
OB
(
Miles
no.
103992)
.

­
21­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Conducted
by
Miles
Inc.
,
Agriculture
Division
fo
Miles
Inc.
MRID#
42755801.

Executive
Summary
:
In
an
acute
neurotoxicity
screening
study,
disulfoton
(
97.8%
pure)
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
(
MRID#
42755801)
.
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.

This
study
is
classified
as
core­
minimum
and
satisfies
the
guideline
requirement
for
an
acute
neurotoxicity
screen
(
81­
8)
.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
­
Rats
CITATION:
L.
P.
Sheets
and
B.
F.
Hamilton
(
1993)
A
subchronic
dietary
neurotoxicity
screening
study
with
technical
grade
disulfoton
(
Di­
Syston
®
)
in
Fischer
344
rats.
Testing
lab.
:
Miles
Inc.
Study#
92­
472­
NS
(
106332)
.
Date:
9/
23/
1993.
MRID#
42977401.
Unpublished
study.

EXECUTIVE
SUMMARY:
In
a
subchronic
neurotoxicity
study
(
MRID#
42977401)
,
disulfoton
(
98.7
 
99.0%
pure)
was
administered
in
the
diet
to
12
male
and
12
female
Fischer
344
rats
at
dietary
levels
of
0,
1,
4,
or
16
ppm
(
0,
0.063,
0.270,
and
1.08
mg/
kg/
day
in
males
and
0,
0.071,
0.315,
and
1.31
mg/
kg/
day
in
females)
.
Of
these
12
rats/
sex/
dose,
6/
sex/
dose
were
used
for
a
neurohistopathological
examination
at
the
end
of
the
study.
At
4
ppm,
females
had
muscle
fasciculations,
urine
staining,
and
increased
food
consumption
(
approximately
110%
of
control)
.
At
16
ppm,
both
males
and
females
had
increased
reactivity,
perianal
staining,
tremors,
increased
defecation,
decreased
forelimb
grip
strength
(
37
 
86%
of
control)
,
decreased
motor
and
locomotor
activity
(
39
 
71%
of
control)
,
decreased
body
weight
gain
(
81
 
83%
of
control)
,
and
corneal
opacities.
At
16
ppm,
males
also
had
muscle
fasciculations
and
appeared
sluggish,
and
one
female
died
due
to
cholinergic
intoxication.
The
study
LOAEL
is
4
ppm
(
0.315
mg/
kg/
day)
and
the
study
NOAEL
is
1
ppm
(
0.071
mg/
kg/
day)
,

­
22­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
based
on
clinical
signs
in
females
consistent
with
neurotoxicologic
effects
of
cholinesterase
inhibition.
Erythrocyte,
plasma,
and
brain
cholinesterase
activities
were
inhibited
by
15
 
23%
,
59
 
80%
,
and
87
 
100%
in
females
at
1,
4,
and
16
ppm,
respectively,
and
20
 
67%
and
66
 
100%
in
males
at
4
and
16
ppm,
respectively.
Males
at
1
ppm
had
a
statistically
significant
inhibition
of
erythrocyte
cholinesterase
at
13
weeks
(
15%
inhibition)
;
other
cholinesterase
activities
in
males
at
1
ppm
were
not
significantly
affected.
The
LOAEL
for
inhibition
of
cholinesterase
activity
is
1
ppm
and
the
NOAEL
for
inhibition
of
cholinesterase
activity
is
less
than
1
ppm.

This
study
is
classified
as
core­
guideline
and
satisfies
the
guideline
requirement
for
a
subchronic
neurotoxicity
screen
(
82­
7)
.

4.10
Metabolism
Disulfoton
is
rapidly
absorbed
and
excreted.
Three
minor
oxidative
metabolites
(
Di­
Syston
sulfone,
Di­
Syston
oxygen
analogue
sulfoxide,
and
Di­
Syston
oxygen
analog
sulfone)
were
identified.
Sex­
related
differences
in
pattern
of
these
metabolites
and
differences
between
the
single
dose
and
the
repeat
dose
groups
were
attributed
to
differences
in
metabolic
rates,
rather
than
different
metabolic
pathways.

870.7485
Metabolism
­
Rat
CITATION:
Lee,
SGK,
Hanna,
LA,
Johnston,
K
and
Ose,
K
(
1985)
Excretion
and
Metabolism
of
Di­
syston
®
in
Rats.
.
Study#
90946.
Dated
December
9,
1985,
September
20,
1988,
May
17,
1990
September
26,
1990
and
April
29,
1992.
Conducted
by
Mobay
Corp.
MRID#
42565101.

EXECUTIVE
SUMMARY:
The
aborption,
distribution,
metabolism
and
excretion
of
Di­
systion
®
were
studied
in
groups
of
male
and
female
Sprague
Dawley
rats
administered
a
single
dose
of
0.2
or
1.0
mg/
kg
Di­
syston
®
­
­
ethylene­
1­
14
C,
or
a
14­
day
repeat
oral
dose
of
0.2
mg/
kg
unlabeled
Di­
Syston
®
followed
by
0.2
mg/
/
kg
[
14
C
]
­
labeled
Di­
Syston
®
on
day
15.
.
[
14
C
]
­
Di­
Syston
®
was
rapidly
absorbed,
distributed,
metabolized
completely
and
eliminated
in
rats
under
all
dosing
regimens.
Over
95%
of
the
recovered
label
was
excreted
in
the
urine
in
all
groups,
and
excretion
was
approximately
90%
complete
within24
hours
of
dosing.
Less
than
2%
of
the
recovered
label
was
in
the
feces.
Bioaccumulation
was
also
not
observed,
with
#
0.3%
of
the
radiolabel
recovered
in
the
tissues
and
#
1%
in
the
carcass.
A
major
metabolite
(
43­
60%
of
the
radioactivity
in
the
urine)
and
a
minor
metabolite
(
6­
20%
of
the
urinary
radioactivity)
were
produced
by
hydrolysis
of
oxidative
metabolites.
These
metabolites
were
identified
as
sulfonyl
[
1­
(
ethylsulfonyl)
­
2­
(
methylsulfinyl)
ethane
]
and
sulfinyl
[
1
­
(
ethylsulfinyl)
­
2­
(
methylsulfinyl)
ethane
]
,
respectively.
Three
minor
oxidative
metabolites
(
Di­
Syston
sulfone,
Di­
Syston
oxygen
analogue
sulfoxide,
and
Di­
Syston
oxygen
analog
sulfone)
were
identified.
Sex­
related
differences
in
pattern
of
these
metabolites
and
differences
between
the
single
dose
and
the
repeat
dose
groups
were
attributed
to
differences
in
metabolic
rates,
rather
than
different
metabolic
pathways.
A
metabolic
pathway
for
Di­
Syston
was
proposed.

