Document ID: EPA-HQ-OPPT-2004-0128-0046
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-12T04:00Z

Proposed
1:
#/
2003
United
States
Environmental
Protection
Agency
Office
of
Pollution
Prevention
and
Toxics
DIMETHYL
SULFATE
(
CAS
Reg.
No.
77­
78­
1)

PROPOSED
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(
AEGLs)

"
PUBLIC
DRAFT"

Federal
Register
­
#
2003
O
S
O
O
O
CH3
C
H3
Proposed
1:
#/
2003
DIMETHYL
SULFATE
(
CAS
Reg.
No.
77­
78­
1)

PROPOSED
ACUTE
EXPOSURE
GUIDELINE
LEVELS
(
AEGLs)
Dimethyl
Sulfate
Proposed
1:
#/
2003
i
PREFACE
Under
the
authority
of
the
Federal
Advisory
Committee
Act
(
FACA)
P.
L.
92­
463
of
1972,
the
National
Advisory
Committee
for
Acute
Exposure
Guideline
Levels
for
Hazardous
Substances
(
NAC/
AEGL
Committee)
has
been
established
to
identify,
review
and
interpret
relevant
toxicologic
and
other
scientific
data
and
develop
AEGLs
for
high
priority,
acutely
toxic
chemicals.

AEGLs
represent
threshold
exposure
limits
for
the
general
public
and
are
applicable
to
emergency
exposure
periods
ranging
from
10
minutes
to
8
hours.
Three
levels
C
AEGL­
1,
AEGL­
2
and
AEGL­
3
C
are
developed
for
each
of
five
exposure
periods
(
10
and
30
minutes,
1
hour,
4
hours,
and
8
hours)
and
are
distinguished
by
varying
degrees
of
severity
of
toxic
effects.
The
three
AEGLs
are
defined
as
follows:

AEGL­
1
is
the
airborne
concentration
(
expressed
as
parts
per
million
or
milligrams
per
cubic
meter
[
ppm
or
mg/
m3])
of
a
substance
above
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
notable
discomfort,
irritation,
or
certain
asymptomatic,
non­
sensory
effects.
However,
the
effects
are
not
disabling
and
are
transient
and
reversible
upon
cessation
of
exposure.

AEGL­
2
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m3)
of
a
substance
above
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
irreversible
or
other
serious,
long­
lasting
adverse
health
effects
or
an
impaired
ability
to
escape.

AEGL­
3
is
the
airborne
concentration
(
expressed
as
ppm
or
mg/
m3)
of
a
substance
above
which
it
is
predicted
that
the
general
population,
including
susceptible
individuals,
could
experience
life­
threatening
health
effects
or
death.

Airborne
concentrations
below
the
AEGL­
1
represent
exposure
levels
that
could
produce
mild
and
progressively
increasing
but
transient
and
nondisabling
odor,
taste,
and
sensory
irritation
or
certain
asymptomatic,
non­
sensory
effects.
With
increasing
airborne
concentrations
above
each
AEGL,
there
is
a
progressive
increase
in
the
likelihood
of
occurrence
and
the
severity
of
effects
described
for
each
corresponding
AEGL.
Although
the
AEGL
values
represent
threshold
levels
for
the
general
public,
including
susceptible
subpopulations,
such
as
infants,
children,
the
elderly,
persons
with
asthma,
and
those
with
other
illnesses,
it
is
recognized
that
individuals,
subject
to
unique
or
idiosyncratic
responses,
could
experience
the
effects
described
at
concentrations
below
the
corresponding
AEGL.
Dimethyl
Sulfate
Proposed
1:
#/
2003
ii
TABLE
OF
CONTENTS
EXECUTIVE
SUMMARY
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1.
INTRODUCTION
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1
2.
HUMAN
TOXICITY
DATA
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3
2.1.
Acute
Lethality
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3
2.1.1
Case
Reports
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3
2.2.
Nonlethal
Toxicity
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4
2.2.1.
Case
Reports
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4
2.2.2.
Epidemiologic
Studies
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8
2.3.
Carcinogenicity
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8
2.4.
Summary
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8
3.
ANIMAL
TOXICITY
DATA
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11
3.1.
Acute
Lethality
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11
3.1.1.
Non­
human
Primates
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11
3.1.2.
Dogs
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11
3.1.3.
Cats
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11
3.1.4.
Rats
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12
3.1.5.
Mice
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13
3.1.6.
Hamsters
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14
3.1.7.
Guinea
Pigs
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15
3.1.8.
Rabbits
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16
3.2.
Nonlethal
Toxicity
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20
3.2.1.
Nonhuman
Primates
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20
3.2.2.
Cats
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3.2.3.
Rats
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20
3.2.4.
Guinea
Pigs
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22
3.2.5.
Rabbits
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22
3.3.
Toxicity
after
Repeated
Exposure
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24
3.4.
Developmental/
Reproductive
Toxicity
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26
3.5.
Sensitization
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27
3.6.
Methylating
Properties
and
Mutagenicity
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27
3.7.
Carcinogenicity
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29
3.8.
Summary
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31
4.
SPECIAL
CONSIDERATIONS
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33
4.1.
Metabolism
and
Disposition
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33
4.2.
Mechanism
of
Toxicity
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35
4.3.
Other
Relevant
Information
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36
4.3.1.
Species
Variability
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37
4.3.2.
Susceptible
Populations
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37
Dimethyl
Sulfate
Proposed
1:
#/
2003
iii
4.3.3.
Concentration­
Exposure
Duration
Relationship
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38
5.
DATA
ANALYSIS
FOR
AEGL­
1
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39
5.1.
Summary
of
Human
Data
Relevant
to
AEGL­
1
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39
5.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
1
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.
39
5.3.
Derivation
of
AEGL­
1
.
.
.
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.
39
6.
DATA
ANALYSIS
FOR
AEGL­
2
.
.
.
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.
41
6.1.
Summary
of
Human
Data
Relevant
to
AEGL­
2
.
.
.
.
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.
41
6.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
2
.
.
.
.
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.
41
6.3.
Derivation
of
AEGL­
2
.
.
.
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.
.
42
7.
DATA
ANALYSIS
FOR
AEGL­
3
.
.
.
.
.
.
.
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.
.
44
7.1.
Summary
of
Human
Data
Relevant
to
AEGL­
3
.
.
.
.
.
.
.
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.
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.
.
.
44
7.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
3
.
.
.
.
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.
44
7.3.
Derivation
of
AEGL­
3
.
.
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44
8.
SUMMARY
OF
AEGLS
.
.
.
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.
.
46
8.1.
AEGL
Values
and
Toxicity
Endpoints
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
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.
.
46
8.2.
Comparison
with
Other
Standards
and
Guidelines
.
.
.
.
.
.
.
.
.
.
.
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.
47
9.
REFERENCES
.
.
.
.
.
.
.
.
.
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.
.
51
APPENDIX
A:
Derivation
of
AEGL
Values
.
.
.
.
.
.
.
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.
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.
56
APPENDIX
B:
Carcinogenicity
Assessment
.
.
.
.
.
.
.
.
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.
60
APPENDIX
C:
Derivation
Summary
for
Acute
Exposure
Guideline
Levels
for
Dimethyl
Sulfate
64
Dimethyl
Sulfate
Proposed
1:
#/
2003
iv
LIST
OF
TABLES
TABLE
1.
Chemical
and
Physical
Properties
.
.
.
.
.
.
.
.
.
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.
.
1
TABLE
2.
Criteria
for
Grading
the
Degree
of
Dimethyl
Sulfate
Intoxication
by
Wang
et
al.

1988
.
.
.
.
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.
9
TABLE
3.
Summary
of
Acute
Lethal
Inhalation
Data
in
Laboratory
Animals
.
.
.
.
.
.
.
.
.
.
.
.
.
.
16
TABLE
4.
Summary
of
Nonlethal
Inhalation
Data
in
Laboratory
Animals
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
23
TABLE
5.
Summary
of
Mutagenicity
Test
Results
.
.
.
.
.
.
.
.
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.
.
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.
.
29
TABLE
6.
Tumor
Incidences
in
Rats/
Mice/
Hamsters
(
Schlögel
1972)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
30
TABLE
7.
Characterization
of
Local
and
Systemic
Effects
of
Dimethyl
Sulfate
.
.
.
.
.
.
.
.
.
.
.
.
35
TABLE
8.
AEGL­
1
Values
for
Dimethyl
Sulfate
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
40
TABLE
9.
AEGL­
2
Values
for
Dimethyl
Sulfate
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
43
TABLE
10.
AEGL­
3
Values
for
Dimethyl
Sulfate
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
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.
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.
.
45
TABLE
11.
Summary
of
AEGL
Values
.
.
.
.
.
.
.
.
.
.
.
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.
46
TABLE
12.
Existent
Standards
and
Guidelines
for
Dimethyl
Sulfate
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
48
LIST
OF
FIGURES
Figure
1:
Main
Pathways
for
the
Methylation
of
Dimethyl
Sulfate
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
34
Figure
2:
Category
Plot
of
Toxicity
Data
compared
to
AEGL
Values
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
47
Dimethyl
Sulfate
Proposed
1:
#/
2003
v
EXECUTIVE
SUMMARY
Dimethyl
sulfate
(
DMSO
4)
is
a
colorless,
oily
liquid
with
a
slight
onion­
like
odor.
A
minimum
odor
threshold
may
not
be
derived.

Dimethyl
sulfate
is
miscible
with
organic
solvents,
and
moderately
soluble
in
water.
It
hydrolyzes
readily
in
contact
with
water
or
moist
surfaces
to
form
monomethyl
sulfate
and
methanol,
and
further
to
form
sulfuric
acid.

Dimethyl
sulfate
is
used
as
an
alkylating
agent
in
the
dye,
agricultural,
pharmaceutical,
surfactant,
and
perfumery
industries
and
exposure
results
exclusively
from
industrial
processes,
mostly
via
inhalation
pathway.

Inhalation
exposure
to
dimethyl
sulfate
results
in
irritation
and
other
adverse
effects
of
upper
respiratory
tract
and
eyes
as
primary
effects,
followed
by
lesions
in
bronchi
and
lung.
Usually
a
latency
period
for
local
effects
of
4
to
12
hours
between
exposure
and
onset
of
effects
was
reported
from
human
case
studies.
From
experimental
studies
on
animals
latency
periods
of
few
minutes
were
given
after
administration
of
high
doses
via
different
pathways.
Systemic
effects
show
no
such
latency
period.

Cogent
evidences
for
developmental
toxicity
are
not
available.
After
single
intraperitoneal
high­
dose
exposure
of
75
mg/
kg
slight
adverse
effects
on
reproduction
of
mice
were
reported
in
a
single
study,
which
were
not
found
in
studies
with
inhalation
exposure.
Sufficient
evidence
for
carcinogenic
effects
in
animals
after
prolonged
inhalation
exposure
is
available.
Genotoxicity
was
observed
in
vitro
and
in
vivo.

Data
on
toxic
effects
in
humans
are
available
from
case
studies
without
qualified
exposure
data
of
dimethyl
sulfate
concentration.

The
AEGL­
1
values
are
based
on
a
14­
day
repeated
exposure
study
in
rats
(
(
6
h/
d,
5
d/
w,
10
exposures)
(
Frame
et
al.
1993;
abstract
publication).
At
0.1
ppm
for
altered
nasal
cell
proliferation
without
histopathological
findings
was
observed.
More
pronounced
effects
above
AEGL­
1
threshold,
as
breathing
difficulties
and
asthmatic­
like
breathing,
were
reported
by
Schlögel
(
1972)
at
0.5
ppm
after
first
treatment
period
of
a
repeated
6­
hour
exposure.
Therefore,
0.1
ppm
is
selected
to
derive
AEGL­
1.
Evidence
of
only
modest
differences
in
toxicokinetics
and
toxicodynamics
is
available,
therefore
an
interspecies
factor
of
3
is
applied.
The
interspecies
factor
is
further
justified
because
the
critical
study
used
repeated
exposure
(
Frame
et
al.
1993).
No
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects,
therefore
an
intraspecies
factor
of
3
is
chosen.
An
overall
uncertainty
factor
of
10
is
applied
on
the
0.1
ppm
concentration.
Suitable
data
to
derive
a
substance
specific
exponent
for
time
extrapolation
in
the
equation
k
=
Cn
x
t
are
available.
Thus,
a
value
of
n
=
2
in
the
exponential
function
was
used
for
extrapolation
from
the
6­
hour
exposure
to
all
durations
except
10
minutes.
Because
extrapolation
from
6
hours
to
short
durations
leads
to
very
high
uncertainty,
the
values
for
10
minutes
are
set
equal
to
the
values
for
30
minutes.
Dimethyl
Sulfate
Proposed
1:
#/
2003
vi
The
AEGL­
2
values
are
based
on
the
effect
concentration
in
rats,
mice,
and
golden
hamsters
following
a
6­
hour
exposure
to
0.5
ppm,
investigated
by
Schlögel
(
1972).
This
concentration
results
in
breathing
problems
and
asthmatic­
like
breathing.
As
reported
by
Frame
et
al.
(
1993)
0.7
ppm
already
leads
to
lesions
of
respiratory
and
olfactory
epithelia
in
rats
after
repeated
exposure
(
2
wk,
6
h/
d,
10
exposures).
Evidence
of
only
modest
species
differences
in
toxicokinetics
and
toxicodynamics
is
available,
therefore
an
interspecies
factor
of
3
is
applied.
No
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects,
therefore
an
intraspecies
factor
of
3
is
chosen.
An
overall
uncertainty
factor
of
10
is
applied
on
the
0.5
ppm
concentration.
Suitable
data
to
derive
a
substance
specific
exponent
for
time
extrapolation
in
the
equation
k
=
Cn
x
t
are
available.
Thus,
a
value
of
n
=
2
in
the
exponential
function
was
used
for
extrapolation
from
the
6­
hour
exposure
to
all
durations
except
10
minutes.
Because
extrapolation
from
6
hours
to
short
durations
leads
to
very
high
uncertainty,
the
values
for
10
minutes
are
set
equal
to
the
values
for
30
minutes.

The
AEGL­
3
values
are
based
on
an
acute
toxicity
study
in
rats,
mice,
guinea
pigs
and
hamsters
in
which
LC
0
and
LC
50
values
were
derived
by
Hein
(
1969).
The
rat
LC
0
of
49
ppm
was
chosen
as
derivation
basis
for
AEGL­
3,
and
it
was
supported
by
other
effect
data.
At
this
concentration
dyspnea
with
inspiratory
stridor
and
lacrimation
were
noticed
during
exposure
and
necropsy
showed
severe
inflation
of
stomach
and
small
intestine
and
occasionally
emphysema
and
edema
of
lungs.
Because
the
derived
AEGL­
values
are
not
based
on
effect
concentrations
in
the
most
susceptible
species,
which
would
be
the
guinea
pig,
an
interspecies
factor
of
10
is
applied.
No
large
differences
in
susceptibility
between
individuals
is
expected
for
unspecific
irritating
effects,
therefore
an
intraspecies
factor
of
3
is
chosen.
An
overall
uncertainty
factor
of
30
is
applied
on
the
49
ppm
concentration.
Suitable
data
to
derive
a
substance
specific
exponent
for
time
extrapolation
in
the
equation
k
=
Cn
x
t
are
available.
Thus,
a
value
of
n
=
2
in
the
exponential
function
was
used
for
extrapolation
from
the
1­
hour
exposure
to
all
durations.

The
carcinogenic
activity
for
life
span
exposure
is
calculated
with
I
conc
=
2.2
mg/
m3
(
ECB
2002).
Concentration
of
dimethyl
sulfate,
that
would
cause
a
theoretical
excess
cancer
risk
of
10­
4
was
calculated
with
411
µ
g/
m3.

The
calculated
values
are
listed
in
the
Table
below.
Dimethyl
Sulfate
Proposed
1:
#/
2003
vii
Summary
of
AEGL
Values
for
Dimethyl
Sulfate
[
ppm
(
mg/
m3)]
*)

Classification
10­
min
30­
min
1­
hour
4­
hour
8­
hour
Endpoint
/
Species
Reference
AEGLB1
(
Nondisabling)
0.035
(
0.18)
0.035
(
0.18)
0.024
(
0.12)
0.012
(
0.062)
0.0087
(
0.045)
nasal
cell
proliferation
rat
Frame
et
al.
(
1993)

AEGLB2
(
Disabling)
0.17
(
0.88)
0.17
(
0.88)
0.12
(
0.62)
0.061
(
0.32)
0.043
(
0.22)
breathing
problems
rat,
mouse,
hamster
Schlögel
(
1972)

AEGLB3
(
Lethal)
4
(
21)
2.3
(
12)
1.6
(
8.3)
0.82
(
4.3)
0.58
(
3.0)
lethality
due
to
emphysema
and
edema
rat
Hein
(
1969)

*)
Relevant
skin
uptake
and
sensitizing
properties
of
dimethyl
sulfate
can
not
be
excluded.
Dimethyl
sulfate
is
a
methylating
and
mutagenic
substance,
classified
as
suspected
human
carcinogen
(
A2:
ACGIH,
1991;
2A:
IARC,
1999;
Carc.
Cat.
2,
R45:
BAuA,
2001).

References
ACGIH,
American
Conference
of
Government
and
Industrial
Hygienists,
1991.
Documentation
of
the
Threshold
Limit
Values
and
Biological
Exposure
Indices:
1,2­
dichloroethylene.
Sixth
ed.,
ACGIH,
Cincinnati,
OH.

BAuA,
Bundesanstalt
für
Arbeitsschutz
und
Arbeitsmedizin,
2001.
Bekanntmachung
der
Liste
der
gefährlichen
Stoffe
und
Zubereitungen
nach
§
4a
der
Gefahrstoffverordnung.
Rw
23.
Diskettenversion,
Version
9/
01,
Wirtschaftsverlag
NW,
Bremerhaven.

Frame,
S.
R.,
A.
S.
Panepinto,
and
M.
Bogdanffy,
1993.
Effects
of
inhalation
exposure
to
dimethyl
sulfate
on
nasal
epithelial
cell
proliferation.
Toxicologist
13:
389.

Hein,
N.,
1969.
Zur
Toxicität
von
Dimethylsulfat.
Med.
Inaug.­
Dissertation,
Universität
Würzburg.

IARC,
International
Agency
for
Research
on
Cancer,
1999.
IARC
Monographs
on
the
Evaluation
of
Carcinogenic
Risks
to
Humans.
Vol.
71.
Re­
Evaluation
of
some
Organic
Chemicals,
Hydrazine
and
Hydrogen
Peroxide
(
Part
1­
3).
WHO,
World
Health
Organization,
Geneva.

Schlögel,
F.
A.,
1972.
Cancerogenität
und
chronische
Toxizität
inhalierten
Dimethylsulfats.
Med.
Inaug.­
Dissertation,
Universität
Würzburg.
Dimethyl
Sulfate
Proposed
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1
1.
INTRODUCTION
Dimethyl
sulfate
(
DMSO
4
­
2)
is
a
colorless,
oily
liquid
with
a
slight
onion­
like
odor,
which
however
seems
not
to
be
perceptible
by
every
individual
(
WHO
1985).
No
minimum
odor
threshold
can
be
indicated.

TABLE
1.
Chemical
and
Physical
Properties
Parameter
Value
Reference
Chem.
Abstr.
Name
Sulfuric
acid,
dimethyl
ester
IARC
(
1999)

Synonyms
Dimethyl
monosulfate;
methyl
sulfate;
sulfuric
acid
dimethyl
ester
ECB
(
2002)

Chemical
formula
C2H6O4S
IARC
(
1999)

Molecular
weight
126.13
IARC
(
1999)

CAS
Reg.
No.
77­
78­
1
IARC
(
1999)

Physical
state
oily
colorless
liquid
IARC
(
1999)

Solubility
in
water
29
g/
l
28
g/
l
at
18
°
C
(
with
hydrolyses)
Druckrey
et
al.
(
1970)
Cartlidge
et
al.
(
1996)

Vapor
pressure
90
Pa
at
25
°
C
80
Pa
at
20
°
C
(
calculated)
NLM
(
2003)

Roßman
and
Gill
(
1952)

Vapor
density
(
air
=
1)
4.35
NLM
(
2003)

Liquid
density
(
water
=
1)
1.3322
g/
cm3
NLM
(
2003)

Melting
point
­
27
°
C
IARC
(
1999)

Boiling
point
188
°
C
(
with
decomposition)
IARC
(
1999)

Hydrolysis
half­
life
1.2
hours
at
pH
7
and
25
°
C
NLM
(
2003)

Conversion
factors
mg/
m3
=
5.16
x
ppm
mg/
m3
=
5.24
x
ppm
IARC
(
1999)
Cartlidge
et
al.
(
1996)

Dimethyl
sulfate
is
miscible
with
polar
organic
solvents
and
aromatic
hydrocarbons,
and
moderately
soluble
in
water.

In
the
environment
dimethyl
sulfate
results
exclusively
from
anthropogenic
sources.
Since
the
beginning
of
the
last
century
it
is
used
in
the
production
of
methyl
esters,
ethers,
and
amines
in
various
substances
in
the
dye,
agricultural,
pharmaceutical,
surfactant,
and
perfumery
industries.
In
World
war
I
it
was
tested
as
a
warfare
agent
as
both
the
liquid
and
the
vapor.
Around
55
Dimethyl
Sulfate
Proposed
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2
companies
use
it
as
a
methylating
agent
in
Great
Britain
(
Cartlidge
et
al.
1996).
WHO
(
1985)
lists
340
tonnes
/
year
for
the
production
of
dimethyl
sulfate
in
the
USA
based
on
calculations
from
1969,
however
a
production
of
45,000
tonnes
was
reported
for
1977.
Worldwide
production
in
2000
was
about
90,000
tonnes
(
Kreiling,
personal
communication
2003).

In
industrial
processes
dimethyl
sulfate
is
used
within
enclosed
plants
and
employees
wear
personal
protective
clothing.
The
closed
systems
are
run
with
underpressure
to
ensure
that
no
dimethyl
sulfate
leaks
out.
Nowadays
exposure
can
occur
during
maintenance,
filling,
unloading,
spillage,
or
accidental
release.
Occupational
exposure
occurs
where
dimethyl
sulfate
is
produced
or
added
to
production
process.
Inhalation
is
the
most
important
exposure
route
for
dimethyl
sulfate,
whereas
dermal
exposure
is
considered
to
occur
only
accidentally.
ECB
(
2002)
lists
workplace
measurements
reported
by
industry
up
to
1
ppm
for
short
term
levels.
Industrial
processes
producing
the
highest
air
concentrations
are
pumping,
connection
of
transfer
lines,
and
sampling.

Several
measurements
of
airborne
dimethyl
sulfate
in
and
around
reactor
sites
and
storage
facilities
indicated
concentrations
below
0.1
ppm
(
Cartlidge
et
al.
1996).
At
leaking
points
of
2
sites
handling
dimethyl
sulfate
in
USA
air
concentrations
of
0.2
­
1
ppm
were
reported
by
ECB
(
2002).
Lee
et
al.
(
1980)
demonstrated,
that
dimethyl
sulfate
is
present
also
in
coal
fly
ash
in
the
environment
and
not
only
limited
to
the
vicinity
of
industrial
plants.
The
measured
concentrations
were
0.74
­
0.84
µ
M/
g.
From
combustion
processes
it
is
presented
in
both
particles
and
in
the
gas
phase
(
Vyskocil
and
Viau
1999).
However,
due
to
the
high
reactivity
of
dimethyl
sulfate
these
values
should
be
regarded
cautiously.

Due
to
the
vapor
pressure
routes
of
exposure
are
by
inhalation
and
additionally
by
dermal
contact.
The
saturated
vapor
concentration
in
the
air
at
20
°
C
is
estimated
as
3720
mg/
m3
(
710
ppm)
(
WHO
1985)
and
3100
mg/
m3
(
592
ppm)
(
ECB
2002),
both
based
on
the
vapor
pressure.
However,
Cartlidge
et
al.
(
1996)
indicate
6000
ppm
at
20
°
C
(
calculated)
as
saturated
vapor
concentration.
Flury
and
Zernik
(
1931)
refer
on
an
inhalation
study
in
guinea
pigs,
where
2072
ppm
(
10,700
mg/
m3)
were
administered.
It
is
not
mentioned
if
that
was
a
saturated
atmosphere.
For
statements
concerning
saturated
vapor
a
concentration
of
592
ppm
is
used
in
this
document.

For
conversion
between
ppm
and
mg/
m3
a
factor
of
5.2
is
used
in
this
document.
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3
2.
HUMAN
TOXICITY
DATA
2.1.
Acute
Lethality
Several
cases
of
lethal
intoxication
are
reported
in
literature
after
inhalation,
dermal
and
oral
exposure.
Unfortunately,
no
measurement
of
concentration
was
conducted
in
any
of
the
reported
cases.
Sometimes
description
of
exposure
scenario
supplies
information
if
intoxication
was
due
to
low
or
high
concentration
of
dimethyl
sulfate,
at
least.
Lethal
intoxication
can
occur
at
low
temperatures
although
due
to
the
vapor
pressure
dimethyl
sulfate
is
not
classified
as
an
extreme
volatile
substance.

2.1.1
Case
Reports
Lethality
after
inhalation
exposure
Weber
(
1902)
reported
one
case
of
lethal
intoxication
after
inhalation
of
dimethyl
sulfate
at
working
place.
The
first
symptoms
of
an
intoxication,
described
as
"
chest,
throat
and
eye
pain"
by
the
worker,
occurred
shortly
after
handling
a
boiler
leaking
vapor
of
dimethyl
sulfate
for
4
hours.
When
the
man
was
taken
to
the
hospital
48
hours
later
he
suffered
from
a
double­
sided
pneumonia
and
died
at
the
same
day.
The
uvula
and
parts
of
the
pharynx
revealed
a
white
discoloration
and
demucosation.
Necropsy
showed
a
spacious
destruction
of
respiratory
tract
mucosa
and
petechiae
of
pericardium,
endocardium,
duodenum,
and
renal
pelvis,
and
the
liver
parenchyma
was
swollen.

One
case
of
lethal
intoxication
via
inhalation
at
4
°
C
(
39.2
°
F)
was
reported
by
Roßmann
and
Grill
(
1952)
and
Thiess
and
Goldmann
(
1967)
after
workplace
exposure
for
about
3
hours
due
to
a
leaky
container.
4
hours
after
onset
of
exposure
the
man
suffered
from
irritation
of
upper
respiratory
tract
and
fever.
During
disease
process
he
developed
irritation
of
conjunctiva
and
a
glottis
edema.
Death
occurred
3
days
later
due
to
pulmonary
and
brain
edema.
The
histopathological
examination
showed
severe
corrosion
of
the
respiratory
tract
(
pharynx,
larynx,
trachea),
congestion
of
organs
in
the
abdominal
cavity
and
a
liver
swelling.
All
parts
of
the
respiratory
tract
up
to
the
bronchial
system
showed
a
greyish­
yellow
coating
and
demucosation
in
parts.
Based
on
values
gained
from
lethality
studies
in
monkeys,
referred
from
Flury
and
Zernik
(
1931),
they
assumed
following
Habers
law
(
n
=
1)
a
lethal
concentration
of
28
mg/
m3
(
5.4
ppm)
for
this
worker
based
on
the
exposure
duration
of
180
minutes.
However,
the
validity
of
the
assumption
is
not
provided
and
the
concentration
was
not
measured.

Lethality
after
dermal
exposure
A
second
intoxication
described
by
Weber
(
1902)
occurred
mistakenly
after
spilling
of
about
20
g
dimethyl
sulfate
on
the
work
clothes.
Hours
later
the
worker
was
troubled
with
diffuse
whole­
body
pain,
and
additionally
burning
of
trachea.
Subsequently
he
developed
inflammation
of
the
whole
respiratory
tract
(
pharyngitis,
tracheitis,
bronchitis,
pneumonia)
and
a
severe
conjunctivitis
with
eyelid
edema.
First
to
third
degree
corrosive
skin
burns
were
diagnosed
locally.
Despite
of
a
temporary
recovery
of
conjunctivitis
and
pharyngitis
the
man
died
4
days
after
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Sulfate
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4
exposure.

Lethality
after
oral
exposure
Von
Nida
(
1947)
reported
a
lethal
case
of
dimethyl
sulfate
intoxication
of
a
38­
year
old
man
after
licking
his
finger
moistened
with
dimethyl
sulfate.
Immediately
after
ingestion,
the
man
felt
an
intensive
nausea
followed
by
an
enhanced
salivation.
12
hours
later
he
suffered
from
a
sudden
dyspnea,
and
a
cyanosis
and
died
of
a
glottis
edema
shortly
thereafter.
The
pathological
examination
revealed
acute
inflammations
of
a
major
part
of
the
respiratory
tract
with
severe
injuries
of
mucosa
(
necrosis
and
demucosation).
Additionally,
injuries
of
digestive
tract
were
reported
(
gastritis,
fibrinous
adhesion
of
caecum
and
lower
ileum).

Bartalini
et
al.
(
1957)
describe
a
lethal
case
after
mistakenly
ingestion
of
two
gulps
of
dimethyl
sulfate.
Following
oral
absorption
onset
of
effects
occurred
already
after
30
minutes
and
comprised
vomiting,
nausea
and
a
burning
pain
in
the
gastro­
intestinal
tract.
Dyspnea,
diarrhea,
cyanosis
and
neurotoxic
effects
followed
these
first
symptoms.
Death
occurred
3
hours
after
ingestion
and
was
due
to
cardiac
failure.

2.2.
Nonlethal
Toxicity
Some
cases
with
a
similar
exposure
pattern
and
comparable
concentrations
as
described
at
lethal
intoxication
did
not
lead
to
mortality.
Unfortunately,
concentration
measurements
were
not
conducted
for
most
of
the
case
studies.
All
of
the
described
cases
showed
a
severe
disease
process
and
recovery
was
more
or
less
prolonged.

2.2.1.
Case
Reports
Nonlethal
toxicity
after
inhalation
exposure
Strothmann
(
1929)
describes
a
nonlethal
intoxication
of
a
19­
year
old
man,
who
was
exposed
to
vapors
of
dimethyl
sulfate
and
alcohol.
Initial
symptoms
were
described
as
lacrimation,
eye
pain
and
burning
pain
of
the
pharynx
and
were
perceived
immediately.
The
clinical
observations
revealed
cyanosis,
panting
breathing,
strong
coughing
reflex,
and
swollen
and
reddened
conjunctiva.
The
upper
respiratory
tract
was
intensive
reddened,
and
a
white,
scurfy
coating
was
observed
in
parts.
Hours
later,
the
patient
developed
severe
edema
of
lung
and
epiglottis.
After
16
days
the
patient
was
recovered
with
exception
of
a
slight
conjunctivitis
and
bronchitis.

In
addition
to
the
abovementioned
lethal
workplace
intoxication
(
Section
2.1.1)
described
by
Roßmann
and
Grill
(
1952)
a
nonlethal
case
under
the
same
conditions,
but
for
8­
hour
exposure
was
reported.
One
hour
after
cessation
of
exposure
signs
of
poisoning
comprised
the
eyes
(
conjunctivitis,
keratitis)
and
the
respiratory
tract
(
cough,
bronchospasm,
dyspnea).
Except
a
long
lasting
dry
cough
and
irritated
conjunctiva
the
patient
was
fully
recovered
after
8
days.
Following
Habers
law
the
authors
assumed
a
concentration
of
7
mg/
m3
(
1.35
ppm)
to
induce
severe
symptoms
after
3
hours
based
on
studies
in
monkeys.
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5
Nebelung
(
1957)
describes
the
case
of
a
60­
year
old
worker
in
the
pharmaceutical
industry
who
was
exposed
to
unknown
concentrations
of
vaporized
dimethyl
sulfate,
which
leaked
from
a
container
overnight
(
about
10
liter).
6
hours
after
exposure
first
discomfort
occurred
including
burning
of
the
eyes
and
difficulties
in
breathing
and
swallowing.
About
7
hours
after
exposure
a
glottis
edema
was
diagnosed,
that
worsened
fast.
Additionally
he
developed
a
pulmonary
edema
that
was
described
as
severe
13
hours
after
exposure
The
next
days
he
developed
pneumonia,
a
putrid
cough
and
conjunctivitis.
During
the
following
year
he
suffered
from
a
recurrent
bronchitis.

Thiess
and
Goldmann
(
1967)
reported
several
cases
of
intoxication
due
to
accidental
inhalation
of
dimethyl
sulfate
vapors
at
workplace.
2
of
5
patients
suffered
from
eye
troubles
(
irritation,
burning
pain,
lacrimation)
and
respiratory
troubles
(
rhinitis,
burning
pain,
feeling
of
dryness,
coughing
reflex).
One
patient
recovered
within
2
days,
the
other
still
revealed
dyspnea
almost
9
month
later.
One
further
patient
felt
a
slight
dyspnea
1
hour
after
exposure
of
"
one
breath"
dimethyl
sulfate,
but
developed
no
health
injury.
Another
patient
only
developed
irritation
and
redness
of
eyes
and
pharynx
that
lasted
for
30
minutes.
The
5th
case
describes
the
inhalation
of
a
20
%­
solution
of
dimethyl
sulfate
with
chloroform
in
an
organic
base
that
leads
to
no
subjective
troubles
at
all.
At
clinical
examination
slight
pathological
respiratory
sounds
were
diagnosed.
For
all
these
cases
it
can
be
assumed
from
disease
process,
that
exposure
concentration
has
been
low,
however
measurement
of
concentrations
has
not
been
conducted.

Savic
(
1971)
as
well
as
Barral­
Chamaillard
and
Roux
(
1979)
summarize
several
cases
of
eye
lesion
after
mistakenly
inhalation
of
low
dimethyl
sulfate
concentrations
at
workplace,
as
can
be
assumed
from
the
long
latency
period
of
several
hours
and
the
rapid
recovery.
All
toxic
effects
observed
by
Savic
were
restricted
to
the
eyes
and
comprise
slight
to
severe
hyperemia
of
conjunctiva
and
lesions
of
cornea.
The
observed
lesions
were
reversible
after
8
days
at
the
latest.
Beyond
these
effects
Barral­
Chamaillard
and
Roux
reported
irritation
of
upper
respiration
tract
(
pharyngonasal
part).

Roux
et
al.
(
1977)
summarize
cases
of
dimethyl
sulfate
poisoning
in
France.
The
exposures
occurred
during
work
and
affected
4
men,
aged
33
to
58.
In
three
cases
the
protection
standards
were
ignored.
All
of
the
patients
showed
rhinorrhea,
lacrimation,
conjunctival
inflammation,
visual
blur
and
dry
cough
as
first
symptoms
(
phase
1
of
poisoning,
as
described
by
the
authors).
The
latency
of
onset
of
intoxication
signs
was
3
to
4
hours
in
3
cases,
and
30
minutes
in
1
case.
The
shorter
the
latency,
the
more
serious
were
the
toxic
effects.
The
phase
2
of
poisoning
includes
mainly
the
eyes,
the
larynx,
the
pharynx,
and
the
lungs
and
was
due
to
the
corrosive
effects
of
dimethyl
sulfate.

Wang
et
al.
(
1988)
reported
62
cases
of
inhalation
dimethyl
sulfate
intoxication
in
China.
The
duration
of
exposure
ranged
from
1
min
to
8
hours.
The
authors
describe
the
same
disease
process
similarly
as
Roux
et
al.
(
1977).
The
initial
symptoms
appeared
20
minutes
to
12
hours
after
exposure.
Following
a
moderate
intoxication
necrosis
and
desquamation
of
respiratory
mucosa
as
well
as
pneumonia
and
myocardial
injuries
were
observed.
The
authors
categorize
it
as
a
severe
intoxication
when
additionally
laryngeal
and
pulmonary
edema,
toxic
shock
and
encephalopathy
Dimethyl
Sulfate
Proposed
1:
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2003
6
occurred.
Some
cases
retained
an
impairment
of
vital
capacity
up
to
12
years.
No
concentrations
were
reported,
but
the
authors
assume,
that
the
exposure
to
500
mg/
m3
(
97
ppm)
for
10
minutes
causes
lethal
injuries.
Exposure
up
to
5
mg/
m3
(
about
1
ppm)
is
assumed
by
the
authors
to
cause
irritative
symptoms
of
the
eyes,
as
concluded
from
literature
data
and
own
investigations.
However,
these
investigations
are
not
described
in
the
publication.
In
case
of
the
described
intoxications
exposure
concentrations
of
dimethyl
sulfate
was
estimated
to
be
in
excess
of
5
mg/
m3.
The
authors
reported,
that
patients
with
peribronchitis,
pneumonia,
and
pulmonary
edema
were
exposed
for
a
longer
time
and
to
higher
concentrations.
Clinical
chemistry
examinations
revealed
leucocytosis
that
increased
with
aggravation
of
the
clinical
conditions.

Two
cases
of
dimethyl
sulfate
intoxication
during
occupational
exposure
of
a
30
and
a
23
years
old
man
were
reported
by
Ip
et
al.
(
1989).
A
few
hours
after
inhalation
contact,
presumably
due
to
vaporized
dimethyl
sulfate,
soreness
of
throat
and
eyes
as
well
as
cough
were
the
first
perceived
symptoms
in
both
cases.
The
work
was
stopped
after
6
hours.
The
following
disease
process
was
only
slight
in
case
2,
but
case
1
developed
severe
lung
injuries
(
hypoxemia,
bilateral
parenchymal
infiltrates,
pulmonary
edema).
Daily
cough
and
sputum
as
well
as
anosmia
remained
for
4
month.

Testud
et
al.
(
1999)
describe
one
case
of
dimethyl
sulfate
poisoning
at
workplace
following
accidental
spilling
from
a
tank.
The
duration
of
exposure
to
vapors
did
not
exceeded
5
minutes.
Itching
of
eyes,
nose
and
throat
were
the
first
symptoms
noticed
by
the
patient,
followed
by
eye
pain,
and
rhinorrhea.
At
hospital
fever,
conjunctivitis,
photophobia,
tachycardia,
and
bronchopneumonitis
were
diagnosed.
Clinical
chemistry
revealed
a
leucocytosis
with
83
%
polymorphonuclear
leucocytes,
respectively,
as
a
result
of
an
inflammation
process.

Goldblatt
(
1955)
lists
concentrations
of
dimethyl
sulfate,
that
produce
effects
in
humans.
15
ppm
(
78
mg/
m3)
cause
severe
toxic
effects
in
persons
exposed
for
1
minute.
10
ppm
(
52
mg/
m3)
for
more
than
a
short
time
may
lead
to
symptoms
of
illness.
5
ppm
(
26
mg/
m3)
is
listed
as
upper
limit
of
concentration
to
satisfactory
conditions
in
general
atmosphere
of
plants.
Patty
(
1962)
evaluates
13
ppm
of
dimethyl
sulfate
in
atmosphere
to
cause
"
effects"
in
human
exposed
for
20
minutes.
These
statements
are
without
sufficient
background
data
and
no
literature
source
is
reported.