­
23­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Study
classification:
The
study
is
classified
as
acceptable.
The
study
satisfies
the
registration
requirements
under
Guideline
85­
1
(
and
Addendum
7)
for
metabolism
in
rats.
Althjough
there
were
minor
deficiencies
in
the
study,
they
did
not
affect
the
overall
study
results
and
conclusion
(
see
Reviewer
 
s
Discussion,
Section
E)
.
A
metabolite
was
not
fully
characterized,
however,
the
testing
laboratory
inducated
that
after
using
different
solvents
the
metabolite
co­
chromatographed
with
a
oxygenated
hydrolytic
product
of
disulfoton,
1­
(
ethylsulfonyl)
­
2­
(
methylsulfinyl)
ethane
and
material
at
the
origin
co­
chromatographed
with
1­
(
ethylsulfinyl)
­
2­
(
methylsulfinyl)
ethane.

870.7600
Dermal
Absorption
­
Rats
Dermal
absorption
was
determined
to
be
36%
.
Since
the
total
amount
absorbed
may
contribute
to
the
toxicity,
total
absorption
at
the
mid­
dose
and
after
the10
hour
skin
wash
was
used
for
risk
assessment
(
32.7%
plus
3.5%
residue
absorbing
after
10
hours)
.

CITATION:
Warren,
D.
L.
(
1994)
Dermal
Absorption
of
14
C­
Disulfoton
from
the
DISYSTON
8
Formulation.
Miles,
Stilwell,
KS.
Study
No.
94­
722­
YP.
August
30,
1994.
MRID
43360201.
Unpublished.

EXECUTIVE
SUMMARY:
In
a
dermal
absorption
study
(
MRID
43360201)
14
C­
Disulfoton
(
99.3%
a.
i.
,
Specific
activity
53
mCi/
mmol;
cold
disulfoton
86.5%
a.
i.
)
in
150
F
l
emulsion
was
applied
to
clipped
backs
(
.
15
cm
2
area)
of
4
male
rats/
dose/
group
at
dose
levels
of
0.85,
8.5,
and
85
F
g/
cm
2
for
1,
4,
and
10
hours
(
MRID#
43360201)
.
At
the
10th
hour
all
the
skins
were
washed
to
terminate
the
exposure.
At
the
termination
of
exposure,
these
animals
were
kept
for
an
additional
168
hours
to
determine
kinetics
of
absorption
and
excretion
of
the
material
remaining
on/
in
the
skin
following
washing.
Following
the
application
of
the
material,
the
rats
were
placed
individually
in
metabolism
cages
and
total
urine
and
feces
collected
separately.
Following
the
wash
of
the
application
site,
the
urine
and
feces
were
collected
in
24
hour
aliquots.
Disulfoton
is
well
absorbed
and
about
31
­
37%
and
2.7
­
3.3%
of
the
administered
dose
was
excreted
in
the
urine
and
feces,
respectively.
Ten
to
30%
of
the
applied
dose
evaporated
during
the
10
hours
exposure
period
in
all
groups.
Skin
residues
as
percent
of
administered
dose
increased
with
dose
and
decreased
with
time
in
all
groups.
The
%
absorbed
increased
with
time,
essentially
equal
with
time.
At
low
dose,
the
%
absorption
at
1,
4,
and
10
hours
was
5.9,
13.7
and
26%
;
at
mid
dose
it
was
4.6,
15.9,
and
32.7%
;
and
at
high
dose
3.6,
12.5
and
25.6%
,
respectively.

The
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
dermal
penetration
study
(
85­
3)
in
the
rat.

4.11
Special/
other
Studies
Special
studies
on
disulfoton
included
3­
5
day
inhalation,
6­
months
cholinesterase
study
and
a
3­
day
dermal
studies
in
rats.
The
3­
5
day
inhalation
study
showed
an
acute
LC50,
and
a
LOAEL
for
cholinesterase
inhibition.
The
6­
month
cholinesterase
study
was
required
because
the
chronic/
carcinogenic
study
in
rats
did
not
show
a
NOAEL
for
cholinesterase.
The
3­
day
dermal
­
24­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
study
was
conducted
to
aid
in
the
assessment
of
pesticide
handler
risk
and
to
determine
a
NOAEL
in
the
rat
for
a
formulated
product.
All
three
studies
were
used
for
risk
assessment.

870.3100
and
Non­
Guideline
Acute
and
3­
5
Day
Inhalation
Study/
Rats
CITATION:
Anonomus
(
1978)
Acute
and
5­
Day
Inhalation
in
the
rat
with
disulfoton.
Study
laboratory:
Bayer
AG
Instit.
Study#
7827.
Date:
9/
27/
78.
MRID#
00147754.
Unpublished.