Nonlethal
toxicity
after
dermal
exposure
Mohlau
(
1920)
reported
2
cases
of
workers
who
were
exposed
together
to
both
the
vapor
and
the
liquid
dimethyl
sulfate.
Shortly
after
exposure
the
men
noticed
slight
irritation
of
their
throats
and
eyes.
Several
hours
later
the
irritations
aggravated
and
additionally
inflammation
of
the
bronchi
developed.
At
hospital
severe
congestion
and
edema
of
the
throat
and
the
lung,
bronchitis,
chemical
pneumonia
and
painful
eye
injuries
(
inflammation,
scars
on
the
cornea),
together
with
photophobia
and
dramatically
reduced
field
of
vision
were
diagnosed.
All
the
mucous
membrane
of
respiratory
tract
had
suffered
a
very
decided
corrosion.
The
temperature
was
moderately
elevated
and
their
pulse
rates
were
fairly
rapid.
Urinary
examinations
revealed
an
increase
in
phosphates
and
sulfates,
with
a
little
trace
of
albumin,
and
hyaline
casts.
Dimethyl
Sulfate
Proposed
1:
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2003
7
Two
cases
of
accidental
dimethyl
sulfate
intoxication
at
workplace
were
reported
by
Littler
and
McConnell
(
1955).
One
case
followed
dermal
exposure
by
breaking
a
2
l­
bottle
in
a
fume
cupboard.
The
liquid
was
poured
over
the
hands
and
trousers,
where
it
soaked
to
genitalia
and
left
thigh.
Until
two
hours
later
the
man
showed
no
symptoms,
however
beginning
three
hours
after
exposure
the
genitalia
were
swollen
and
pink,
and
he
had
troubles
with
his
eyes
(
bloodshot,
painful,
blurred
vision,
gross
lid
edema,
extensive
excoriation
of
the
corneal
epithelium;
listed
in
chronological
order).
Later
on
he
developed
difficulties
in
breathing,
retrosternal
pain,
slight
fever,
running
nose,
and
hoarseness.
His
uvula
was
swollen
and
there
was
a
marked
bronchospasm.
Large
blisters
on
exposed
skin
parts
were
noticed
13
hours
after
the
accident.
Clinical
chemistry
revealed
a
leucocytosis,
a
slightly
elevated
erythrocyte
count,
and
a
moderate
amount
of
albumin
and
erythrocytes
in
urine.
About
3
weeks
after
the
accident
the
man
was
completely
recovered
except
for
the
granulating
areas
on
the
genitalia.

For
the
other
case
a
specific
intoxication
pathway
could
not
be
figured
out.
Regarding
the
symptoms
a
dermal
exposure
can
be
assumed,
too.
As
first
signs
of
intoxication
the
man
lost
the
sense
of
smell
and
sight.
Twelve
hours
after
first
symptoms
he
suffered
from
edema
of
eyelids,
bulbus,
soft
palate
and
uvula,
additionally
excoriation
of
corneae,
bronchospasm
and
fever
were
diagnosed.
About
2
weeks
after
onset
of
symptoms
he
was
recovered,
but
still
complained
of
photophobia.

Bartalini
et
al.
(
1957)
describe
3
cases
of
dimethyl
sulfate
poisoning
after
exposure
of
splashes
on
the
face
and
in
the
eyes.
The
authors
reported
skin
edema,
blisters,
conjunctival
irritations
and
alterations
of
the
visual
organ
(
enlargement
of
the
blind
spot,
permanent
limitation
of
the
visual
field).
The
lesions
appeared
after
a
latency
period
of
about
12
hours.

Thiess
and
Goldmann
(
1967)
reported
cases
of
dimethyl
sulfate
intoxication
due
to
accidental
dermal
exposure
("
a
few
splashes")
at
workplace.
For
all
3
cases
redness
and
swelling
of
the
concerning
parts
of
the
skin
were
reported,
as
well
as
corrosive
alterations
that
developed
several
hours
after
exposure
(
between
3
and
more
than
12
hours).
The
patients
revealed
no
signs
of
disease
that
could
have
been
resulted
from
an
additional
inhalation
of
dimethyl
sulfate.

One
case
of
poisoning
of
face
and
upper
part
of
the
body
at
the
workplace
was
described
by
Testud
et
al.
(
1999).
Immediately
after
eye
contact
the
patient
noticed
intensive
pain.
Later
on
he
developed
a
severe
rhinorrhea,
pain
in
pharynx,
and
difficulties
in
breathing,
that
got
worse
rapidly.
At
hospital
burns
of
2nd
degree
were
observed
at
exposed
skin
parts.
Clinical
chemistry
revealed
a
leucocytosis
with
85
%
polymorphonuclear
leucocytes.
The
patient
developed
edema
of
uvula
and
lung,
congestion
of
vocal
ligaments,
and
extensive
ulceration
of
cornea.

Nonlethal
toxicity
after
oral
exposure
A
nonlethal
intoxication
after
accidentally
ingestion
of
a
"
few
drops
at
the
most"
(
description
by
the
patient)
of
dimethyl
sulfate
was
reported
by
Bodenstein
(
1921).
Immediately
after
exposure
the
patient,
a
47­
year
old
woman,
suffered
from
a
burning
pain
and
enhanced
salivation.
The
following
hours,
she
vomited
several
times
and
reddening
and
edema
of
the
upper
respiratory
tract
Dimethyl
Sulfate
Proposed
1:
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2003
8
were
diagnosed
at
the
clinical
examination
about
12
hours
after
ingestion.
Parts
of
the
respiratory
tract
revealed
a
scurfy
mucosa
that
increased
the
following
two
days
and
healed
up
afterwards.
One
month
later,
the
patient
was
cured
nearly
completely.
Dimethyl
Sulfate
Proposed
1:
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2003
9
2.2.2.
Epidemiologic
Studies
Clinico­
hygienic,
immunological
and
cytogenetic
investigations
on
23
workers
with
long­
term
mixed
inhalation
and
dermal
exposure
to
dimethyl
sulfate
and
19
unexposed
control
persons
were
conducted
by
Molodkina
et
al.
(
1985).
The
concentration
at
workplace
is
indicated
of
about
19
ppm
(
100
mg/
m3),
where
the
workers
spend
between
5
and
30
%
of
the
daily
working
hours
using
breathing
apparatus.
No
information
was
delivered
if
workplace
measurements
are
based
on
area
sampling
or
personal
monitoring.
Measurements
of
the
skin
revealed
concentrations
of
2.09
±
0.07
mg/
dm2.
Half
of
the
workers
revealed
alterations
of
upper
respiratory
tract
mucosa
with
chronic
inflammation
of
pharynx.
Clinico­
chemical
investigations
suggest
an
injury
of
hepatocyte
membrane
(
increase
of
transaminase
activity,
alteration
of
bilirubin
composition,
glucuronic
acid
conjugates).
Immunological
examinations
revealed
alterations
in
the
rosette
test
(
decreased
adhesion
of
lymphocytes
to
sheep
erythrocyte;
increased
auto­
rosette
formation).
Cytogenetic
investigations
resulted
in
elevation
of
altered
cells
(
single­
strand
fragments
and
double­
strands)
in
all
except
2
workers.

Zhao
(
1989)
investigated
workers
exposed
to
vapors
of
dimethyl
sulfate
for
a
longer
time
in
a
Petroleum
Chemistry
Factory
in
LioNing,
China,
and
unexposed
volunteers
(
abstract
publication).
The
study
participants
were
checked
for
ophthalmology
including
history,
functional
examination
and
physical
examination
of
the
eyes.
Many
involved
workers
suffer
from
eye
pains,
lacrimation
and
related
troubles.
Statistically
(
p
<
0.05
and
p
<
0.01)
more
exposed
workers
showed
blurred
vision
and
conjunctival
congestion
than
the
volunteers
in
the
unexposed
control
group.
The
workplace
concentration
of
dimethyl
sulfate
is
indicated
by
the
author
as
2.89
­
0.07
mg/
m3
(
0.56
­
0.014
ppm).

2.3.
Carcinogenicity
Druckrey
et
al.
(
1966)
reported
one
case
of
a
worker
exposed
to
dimethyl
sulfate
for
11
years,
who
developed
an
oat­
cell
bronchial
carcinoma
(
upper
trachea
to
bronchi)
with
metastasis.
From
the
location
of
carcinoma
the
authors
assume
dimethyl
sulfate
to
be
responsible.
3
out
of
6
to
10
co­
workers,
that
were
exposed
to
dimethyl
sulfate
and
other
substances
died
of
bronchial
carcinoma.
No
other
details
are
provided.

Pell
(
1972)
conducted
an
epidemiological
study
in
dimethyl
sulfate
exposed
workers
revealing
a
tumor
incidence
(
lung
cancer)
of
4
out
of
386
and
257
out
of
43
000,
respectively.
The
study
shows
no
excess
incidence
of
cancer
of
respiratory
tract
among
the
examined
workers.
All
data
are
of
limited
quality
and
no
information
on
other
clinical
signs
or
controls
is
given.

2.4.
Summary
Due
to
the
use
of
dimethyl
sulfate
as
a
methylating
agent
in
many
different
industrial
processes
several
cases
of
lethal
intoxication
are
reported
in
literature,
mainly
after
accidental
exposure
or
exposure
due
to
carelessness
at
workplace.
For
most
of
these
cases
intoxication
occurred
via
Dimethyl
Sulfate
Proposed
1:
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2003
10
inhalation,
one
lethal
intoxication
each
occurred
after
dermal
exposure
and
after
oral
exposure,
respectively.

A
major
cause
of
lethality
after
inhalation
exposure
to
dimethyl
sulfate
results
from
respiratory
failure
due
to
direct
dimethyl
sulfate
effect
(
lesions
of
mucosa,
demucosation,
infectious
diseases,
e.
g.
chemical
induced
bronchitis
and
pneumonia)
(
Weber
1902;
Roßmann
and
Grill
1952;
Thiess
and
Goldmann
1967).
Beside
glottis
and
pulmonary
edema,
alterations
of
other
organs
are
reported,
e.
g.
congestion
and
petechiae
of
organs,
swollen
liver,
or
brain
edema.
Additionally,
coating
of
parts
of
respiratory
tract
was
reported
by
several
authors
(
Strothmann
1929;
Roßmann
and
Grill
1952;
Thiess
and
Goldmann
1967).
There
exist
no
sharp
line
between
lethal
and
nonlethal
intoxication,
therefore
some
or
all
of
these
symptoms
are
also
described
in
case
studies
without
exposure
to
a
deadly
dose.
Based
on
data
from
animal
experiments,
Roßmann
and
Grill
(
1952)
assume
a
lethal
intoxication
at
5.4
ppm
for
one
exposed
worker
for
a
3­
hour
duration.
An
estimated
lethal
intoxication
after
10
minutes
exposure
to
97
ppm
was
reported
by
Wang
et
al.
(
1988).
If
intoxication
is
not
lethal,
recovery
is
usually
complete,
independently
of
pathway
of
intoxication,
but
slight
to
moderate
symptoms
can
persist
for
month
or
years
(
Ip
et
al.
1989;
Bodenstein
1921;
Nebelung
1957;
Strothmann
1929;
Wang
et
al.
1988).

Exposure
to
dimethyl
sulfate
via
inhalation
and
dermal
pathway
leads
to
very
similar
effects,
as,
for
example,
demonstrated
by
Testud
et
al.
(
1999).
It
can
be
assumed,
that
effects
following
dermal
exposure
are
due
to
the
vaporized
dimethyl
sulfate
from
skin
to
a
large
part.
Following
inhalation
and
dermal
contact
to
dimethyl
sulfate
problems
with
the
eyes,
e.
g.
swollen
eyelids,
conjunctivitis,
photophobia,
were
reported
by
all
authors.
According
to
Barral­
Chamaillard
and
Roux
(
1979)
as
well
as
Savic
(
1971)
irritation
of
eyes
and
upper
respiration
tract
are
the
only
signs
of
a
slight
intoxication.
This
agrees
with
the
investigations,
Zhao
(
1989)
conducted
on
exposed
workers
and
unexposed
volunteers,
where
effects
were
restricted
to
disturbances
of
vision.
As
observed
by
Savic
and
Zhao
the
eyes
seem
to
be
a
highly
sensitive
organ,
presumably
due
to
the
reaction
of
dimethyl
sulfate
with
lacrimal
fluid.
After
exposure
to
higher
concentrations,
glottis
edema
was
observed
after
inhalation
(
Strothmann
1929;
Nebelung
1957;
Roßmann
and
Grill
1952;
Thiess
and
Goldmann
1967)
as
well
as
after
oral
exposure
(
von
Nida
1947).
The
typical
symptoms
of
a
glottis
edema
are
stridor
at
inhalation,
hoarseness,
pain
in
swallowing,
and
fever.
All
or
some
of
these
symptoms
were
also
described
by
several
other
authors
(
Littler
and
McConnell
1955;
Roux
et
al.
1977;
Wang
et
al.
1988;
Ip
1989).
Chemical
induced
glottis
edema
seems
to
be
a
typical
effect
of
dimethyl
sulfate.
Beside
glottis,
other
parts
of
the
respiratory
tract
can
develop
inflammations
as
well
as
edema
(
lung,
uvula,
larynx).

Wang
et
al.
(
1988)
categorized
the
degree
of
dimethyl
sulfate
intoxication
criteria
for
grading,
what
corresponds
in
general
to
the
observations
reported
by
other
authors
(
see
Table
2).
Additional,
some
authors
describe
further
effects
on
eyes
as
signs
of
a
slight
to
moderate
intoxication
(
lacrimation,
burning,
itching,
lid
and
conjunctival
edema)
(
Strothmann
1929;
Roßmann
and
Grill
1952;
Nebelung
1957;
Thiess
and
Goldmann
1967;
Savic
1971;
Roux
et
al.
1977).

Ingestion
of
dimethyl
sulfate
leads
to
vomititing,
nausea,
burning
pain,
and
enhanced
salivation
Dimethyl
Sulfate
Proposed
1:
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2003
11
immediately
or
soon
after
exposure
(
Bodenstein
1921;
von
Nida
1947;
Bartalini
et
al.
1957).
The
life­
endangering
factors
after
oral
exposure
result
from
troubles
with
respiratory
and
gastrointestinal
tract,
and
disease
process
can
be
different
from
inhalation
and
dermal
contact
(
Bodenstein
1921;
von
Nida
1947;
Bartalini
1957).
However,
lethal
glottis
edema,
dyspnea
and
demucosation
were
also
observed
after
oral
exposure
(
von
Nida
1947).

TABLE
2.
Criteria
for
Grading
the
Degree
of
Dimethyl
Sulfate
Intoxication
by
Wang
et
al.
1988
Grading
Symptoms
Irritative
reactions
mucosal
irritation
in
eyes,
nose,
and
pharynx;
no
leucocytosis;
no
systemic
signs
of
intoxication
Mild
intoxication
additionally
irritative
and
erosive
actions
on
the
respiratory
tract;
congestion
of
pharynx,
larynx,
uvula,
abnormal
breath
sounds;
peribronchitis
and
/
or
leucocytosis
Moderate
intoxication
additionally
necrosis
and
desquamation
of
respiratory
mucosa;
pneumonia
or
interstitial
pneumonia;
leucocytosis;
myocardial
damage
Severe
intoxication
additionally
laryngeal
edema;
pulmonary
edema;
and/
or
toxic
shock;
and/
or
toxic
encephalopathy;
and/
or
toxic
myocardial
damage
Human
data
concerning
the
carcinogenic
potential
of
dimethyl
sulfate
reported
by
Druckrey
et
al.
(
1966)
are
of
limited
quality,
however
give
indications
of
carcinogenic
effects.
Dimethyl
Sulfate
Proposed
1:
#/
2003
12
3.
ANIMAL
TOXICITY
DATA
3.1.
Acute
Lethality
3.1.1.
Non­
human
Primates
Lethality
after
inhalation
exposure
Flury
and
Zernik
(
1931)
conducted
studies
in
monkey(
s)
(
number
of
animals
not
given)
that
were
inhalatively
exposed
to
25.5
ppm
(
132
mg/
m3)
for
40
minutes.
The
animal(
s)
died
3
days
after
inhalation.
Following
Habers
law
Roßmann
and
Grill
(
1952)
calculated
a
(
C1)(
t)
product
of
about
5200
(
mg/
m3
x
minutes)
for
lethality.
However,
they
did
not
show
the
validity
to
use
Habers
law
with
n
=
1.
No
further
details
are
reported.

3.1.2.
Dogs
Lethality
after
inhalation
exposure
Weber
(
1902)
exposed
one
dog
to
unknown
concentrations
("
dimethyl
sulfate
mixed
with
very
much
air",
according
to
the
author)
in
an
approx.
100
liter
glass
cover
for
several
minutes.
Dimethyl
sulfate
vapors
were
produced
by
heating
in
a
flask
connected
to
the
glass
cover.
6
minutes
exposure
led
to
lethal
effects
within
24
hours
due
to
pulmonary
edema
after
the
dog
suffered
from
cough
with
vomiting
of
mucoid
pulp
for
several
hours.
Necropsy
revealed
additional
inflammations
of
upper
parts
of
the
respiratory
tract.

3.1.3.
Cats
Lethality
after
inhalation
exposure
Whole­
body
inhalation
studies
with
exposure
to
3
different
concentrations
(
19,
78,
and
174
ppm)
for
11
minutes
were
conducted
by
Flury
and
Zernik
(
1931)
in
cats
(
number
of
animals
not
reported).
Determination
of
dimethyl
sulfate
concentration
was
conducted
with
alkali
and
subsequent
measurement
of
the
precipitated
barium
sulfate.
At
all
concentrations
lethality
due
to
respiratory
failure
was
observed
after
a
few
days
up
to
1
1/
2
weeks
following
exposure,
depending
on
concentration.
Presumably
all
animals
died
at
78
and
174
ppm,
respectively.
The
lowest
concentration
was
not
lethal
for
all
animals,
however
no
mortality
rate
was
reported
for
any
concentration.
Flury
describe
the
lethality
observed
at
19
ppm
as
"
animals
died
at
certain
circumstances".
No
details
are
reported.
Dimethyl
Sulfate
Proposed
1:
#/
2003
13
3.1.4.
Rats
Lethality
after
inhalation
exposure
Hein
(
1969)
investigated
the
acute
toxicity
of
dimethyl
sulfate
after
whole­
body
inhalation
exposure
of
one
hour
to
various
concentrations
in
rats,
mice,
guinea
pigs
and
hamsters
(
see
following
Sections)
and
determined
the
average
period
of
survival.
The
animals
were
exposed
in
a
steel­
glass
chamber
of
about
224
l
volume
(
whole
body).
Exposure
concentrations
were
given
as
analytical
concentrations,
measured
by
gas
chromatography.
A
period
of
more
than
3
weeks
survival
was
determined
as
"
no
mortality".
Groups
of
5
female
Wistar
rats
each
(
100
­
300
g
body
weight)
were
exposed
to
10,
49,
64,
71,
and
127
ppm.
From
49
ppm
onwards
lacrimation,
and
dyspnea
with
inspiratory
stridor
were
observed.
After
exposure
to
127
ppm
all
animals
developed
a
severe
conjunctivitis
and
died
about
26
hours
after
exposure.
The
stomach
and
small
intestine
were
severe
inflated
even
at
49
ppm.
At
necropsy
surviving
animals
revealed
emphysema
and
edema
of
lungs.
The
period
of
survival
was
more
than
3
weeks
for
animals
of
the
10
and
49
ppm
group.
The
animals
survived
97
hours
on
average
after
exposure
to
64
ppm,
84
hours
at
71
ppm,
and
26
hours
at
127
ppm.
The
LC
50
for
1
hour
was
calculated
as
64
ppm
(
57
­
71.6
ppm
confidential
interval)
using
the
Litchfield
and
Wilcoxon­
method
(
Litchfield
and
Wilcoxon
1949).
Schlögel
(
1972)
concludes
that
34
ppm
were
a
sublethal
concentration
(
LC
0).
Further
results
are
provided
in
Table
3.
Benchmark
recalculation
largely
confirmed
the
LC
0
and
the
LC
50
with
a
BMCL
05
(
lower
confidence
limit
of
benchmark
concentration
for
5
%
lethality)
of
32
ppm
and
a
LC
50
of
65
ppm.

Smyth
et
al.
(
1951)
reported
a
maximum
time
for
no
death
after
inhalation
of
dimethyl
sulfate
in
saturated
vapor
of
2
minutes
in
albino
rats.
A
4­
hour
inhalation
to
30
ppm
(
nominal
concentration)
caused
lethality
in
5
of
6
animals
after
14
days.
No
lethality
was
observed
after
a
4­
hour
exposure
to
15
ppm
(
number
of
animals
not
given).
No
further
details
concerning
exposure
scenario
and
observed
effects
were
reported.

Ghiringhelli
et
al.
(
1957)
exposed
16
rats
to
75
ppm
dimethyl
sulfate
(
390
mg/
m3)
in
an
inhalation
chamber
and
measured
the
time
to
death
of
50
%
of
the
animals
(
LT
50).
Determination
of
dimethyl
sulfate
concentration
was
conducted
with
sodium
hydroxide
and
subsequent
measurement
of
the
precipitated
barium
salt.
The
exposition
chamber
contained
8
l
and
was
charged
with
a
dimethyl
sulfate­
air
mixture
of
controlled
concentration
at
25
°
C.
After
exposure
for
26.1
minutes
(
calculated)
50
%
of
the
rats
died
a
few
days
later.
All
animals
developed
irritation
of
conjunctiva
and
of
the
respiratory
tract
as
well
as
signs
of
impairment
of
the
nervous
system.
The
lesions
observed
at
necropsy
covered
congestion
of
kidneys,
spleen,
liver
and
lungs.
On
histopathological
examination,
additional
injuries
were
observed
within
the
lungs
(
emphysema,
peribronchitis)
and
the
liver
(
cloudy
swelling,
fatty
degeneration
and
necrosis).

Batsura
et
al.
(
1980)
exposed
rats
to
45
mg/
m3
(
8.65
ppm)
dimethyl
sulfate
for
4
hours.
In
secondary
literature
this
concentration
is
cited
as
lethal
("
LC
50").
However,
in
this
study
the
animals
were
sacrificed
and
no
lethality
concentration
was
determined.
Dimethyl
Sulfate
Proposed
1:
#/
2003
14
BASF
(
1968)
conducted
an
IRT
(
inhalation­
risk
test)
in
dimethyl
sulfate
saturated
atmosphere
(
5
cm
dimethyl
sulfate
layer,
air
flow
through)
at
20
°
C
(
according
to
the
rapporteur
592
ppm
=
3100
mg/
m3)
and
reported
100
per
cent
mortality
after
exposure
of
30
minutes
(
12
of
12
animals)
and
one
hour
(
6
of
6
animals).
All
animals
(
6
and
12,
respectively)
survived
3
and
10
minutes,
respectively,
in
saturated
atmosphere,
however
period
of
survival
is
unknown
due
to
subsequent
sacrifice.
In
the
beginning
of
exposure,
attempts
to
escape
were
observed.
The
clinical
symptoms
comprised
irritations
of
mucosa
and
labored
breathing.
At
necropsy,
pulmonary
edema
was
observed
occasionally.
No
strain
and
no
data
on
exposure
measurement
were
provided.

DuPont
(
1971)
conducted
an
inhalation
study
on
young
adult
male
CHR­
CD
rats
(
initial
body
weight
250
­
285
g).
6
rats
were
whole­
body
exposed
for
one
hour
in
a
chamber
delivered
with
dimethyl
sulfate
vapors
by
a
metered
stream
of
air
passing
through
a
stainless
steel
T­
tube.
The
animals
were
exposed
to
analytical
concentrations
of
58
ppm,
90
ppm
(
2
groups),
105
ppm,
and
120
ppm.
The
surviving
animals
were
held
14
days
after
exposure
for
observation.
At
exposure
difficulties
in
breathing,
face
washing,
and
gasping
were
observed
at
all
groups,
additionally
lacrimation
and
face
pawing
were
observed
from
90
ppm
onwards,
and
gasping
aggravated.
No
mortality
was
observed
at
58
ppm,
one
animal
each
died
at
90
ppm
(
second
testing)
and
105
ppm,
2
animals
died
at
90
ppm
at
first
testing,
and
a
LC
100
was
reported
for
120
ppm.
From
these
results
a
LC
50
of
100
ppm
was
calculated
based
on
the
method
by
Litchfield
and
Wilcoxon
(
Litchfield
and
Wilcoxon
1949).
Animals
of
all
groups
showed
nasal
discharge
and
persisting
corneal
opacity.
Death
occurred
within
2
days.
Histology
suggested
acidic
type
of
attack
to
lungs
and
eyes
at
lower
concentration.

Lethality
after
exposure
to
other
routes
Druckrey
et
al.
(
1966)
determined
LD
50­
values
for
oral
administration
(
gavage)
of
440
mg/
kg,
for
subcutaneous
application
(
oily
solution)
of
100
mg/
kg
and
for
intravenous
injection
(
aqueous
solution)
of
40
mg/
kg.

A
twice
lower
oral
LD
50
of
205
mg/
kg
was
reported
by
Molodkina
et
al.
(
1979).
A
LD
50
of
107
mg/
kg
was
reported
by
BASF
(
1968)
following
oral
exposure
to
a
0.5
­
1
%
solution
of
water
with
traganth
after
7
days
observation.

3.1.5.
Mice
Lethality
after
inhalation
exposure
Hein
(
1969)
exposed
female
NMRI
mice
(
17
­
24
g
body­
weight)
to
10
ppm,
42
ppm
and
49
ppm
(
20
animals
each)
as
well
as
to
64
ppm,
71
ppm,
and
127
ppm
(
10
animals
each)
(
wholebody
For
detailed
study
design
see
Section
3.1.4.
At
10
ppm
the
first
symptoms
were
observed
after
30
minutes
and
comprise
retardation
of
movement,
cleaning
reflexes,
and
closed
eyes.
Additionally
thoracic
respiration
was
observed
in
some
animals,
which
is
possibly
due
to
difficulties
of
breathing.
The
higher
the
concentrations,
the
earlier
these
symptoms
set
on.
2
hours
after
exposure
period
most
of
the
animals
revealed
a
slight
stridor
at
inhalation.
At
the
highest
Dimethyl
Sulfate
Proposed
1:
#/
2003
15
concentration
of
127
ppm
animals
already
were
dyspneic
during
exposure,
which
got
worse
up
to
2
hours
after
exposure
and
came
along
with
a
slight
irritation
of
conjunctiva.
8
out
of
10
animals
died
at
this
concentration.
The
surviving
animals
recovered
from
these
symptoms
within
24
hours.
The
period
of
survival
was
more
than
3
weeks
for
all
animals
of
the
49
ppm
group.
1
animal
each
of
the
10
ppm
and
the
42
ppm
group
died
after
16,
and
96
hours,
respectively.
The
animals
of
the
64
ppm,
71
ppm,
and
127
ppm
group
survived
on
average
192,
108,
and
103
hours,
respectively.
At
necropsy
pulmonary
emphysema,
dilatation
of
capillaries
and
of
trachea
were
diagnosed
beginning
at
42
ppm.
Within
the
10
ppm
group
no
pathological
findings
were
observed
except
lung
dissection
revealing
a
hemorrhagic
spot
in
one
animal.
It
is
not
mentioned
if
this
finding
was
in
the
one
deceased
animal
at
this
concentration.
At
the
highest
concentration
of
127
ppm,
stomach
and
small
intestine
were
inflated.
A
LC
50
(
1
h)
of
98
ppm
(
76.6
­
120
ppm
confidential
interval)
was
calculated
using
the
Litchfield
and
Wilcoxon­
method
(
Litchfield
and
Wilcoxon
1949).
Schlögel
(
1972)
concludes
that
48
ppm
were
a
sublethal
concentration
(
LC
0).
Further
results
are
provided
in
Table
3.
Benchmark
recalculation
largely
confirmed
the
LC
0
and
the
LC
50
with
a
BMCL
05
(
lower
confidence
limit
of
benchmark
concentration
for
5
%
lethality)
of
44
ppm
and
a
LC
50
of
96
ppm,
however
no
clear
dose­
response
relationship
has
been
observed
at
low
doses.

Ghiringhelli
et
al.
(
1957)
exposed
40
mice
to
75
ppm
dimethyl
sulfate
(
390
mg/
m3)
in
an
inhalation
chamber
and
measured
the
time
to
death
of
50
%
of
the
animals
(
LT
50)
(
for
study
details
see
Section
3.1.4.).
After
exposure
of
17.6
minutes
(
calculated)
50
%
of
the
mice
died.
All
animals
developed
irritation
of
conjunctiva
and
of
the
respiratory
tract
as
well
as
signs
of
impairment
of
the
nervous
system.
The
lesions
observed
at
necropsy
covered
congestion
of
kidneys,
spleen,
liver
and
lungs.
On
histopathological
examination,
additional
injuries
were
observed
within
the
lungs
(
emphysema,
peribronchitis)
and
the
liver
(
cloudy
swelling,
fatty
degeneration
and
necrosis).

Lethality
after
oral
exposure
Schmezer
and
Schmähl
(
1987)
reported
a
LD
50
of
140
mg/
kg
after
oral
exposure
in
mice.

3.1.6.
Hamsters
Lethality
after
inhalation
exposure
Hein
(
1969)
exposed
5
female
golden
hamsters
each
(
25
­
50
g
body
weight)
to
33
ppm,
40
ppm,
49
ppm,
64
ppm,
71
ppm,
and
127
ppm
(
whole­
body).
For
detailed
study
design
see
Section
3.1.4.
33
ppm
and
40
ppm
caused
only
slight
effects
similar
to
that
observed
in
mice,
and
1
animal
each
died
at
these
concentrations.
At
64
ppm,
71
ppm,
and
127
ppm
behavioral
changes
were
observed.
The
animals
showed
a
staggering
gait
and
affected
righting
and
postural
reflexes.
The
author
does
not
preclude,
that
these
effects
are
due
to
nervous
injury.
1
animal
each
of
the
33
ppm
and
the
40
ppm
group
died
after
72.5,
and
80
hours,
respectively.
The
animals
of
the
49
ppm,
64
ppm,
71
ppm
and
127
ppm
group
survived
on
average
123,
204,
136
and
71
hours,
respectively.
No
pathological
abnormities
were
observed
up
to
40
ppm.
At
higher
concentrations
pulmonary
emphysema
and
inflation
of
gastrointestinal
tract
were
observed
and
1
animal
of
the
49
ppm­
group
revealed
an
enlarged
liver.
A
LC
50
(
1
h)
of
56
ppm
(
37.4
­
84
ppm
confidential
interval)
was
Dimethyl
Sulfate
Proposed
1:
#/
2003
16
calculated
using
the
Litchfield
and
Wilcoxon­
method
(
Litchfield
and
Wilcoxon
1949).
Further
results
are
provided
in
Table
3.
Benchmark
recalculation
largely
confirmed
the
LC
0
and
the
LC
50
with
a
BMCL
01
(
lower
confidence
limit
of
benchmark
concentration
for
1
%
lethality)
of
12.6
ppm
and
a
LC
50
of
52
ppm.
This
is
in
accordance
to
relevant
lethality
already
after
first
or
second
exposure
in
the
chronic
study
with
Asublethal@
concentration
in
this
species
(
Schlögel,
1972).
Hence,
10
ppm
are
used
as
lethality
threshold
in
the
study
conducted
by
Schlögel.

3.1.7.
Guinea
Pigs
Lethality
after
inhalation
exposure
Hein
(
1969)
exposed
5
guinea
pigs
each
(
250
­
350
g
body
weight;
sex
not
indicated)
to
10
ppm,
33
ppm,
40
ppm,
and
71
ppm.
For
detailed
study
design
see
Section
3.1.4.
The
most
sensitive
endpoint
in
guinea
pigs
seems
to
be
the
eye.
No
lethality
was
observed
at
10
ppm.
At
33
ppm
all
animals
were
presumably
blind
and
died
one
week
after
exposure.
The
period
of
survival
was
more
than
3
weeks
for
all
animals
of
the
10
group.
The
animals
survived
33.5
hours
on
average
after
exposure
to
33
ppm,
45
hours
at
40
ppm,
and
19
hours
at
71
ppm.
Red
infiltrations,
partly
hemorrhagic,
were
observed
in
lung
tissues,
however
emphysema
were
seen
at
71
ppm
only.
Among
all
species
(
see
previous
Sections)
examined
by
Hein,
guinea
pigs
developed
the
most
severe
inflation
of
gastrointestinal
tract.
A
LC
50
(
1
h)
of
32
ppm
(
23.4
­
43.8
ppm
confidential
interval)
was
calculated
using
the
Litchfield
and
Wilcoxon­
method
(
Litchfield
and
Wilcoxon
1949).
Further
results
are
provided
in
Table
3.
Benchmark
recalculation
largely
confirmed
the
LC
0
and
the
LC
50
with
a
BMCL
05
(
lower
confidence
limit
of
benchmark
concentration
for
5
%
lethality)
of
5.8
ppm
and
a
LC
50
of
28
ppm..
10
ppm
could
be
taken
as
LC
0
if
the
incidence
in
the
experiment
is
used.
However,
if
confidence
limits
are
included
the
marginally
lower
BMCL
05
of
5.8
ppm
is
derived.

Flury
and
Zernik
(
1931)
reported
a
lethal
concentration
of
2073
ppm
(
10.7
g/
m3)
for
guinea
pigs
after
unreported
duration.
No
further
details
are
described.

DuPont
(
1943)
conducted
an
inhalation
study
on
one
guinea
pig
exposed
to
undiluted
dimethyl
sulfate
mist
in
a
bell
jar
of
7
l
capacity
for
one
hour.
Within
the
first
minute
of
exposure
severe
tearing
and
signs
of
irritation
to
the
nose
were
observed
and
aggravated
after
cessation
of
exposure,
accompanied
by
respiratory
embarrassment
(
coughing,
gasping,
cyanosis).
At
necropsy
and
histopathology
lung
appear
pale,
inflated
and
albuminous
material
was
noted
in
the
large
bronchi,
that
occasionally
plugged
their
lumen,
as
well
as
desquamation
of
bronchial
epithelium.
Portions
of
the
lung
were
emphysematous.

Ghiringhelli
et
al.
(
1957)
exposed
16
guinea
pigs
to
75
ppm
dimethyl
sulfate
(
390
mg/
m3)
in
an
inhalation
chamber
and
measured
the
time
to
death
of
50
%
of
the
animals
(
LT
50)
(
for
study
details
see
3.1.4.).
After
exposure
of
23.9
minutes
(
calculated)
50
%
of
the
guinea
pigs
died.
All
animals
developed
irritation
of
conjunctiva
and
of
the
respiratory
tract
as
well
as
signs
of
impairment
of
the
nervous
system.
The
lesions
observed
at
necropsy
covered
congestion
of
kidneys,
spleen,
liver
and
Dimethyl
Sulfate
Proposed
1:
#/
2003
17
lungs.
On
histopathological
examination,
additional
injuries
were
observed
within
the
lungs
(
emphysema,
peribronchitis)
and
the
liver
(
cloudy
swelling,
fatty
degeneration
and
necrosis).

3.1.8.
Rabbits
Lethality
after
inhalation
exposure
Mohlau
(
1920)
investigated
a
rabbit
that
was
poisoned
with
dimethyl
sulfate
through
a
saturated
cotton
swab,
placed
together
under
a
bell
jar.
The
animal
died
shortly
afterward.
The
autopsy
and
histopathology
revealed
intensive
congestion
and
parenchymatous
degeneration
of
all
organs,
most
marked
changes
being
in
the
liver.
Smears
of
blood
showed
a
normal
count,
however
a
relative
lymphocytosis
was
present.
The
author
assume,
that
the
degenerative
effects
on
tissues
is
due
to
distribution
of
dimethyl
sulfate
by
the
blood
stream
to
the
various
organs.

Lethality
after
exposure
to
other
routes
Weber
(
1902)
conducted
several
studies
on
application
of
dimethyl
sulfate
via
different
pathways
(
dermal,
oral,
subcutaneous)
in
rabbits.
One
rabbit
was
dermally
exposed
to
5
ml
dimethyl
sulfate
rubbed
on
the
shaved
back.
The
animal
developed
a
dyspnea
and
irritation
of
conjunctiva
after
3
hours
and
died
after
22
hours.
Necropsy
showed
inflammation
and
submucosal
hemorrhage
of
larynx,
trachea,
and
pharynx.
Oral
application
of
dimethyl
sulfate
via
gavage
to
several
rabbits
revealed
indigestion
and
local
lesions
of
stomach
at
both
dosages
(
single
application
of
50
mg/
kg
and
of
260
mg/
kg).
The
high­
dose
animal
stayed
comatose
until
death
occurred
after
2
hours.
At
necropsy
hyperemia
and
hemorrhage
of
stomach
and
hemorrhage
of
pia
mater
were
observed.
Convulsions,
additionally
alteration
in
respiration
as
systemic
effect
of
dimethyl
sulfate
were
also
reported
after
subcutaneous
application
of
53
mg/
kg
and
290
mg/
kg
within
a
few
minutes.
Within
both
dose
groups
death
occurred
after
2
hours
and
45
minutes
respectively.