Executive
Summary
:
Disulfoton,
technical
(
94.4%
)
was
administered
to
20
Wistar
rats/
sex/
group
at
0,
34,
48,
51,
64,
78
or
96
F
g/
L
for
males
and
0,
3.4,
5,
7,
10,
13
or
20
F
g/
L
for
females
for
4
hours
in
a
nose
only
experiment
(
MRID
No.
:
Accession#
258569)
.
The
NOAEL
for
death
was
34
F
g/
L
for
males
and
3.4
F
g/
L
for
females.
LC50
for
males
was
60
F
g/
L
with
animals
dying
at
$
48
F
g/
L.
The
LC50
for
females
was
15
F
g/
L
with
animals
dying
at
$
5
F
g/
L.
In
addition,
10
rats/
sex
were
administered
disulfoton
for
4
hour/
day
for
5
days
by
inhalation
at
0,
0.5,
1.8
or
9.8
F
g/
L
in
a
nose
only
exposure;
the
following
cholinesterase
inhibition
studies
were
conducted
on
5
rats/
sex/
group
after
one
of
the
five
4
hour
exposures
in
the
5
day
study.
After
1
exposure
in
males,
plasma
cholinesterase
inhibition
(
$
17%
)
occurred
at
$
1.8
F
g/
L
and
erythrocyte
cholinesterase
inhibition
(
$
15%
)
occurred
at
9.8
F
g/
L.
After
1
exposure
in
females,
plasma
cholinesterase
inhibition
(
$
40%
)
occurred
at
$
1.8
F
g/
L
and
erythrocyte
cholinesterase
inhibition
(
$
23%
)
occurred
at
$
9.8
F
g/
L.
After
3
to
5
exposures
in
males,
plasma
cholinesterase
inhibition
was
reduced
(
$
40%
)
and
erythrocyte
cholinesterase
inhibition
(
$
16%
)
at
$
1.8
F
g/
L.
After
3
to
5
exposures
in
females,
plasma
cholinesterase
inhibition
was
reduced
(
$
31%
)
at
$
0.5
F
g/
L
and
erythrocyte
cholinesterase
inhibition
was
reduced
(
$
17%
)
at
$
1.8
F
g/
L.
No
deaths
occurred
after
one
4
hours
exposure
at
9.8
F
g/
L
in
either
males
or
females,
however,
deaths
occurred
in
females
after
the
3rd
exposure
at
9.8
F
g/
L.
The
acute
inhalation
NOAEL/
LOAEL
for
males
and
females
are
0.0005/
0.0018
mg/
L
based
on
increased
plasma
cholinesterase
inhibition
and
NOAEL/
LOAEL
of
0.0018/
0.0098
mg/
L
for
males
and
females
based
on
increased
erythrocyte
cholinesterase
inhibition
after
1
exposure
.
After
3
to
5
exposures,
males
showed
NOAEL/
LOAEL
of
0.0005/
0.0018
mg/
L
based
on
increased
plasma
and
erythrocyte
cholinesterase
inhibition.
Females
showed
NOAEL/
LOAEL
of
<
0.0005/
0.0005
mg/
L
based
on
increased
plasma
cholinesterase
inhibition
after
3
to
5
exposures
and
the
NOAEL/
LOAEL
are
0.0005/
0.0018
mg/
L
based
on
increased
erythrocyte
cholinesterase
after
3
to
5
exposures
.

The
study
is
acceptable
under
Guideline
81­
3
for
acute
inhalation
in
rats
and
is
acceptable
for
a
NG
3­
5­
day
inhalation
study
in
rats.

Non­
Guideline
Special
6­
Month
Cholinesterase
Study
CITATION:
W.
R.
Christenson,
B.
S.
Wahle
(
1993)
Technical
grade
disulfoton
(
Di­
Syston
®
)
:
A
­
25­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
special
6­
month
feeding
study
to
determine
a
cholinesterase
no­
observed­
effect
level
in
the
rat.
Study#
91­
972­
IR,
(
12/
3/
1993)
,
conducted
at
Miles
Inc.
,
Agricultural
Division,
Toxicology
Stilwell,
Kansas
for
Miles
Inc.
,
Agricultural
Division,
Kansas
City,
Missouri.
MRID
No.
:
43058401.
Unpublished
Report.

EXECUTIVE
SUMMARY:
In
a
6­
month
study
designed
to
establish
a
NOAEL
and
LOAEL
for
cholinesterase
inhibition,
technical
grade
disulfoton
(
98­
99%
pure)
was
administered
in
the
diet
to
35
male
and
female
Fischer
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)
(
MRID#
43058401)
.
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)
.

Core
classification:
The
special
non­
guideline
study
is
acceptable
for
the
requested
6­
months
cholinesterase
study
in
rats.

Non
Guideline
3­
Day
Dermal
study
­
Rats
CITATION:
Croutch,
CR
and
Sheets,
LP
(
2000)
.
Repeat­
Exposure
(
3­
Day)
Dermal
Toxicity
Study
with
1%
G
Di­
Syston
®
)
in
Rats.
Testing
Laboratory
name
Bayer
Corp.
,
Stilwell,
KA.
Laboratory
report
number:
109956,
Study#
00­
S22­
BS.
October
16,
2000.
MRID#
45239602.
Unpublished
SPONSOR:
Bayer
Corp.
,
Stilwell
KA
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
­
26­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
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
shave
the
test
site
(
about
10%
of
the
body
surface)
,
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
cholinestersase
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
day
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
(
equivant
to
1.0
mg
a.
i.
/
kg)
with
a
LOAEL
of
200
mg/
kg/
day
(
equivalent
to
2.0
mg
a.
i.
/
kg)
based
female
plasma
cholinesterase
deprssion
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
a
(
NG)
1­
day
or
3­
day
dermal
study
in
the
rat.

5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
8.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
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
after
the
skin
wash
10
hours
post­
application
was
approximately
36%
at
the
mid­
dose
(
MRID#
43360201)
.

Dermal
Aborption
Factor:
36%

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.

­
27­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
5.3
Classification
of
Carcinogenic
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.