Several
experiments
on
intravenous
application
of
dimethyl
sulfate
were
conducted
in
one
rabbit
each
(
Wachtel
1920).
5
ml
of
a
4
%
dimethyl
sulfate
solution
with
a
sodium
chloride
solution
(
0.2
ml
dimethyl
sulfate
at
final
volume)
led
to
a
decreased
respiratory
rate
and
breathing
irregularities
immediately
after
injection.
11
minutes
later
death
occurred
due
to
respiratory
arrest.
At
lower
dose
of
0.02
ml
dimethyl
sulfate
at
a
final
concentration
no
alterations
of
pulse
and
respiratory
rate
were
observed
and
death
was
due
to
cachexia
following
continuous
weight
reduction.
Dimethyl
Sulfate
Proposed
1:
#/
2003
18
TABLE
3.
Summary
of
Acute
Lethal
Inhalation
Data
in
Laboratory
Animals
Species
Conc.
(
ppm)
Exposure
Result
Number
of
animals
Most
important
effects
Reference
monkey
12.8
20
min
LC0
number
of
animals
not
given
severe
disease
process
Flury
and
Zernik
(
1931)

monkey
25.5
40
min
LC
number
of
animals
not
given
death
after
3
days
Flury
and
Zernik
(
1931)

dog
unknown
6
min
LC
1
animal
death
after
24
h
of
pulmonary
edema
Weber
(
1902)

cat
19
11
min
LC
number
of
animals
not
given
respiratory
failure;
not
all
animals
died
Flury
and
Zernik
(
1931)

cat
78
11
min
LC
number
of
animals
not
given
respiratory
failure;
presumably
all
animals
died
Flury
and
Zernik
(
1931)

rat
saturated
10
min
LC0
no
strain
and
no
data
on
exposure
measurement
provided
BASF
(
1968)

rat
saturated
30
min
LC100
6
animals
pulmonary
edema
BASF
(
1968)

rat
75
26.1
min
LT50
16
animals
congestion
of
organs
Ghiringhelli
et
al.
(
1957)

rat
58
1
h
LC0
6
animals
nasal
discharge;
persisting
corneal
opacity
DuPont
(
1971)

rat
100
1
h
LC50
calculated
by
Litchfield
and
Wilcoxon­
method
DuPont
(
1971)

rat
120
105
90
90
58
1
h
LC
6/
6
animals
1/
6
1/
6
2/
6
0/
6
respiratory
failure
analytical
concentration
DuPont
(
1971)

rat
127
71
64
49
10
1
h
LC
5/
5
animals
3/
5
3/
5
0/
5
0/
5
pulmonary
congestion,
hemorrhage
analytical
concentration
Hein
(
1969)
Dimethyl
Sulfate
Proposed
1:
#/
2003
Species
Conc.
(
ppm)
Exposure
Result
Number
of
animals
Most
important
effects
Reference
19
rat
64
1
h
LC50
calculated
by
Litchfield
and
Wilcoxon­
method
Hein
(
1969)

rat
32
1
h
BMCL05
calculated,
based
on
data
from
Hein
(
1969)
This
TSD
(
see
Section
3.1.4)

rat
15
4
h
LC0
number
of
animals
not
given
no
further
details
available
Smyth
(
1956)

rat
30
4
h
LC
5
of
6
animals
died
no
further
details
available
Smyth
(
1951)

rat
32
4
h
LC50
number
of
animals
not
given
no
further
information
available
Kennedy
and
Graepel
(
1991)

mouse
75
17.6
min
LT50
40
animals
congestion
of
organs
Ghiringhelli
et
al.
(
1957)

mouse
98
1
h
LC50
calculated
by
Litchfield
and
Wilcoxon­
method
Hein
(
1969)

mouse
127
71
64
49
42
10
1
h
LC
8/
10
animals
2/
10
2/
10
0/
20
1/
20
1/
20
pulmonary
emphysema
analytical
concentration
Hein
(
1969)

mouse
44
1
h
BMCL05
calculated,
based
on
data
from
Hein
(
1969)
This
TSD
(
see
Section
3.1.5)

mouse
54
4
h
LC50
number
of
animals
not
given
no
further
data
available
Molodkina
et
al.
(
1986)

hamster
56
1
h
LC50
calculated
by
Litchfield
and
Wilcoxon­
method
Hein
(
1969)

hamster
127
71
64
49
40
33
1
h
LC
5/
5
animals
5/
5
3/
5
2/
5
1/
5
1/
5
pulmonary
emphysema
analytical
concentration
Hein
(
1969)

hamster
12.6
1
h
BMCL01
calculated,
based
on
data
from
Hein
(
1969)
This
TSD
(
see
Section
3.1.6)

guinea
pig
75
23.9
min
LT50
16
animals
congestion
of
organs
Ghiringhelli
et
al.
(
1957)

guinea
32
1
h
LC50
calculated
by
Litchfield
and
Hein
(
1969)
Dimethyl
Sulfate
Proposed
1:
#/
2003
Species
Conc.
(
ppm)
Exposure
Result
Number
of
animals
Most
important
effects
Reference
20
pig
Wilcoxon­
method
guinea
pig
71
40
33
10
1
h
LC
5/
5
animals
3/
5
4/
5
0/
5
pulmonary
emphysema
analytical
concentration
Hein
(
1969)

guinea
pig
5.8
1
h
BMCL05
calculated,
based
on
data
from
Hein
(
1969)
This
TSD
(
see
Section
3.1.7)

guinea
pig
mist
1
h
LC
1
animal
pale,
inflated
lung;
bronchi
plugged
by
albuminous
material
DuPont
(
1943)

guinea
pig
2073
unknown
LC
number
of
animals
not
given
lethal
intoxication
Flury
and
Zernik
(
1931)

rabbit
unknown
10
and
12
min
LC
1
animal
each
hemorrhage
of
larynx
and
brain
Weber
(
1902)

rabbit
unknown
unknown
LC
1
animal
congestion
and
parenchymatous
degeneration
of
organs
Mohlau
(
1920)
Dimethyl
Sulfate
Proposed
1:
#/
2003
21
3.2.
Nonlethal
Toxicity
3.2.1.
Nonhuman
Primates
Nonlethal
toxicity
after
inhalation
exposure
Flury
and
Zernik
(
1931)
conducted
studies
in
monkey(
s)
(
number
of
animals
not
given)
that
were
inhalatively
exposed
to
12.8
ppm
(
67
mg/
m3)
for
20
minutes.
The
animal(
s)
developed
"
extreme
illness"
after
inhalation
with
a
recovery
after
4
weeks.
Following
Habers
law
Roßmann
and
Grill
(
1952)
calculated
a
(
C1)(
t)
product
of
about
1320
(
mg/
m3
x
minutes)
for
severe
effects
observed
in
this
study.
However,
they
did
not
show
the
validity
to
use
Habers
law
with
n
=
1.
No
further
details
are
reported.

3.2.2.
Cats
Nonlethal
toxicity
after
inhalation
exposure
Cats
exposed
to
19
ppm
(
whole­
body
inhalation)
for
11
minutes
revealed
salivation
and
lacrimation,
as
well
as
reddening
of
visible
mucosal
membranes
(
Flury
and
Zernik
1931).
After
a
latency
period
of
one
to
several
hours
severe
inflammations,
that
were
putrid
in
most
cases,
developed.
The
eye
lids
were
closed
and
eyes
and
nose
secreted
a
suppurative
fluid.
Soon
after,
breathing
difficulties,
respiratory
sounds
and
cough
were
observed.

3.2.3.
Rats
Nonlethal
toxicity
after
inhalation
exposure
Schlögel
(
1972)
investigated
the
carcinogenic
effect
and
chronic
toxicity
of
dimethyl
sulfate
in
Wistar
rats,
NMRI
mice,
and
Syrian
golden
hamster,
all
of
both
sexes
(
for
detailed
information
see
Section
3.3).
Observations
were
made
after
the
first
exposure
period,
as
confirmed
in
personal
communication
(
Schlögel
2003),
including
alterations
in
behavior
and
clinical
examinations
observed
within
some
animals
of
all
species
already
after
20
minutes
(
closed
or
half­
closed
eyes;
ruffled
fur)
at
0.5
ppm.
After
exposure,
the
animals
were
apathic,
eyes
were
half­
open
or
closed,
and
breathing
problems
were
apparent.
They
coughed
and
sneezed
occasionally
and
breathed
sometimes
with
a
loud
expiration
similar
to
asthma
bronchiale.
These
effects
revealed
a
doserelationship
in
severity,
duration,
and
time
of
onset.
At
2
ppm
all
effects
observed
at
0.5
ppm
proceeded
more
severe
and
with
a
higher
incidence,
additionally
conjunctivitis
and
sensitivity
to
light
exposure
was
diagnosed.
Recovery
from
respiratory
problems
occurred
soon
after
cessation
of
exposure,
however
conjunctivitis
remained
for
several
days.

Further
investigations
by
Schlögel
were
conducted
with
sublethal
concentrations
calculated
from
Hein
(
1969)
(
mice
48
ppm,
rats
34
ppm,
golden
hamsters
20
ppm).
4
hours
after
exposure,
a
severe
dyspnea
was
observed
within
all
animals.
The
eyes
were
kept
closed
or
half­
closed.
The
symptoms
aggravated
the
following
2
days,
and
a
recovery
was
not
observed
until
7th
days
after
Dimethyl
Sulfate
Proposed
1:
#/
2003
22
exposure.
For
animals
that
died
early
after
exposure
presumably
a
glottis
edema
was
responsible
for
lethality,
as
was
assumed
by
the
author
due
to
inspiration
sounds
and
severe
edema
at
the
glottis
area.
No
incidences
of
lethality
were
reported.

Smyth
et
al.
(
1951)
reported
a
maximum
time
of
2
minutes
for
an
inhalation
exposure
to
saturated
vapor
of
dimethyl
sulfate
not
leading
to
death
in
albino
rats.
A
4­
hour
inhalation
to
15
ppm
did
not
produce
lethal
effects.
No
information
on
time­
to­
death
or
follow­
up
observations
are
given.
Later,
based
on
his
investigations
and
other
available
data,
he
judged
the
threshold
limit
of
1
ppm
that
was
valid
at
that
time,
as
low
enough
to
protect
against
lung
injury,
but
presumably
not
to
prevent
from
bronchial
irritation
(
Smyth
1956).

Hein
(
1969)
exposed
female
Wistar
rats
(
100
­
300
g)
to
10
ppm,
and
49
ppm,
respectively,
and
reported
no
lethality
at
these
concentrations
(
for
study
description
see
Section
3.1.4.).
All
animals
showed
dyspnea
with
stridor
after
45
minutes
at
49
ppm,
but
not
at
10
ppm.
Flatulence
of
stomach
and
small
intestine
was
observed
at
49
ppm.
In
2
animals
of
the
10
ppm­
group
the
lung
revealed
hyperemic
zones
and
enlarged
liver
at
necropsy
and
the
frequency
of
these
observation
increased
with
increasing
concentration.

Batsura
et
al.
(
1980)
exposed
rats
to
45
mg/
m3
(
8.65
ppm)
dimethyl
sulfate
for
4
hours.
It
is
not
explicitely
stated,
whether
this
was
a
nominal
or
analytical
concentration.
The
animals
were
sacrificed
immediately
after
exposure
and
at
intervals
thereafter.
After
exposure
the
animals
were
dyspneic
and
some
of
them
had
nasal
discharge.
The
first
section
group
revealed
cyanosis
of
the
mucosa,
hyperemia
of
the
lungs,
and
hemorrhages
in
the
internal
organs.
At
histopathological
examination
the
lung
presented
hemorrhage
and
coagulated
proteins
in
the
alveoli.
The
subsequently
sacrificed
animals
developed
an
accumulation
of
edematous
fluid
in
the
airspaces
after
a
latency
period
of
5
­
6
hours,
which
progressed
worse
over
24
to
48
hours
(
acute
progressive
respiratory
failure).
The
authors
observed
further
a
thickening
of
the
blood­
brain
barrier
and
disturbances
of
microcirculation.

Mathison
et
al.
(
1995)
conducted
an
inhalation
study
with
plethysmographic
measurements
to
determine
if
dimethyl
sulfate
exposure
resulted
in
changes
of
ventilation.
Male
CrlCD:
BR
rats
in
pairs
were
nose/
head­
only
exposed
to
0,
1,
3,
8,
and
22
ppm
for
20
minutes.
The
measurements
of
respirations
per
minute,
inspiratory
time,
expiratory
time,
and
tidal
volume
were
conducted
at
15­
sec
intervals.
A
transient
increase
in
respirations
per
minute
was
observed
in
rats
exposed
to
8
ppm,
but
not
to
1
or
3
ppm,
compared
with
the
unexposed
control
group.
With
further
exposure
a
decreased
respiratory
rate
of
78
%
compared
with
control
group
(
100
%)
was
observed
at
22
ppm,
which
correlated
with
an
increased
inspiratory
time.
However,
the
animals
revealed
no
signs
of
discomfort
or
stress
in
response
to
the
dimethyl
sulfate
exposure
at
any
concentration.
The
authors
assume
from
these
results,
that
the
increased
inspiration
time
is
due
to
inspiratory
resistance
caused
by
nasal
constriction.

Nonlethal
toxicity
after
exposure
to
other
routes
Dimethyl
Sulfate
Proposed
1:
#/
2003
23
For
investigations
on
carcinogenic
potency
of
dimethyl
sulfate
in
albino
BD
II
rats
Druckrey
et
al.
(
1966)
determined
concentrations
of
no
acute
effects
in
a
dose
finding
study.
16
mg/
kg
(
8
animals
used)
following
a
subcutaneous
application
caused
local
necrosis
that
healed
up
quickly.
At
8
mg/
kg
(
12
animals
used)
no
necrosis
was
observed.
Assuming
a
body
weight
of
350
g
a
dose
of
2.8
mg
(
2.1
µ
l)
dermally
applied
would
resulted
in
no
local
effects
and
5.6
mg
(
4.2
µ
l)
in
slight
effects.

3.2.4.
Guinea
Pigs
Nonlethal
toxicity
after
inhalation
exposure
Hein
(
1969)
exposed
5
guinea
pigs
to
10
ppm
(
whole­
body).
For
detailed
study
design
see
Section
3.1.4.
All
animals
revealed
closed
eyes,
cleaning
reflexes
and
intensive
lacrimation
and
salivation
after
cessation
of
exposure.
Additionally,
a
macerated
cornea
after
3
hours,
that
became
cloudy
5
hours
later,
and
a
rhinitis
with
frothy
secretion
was
diagnosed
within
all
animals.
At
necropsy
red
infiltrations,
partly
hemorrhagic,
were
observed
in
lung
tissues.
The
animals
recovered
3
days
after
exposure.

3.2.5.
Rabbits
Nonlethal
toxicity
after
inhalation
exposure
Weber
(
1902)
conducted
inhalation
studies
with
2
rabbits
to
unknown
concentrations
("
dimethyl
sulfate
mixed
with
very
much
air",
according
to
the
author)
in
a
glass
cover
for
several
minutes.
Dimethyl
sulfate
vapors
were
produced
by
heating
in
a
flask
connected
to
the
glass
cover.
One
animal
each
was
exposed
to
dimethyl
sulfate
for
10
and
12
minutes,
respectively.
Compared
to
dogs
rabbits
seem
to
be
less
sensitive
against
vapors
of
dimethyl
sulfate,
since
effects
on
respiratory
tract,
except
rubbing
of
nose
and
eyes,
were
not
observed
during
exposure.
Rabbits
showed
salivation
and
intensified
lacrimation
after
exposure
and
conjunctivitis,
opacity
of
cornea,
and
dyspnea
1
1/
2
hours
later.
After
24
hours
condition
was
unchanged,
additionally
eyes
were
closed
due
to
lid
edema.
One
animal
was
sacrificed
3
days
later,
the
other
one
after
unknown
time.
Autopsy
revealed
hemorrhage
of
larynx,
irritation
and
corrosion
of
trachea,
pneumonia,
tracheitis,
bronchitis,
and
bronchiolitis.
The
renal
cortex
and
the
region
between
cortex
and
medulla,
respectively,
showed
punctate
hemorrhage.

Nonlethal
toxicity
after
exposure
to
other
routes
Dimethyl
sulfate
was
estimated
by
Smyth
et
al.
(
1951)
as
substance
with
a
marked
eye
injury
potency
after
application
of
5
µ
l
directly
into
the
eyes
of
albino
rabbits.
In
an
injury
scale
of
1
(
least
damage)
to
10
(
most
damage)
dimethyl
sulfate
was
ranked
with
8.
Correspondingly,
dimethyl
sulfate
was
ranked
with
6
for
primary
skin
irritation
grading
on
rabbits,
with
10
classified
as
most
damage.
Dimethyl
Sulfate
Proposed
1:
#/
2003
24
Irritation
and
corrosive
injury
were
investigated
by
BASF
(
1968)
on
back
skin
and
eyes
of
rabbits
(
number
of
animals
not
reported).
Skin
corrosion
was
observed
after
application
of
undiluted
dimethyl
sulfate
to
rabbits.
Application
for
1
minute
caused
no
effects
at
observation
after
1
and
8
days.
Five
minutes
treatment
caused
slight
erythema
after
24
hours
that
had
disappeared
after
8
days.
Slight
erythema
after
24
hours
that
worsened
up
to
8
days
was
observed
following
treatment
for
15
minutes.

Guillot
et
al.
(
1982)
investigated
the
ocular­
irritating
potential
of
dimethyl
sulfate
on
male
albino
rabbits
(
New
Zealand
strain,
6
animals
each)
after
instilling
0,1
ml
(
undiluted)
(=
133
mg
=
25.6
ppm)
into
the
lower
lid
of
one
eye.
The
authors
classified
dimethyl
sulfate
as
an
extreme
ocular­
irritant.

TABLE
4.
Summary
of
Nonlethal
Inhalation
Data
in
Laboratory
Animals
Species
Conc.
(
ppm)
Exposure
Time
Number
of
animals
Most
important
effects
Reference
monkey
12.8
20
min
number
of
animals
not
given
severe
disease
process
Flury
and
Zernik
(
1931)

rat
saturated
3
min
and
10
min
6
and
12
animals
no
lethality
BASF
(
1968)

rat
8
20
min
2
animals
increased
respiratory
rate
Mathison
et
al.
(
1995)

rat
22
20
min
2
animals
decreased
respiratory
rate
Mathison
et
al.
(
1995)

rat
10
1
h
5
animals
hyperemic
lung
parts
Hein
(
1969)

rat
49
1
h
5
animals
dyspnea,
hyperemic
lung
parts
Hein
(
1969)

rat
15
4
h
6
animals
survived
Smyth
(
1951)

rat
0.5
6
h/
d
2x
per
wk;
15
month
10
animals
per
sex
eye
troubles;
animals
coughed
and
sneezed;
seen
after
first
exposure
Schlögel
(
1972)
see
Section
3.3.

rat
2
6
h/
d
1x
per
2
wk
15
month
15
animals
per
sex
eye
troubles;
animals
coughed
and
sneezed;
conjunctivitis;
seen
after
first
exposure
Schlögel
(
1972)
see
Section
3.3.

rat
34
1
h/
d
4
times
/
year
15
animals
per
sex
same
symptoms
as
at
2
ppm,
additionally
severe
dyspnea
Schlögel
(
1972)
see
Section
3.3.

rat
0.1
6
h/
d
5
d/
wk
number
of
animals
not
given
nasal
epithelial
cell
proliferation
Frame
et
al.
(
1993)
see
Section
3.3.
Dimethyl
Sulfate
Proposed
1:
#/
2003
Species
Conc.
(
ppm)
Exposure
Time
Number
of
animals
Most
important
effects
Reference
25
2
wk
rat
0.7
6
h/
d
5
d/
wk
2
wk
number
of
animals
not
given
lesions
of
nasal
and
respiratory
epithelium
Frame
et
al.
(
1993)
see
Section
3.3.

rat
0.7
6
h/
d
5
d/
wk
2
wk
25
animals
reduced
weight
gain
Alvarez
et
al.
(
1997)
see
Section
3.3.

mouse
0.5
6
h/
d
2x
per
wk
15
month
10
animals
per
sex
eye
troubles;
animals
coughed
and
sneezed
Schlögel
(
1972)
see
Section
3.3.

mouse
2
6
h
1x
per
2
wk
15
month
15
animals
per
sex
eye
troubles;
animals
coughed
and
sneezed;
conjunctivitis
Schlögel
(
1972)
see
Section
3.3.

mouse
48
1
h
4
times
/
year
15
animals
per
sex
same
symptoms
as
at
2
ppm,
additionally
severe
dyspnea
Schlögel
(
1972)
see
Section
3.3.

hamster
0.5
6
h
2x
per
wk
15
month
10
animals
per
sex
eye
troubles;
animals
coughed
and
sneezed
Schlögel
(
1972)
see
Section
3.3.

hamster
2
6
h
1x
per
2
wk
15
month
15
animals
per
sex
eye
troubles;
animals
coughed
and
sneezed;
conjunctivitis
Schlögel
(
1972)
see
Section
3.3.