5.3.1
Quantification
of
Carcinogenic
Potential
Not
applicable
6.0
FQPA
Considerations
Adequacy
of
Toxicology
Database
The
toxicology
database
is
adequate
for
FQPA
considerations.
On
January
19,
2000,
the
HIARC
reviewed
the
submitted
acute
delayed
neurotoxicity
study
with
disulfoton
in
the
hen
which
was
previously
identified
as
data
gap.
The
HIARC
determined
that
this
study
is
acceptable
and
therefore,
the
toxicology
database
is
now
adequate
according
to
the
standard
Subdivision
F
and/
or
OPPTS
Series
870
Guideline
requirements
for
a
food­
use
chemical.

a.
Evaluation
of
Neurotoxicity
The
repeat
acute
delayed
neurotoxicity
study
in
hens
(
required
by
HIARC
during
the
Hazard
Assessment
of
the
Organophosphates;
May
12­
14,
1998)
has
been
received
and
reviewed,
and
found
to
be
negative
for
organophosphate
induced
delayed
neuropathy
(
OPIDP)
.

There
are
also
acute
and
subchronic
neurotoxicity
studies
with
disulfoton
in
rats.
The
acute
study
shows
neurotoxicity
in
the
form
of
tremors
and
muscle
twitching
and
decreased
motor
activity,
but
no
neuropathology
(
MRID
No.
42755801)
.
The
subchronic
study
shows
similar
neurotoxicity
and
nominal
increased
incidence
of
neuropathy
in
the
form
of
nerve
fiber
degeneration
in
the
optic
nerve
and
thoracic
spinal
cord
at
the
highest
dose
tested
(
MRID
No.
42977401)
.
On
January
19,
2000,
the
HIARC
concluded
that
the
differences
in
the
effects
observed
between
the
high
dose
animals
and
control
animals
in
the
subchronic
neurotoxicity
study
in
rats,
were
not
sufficiently
great
to
indicate
that
a
treatment­
related
effect
had
occurred.

b.
Developmental
Toxicity
In
a
prenatal
developmental
toxicity
study
in
rats,
developmental
toxicity
occurred
only
in
the
presence
of
maternal
toxicity
(
MRID
No.
00129458)
.

­
28­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
In
a
prenatal
developmental
toxicity
study
in
rabbits,
there
was
no
evidence
of
developmental
toxicity
even
at
the
highest
dose
tested
(
MRID
No.
00147886)
.

c.
Reproductive
Toxicity
In
a
two­
generation
reproduction
study
rats,
the
effects
in
pups
were
caused
by
maternal
toxicity
and
not
the
direct
toxicity
of
disulfoton
on
pups
(
MRID
No.
44440801)
.

6.1
Special
Sensitivity
to
Infants
and
Children
Prenatal
developmental
toxicity
studies
in
rats
and
rabbits
provided
no
indication
of
increased
susceptibility
of
rat
or
rabbit
fetuses
to
in
utero
exposure
to
disulfoton.
There
was
no
indication
of
increased
susceptibility
in
the
offspring
as
compared
to
parental
animals
in
the
two
generation
reproduction
study.
In
these
studies,
effects
in
the
fetuses/
offspring
were
observed
only
at
or
above
treatment
levels
which
resulted
in
evidence
of
maternal/
parental
toxicity.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
On
January
19,
2000,
the
HIARC
concluded
that
although
a
developmental
neurotoxicity
study
(
DNT)
with
disulfoton
in
rats
has
been
required
as
part
of
the
Data­
Call­
In
for
select
organophosphates,
this
requirement
was
not,
however,
 
triggered
 
by
a
special
concern
for
the
developing
fetuses
or
young
which
are
generally
used
for
requiring
a
DNT
study
and
an
FQPA
safety
factor
(
e.
g.
:
neuropathy
in
adult
animals;
CNS
malformations
following
prenatal
exposure;
brain
weight
or
sexual
maturation
changes
in
offspring;
and/
or
functional
changes
in
offspring)
.

7.0
RERERENCES
00069966
Carpy,
S.
;
Klotzsche,
C.
;
Cerioli,
A.
(
1975)
Disulfoton:
2­
Year
Feeding
Study
in
Rats.
Sandoz,
Ltd.
,
Switzerland.
Report
No.
47069.
December
15,
1976.
MRID
00069966.
Unpublished.

00073348
Hoffman,
K.
;
Weischer,
C.
H.
;
Luchaus,
G.
;
et
al.
(
1975)
S
276
(
Disulfoton)
Chronic
Toxicity
Study
in
Dogs
(
Two­
year
Feeding
Experiment)
.
Bayer,
AG,
W.
Germany.
Report
No.
45287.
December
15,
1976.
MRID
00073348.
Unpublished.

00129456
Hayes,
R.
H
(
1983)
Oncogenicity
study
of
disulfoton
technical
on
mice.
Corporate
Toxicology
Department,
Mobay
Chemical
Corporation,
Stilwell,
KS.
Study
No.
80­
271­
04.
August
10,
1983.
MRID
00129456.
Unpublished
study.

00129458
Lamb­
DW
and
Hixson­
EJ
(
1983)
Embyrotoxic
and
teratogenic
effects
of
Disulfoton.
Study#
81­
611­
02
submitted
by
Mobay
Chem.
Corp.
May
13,
1983.
MRID#
:
00129458.
Unpublished
Report.

­
29­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
00146873
Hayes,
R.
H
(
1985)
Chronic
feeding/
oncogenicity
study
of
technical
disulfoton
(
Di­
SYSTON)
with
rats.
Mobay
Chemical
Corporation,
Stilwell,
KS.
Study
No.
82­
271­
01.
June
25,
1985.
MRID
#
s
00146873.
Unpublished.
and
Supplementary
data
upgrading
MRID#
00146873
from
supplementary
to
acceptable
on
the
Harderian
gland
(
MRID#
41850001)
and
optical
and
optic
nerve
lesions
(
MRID#
41850002)
.

00147754
CITATION:
Anonomus
(
1978)
Acute
and
5­
Day
Inhalation
in
the
rat
with
disulfoton.
Study
laboratory:
Bayer
AG
Instit.
Study#
7827.
Date:
9/
27/
78.
MRID#
00147754.
Unpublished.

00147886
Tesh­
JM
et
al.
(
1982)
S276:
Effects
of
oral
administration
upon
pregnancy
in
the
rabbit.
An
unpublished
report
(
Bayer
No.
R
2351)
prepared
by
Life
Science
Research,
Essex,
England
and
submitted
to
Bayer
AG,
Wuppertal,
Germany.
Dated
December
22,
1982.
MRID#
00147886.
Unpublished
Report.

00157511
Hixson,
EJ
and
Hathaway,
TR
(
1986)
Effect
of
disulfoton
(
Di­
Syston
®
)
on
reproduction
in
the
rat.
Conducting
laboratory:
Mobay
Chem.
Date:
2/
12/
86.
Study#
82­
671­
02.
MRID#
00157511.
Unpublished
Study.

00162338
Flucke,
W.
(
1986)
Study
of
Subacute
Dermal
Toxicity
to
Rabbits.
Bayer
AG,
Fachbereich
Toxikologie,
Wuppertal
­
Elberfeld,
F.
R.
Germany.
Study
No.
:
14747.
June
20,
1986.
MRID
00162338.
Unpublished.

41224301
Shiotsuka,
RN
(
1989)
Subchronic
inhalation
study
of
technical
grade
disulfoton
(
Di­
Syston
®
)
inhalation
in
rats.
Testing
Lab:
Mobay
Corp.
Study#
88­
141­
AU/
99648.
Date:
7/
31/
89.
MRID#
41224301.
Unpublished
study.

42565101
Lee,
SGK,
Hanna,
LA,
Johnston,
K
and
Ose,
K
(
1985)
Excretion
and
Metabolism
of
Di­
syston
®
in
Rats.
.
Study#
90946.
Dated
December
9,
1985,
September
20,
1988,
May
17,
1990
September
26,
1990
and
April
29,
1992.
Conducted
by
Mobay
Corp.
MRID#
42565101.

42755801
Sheets,
LP
and
Lake,
SG
(
1993)
An
acute
oral
neurotoxicity
screening
study
with
technical
grade
disulfoton
(
Di­
Syston
®
)
in
rats
Study
number
92­
412­
OB
(
Miles
no.
103992)
.
Conducted
by
Miles
Inc.
,
Agriculture
Division
fo
Miles
Inc.
MRID#
42755801.
Unpublished.

42977401
Sheets,
LP
and
Hamilton,
BF
(
1993)
A
subchronic
dietary
neurotoxicity
screening
study
with
technical
grade
disulfoton
(
Di­
Syston
®
)
in
Fischer
344
rats.
Testing
lab.
:
Miles
Inc.
Study#
92­
472­
NS
(
106332)
.
Date:
9/
23/
1993.
MRID#
42977401.
Unpublished.

43058401
W.
R.
Christenson,
B.
S.
Wahle
(
1993)
Technical
grade
disulfoton
(
Di­
Syston
®
)
:
A
­
30­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
special
6­
month
feeding
study
to
determine
a
cholinesterase
no­
observed­
effect
level
in
the
rat.
Study#
91­
972­
IR,
(
12/
3/
1993)
,
conducted
at
Miles
Inc.
,
Agricultural
Division,
Toxicology
Stilwell,
Kansas
for
Miles
Inc.
,
Agricultural
Division,
Kansas
City,
Missouri.
MRID
No.
:
43058401.
Unpublished
Report.

43360201
Warren,
D.
L.
(
1994)
Dermal
Absorption
of
14
C­
Disulfoton
from
the
DISYSTON
8
Formulation.
Miles,
Stilwell,
KS.
Study
No.
94­
722­
YP.
August
30,
1994.
MRID
43360201.
Unpublished.

44248002
Jones,
R.
D.
and
T.
F.
Hastings
(
1997)
Technical
grade
Disulfoton:
A
chronic
toxicity
feeding
study
in
the
Beagle
dog.
Bayer
Corporation,
Stillwell,
KS.
Study
Number
94­
276­
XZ.
Report
No.
107499.
February
5,
1997.
MRID
44248002.
Unpublished.

44440801
Astroff,
A
Barry
(
1997)
A
Two
Generation
Reproductive
Toxicity
Study
with
Disulfoton
Technical
(
Disyston
®
)
in
the
Sprague
Dawley
Rat.
Laboratory
name
Bayer
Corp.
,
Stilwell,
KA.
Laboratory
report
number:
95­
672­
FZ,
report#
108002,
File
8368.
November
19,
1997.
MRID#
44440801.
Unpublished
44996401
Andrews,
P
and
Popp,
A
(
1999)
S
S276(
c.
n.
:
Disulfoton)
Study
for
Delayed
neurotoxicity
following
Acute
Oral
Administration
to
Hens,
EPA
Guideline
81­
7,
Bayer
Report
No.
109423.
75
pages.
November
5,
1999.
MRID
44996401.

45239601
Flucke,
W
(
1988)
S
276
Technical
grade
Disulfoton:
Study
of
the
Subacute
Dermal
Toxicity
to
Rabbits.
Bayer
AG.
,
Germany.
Study
Number
98347.
Report
No.
116342,
January
5,
1988.
MRID
45239601.
Unpublished.