hamster
20
1
h
4
times
/
year
15
animals
per
sex
same
symptoms
as
at
2
ppm,
additionally
severe
dyspnea
Schlögel
(
1972)
see
Section
3.3.

guinea
pig
10
1
h
5
animals
lacrimation,
salivation,
macerated
cornea,
hemorrhagic
infiltrations
Hein
(
1969)

3.3.
Toxicity
after
Repeated
Exposure
Schlögel
(
1972)
investigated
the
carcinogenic
effect
and
chronic
toxicity
of
dimethyl
sulfate
in
Wistar
rats
(
196.2
g
body
weight
in
average),
NMRI
mice
(
29.2
g
body
weight
in
average)
and
Syrian
golden
hamster
(
71.1
g
body
weight
in
average)
all
of
both
sexes.
An
unexposed
control
group
was
used.
The
steel­
glass
exposure
chamber
had
a
volume
of
940.5
l
(
110
x
90
x
95
cm)
and
was
charged
with
a
dimethyl
sulfate­
air
mixture
with
controlled
concentration
at
several
positions
in
different
height.
Quantification
of
the
dimethyl
sulfate
was
conducted
using
gas
chromatography
every
30
minutes.
Exposure
was
conducted
via
inhalation
(
whole­
body)
for
6
hours
at
0.5
ppm
(
10
animals
of
each
sex,
twice
a
week
on
Tuesday
and
Friday)
and
2
ppm
(
15
animals
of
each
sex,
once
every
14
days).
The
entire
duration
of
exposure
was
about
15
month
for
Dimethyl
Sulfate
Proposed
1:
#/
2003
26
all
animals.
The
animals
were
observed
during
each
exposure.
The
following
observations
were
made
already
after
first
exposure,
as
verified
in
personal
communication
(
Schlögel
2003):
At
0.5
ppm
alterations
in
behavior
and
clinical
examinations
were
observed
within
some
animals
of
all
species
already
after
20
minutes
(
closed
or
half­
closed
eyes;
ruffled
fur).
It
was
not
able
to
find
out,
how
many
animals
have
been
affected
at
first
exposure
and
if
a
worsening
of
effects
happened
during
exposure.
The
author
could
not
exclude
some
experimental
influence
caused
by
air
circulation
(
personal
communication,
Schlögel
2003).
After
exposure,
the
animals
were
apathic,
eyes
were
half­
open
or
closed,
and
breathing
problems
were
apparent.
They
coughed
and
sneezed
occasionally
and
breathed
sometimes
with
a
loud
expiration
similar
to
asthma
bronchiale.
These
effects
revealed
a
dose­
relationship
with
regard
to
severity,
duration,
and
time
of
onset.
Dimethyl
sulfate­
exposed
animals
of
all
species
revealed
a
higher
incidence
of
inflammation
of
the
lungs
during
overall
exposure
duration.
At
2
ppm
all
effects
observed
at
0.5
ppm
proceeded
more
severe,
additionally
conjunctivitis
and
sensitivity
to
light
exposure
was
diagnosed.
Recovery
from
respiratory
problems
occurred
soon
after
cessation
of
exposure,
however
conjunctivitis
remained
for
several
days.

Further
investigations
by
Schlögel
(
1972)
were
conducted
with
sublethal
concentrations
calculated
from
Hein
(
1969)
(
mice
48
ppm,
rats
34
ppm,
golden
hamsters
20
ppm)
in
an
exposure
chamber
with
223.9
l
volume
(
74
x
55
x
55
cm).
Quantification
of
the
dimethyl
sulfate
concentration
was
conducted
every
10
minutes.
15
animals
of
each
sex
were
exposed
every
4th
month
for
1
hour
and
revealed
similar
behavioral
alterations
observed
at
2
ppm.
However,
4
hours
after
exposure
a
severe
dyspnea
was
observed
within
all
animals.
The
eyes
were
kept
closed
or
half­
closed.
The
symptoms
aggravated
the
following
2
days,
and
a
recovery
was
observed
not
until
7th
days
after
exposure.
The
significantly
reduced
life
span
in
animals
exposed
to
the
sublethal
concentration
indicate
that
these
concentrations
are
above
sublethality.
13.9
%
of
all
animals
survived
exposure
duration.
For
animals
that
died
early
after
exposure
presumably
a
glottis
edema
was
responsible
for
lethality,
as
was
assumed
by
the
author
due
to
inspiration
sounds
and
severe
edema
at
glottis
area.
No
incidences
of
lethality
were
reported,
however
it
was
stated
that
lethality
was
high,
especially
in
the
hamster­
group,
therefore
the
study
was
terminated
after
the
4th
exposure.
Due
to
the
high
mortality,
16
additional
hamsters
of
each
sex
had
been
taken
into
the
study
group
already
after
the
second
exposure.
From
the
supplied
figures,
it
can
be
derived,
that
isolated
lethality
occurred
already
after
first
exposure
in
hamsters
and
rats
with
a
latency
period
of
several
days.
However,
no
such
figures
were
given
for
the
unexposed
control
group,
therefore
the
statements
concerning
lethality
are
uncertain.

Frame
et
al.
(
1993,
abstract
publication)
reported
injuries
due
to
dimethyl
sulfate
exposure
on
the
respiratory
tract
in
rats
(
abstract
publication).
The
animals
(
number
not
indicated)
were
exposed
nose­
only
to
0,
0.5,
3.7,
and
6.3
mg/
m3
(
0,
0.1,
0.7,
and
1.5
ppm)
for
2
weeks
(
6
h/
day,
5
d/
week,
excluding
the
weekend).
Dose­
dependent
lesions
of
respiratory
and
olfactory
epithelium
(
erosion,
ulceration,
atrophy)
were
observed
at
the
two
highest
concentrations.
At
all
concentrations
tested
nasal
epithelial
cell
proliferation
was
observed,
which
was
measured
by
means
of
5­
bromo­
2­
deoxyuridine
(
BrdU)
incorporation.
Labeling
indexes
(
rate
of
DNA
producing
cells
in
the
S­
phase)
for
respiratory
epithelium
were
slightly
depressed
at
0.1
ppm
(
not
significant),
equal
to
control
at
0.7
ppm,
and
elevated
in
the
1.5
ppm
group.
For
olfactory
Dimethyl
Sulfate
Proposed
1:
#/
2003
27
epithelium,
labeling
indexes
were
dose­
dependent
elevated
in
all
groups.
Severity
of
this
lesions
decreased
from
anterior
to
posterior
regions.
Hypertrophy,
hyperplasia,
and
squamous
metaplasia
were
restricted
to
respiratory
epithelium.
For
0.1
ppm
these
effects
were
described
as
"
slight".

Alvarez
et
al.
(
1997)
conducted
a
nose­
only
study
on
pregnant
Crl:
CD7BR
rats
(
see
study
description
in
Section
3.4).
All
female
rats
survived
the
testing
period.
Sacrifice
was
conducted
on
day
22
of
gestation
and
dams
were
examined
extensively.
Maternal
rats
exposed
to
either
0.7
or
1.5
ppm
dimethyl
sulfate,
but
not
to
0.1
ppm
revealed
a
significant
reduced
body
weight
gain
between
day
7
and
day
16
of
gestation
(
72
%
of
the
controls
at
0.7
ppm,
30
%
at
1.5
ppm).
Beside
of
signs
related
to
stress
of
restraint
observed
in
exposed
and
control
animals
(
alopecia,
as
well
as
facial,
periocular
and
perinasal
staining)
no
compound
related
effects
on
the
incidence
of
clinical
observations
were
seen.
No
irritation
or
eye
effects
were
reported
at
any
concentration.
However,
they
were
not
explicitly
excluded.

Repeated
inhalation
exposure
to
2.64
±
0.043
mg/
m3
(
0.5
±
0.008
ppm)
for
4
month
conducted
by
Molodkina
et
al.
(
1986)
in
rats
and
guinea
pigs,
induced
changes
in
the
nervous
system
function,
liver
(
fatty
degeneration
of
single
hepatocytes),
kidney
(
degeneration
of
single
renal
tubuli),
respiratory
organs
(
bronchitis),
and
peripheral
blood
parameters.
A
4­
month
exposure
to
0.29
±
0.02
mg/
m3
(
0.056
±
0.004
ppm)
led
to
marginal
changes
(
increased
body
weight,
decreased
hippuric
acid
elimination)
without
morphological
alterations.
No
further
information
concerning
number
of
animals,
exposure
duration
per
day,
and
examined
parameters
is
given.

3.4.
Developmental/
Reproductive
Toxicity
Developmental
/
reproductive
toxicity
after
inhalation
exposure
Alvarez
et
al.
(
1997)
investigated
the
developmental
toxicity
of
dimethyl
sulfate
in
pregnant
Crl:
CD7BR
rats
after
inhalation
exposure.
Groups
of
25
animals
were
nose­
only
exposed
to
0,
0.1,
0.7
or
1.5
ppm
dimethyl
sulfate
(
purity
greater
than
99.5
%)
by
inhalation
for
6
hr/
day
from
day
7
through
16
of
gestation
(
10
exposures).
Each
rat
was
individually
kept
in
a
glass
and
stainless
steel
150­
liter
chamber
so
that
only
the
nose
protruded
into
the
chamber.
The
chambers
were
operated
with
16
air
changes
per
hour
in
a
flow­
through
mode.
Weight,
feed
consumption
and
clinical
signs
were
recorded
regularly.
Individual
clinical
signs
were
recorded
each
morning
and
afternoon
throughout
the
exposure
period.
None
of
the
reproductive
parameters
was
altered
in
any
of
the
treatment
groups
compared
to
control
group.
No
significant
differences
in
the
incidence
of
malformation
or
clinical
observations
were
reported.
Dimethyl
sulfate
revealed
no
embryo
toxicity
in
the
rat
following
inhalation
exposure
up
to
1.5
ppm
(
7.8
mg/
m3)
during
period
the
of
major
organogenesis.

Molodkina
et
al.
(
1986)
observed
no
effects
of
dimethyl
sulfate
on
reproductive
organs,
spermatogenesis
and
sperm
morphology
in
rats
and
guinea
pigs
exposed
to
2.64
±
0.043
mg/
m3
(
0.5
±
0.008
ppm)
and
to
0.29
±
0.02
mg/
m3
(
0.056
±
0.004
ppm).
No
further
information
concerning
number
of
animals,
exposure
duration
per
day,
and
examined
parameters
is
given.
Dimethyl
Sulfate
Proposed
1:
#/
2003
28
In
ACGIH
(
1991)
a
reproduction
/
developmental
toxicity
study
is
reported.
In
mice
and
rats,
inhalation
of
0.1
­
4
ppm
dimethyl
sulfate
throughout
pregnancy
caused
preimplantation
losses
and
embryotoxic
effects,
including
anomalies
of
the
cardiovascular
system.
No
further
information
is
available.

Developmental
/
reproductive
toxicity
after
intraperitoneal
injection
Bishop
et
al.
(
1997)
reported
slight,
but
significantly
reduced
litter
size
of
dimethyl
sulfatetreated
females
compared
to
control
group.
To
10
­
12
weeks
old
female
mice
a
single
intraperitoneal
injection
of
75
mg/
kg
was
administered.
In
the
morning
following
the
day
of
injection,
females
were
caged
individually
with
untreated
males.
For
ovarian
histology
females
were
sacrificed
15
days
after
injection
and
examined
for
small
follicles
as
this
represent
the
most
reliable
data
because
they
were
the
easiest
to
count
accurately.
The
lower
litter
size
was
associated
with
a
slight
but
significant
reduction
in
small
follicles.

3.5.
Sensitization
Dimethyl
sulfate
was
active
in
the
local
lymph
node
assay
(
LLNA)
after
application
of
0.25,
0.5,
or
1.0
%
dimethyl
sulfate
in
acetone/
olive
oil
80/
20
(
3
consecutive
days)
on
the
dorsum
of
both
ears
of
mice
(
number
of
animals
not
given),
conducted
by
Ashby
et
al.
(
1995).
For
determination
of
cell
proliferation
in
the
lymph
nodes
animals
were
injected
intravenously
with
[
3H]
thymidine
and
radio
activity
was
measured
as
a
function
of
isotope
incorporation
in
draining
auricular
lymph
nodes.
Stimulation
indices
(
T/
C
ratios)
of
0.8,
1.9,
and
12.0
were
measured.

3.6.
Methylating
Properties
and
Mutagenicity
As
a
directly
alkylating
agent
dimethyl
sulfate
can
cause
changes
in
nucleic
acids
(
WHO
1985).
Because
of
the
S
N
2­
type
alkylating
mechanism
dimethyl
sulfate
reacts
predominantly
with
the
N­
7
of
guanine
and
forms
small
amounts
of
other
DNA
adducts
as
could
be
demonstrated
from
in
vivo
and
in
vitro
tests
(
ECB
2002).
Swann
and
McGee
(
1968)
reported
that
a
single
dose
of
80
mg/
kg
to
rats
increased
formation
of
N7­
methylguanine,
however
concentrations
are
low
compared
to
other
alkylating
agents,
such
as
dimethylnitrosamine.
A
much
higher
degree
of
DNA
alkylation
in
lung
and
brain
than
in
liver
and
kidney
was
observed.
The
authors
conclude
that
dimethyl
sulfate
reveals
an
early
breakdown
in
organs
that
are
reached
at
first.

Methylating
properties
in
vivo
Löfroth
et
al.
(
1974)
detected
N7­
methylguanine
(
N7­
MeGua),
N3­
methyladenine
(
N3­
MeAd)
and
N1­
methyladenine
(
N1­
MeAd)
after
exposure
of
male
NMRI
mice
to
an
average
concentration
of
0.32
mg
dimethyl
sulfate
/
m3
(
0.062
ppm)
(
for
60
minutes)
or
16.3
mg/
m3
(
3.16
ppm)
(
for
135
minutes).
4
animals
each
were
exposed
to
dimethyl
sulfate
labeled
with
3H
in
a
6­
lglass
flask.
After
exposure
animals
were
placed
in
a
metabolic
cage.
Urine
was
collected
in
two
periods
from
0
to
24
hours
and
24
to
48
hours,
respectively,
and
labeled
methylated
purines
were
determined.
The
excretion
rate
of
N7­
MeGua
was
estimated
with
a
t
1/
2
of
about
1
day.
The
ratio
of
Dimethyl
Sulfate
Proposed
1:
#/
2003
29
N7­
MeGua,
N3­
MeAd
and
N1­
MeAd
was
about
88:
7:
4
for
the
higher
dimethyl
sulfate
concentration,
and
10:
10:
1
for
the
lower
concentration.

For
DNA
adduct
measurements,
Mathison
et
al.
(
1995)
exposed
adult
male
CrlCD:
BR
rats
for
20
minutes
to
dimethyl
sulfate
concentrations
of
0,
1,
3,
8,
and
22
ppm
in
a
closed­
chamber
nose/
head­
only
apparatus.
At
various
time
points
following
exposure,
animals
were
sacrificed
and
respiratory
and
olfactory
mucosa
and
lung
were
collected
for
DNA
adduct
data.
A
dose­
response
relationship
up
to
22
ppm
for
N7­
MeGua
and
N3­
MeAd
was
measured
in
respiratory
and
olfactory
mucosa
with
a
ratio
of
N7­
MeGua
and
N3­
MeAd
of
approximately
5:
1.
Methylation
of
lung
DNA
was
low,
possibly
due
to
poor
DNA
isolation
and
contamination
of
DNA
with
RNA,
as
concluded
by
the
authors.
However,
reduced
DNA
alkylation
of
lung
tissue
can
also
be
a
result
of
early
breakdown
of
dimethyl
sulfate,
as
illustrated
by
Swann
and
McGee
(
1968).
Methylating
properties
in
vitro
Investigations
on
in
vitro
DNA­
methylation
were
conducted
in
several
cell­
line
systems,
as
in
hamster
dermal
fibroblasts,
V­
79
cells,
and
calf
thymus
cells
(
ECB
2002).
Methylation
of
the
N7
position
(
MeAd
and
MeGua)
were
mainly
produced,
besides
this
the
methylating
products
N3­
MeAd
and
O6­
MeGua
were
detected.

Mutagenicity
Genotoxic
effects
of
dimethyl
sulfate
have
been
investigated
in
bacterial,
fungal,
and
mammalian
(
animals
and
cell
lines)
test
systems
(
ECB
2002).
Positive
results
were
obtained
from
Ames
tests
with
the
strains
TA98,
TA100,
TA1535,
TA1537,
TA1538,
TS1121,
and
TS1157
(
reverse
mutation
test)
(
Skopek
et
al.
1978;
Braun
et
al.
1977;
Quillardet
et
al.
1985;
Hoffmann
et
al.
1988).
The
forward
mutation
assay
to
8­
azaguanine
resistance
revealed
also
positive
results
in
TM35
and
TM677
(
Skopek
et
al.
1978).
Also
positive
tests
were
conducted
in
a
SOS
test
in
Salmonella
typhimurium
(
Nakamura
et
al.
1987)
and
in
E.
coli
PQ37
(
Quillardet
et
al.
1985).

HGPRT
gene
mutation
assay,
chromosomal
aberration
test,
and
sister
chromatid
exchange
(
SCE)
test
in
Chinese
hamster
cells
(
ovary
(
CHO)
and
V­
79)
cells
gave
positive
results
with
dose
dependent
increase
(
Connell
and
Medcalf
1982;
Couch
et
al.
1978;
Newbold
et
al.
1980;
Tan
et
al.
1983).
Unscheduled
DNA
synthesis
(
UDS)
tests
and
SCE
tests
with
human
fibroblasts
and
UDS
in
primary
rat
hepatocytes
delivered
also
positive
results
(
Wolff
et
al.
1977;
Cleaver
1977;
Probst
et
al.
1981).

Two
tests
in
mammals
(
dominant
lethal
test
assay
and
mouse
spot
test)
revealed
no
evidence
for
in
vivo
mutagenicity
(
Epstein
and
Shafner
1968;
Braun
et
al.
1984).
Enhanced
DNA
fragmentation
was
observed
following
alkaline
elution
test
in
6
dimethyl
sulfate
treated
male
albino
Sprague­
Dawley
rats
(
0.25
mmol/
kg
in
0.01
ml
vehicle/
g
body
weight;
i.
v.)
(
Robbiano
and
Brambilla
1987).
Rats
were
sacrificed
1
hour
after
treatment
and
brain
tissue
was
used
for
the
assay.
Brain
DNA
fragmentation
was
significantly
(
p
<
0.01)
enhanced
compared
with
vehicletreated
control
group.
The
authors
conclude,
that
dimethyl
sulfate
shows
a
potential
to
induce
tumors
of
the
central
nervous
system.
Dimethyl
Sulfate
Proposed
1:
#/
2003
30
Repeated
inhalation
exposure
to
0.29
±
0.02
mg/
m3
(
0.056
±
0.004
ppm),
2.64
±
0.043
mg/
m3
(
0.5
±
0.008
ppm)
and
20.26
±
1.34
mg/
m3
(
3.93
±
0.26
ppm)
for
4
month
did
not
induce
dominant
lethal
mutations
in
germ
cells
of
rats
(
Molodkina
et
al.
1986).
Dose­
dependent
increase
in
chromosomal
aberrations
in
bone­
marrow
cells
of
mice
and
rats
were
reported
after
inhalation
exposure
to
0.5
±
0.008
ppm
and
0.056
±
0.004
ppm
(
rats)
respectively
to
0.24
±
0.2
mg/
m3
(
0.047
±
0.004
ppm),
4.32
±
0.75
mg/
m3
(
0.84
±
0.15
ppm),
and
22.1
±
2.35
mg/
m3
(
4.28
±
0.46
ppm)
(
mice).
No
further
information
concerning
number
of
animals,
exposure
duration
per
day,
and
examined
parameters
is
given.