45239602
Croutch,
CR
and
Sheets,
LP
(
2000)
.
Repeat­
Exposure
(
3­
Day)
Dermal
Toxicity
Study
with
1%
G
Di­
Syston
®
)
in
Rats.
Testing
Laboratory
name
Bayer
Corp.
,
Stilwell,
KA.
Laboratory
report
number:
109956,
Study#
00­
S22­
BS.
October
16,
2000.
MRID#
45239602.
Unpublished
­
31­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
8.0
APPENDICES
Tables
for
Use
in
Risk
Assessement
­
32­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
8.1
Toxicity
Profile
Summary
Tables
8.1.1
Acute
Toxicity
Data
Table
on
disulfoton
Guideline
No.
Study
Type
MRID
#
(
S)
.
Results
Toxicity
Category
870.1100
Acute
Oral
00139595,
Doc#
003958,
p41
LD50
=
M:
6.2
mg/
kg;
F:
1.9
mg/
kg
I
870.1200
Acute
Dermal
Acc#
07793,
Doc#
03958,
p71
&
004223,
p24
LD50
=
M:
15.9
mg/
kg;
F:
3.6
mg/
kg
I
870.1300
Acute
Inhalation
00147754,
Doc#
05789
LC50
=
M:
0.06
mg/
L;
F:
0.015
mg/
L
I
870.2400
Primary
Eye
Irritation
Data
requirement
waived.
Doc#
03958,
p12;
004223,
p14
Defaults
to
most
severe
category
870.2500
Primary
Skin
Irritation
Data
requirement
waived.
Doc#
03958,
p12;
004223.
p14
Defaults
to
most
severe
category
870.2600
Dermal
Sensitization
Data
requirement
waived.
Doc#
03958,
p12
Defaults
to
most
severe
category
870.6100
Acute
Delayed
Neurotoxicity/
Hen
44996401,
Doc#
013957
Negative
for
OPIDP
and
NTE
effects
870.6200
Acute
Neurotoxicity/
Rat
42755801
Reversible
neurotoxic
signs
with
cholinesterase
inhibition
NOAEL
=
0.25
mg/
kg
LOAEL
=
0.75
mg/
kg
8.1.2
Subchronic,
Chronic
and
other
Toxicity
Tables
Table
A
and
B
are
respectively,
the
Toxicity
Profile
for
Disulfoton
Technical
and
a
1%
granular
formulation
­
33­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
used
for
Short­
Term
occupational/
residential
exposure.

Table
A:
Toxicity
Profile
for
Disulfoton,
Technical
Guideline
No.
/
Type
of
Study
MRID
No.
(
year)
/
Classification/
Doses
Results
Non­
guideline
Acute
Inhalation
­
Rat
(
1
day
in
a
3­
5
day
exposure
study)
00147754
(
1978)
Acceptable
0,
0.0005,
0.0018
or
0.0098
mg/
mL
NOAEL
(
ChE
Inhibition)
=
0.0005
mg/
L
LOAEL
(
ChE
Inhibition)
=
0.0018
mg/
L
21­
Day
Dermal
Toxicity­
Rabbit
00162338
(
1986)
Acceptable
0,
0.4,
1.6
or
6.5
mg/
kg/
day
NOAEL
(
Systemic)
=
1.6
mg/
kg/
day
LOAEL
(
Systemic)
=
6.5
mg/
kg/
day
NOAEL
(
ChE
Inhibition)
=
0.4
mg/
kg/
day
LOAEL
(
ChE
Inhibition)
=
1.6
mg/
kg/
day
21­
Day
Dermal
Toxicity­
Rabbit
45239601
(
1988)
Acceptable
0,
0.8,
1.0,
or
3.0
mg/
kg/
day
NOAEL
(
Systemic)
=
1.0
mg/
kg/
day
LOAEL
(
Systemic)
=
3.0
mg/
kg/
day
NOAEL
(
ChE
Inhibition)
=
0.8
mg/
kg/
day
LOAEL
(
ChE
Inhibition)
=
1.0
mg/
kg/
day
870.3465
Subchronic
Inhalation
­
Rat
41224301
(
1989)
Acceptable
0,
0.000018,
0.00016,
or
0.0014
mg/
mL
NOAEL
=
(
ChE
Inhibition)
=
0.00016
mg/
L
LOAEL
=
(
ChE
Inhibition)
=
0.0014
mg/
L
Subchronic­
Feeding­
Rat
Data
waived
because
an
adequate
chronic
study
was
available
Subchronic­
Feeding­
Dog
Data
waived
because
an
adequate
chronic
dog
study
was
available
870.4100
Chronic­
Feeding­
Dog
(
1­
year)
44248002
(
1997)
Acceptable
Males­
0,
0.015,
0.121
or
0.321
mg/
kg/
day;
Females­
0,
0.013,
0.094
or
0.283
mg/
kg/
day
NOAEL
(
ChE
Inhibition)
=
0.013
mg/
kg/
day
LOAEL
(
ChE
Inhibition)
=
0.094
mg/
kg/
day
­
34­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
870.4100
Chronic­
Feeding­
Dog
(
1­
year)
00073348
(
1975)
Acceptable
0,
0.0125,
0.025
or
0.05/
0.125/
0.2
mg/
kg/
day
NOAEL
=
(
ChE
Inhibition)
=
0.025
mg/
kg/
day
LOAEL
(
ChE
Inhibition)
=
0.05
mg/
kg/
day
870.4300
Chronic
toxicity/
Carcinogenicity­
Rat
00146873;
41850001;
41850002
(
1985)
Acceptable
0,
0.04,
0.165
or
0.650
mg/
kg/
day
NOAEL
(
systemic)
=
0.04
mg/
kg/
day
LOAEL
(
systemic)
=
0.165
mg/
kg/
day
(
HDT)
NOAEL
(
ChE
Inhibition)
=
Not
demonstrated
LOAEL
(
ChE
Inhibition)
=
0.04
mg/
kg/
day
(
LDT)
No
evidence
of
carcinogenicity
870.4300
Chronic
toxicity/
Carcinogenicity­
Rat
00069966
(
1976)
Unacceptable
Males­
0,
0.0215/
0.19,
0.456
or
0.0893
mg/
kg/
day;
Females­
0,
0.0267/
0.196,
0.0419
or
0.103
mg/
kg/
day
NOAEL
(
ChE
inhibition)
=
0.042
mg/
kg/
day
LOAEL
(
ChE
inhibition)
=
0.103
mg/
kg/
day
870.4200
Carcinogenicity
­
Mouse
00129456;
00139598
(
1983)
Acceptable
0,
0.15,
0.6
or
2.4
mg/
kg/
day
NOAEL
(
ChE
Inhibition)
=
0.6
mg/
kg/
day
LOAEL
(
ChE
Inhibition)
=
2.4
mg/
kg/
day
(
HDT)
No
evidence
of
carcinogenicity
870.3700
Developmental
Toxicity­
Rat
00129458
(
1983)
Acceptable
0,
0.1,
0.3
or
1.0
mg/
kg/
day
Maternal
NOAEL
=
0.1
mg/
kg/
day
LOAEL
=
0.3
mg/
kg/
day
Developmental
NOAEL
=
0.3
mg/
kg/
day
LOAEL
=
1.0
mg/
kg/
day
870.3700
Developmental
Toxicity­
Rabbit
00147886
(
1982)
Acceptable
0,
0.3,
1.0
or
3.0
mg/
kg/
day
Maternal
NOAEL
=
1.0
mg/
kg/
day
LOAEL
=
1.5
mg/
kg/
day
Developmental
NOAEL=
>
3.0
mg/
kg/
day
LOAEL
=
>
3.0
mg/
kg/
day
­
35­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
870.3800
Reproductive
Toxicity
­
Rat
44440801
(
1997)
Acceptable
0,
0.25,
0.10
or
0.45
Parental/
Systemic:
NOAEL
=
Not
established
LOAEL
=
0.025
mg/
kg/
day
(
LDT)
Offspring
NOAEL
=
0.10
mg/
kg/
day
LOAEL
=
0.45
mg/
kg/
day
(
HDT)