TABLE
5.
Summary
of
Mutagenicity
Test
Results
Test
Result
Comments
Reference
Ames
test
S.
typhimurium
pos.
positive
in
reverse
mutations:
TA98,
TA100,
TA1535,
TA1537,
TA1538,
TS1121,
TS1157
positive
in
forward
mutations:
TM35,
TS1157
Skopek
et
al.
(
1978)
Braun
et
al.
(
1977)
Quillardet
et
al.
(
1985)
Hoffmann
et
al.
(
1988)

SOS
chromotest
pos.
Forward
mutation
assay
without
activation
E.
coli
PQ37
Quillardet
et
al.
(
1985)

SOS
chromotest
pos.
Forward
mutation
assay
without
activation
S.
typhimurium
Nakamura
et
al.
(
1987)

UDS
test
SCE
test
pos.
mammalian
cells
human
fibroblasts
primary
rat
hepatocytes
Wolff
et
al.
1977)
Cleaver
(
1977)
Probst
et
al.
(
1981)

chromosomal
aberration
test
SCE
test
HGPRT
assay
pos.
positive
test
results
in
mammalian
cells
V
79­
cells
/
CHO­
cells
Connell
and
Medcalf
(
1982)
Couch
et
al.
(
1978)
Newbold
et
al.
(
1980)
Tan
et
al.
(
1983)

dominant
lethal
assay
mouse
spot
test
neg.
mammals
Epstein
and
Shafner
(
1968)
Braun
et
al.
(
1984)

dominant
lethal
mutations
neg.
rats,
germ
cells
Molodkina
et
al.
(
1986)

chromosomal
aberrations
pos.
mice
and
rats,
bone­
marrow
cells
Molodkina
et
al.
(
1986)

alkaline
elution
assay
pos.
enhanced
brain
DNS
fragmentation
in
rats
treated
with
0.25
mmol/
kg
Robbiano
and
Brambilla
(
1987)

3.7.
Carcinogenicity
Dimethyl
Sulfate
Proposed
1:
#/
2003
31
Druckrey
et
al.
(
1970)
investigated
the
tumorigenic
effect
of
dimethyl
sulfate
after
inhalation
exposure
of
27
rats
to
10
ppm
(
55
mg/
m3).
The
treatment
was
conducted
in
an
inhalation
chamber
of
1
m3
for
5
days/
week
for
1
hour.
12
rats
died
during
treatment
period
(
no
exact
time­
to­
death
reported)
due
to
pneumonia
and
purulent
inflammations
of
nasal
cavity.
Hence,
treatment
was
stopped
after
130
days.
Of
the
15
rats
that
survived
treatment
5
died
with
squamous
cell
carcinoma
in
nasal
cavity
(
3
animals),
gliosarcoma
in
cerebellum
(
1
animal)
and
lymphosarcoma
within
the
thorax
(
1
animal).
In
a
second
treatment
group,
20
rats
were
exposed
to
3
ppm
(
17
mg/
m3).
Despite
of
the
lower
concentration,
almost
all
animals
developed
a
purulent
inflammation
of
nasal
cavity.
A
few
animals
died,
therefore
treatment
was
also
stopped
after
130
days.
Beyond
non­
carcinogenic
lethal
causes,
one
animal
each
died
with
peripheral
glioma
of
trigeminal
nerve,
of
an
esthesioneuroepithelioma,
and
of
squamous
cell
carcinoma,
the
latter
two
in
the
nasal
cavity.
The
authors
conclude
that
the
severe
purulent
inflammations
seem
to
inhibit
tumor
formation
due
to
necrosis
of
cells.

Schlögel
(
1972)
conducted
a
cancer
study
with
inhalation
exposure
on
male
and
female
Wistar
rats,
NMRI
mice,
and
Syrian
golden
hamsters.
The
animals
were
exposed
either
to
2.6
mg
dimethyl
sulfate
/
m3
(
0.5
ppm)
(
6
hours/
day,
2
days/
week
on
Tuesday
and
Friday),
to
10.5
mg/
m3
(
2
ppm)
(
6
hours/
day,
1
day/
2
week),
or
to
178
mg/
m3
(
34
ppm)
(
rats),
252
mg/
m3
(
48
ppm)
(
mice),
and
105
mg/
m3
(
20
ppm)
(
hamsters)
every
4th
month
for
1
hour.
For
further
study
details
see
Section
3.3.
The
incidence
of
malignant
nose
and
lung
cancer
(
nasal
and
lung
carcinoma)
was
slightly
elevated
in
the
0.5
ppm
group
(
5/
97
animals
compared
to
2/
70
animals
of
control
group)
and
moderately
elevated
in
2
ppm
groups
(
10/
74
animals)
(
see
Table
6).
Rats
were
most
sensitive
to
tumor
induction
(
3/
37
animals
at
0.5
ppm,
6/
27
animals
at
2
ppm),
while
hamsters
were
the
least
sensitive
(
0/
28
and
1/
22
animals
at
0.5
and
2
ppm,
respectively).
Female
animals
were
more
sensitive
than
male
animals
of
all
species
(
5
females
out
of
18
exposed
animals
with
tumors).
4
exposures
to
the
sublethal
dose
led
to
malignant
tumor
induction
only
in
rats
(
34
ppm).
Control
animals
revealed
no
malignant
tumors
in
the
lungs,
however
2
tumors
occurred
at
other
unspecified
sites.

TABLE
6.
Tumor
Incidences
in
Rats/
Mice/
Hamsters
(
Schlögel
1972)

tumors
control
0.5
ppm
2
ppm
sublethal
malignant
lung
tumor
0/
0/
0
2/
0/
0
6/
0/
0
1/
0/
0
malignant
nose
tumor
0/
0/
0
1/
1/
0
0/
3/
1
1/
0/
0
benign
lung
tumor
2/
5/
0
0/
5/
0
4/
7/
0
2/
3/
1
A
very
limited
reported
carcinogenic
study
was
conducted
by
Molodkina
et
al.
(
1986)
in
90
male
and
female
CBAxC57BC/
GI
mice
after
6­
month
inhalation
to
3
different
dimethyl
sulfate
concentrations
(
0.38
±
0.08
mg/
m3
[
0.074
±
0.015
ppm],
1.62
±
0.17
mg/
m3
[
0.31
±
0.06
ppm]
or
20.26
±
1.34
mg/
m3
[
3.93
±
0.26
ppm])
for
2
hours
per
day,
5
days
a
week.
In
high
and
intermediate
dose
group
a
significant
increase
in
tumor
incidence,
mainly
lung
adenoma,
was
observed.
Dimethyl
Sulfate
Proposed
1:
#/
2003
32
According
to
WHO
(
1985)
concentrations
of
3
mg/
m3
(
0.6
ppm)
induce
respiratory
tract
tumors
in
nasal
cavity
and
air
passages
in
rats
after
a
15
month
treatment
period
(
literature
source
not
indicated).
Low
incidence
of
carcinogenicity
detected
in
animals
exposed
intravenously
to
dimethyl
sulfate
seems
to
be
closely
related
to
the
rapid
disappearance
of
dimethyl
sulfate
from
the
bloodstream
and
the
low
level
of
DNA
alkylation
(
WHO
1985).
The
German
DFG
(
Henschler
1972)
classified
dimethyl
sulfate
as
a
substance
with
a
moderate
carcinogenic
potential
presumably
due
to
the
rapid
hydrolysis
on
mucous
tissues.
Almost
all
observed
tumors
developed
from
inhalation
exposure
occurred
locally
at
the
site
of
exposure.

3.8.
Summary
Dimethyl
sulfate
is
classified
as
very
toxic
by
inhalation
in
various
animals
(
1­
hour
LC
50
between
32
and
98
ppm)
causing
irritation
of
respiratory
tract
and
eyes
at
low
concentration
as
well
as
respiratory
impairment
and
tissue
damage
(
pulmonary
edema,
emphysema,
peribronchitis)
beginning
at
concentrations
of
10
ppm,
with
aggravation
of
symptoms
at
increasing
concentration
(
Weber
1902;
Flury
and
Zernik
1931;
Ghiringhelli
et
al.
1957).
At
higher
concentrations,
congestion,
hemorrhage,
and
parenchymatous
degeneration
of
various
organs
(
liver,
kidneys,
spleen,
lung)
were
observed
(
Weber
1902;
Mohlau
1920;
Ghiringhelli
et
al.
1957).
As
cause
of
death,
Hein
(
1969)
stated
pulmonary
emphysema,
pulmonary
edema
(
at
animals
with
short
period
of
survival)
or
bronchopneumonia
(
at
animals
with
long
period
of
survival).

Dermal
application
of
lethal
dimethyl
sulfate
doses
leads
to
injuries
of
respiratory
tract
and
death
is
caused
by
respiratory
failure
(
Weber
1902).
Dimethyl
sulfate
is
of
moderate
acute
oral
toxicity
in
animals,
with
LD
50
values
of
about
140
­
440
mg/
kg
(
Schmezer
and
Schmähl
1987;
Smyth
et
al.
1951;
Molodkina
et
al.
1979)
and
is
classified
as
toxic
in
terms
of
acute
toxicity.
Lesions
of
gastrointestinal
tract
and
effects
on
the
nervous
system
were
observed
by
Weber
et
al.
(
1902)
following
single
applications
of
a
lethal
dose.
Alterations
in
respiration
and
apnea
seem
to
be
the
most
important
physiological
alterations
observed
after
systemic
administration
via
intravenous
and
subcutaneous
pathway
(
Weber
1902;
Wachtel
1920).

The
cardinal
symptoms
observed
within
most
of
the
animals
after
acute
nonlethal
inhalation
dimethyl
sulfate
treatment
are
coughing
and
sneezing
as
well
as
closed
eyes
and
conjunctivitis
(
Schlögel
1972).
These
symptoms
are
observed
at
0.5
­
2
ppm.
At
higher
concentrations
of
10
ppm
and
above
respiratory
embarrassment
and
lesions,
e.
g.
breathing
difficulties,
inflammations,
dyspnea
and
hyperemic
zones,
as
well
as
eye
effects
(
lacrimation,
salivation,
cornea
lesions)
were
observed
(
Weber
1902;
Flury
and
Zernik
1931;
Hein
1969;
Mathison
et
al.
1995).

No
effects
on
fetal
development
were
seen
by
Alvarez
et
al.
(
1997)
in
rats
after
inhalation
exposure
to
0.1,
0.7
or
1.5
ppm
dimethyl
sulfate
during
gestation.
A
slight
alteration
in
number
of
small
follicles,
leading
to
a
marginal
reduced
litter
size
in
dimethyl
sulfate­
treated
mice
after
intraperitoneal
injection
of
75
mg/
kg
was
reported
by
Bishop
et
al.
(
1997).

Sensitization
was
positively
tested
by
Ashby
et
al.
(
1995)
in
the
murine
local
lymph
node
assay.
Therefore,
dimethyl
sulfate
is
classified
as
a
potential
sensitizer
(
risk
phrase
R43:
May
cause
Dimethyl
Sulfate
Proposed
1:
#/
2003
33
sensitization
by
skin
contact).

The
methylating
potency
of
dimethyl
sulfate
was
observed
in
several
studies
(
Löfroth
et
al.
1974;
Mathison
et
al.
1995;
ECB
2002).
From
in
vivo
and
in
vitro
investigations,
methylation
of
the
N7
position
(
MeAd
and
MeGua)
were
mainly
produced,
besides
this
the
methylating
products
N3­
MeAd
and
O6­
MeGua
were
detected.
Most
of
the
conducted
mutagenicity
tests
revealed
positive
test
results
(
Skopek
et
al.
1978;
Braun
et
al.
1977;
Quillardet
et
al.
1985;
Hoffmann
et
al.
1988;
Nakamura
et
al.
1987;
Connell
and
Medcalf
1982;
Couch
et
al.
1978;
Newbold
et
al.
1980;
Wolff
et
al.
1977;
Cleaver
et
al.
1977;
Probst
et
al.
1981)
however
no
mutagenicity
was
observed
in
in
vivo
tests
(
Epstein
and
Shafner
1968;
Braun
et
al.
1984).
Although
results
on
in
vivo
test
deserves
more
relevance
than
a
bacterial
or
in
vitro
cell
test
for
human
mutagenic
effects,
the
negative
results
from
mammal
test
do
not
invalidate
the
majority
of
positive
results
obtained
in
vitro.

Although
the
quality
of
the
carcinogenicity
studies
is
restricted,
there
is
sufficient
evidence
for
the
tumor
inducing
potential
of
dimethyl
sulfate
after
prolonged
inhalation
exposure
in
animals.
All
tumors
observed
by
Schlögel
(
1972)
in
rats,
mice
and
hamsters
occurred
locally
(
nasal
and
lung
carcinoma
after
0.5,
2
and
34
ppm).
Additionally
to
tumors
of
nasal
cavity
Druckrey
et
al.
(
1970)
observed
gliosarcoma
in
cerebellum
and
lymphosarcoma
(
3
and
10
ppm,
5
days
/
week
for
1
hour
for
130
days).
The
authors
assume
that
tumors
of
the
deep
respiratory
tract
(
e.
g.
bronchus
or
lung)
cannot
occur,
because
dimethyl
sulfate
breakdown
already
happens
in
the
upper
mucosal
tissues.
However,
malignant
lung
tumors
were
observed
by
Schlögel
(
1972).

A
carcinogenic
risk
calculation
conducted
by
ECB
(
2002)
lists
a
risk
for
malignant
tumors
for
occupational
exposure
scenario
after
repeated
inhalation
exposure.
These
calculations
to
assess
the
carcinogenic
activity
of
dimethyl
sulfate
are
based
on
the
Schlögel­
study
after
exposure
to
2
ppm
(
Schlögel
1972).
This
study
is
only
considered
as
a
rough
indication
of
the
carcinogenic
potency
due
to
the
limited
quality
(
low
number
of
animals,
short
duration,
high
dose
level).
No
doseresponse
relationship
can
be
observed
in
this
study
at
concentrations
of
0.5
ppm,
2
ppm
and
sublethal
dose
(
rats
48
ppm,
mice
34
ppm,
golden
hamsters
20
ppm).
Calculations
based
on
the
2
ppm
exposure
gained
a
carcinogenic
activity
attributable
to
the
exposure
to
the
substance
per
unit
concentration
(
expressed
per
mg/
m3),
expressed
as
I
conc.
The
carcinogenic
activity
for
life
span
exposure
is
calculated
with
I
conc
=
2.2
mg/
m3
(
for
detailed
calculations
see
Appendix
B).
Dimethyl
Sulfate
Proposed
1:
#/
2003
34
4.
SPECIAL
CONSIDERATIONS
4.1.
Metabolism
and
Disposition
Following
inhalation
dimethyl
sulfate
is
well
absorbed
to
over
84
%
(
Cartlidge
et
al.
1996).
A
rapid
respiratory
absorption
is
observed
up
to
50.3
mg/
m3
(
about
10
ppm),
which
decreased
at
higher
dose
levels,
probably
due
to
a
decreased
minute
volume
(
ECB
2002).
From
dermal
exposure
it
can
be
assumed,
that
intoxication
occurs
via
inhalation
pathway
to
a
large
part
due
to
the
vaporization
of
dimethyl
sulfate.

Dimethyl
sulfate
is
readily
absorbed
through
skin
and
mucosa
(
Vyskocil
and
Viau
1999),
however
ECB
(
2002)
remarks
that
data
on
dermal
absorption
are
limited
and
insufficient
to
draw
conclusions.
Schettgen
et
al.
(
2002;
2004)
assume
a
considerable
dermal
absorption
due
to
their
measurements
of
the
dimethyl
sulfate­
specific
globin
adduct
N­
methylvaline
in
62
dimethyl
sulfate
exposed
workers.
A
maximum
of
184.7
µ
g
N­
methylvaline
/
l
blood
was
measured
in
dermally
exposed
persons.
Unexposed
control
persons
(
n
=
12)
usually
showed
concentrations
of
about
10
µ
g
N­
methylvaline
/
l
blood.
40
µ
g/
l
correspond
to
0.2
mg/
m3
(
0.385
ppm)
dimethyl
sulfate.

Mathison
et
al.
(
1995)
exposed
adult
male
CrlCD:
BR
rats
for
either
20
or
40
minutes
to
dimethyl
sulfate
concentrations
of
0.9,
1.4,
3.1,
9.6,
or
24.2
ppm
in
a
nose/
head­
only
chamber
for
characterization
of
vapor
uptake
kinetics.
Dimethyl
sulfate
uptake
from
the
chamber
was
measured
at
1­
min
intervals.
Blank
chambers
were
run
intermittently
at
the
same
levels
to
evaluate
dimethyl
sulfate
decomposition
rates.
Dimethyl
sulfate
vapor
clearance
appears
to
increase
with
increasing
concentration
between
0.9
and
10
ppm
and
was
calculated
from
69
%
for
0.9
ppm
dimethyl
sulfate
to
89
%
for
9.6
ppm
dimethyl
sulfate
after
40
minutes.
For
24.2
ppm
a
noticeable
decrease
in
uptake
was
observed
(
74.5
%
clearance),
although
the
animals
revealed
no
signs
of
discomfort
or
stress
in
response
to
the
dimethyl
sulfate
exposure.
Decomposition
of
dimethyl
sulfate
in
the
blank
chamber
was
of
about
10
­
20
%
of
initial
dimethyl
sulfate
concentration.
This
study
provides
information
of
dimethyl
sulfate
uptake,
however
allows
no
quantification
of
absorption
rate.

Dimethyl
sulfate
hydrolyzes
readily
in
contact
with
water
or
in
humidity
to
form
sulfuric
acid,
methanol
and
methyl
hydrogen
sulfate
(
monomethyl
sulfate)
(
Wang
et
al.
1988).
In
aqueous
solution
dimethyl
sulfate
hydrolyzation
occurs
with
a
half­
time
of
about
20
minutes
at
35
°
C
to
methanol
and
methyl
hydrogen
sulfate
(
Cartlidge
et
al.
1996).
A
hydrolyzation
half­
time
of
1.2
hours
at
25
°
C
and
pH
7
was
reported
by
NLM
(
2002).
WHO
(
1985)
reported
a
half­
time
of
4.5
hours
in
pH
7
buffered
aqueous
solution
for
hydrolysis
to
methyl
hydrogen
sulfate
and
methanol
in
mammalian
tissues,
while
conversion
to
sulfuric
acid
occurs
more
slowly.
Natural
decomposition
is
dependent
on
humidity.
The
in
vivo
breakdown
of
dimethyl
sulfate
occures
faster,
probably
due
to
the
high
reactivity
with
cellular
constituents.
In
rats
Swann
and
McGee
(
1968)
reported
no
detectable
dimethyl
sulfate
5
minutes
after
a
single
i.
v.
injection
of
75
mg/
kg
body
weight
to
Wistar
rats.

Dimethyl
sulfate
binds
to
tissue
proteins
and
nucleobases
of
DNA
(
Leng
and
Lewalter
2002).
It
is
metabolized
in
humans
and
animals
via
enzymatic
and
non­
enzymatic
pathways.
The
Dimethyl
Sulfate
Proposed
1:
#/
2003
35
enzymatic
pathways
involve
cytochrome
P450,
glutathion
S­
transferase,
and
 ­
lyases
(
Leng
and
Lewalter
2002;
Dahl
and
Hadley
1983).
Metabolization
via
cytochrome
P450
enzymes
was
investigated
by
Dahl
and
Hadley
(
1983).
Incubation
of
rat
liver
and
nasal
microsomes
with
dimethyl
sulfate
(
2
mM
in
water)
led
to
little
amounts
of
formaldehyde
in
liver
microsomes,
and
to
traces
in
nasal
microsomes.
For
phase
II
biotransformation
the
glutathion­
dependent
pathway
is
qualitatively
considered
as
the
major
one.