870.3800
Reproductive
Toxicity
­
Rat
00157511
(
1986)
Acceptable
0,
0.04,
0.12
or
0.36
mg/
kg/
day
Parental/
Systemic:
NOAEL
=
0.04
mg/
kg/
day
LOAEL
=
0.12
mg/
kg/
day
Offspring
NOAEL
=
0.04
mg/
kg/
day
LOAEL
=
0.12
mg/
kg/
day
870.5100
Gene
Mutation
­
Salmonella
Acc#
00028625,
Doc#
003958,
012190
(
1979)
Acceptable
Non­
mutagenic
(
±
)
activation.

870.5300
Gene
Mutation
­
HGPRT
40638401
(
1988)
Unacceptable
0.001­
10.0
F
L/
mL
Assumed
positive
because
tested
at
partially
soluble
conditions.
Response
was
greater
(
­
)
activation.

870.5395
Mouse
micronucleus
Chromosomal
aberrations
43615701,
Doc#
012292
(
1995)
Acceptable
8
mg/
kg
Non­
mutagenic
(
±
)
activation.

870.5500
Bacterial
DNA
Damage/
Repair
00146894,
Acc#
072293,
Doc#
004698
(
1983)
Acceptable
625­
10000
F
g/
plate
Non­
mutagenic
(
±
)
activation
870.5577
Mitotic
Recombination
Acc#
00028625,
Doc#
003958,
012190
(
1979)
Acceptable
Non­
mutagenic
(
±
)
activation
870.5900
Sister
Chromatid
Exchange
40495001
(
1987)
Acceptable
0.013
­
0.2
F
L/
mL
Mutagenic
(
­
)
activation,
but
non­
mutagenic
(
+
)
activation.

870.5900
Sister
Chromatid
Exchange
Acc#
072293,
Doc#
0044223
Acceptable
up
to
80
F
g/
mL
Non­
mutagenic
(
±
)
activation
­
36­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
870.5550
Unscheduled
DNA
Synthesis
Acc#
028625,
Doc#
003958
(
1979)
,
Acceptable
Mutagenic
(
­
)
activation,
but
non­
mutagenic
(
+
)
activation
870.5300
Mouse
Lymphoma
EPA­
600/
1­
84­
003
Mutagenic
(
­
)
activation,
but
non­
mutagenic
(
+
)
activation.

870.5395
Mouse
Micronucleus
EPA­
600/
1­
84­
003
Non­
mutagenic.

870.5900
Sister
Chromatid
Exchange
EPA­
600/
1­
84­
003
Weakly
mutagenic
(
+
)
activation,
but
non­
mutagenic
(
­
)
activation
870.6100
Acute
Delayed
Neurotoxicity­
Hen
44996401
(
1999)
Acceptable
40
mg/
kg
No
demonstrated
acute
delayed
neuropathy
(
OPIDP)

870.6200
Acute
Neurotoxicity
­
Rat
42755801
(
1993)
Acceptable
Males­
0,
0.25,
1.5
or
5.0
mg/
kg;
Females­
0,
0.25,
0.75
or
1.5
mg/
kg
NOAEL
(
ChE
Inhibition)
=
0.25
mg/
kg
LOAEL
(
ChE
Inhibition
&
clinical
signs)
=
0.75
mg/
kg/
day
870.6200
Subchronic
Neurotoxicity
­
Rat
42977401
(
1993)
Acceptable
Males:
0,
0.063,
0.270
or
1.08
mg/
kg/
day;
Females
0,
0.071,
0.315
or
1.31
mg/
kg/
day
NOAEL
(
Clinical
signs)
=
0.071
mg/
kg/
day
LOAEL
(
Clinical
signs)
=
0.315
mg/
kg/
day
(
HDT)
NOAEL
(
ChE
Inhibition)
=
Not
established.
LOAEL
(
ChE
Inhibition)
=
<
0.071mg/
kg/
day
(
LDT)

870.7485
Metabolism­
Rat
42565101
(
1985)
Acceptable
0.2
or
1.0
mg/
kg/
day
Greater
than
90
percent
of
the
administered
radioactivity
was
metabolized
completely
and
eliminated
within
24
hours.
About
95
percent
of
the
radiolabel
was
recovered
in
the
urine,
<
2
percent
in
the
feces,
<
0.3
percent
in
tissues
and
<
1
percent
in
the
carcass.
No
bioaccummulation
was
noted.
Sex
related
differences
were
attributed
to
different
metabolic
rates
rather
than
different
profiles.
The
(
toxicologically
inactive)
major
and
minor
metabolites
were
produced
by
hydrolysis
of
oxygen
metabolites.

­
37­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
870.7600
Dermal
Absorption
­
Rats
43360201
(
1994)
Acceptable
0.85,
8.5
or
85
F
g/
cm
2
Dermal
absorption
is
considered
to
be
36
percent
after
skin
wash
at
10
hours
Non­
guideline
Subacute
Inhalation
­
Rat
(
3­
5
day
exposure)
00147754
(
1978)
Acceptable
0,
0.0005,
0.0018
or
0.0098
mg/
L
NOAEL
(
ChE
Inhibition)
=
Not
established
LOAEL
(
ChE
Inhibition)
=
0.0005
mg/
L
Non­
guideline
Special
6­
Month
Cholinesterase
­
Rat
­
(
Non­
guideline
study)
43058401
(
1993)
Acceptable
Males­
0,
0.02,
0.03
or
0.6
mg/
kg/
day;
females­
0,
0.02,
0.03,
or
0.07
mg/
kg/
day
NOAEL
(
ChE
Inhibition)
=
0.03
mg/
kg/
day
LOAEL
(
ChE
Inhibition)
=
0.07
mg/
kg/
day
Table
B:
Summary
data
on
a
1%
granular
formulation
used
for
occupational/
residential
exposure
Non­
guideline
3­
Day
Dermal
Toxicity
­
Rat
1%
granular
formulation
Non­
guideline
study)
45239602
(
2000)
Acceptable
0,
0.5,
1.0,
2.0
or
5.0
mg
a.
i.
/
kg/
day
NOAEL
=
1.0
mg
a.
i.
/
kg/
day
LOAEL
(
ChE
Inhibition)
=
2.0
mg
a.
i.
/
kg/
day
­
38­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
8.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Disulfoton
for
Use
in
Human
Risk
Assessment.
1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary,
females
13­
50
years
of
age
None
Acute
Dietary
general
population
including
infants
and
children
NOAEL
=
0.25
mg/
kg
UF
=
100
Acute
RfD
=
0.0025
mg/
kg
FQPA
SF
=
1
aPAD
=
Acute
RfD
FQPA
SF
=
0.0025
mg/
kg
Acute
Neurotoxicity
­
Rat
LOAEL
=
0.75
mg/
kg
based
on
neurotoxic
signs
and
plasma,
erythrocyte
cholinesterase
inhibition
in
female
rats.

Chronic
Dietary
all
populations
NOAEL
=
0.013
mg/
kg/
day
UF
=
100
cRfD
=
0.00013
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
cRfD
FQPA
SF
=
0.00013
mg/
kg/
day
Chronic
Feeding
­
Dog
LOAEL
=
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.

Short­
Term
oral
(
1­
7
days)
NOAEL
=
0.25
mg/
kg
UF
=
100
Acute
RfD
=
0.0025
mg/
kg
FQPA
SF
=
1
aPAD
=
Acute
RfD
FQPA
SF
=
0.0025
mg/
kg
Acute
Neurotoxicity
­
Rat
LOAEL
=
0.75
mg/
kg
based
on
neurotoxic
signs
and
plasma,
erythrocyte
cholinesterase
inhibition
in
female
rats.

Intermediate­
Term
Oral
(
1
week
to
several
months)
Oral
study
NOAEL
=
0.03
mg/
kg/
day
LOC
or
MOE
=
100
(
Residential
includes
the
FQPA
SF)
Special
6­
months
Cholinesterase
study
in
Rats
LOAEL
=
0.07
mg/
kg/
day
based
on
plasma,
erythrocyte
and
brain
cholinesterase
inhibition
in
females.

Short­
Term
Dermal
(
1­
7
days)
(
Occupational/
residential)
Dermal
study
NOAEL
=
0.5
mg/
kg/
day
UF
=
100
LOC
or
MOE
=
100
(
Occupational)
LOC
or
MOE
=
100
(
Residential,
includes
FQPA
SF)
3­
day
Dermal
Study
in
Rats
LOAEL
=
1.0
mg/
kg/
day
based
plasma
and
brain
cholinesterase
inhibition
in
females.

­
39­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
Intermediate­
Term
Dermal
(
1
week
to
several
months)
(
Occupational/
residential)
Oral
study
NOAEL
=
0.03
mg/
kg/
day
Dermal
absorption
rate
=
36%
LOC
or
MOE
=
100
(
Occupational)
LOC
or
MOE
=
100
(
Residential,
includes
FQPA
SF)
Special
6­
months
Cholinesterase
study
in
Rats
LOAEL
=
0.07
mg/
kg/
day
based
on
plasma,
erythrocyte
and
brain
cholinesterase
inhibition
in
females.

Long­
Term
Dermal
(
Several
months
to
life
time)
(
Occupational/
resi
dential)
Oral
study
NOAEL
=
0.013
mg/
kg/
day
Dermal
absorption
rate
=
36%
LOC
or
MOE
=
100
(
Occupational)
LOC
or
MOE
=
100
(
Residential,
includes
FQPA
SF)
Chronic
feeding
study
in
dogs
LOAEL
=
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.

Inhalation
(
all
time
periods)
Inhalation
study
NOAEL
=
0.00016
mg/
mL
LOC
or
MOE
=
100
(
Occupational)
LOC
or
MOE
=
100
(
Residential,
includes
FQPA
SF)
90­
day
Inhalation
study
in
Rats
LOAEL
=
0.0014
mg/
mL
based
on
plasma,
erythrocyte
and
brain
cholinesterase
inhibition
in
males
and
females.

Cancer
(
oral)
Cancer
classification:
E,
not
likely
to
be
a
human
carcinogen
None
No
treatment
related
tumors
in
the
rat
or
the
mouse
in
adequate
studies
1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
population
adjusted
dose
(
a=
acute,
c
=
chronic)
,
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
ex.
posure
­
40­
Disulfoton/
June/
2001
RED
Toxicology
Chapter
SignOff
Date:
6/
25/
01
DP
Barcode:
D275193
HED
DOC
Number:
014606
Toxicology
Branch:
RRB2
­
41­