Löfroth
et
al.
(
1974)
exposed
4
mice
to
vapors
of
radiolabeled
dimethyl
sulfate
in
a
6­
l­
glass
(
whole­
body)
at
about
3
ppm
for
135
minutes
and
60
ppb
for
60
minutes.
About
70
%
of
the
total
dimethyl
sulfate
was
collected
in
the
urine
up
to
24
hours
after
exposure
to
both
concentrations.

In
the
blood
and
urine
of
guinea
pigs
exposed
to
vapors
of
dimethyl
sulfate
(
75
ppm)
for
18
minutes
methanol
was
found
(
Ghiringhelli
et
al.
1957).
A
maximum
level
of
2
mg
/
100
mg
was
indicated
for
blood
concentration
at
various
intervals
(
not
specified).
Concentrations
of
methanol
in
urine
were
reported
between
0.064
and
0.156
mg
in
the
first
two
days
after
exposure.
The
amounts
of
methanol
were
far
less
than
expected
from
extensive
hydrolysis
and
were
regarded
as
toxicologically
not
significant.
Methanol
was
found
as
the
only
urinary
metabolite
(
WHO
1985).
Dimethyl
Sulfate
Proposed
1:
#/
2003
36
Figure
1:
Main
Pathways
for
the
Methylation
of
Dimethyl
Sulfate
(
most
relevant
pathways
are
illustrated
by
thick
arrows).

4.2.
Mechanism
of
Toxicity
Only
the
intact
dimethyl
sulfate­
molecule
has
alkylating
properties.
This
step
is
non­
enzymatic
and
should
already
begin
within
the
first
minutes
after
tissue
contact,
leading
to
methylation
(
and
deactivation)
of
proteins,
essential
amines,
nucleobases
and
other
cellular
molecules.
Also
in
the
extracellular
compartments
dimethyl
sulfate
exerts
methylating
properties,
simple
hydrolysis
being
a
competitive
reaction.
Cells
may
be
damaged
in
multiple
ways.
After
cleavage
of
the
first
methylester
function
(
leading
to
methyl
hydrogen
sulfate)
the
second
has
no
alkylating
properties.
This
can
be
assumed
from
comparative
in
vitro
investigations
with
dimethyl
sulfate
and
methyl
hydrogen
sulfate
by
Tan
et
al.
(
1983),
where
only
dimethyl
sulfate
was
cytotoxic
and
mutagenic
to
CHO
cells.
The
methylgroup
may
be
hydroxylated
via
cytochromes
with
a
subsequent
formation
of
formaldehyde
and
sulfuric
acid
which
upon
intracellular
formation
may
contribute
to
the
total
cytotoxic
impact.

Exposure
to
dimethyl
sulfate
results
in
local
and
systemic
effects
depending
on
extent
and
duration
of
exposure.
In
evaluating
the
toxicity
of
dimethyl
sulfate
local
effects
are
in
the
foreground
for
nonlethal
and
lethal
intoxication
and
occur
at
concentrations
much
lower
than
those
producing
systemic
effects.
Roux
et
al.
(
1977)
assume,
that
toxic
effects
are
caused
by
the
corrosive
potential
of
sulfuric
acid
and
the
effects
of
methanol
to
the
nervous
system.
Formation
of
methanol
leads
to
headache,
dizziness,
wariness,
visual
disturbances,
seizures,
coma,
paralysis,
and
kidney
injury
(
Roux
et
al.
1977).
It
can
be
supposed
from
methanol
toxicity
data,
that
the
concentrations
produced
via
hydrolysis
of
dimethyl
sulfate
are
not
high
enough
to
cause
the
mentioned
effects.
For
example,
Chuwers
et
al.
(
1995)
conducted
a
study
on
26
volunteers
exposed
to
200
ppm
methanol
and
observed
only
slight
alterations
in
neurological
and
psychological
tests,
that
were
judged
as
not
meaningful.
In
accordance
with
Roux
et
al.
(
1977)
Hein
(
1969)
reported,
that
the
toxicity
of
dimethyl
sulfate
is
caused
on
the
one
hand
by
the
intact
molecule,
and
by
sulfuric
acid
formed
by
hydrolysis
on
the
other
hand.
Sulfuric
acid
should
be
responsible
for
the
local
corrosive
injuries,
but
the
systemic
effects
are
caused
by
the
absorbed
dimethyl
sulfate
molecule.
A
major
cause
of
effects
in
inhalation
dimethyl
sulfate
intoxication
is
respiratory
failure
as
consequence
of
mucosal
inflammation
and
edema
of
respiratory
tract.

TABLE
7.
Characterization
of
Local
and
Systemic
Effects
of
Dimethyl
Sulfate
local
effects
systemic
effects
caused
by
methylation
of
dimethyl
sulfate
caused
by
intact
molecule
latency
period
onset
of
effects
immediately
irritation
and
corrosion
hypotension,
decrease
in
respiration
rate,
apnea
lesions
of
respiratory
tract,
inflammation,
demucosation,
edema
organ
failure
(
kidney,
liver,
heart)
Dimethyl
Sulfate
Proposed
1:
#/
2003
37
secondary
effects
of
inflammation
convulsion,
paralysis,
delirium,
coma
From
investigations
on
high
concentration
inhalation
(
undiluted
mist
of
dimethyl
sulfate)
in
guinea
pigs
DuPont
(
1943)
concluded,
that
irritation
is
confined
to
the
bronchi
and
bronchiole,
and
dimethyl
sulfate­
mist
does
not
get
far
enough
to
cause
irritation
of
the
lung
tissue
itself,
indicated
by
lacking
of
congestion
or
edema
of
alveolar
walls
and
exudate
in
alveolar
cavity.

Usually
a
latency
period
of
4
to
12
hours
between
exposure
and
onset
of
effects
was
reported
from
human
case
studies.
From
experimental
studies
on
animals
latency
periods
of
few
minutes
were
reported
after
administration
of
high
doses
via
different
pathways
(
Weber
1902).
As
indicated
above,
the
local
effects
on
skin
and
mucosa
are
not
due
to
the
intact
molecule,
but
to
sulfuric
acid.
The
delayed
hydrolysis
of
dimethyl
sulfate
to
sulfuric
acid,
as
described
by
WHO
(
1985),
is
presumably
responsible
for
this
latency
period.
Delayed
effects
after
several
hours
are
also
described
for
S­
Lost
and
phosgene
(
NRC
2003,
2002)
and
may
be
a
characterization
of
irritative
acting
gas,
where
decomposition
products
(
e.
g.
hydrochloric
acid)
contribute
to
the
effects.

Von
Nida
(
1947)
assumes
from
a
lethal
intoxication
after
accidental
oral
intake
of
dimethyl
sulfate,
that
the
first
slight
symptoms
are
caused
by
decomposition
of
dimethyl
sulfate
at
the
mucosa,
which
set
in
immediately.
The
more
dangerous
component
is
the
intact
molecule
that
evaporates
in
the
oral
cavity
and
is
spread
out
in
the
respiratory
and
digestive
tract.

No
neurotoxicity
was
seen
after
inhalation
exposure,
besides
local
analgesic
effects.

Experimental
studies
revealed
a
tumorigenic
potential
of
dimethyl
sulfate
after
inhalation
exposure
to
concentrations
of
17
mg/
m3
(
3.3
ppm),
and
2.6
mg/
m3
(
0.5
ppm),
respectively
(
Druckrey
et
al.
1970;
Schlögel
1972).
Dimethyl
sulfate
acts
as
a
directly
genotoxic
agent
due
to
its
potential
to
react
with
nucleophilic
groups
of
nucleic
acids
(
Löfroth
et
al.
1974;
Mathison
et
al.
1995;
Swann
and
McGee
1968).

4.3.
Other
Relevant
Information
Due
to
the
only
slightly
pronounced
odor
and
the
anesthetic
effect
on
mucosa,
what
leads
to
anosmia,
respiratory
tract
and
lungs
alarm
signs
are
absent.
Littler
and
McConnell
(
1955)
reported
for
one
case
of
dimethyl
sulfate
intoxication,
that
the
patient
required
no
analgesics
for
one
week.
From
there
it
is
possible
to
be
exposed
to
high
toxic
or
even
lethal
concentrations
without
noticing.
Very
different
onset
of
first
perceptions
of
poisoning
is
reported
in
literature.
For
example,
a
slight
dyspnea
was
noticed
1
hour
after
exposure
to
"
one
breath"
reported
by
Thiess
and
Goldmann
(
1967),
however
4
hours
of
exposure
to
a
deadly
concentration
remained
unnoticed
in
a
case
study
described
by
Weber
(
1902).
For
all
cases
a
delay
in
developing
symptoms
of
toxicity
were
reported
after
inhalation,
and
time
of
appearance
correlates
with
exposure
extent
in
general.
For
lethal
poisoning
health
effects
started
after
4
hours
in
average
(
Weber
1902;
Roßmann
and
Grill
1952)
Dimethyl
Sulfate
Proposed
1:
#/
2003
38
and
for
nonlethal
exposure
after
10
hours
in
average
for
low
dose
exposure
(
Roßmann
and
Grill
1952;
Nebelung
1957;
Wang
1988).

4.3.1.
Species
Variability
No
relevant
data
on
species
specific
differences
in
absorption,
metabolism,
or
elimination
are
known
for
dimethyl
sulfate.
Non­
enzymatic
hydrolysis
is
not
expected
to
differ
greatly
between
different
species.
For
irritation
and
corrosive
effects,
no
major
toxicodynamic
differences
are
relevant.
Moreover,
very
similar
lesions
are
observed
in
various
species.
Due
to
the
damage
resulting
from
direct
contact
of
dimethyl
sulfate
with
epithelial
surfaces
an
order­
of­
magnitude
variability
among
species
is
not
likely.
However,
existing
data
on
quantitative
species
differences
are
limited
and
moderate
species
differences
are
documented
in
case
of
lethality
data.

In
comparing
LC
50
or
benchmark
concentrations
for
lethality
data
from
Hein
(
1969;
see
Table
3)
some
variability
in
effect
sizes
may
be
observed,
although
clearly
less
than
an
order
of
magnitude.
Guinea
pigs
seem
to
be
more
susceptible
against
vapors
of
dimethyl
sulfate
(
1­
hour
exposure)
than
mice.
Rats
and
hamsters
show
sensitivity
in
between
these
two
species.
Guinea
pigs
show
a
very
steep
time­
mortality
curve
with
a
maximal
period
of
survival
of
50
hours
at
71
ppm
(
first
death
3
hours
after
exposure),
compared
to
mice,
where
no
lethality
was
observed
during
this
period
(
first
death
approximately
80
hours
after
exposure).

According
to
investigations
on
carcinogenic
potential
of
dimethyl
sulfate
Schlögel
(
1972)
reveals,
that
rats
are
more
susceptible
than
mice
and
hamsters
regarding
tumor
induction.
Limited
data
from
dimethyl
sulfate
exposure
on
monkeys
reported
by
Roßmann
and
Grill
(
1952)
and
on
cats
reported
by
Flury
and
Zernik
(
1931)
suggest
some
but
no
extensive
differences
in
susceptibility
between
species.

It
can
be
assumed,
that
dimethyl
sulfate
causes
lesions
in
other
parts
of
the
respiratory
tract
of
humans
than
in
experimental
animals
due
to
differences
in
breathing
technique.
Kalberlah
et
al.
(
1999)
report
that
the
extrathoriatic
region
shows
a
lesser
filtering
potency
in
humans
than
in
experimental
animals,
therefore
higher
concentrations
of
contaminants
are
able
to
reach
the
pulmonary
region.
However
this
is
partly
compensated
by
a
larger
surface
of
the
pulmonary
region
in
humans
leading
to
similar
area
doses
in
animals
and
humans.

4.3.2.
Susceptible
Populations
There
are
no
major
toxicokinetic
differences
between
individuals
expected
to
be
relevant
after
dimethyl
sulfate
exposure.
Unspecific
irritating
and
corrosive
action
is
also
assumed
to
be
similar
between
different
individuals.
However,
susceptibility
to
dimethyl
sulfate
effects
may
differ
as
evidenced
by
some
human
case
studies
and
the
variability
in
lethality
concentrations
within
one
animal
species
(
Hein
1969).

Ip
et
al.
(
1989)
reported
exposure
of
two
workers:
one
developing
slight
discomforts
and
the
other
suffering
from
severe
injuries
of
respiratory
tract.
Although,
no
statement
can
be
made
Dimethyl
Sulfate
Proposed
1:
#/
2003
39
according
to
underlying
factors
of
intraspecies
variability
it
is
conspicuous,
that
intoxication
with
similar
exposure
scenario
and
exposure
concentrations
can
show
a
varying
course
of
disease,
including
nonlethal
and
lethal
effects.
This
can
be
at
least
partly
explained
by
different
first
aid
measures
and
therapy.
Due
to
use
medication
to
handle
respiratory
tract
secondary
infections,
e.
g.
laryngitis,
bronchitis,
pneumonia,
caused
by
mucosa
injury
dimethyl
sulfate
intoxications
show
a
more
advantageous
disease
progress
nowadays.
In
summary,
some
degree
of
heterogenic
response
to
exposure
towards
dimethyl
sulfate
can
not
be
excluded.

4.3.3.
Concentration­
Exposure
Duration
Relationship
As
demonstrated
by
Schlögel
(
1972)
and
Hein
(
1969)
irritative
effects
on
respiratory
tract
aggravated
with
longer
exposure
duration.

Roßmann
and
Grill
(
1952)
calculated
effect
concentrations
for
human
exposure
based
on
animal
data
using
Habers
law
and
gave
a
C1
x
t
product
of
5200
(
mg/
m3
x
hours)
for
lethal
effects
and
of
1320
for
severe
disease
process
in
monkeys.
This
calculation
has
not
been
validated
and
existing
data
are
too
poor
to
derive
an
exponent
to
be
used
for
time
extrapolation
based
on
these
calculations.
However,
LC
50
values
derived
in
rats
of
64
ppm
for
an
1­
hour
duration
(
Hein
1969)
and
of
32
ppm
for
a
4­
hour
exposure
(
Kennedy
and
Graepel
1991)
support
the
equation
C2
x
t
=
k.
A
similar
time
relationship
was
observed
within
mice,
for
which
LC
50
values
of
98
ppm
and
54
ppm
were
reported
for
an
1­
hour
and
a
4­
hour
exposure,
respectively
(
Hein
1969;
Molodkina
et
al.
1986).
Dimethyl
Sulfate
Proposed
1:
#/
2003
40
5.
DATA
ANALYSIS
FOR
AEGL­
1
5.1.
Summary
of
Human
Data
Relevant
to
AEGL­
1
There
are
no
scientific
human
data
to
be
used
for
derivation
of
an
AEGL­
1.
Some
suggestions
of
irritating
concentrations
or
thresholds
are
reported
in
literature
(
Wang
1988;
Smyth
1956),
but
they
are
not
supported
by
study
reports.
Wang
et
al.
(
1988)
assume
from
literature
data
and
own
investigations
(
not
shown)
that
concentrations
below
1
ppm
can
cause
slight
irritation
of
eyes.
No
details
are
provided.

5.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
1
Frame
et
al.
(
1993,
abstract
publication)
reported
changes
in
the
nasal
cell
proliferation
(
decreased
labeling
index
for
respiratory
epithelium;
increased
labeling
index
for
olfactory
epithelium)
in
rats
repeatedly
nose­
only
exposed
to
0.1,
0.7
and
1.5
ppm
for
6
hours/
d
(
2
weeks,
10
exposures).
At
0.7
and
1.5
ppm,
but
not
at
0.1
ppm,
histopathology
revealed
dimethyl
sulfaterelated
lesions
(
erosion,
ulceration
and
atrophy
of
respiratory
and
olfactory
epithelia),
that
increased
in
severity
with
higher
exposure
concentration.

At
0.5
and
2
ppm
dose­
dependent
effects
on
eyes
and
respiration
tract
were
reported
by
Schlögel
(
1972)
in
rats,
mice
and
golden
hamster
in
a
repeated
study
with
6­
hour
inhalation
duration.
The
lowest
exposure
concentration
of
0.5
ppm
led
to
changes
in
behavior
and
clinical
findings
in
some
animals
of
all
species
already
after
20
minutes
(
closed
or
half­
closed
eyes;
ruffled
fur).
After
6
hours
exposure,
the
animals
developed
delayed
breathing
problems.
They
coughed
and
sneezed
occasionally
and
revealed
asthmatic­
like
breathing
sounds.
After
inhalation
exposure
to
2
ppm
dimethyl
sulfate
for
6
hours
all
effects
described
at
0.5
ppm
aggrevated,
additionally
conjunctivitis
with
sensitivity
to
light
and
expiration
sounds
were
reported.
All
described
effects
occurred
already
after
first
exposure
as
reported
in
personal
communication
(
Schlögel
2003).

No
substance
related
effects
have
been
reported
by
Alvarez
et
al.
(
1997)
at
clinical
examination
during
exposure
in
a
repeated
nose­
only
inhalation
study
with
dimethyl
sulfate
concentrations
of
0.1,
0.7,
and
1.5
ppm
(
10
exposures)
in
rats.
However,
due
to
the
kind
of
investigations
as
a
developmental
study,
detailed
examination
on
local
irritating
effects
might
not
have
been
not
performed
or
observations
were
not
described.

5.3.
Derivation
of
AEGL­
1
For
the
derivation
of
AEGL­
1
values
irritations
of
eyes
and
respiratory
tract
are
the
most
relevant
effects.
No
human
studies
with
single
exposure
investigating
irritative
effects
are
available.
At
concentrations
relevant
for
AEGL­
1
no
qualified
observations
at
workplace
are
documented.
In
laboratory
animals,
at
0.5
and
2
ppm
irritative
effects
of
dimethyl
sulfate
were
observed
by
Schlögel
(
1972)
after
6­
hour
exposure
in
rats,
mice
and
golden
hamster.
The
irritating
symptoms
aggravated
clearly
with
increasing
concentration.
Effects
observed
at
0.5
ppm
after
6
hours
(
sneezing,
cough,
asthmatic­
like
breathing
sounds)
are
already
judged
as
above
AEGL­
1
level.
In
Dimethyl
Sulfate
Proposed
1:
#/
2003
41
the
same
study,
rough
fur
and
eye
lid
closure
were
observed
in
rats
soon
after
onset
of
exposure
(
after
20
minutes).
These
effects
seem
of
questionable
relevance
for
health
risk
assessments
in
humans.
Also,
these
effects
were
not
reported
in
repeated
exposure
studies
with
similar
exposure
concentrations
(
Frame
et
al.
1993;
Alvarez
et
al.
1997)
or
in
human
studies
with
low
exposure.
Therefore,
only
the
well
established
effects
after
6
hours
exposure
are
regarded
further.
Slight
effects
are
reported
from
studies
with
repeated
exposure.
Frame
et
al.
(
1993)
describe
altered
nasal
cell
proliferation
without
histopathological
findings
at
0.1
ppm
for
6­
hour
exposures
in
rats
in
an
abstract
publication.
Due
to
the
lack
of
adequate
data
from
single
exposure
the
study
by
Frame
et
al.
(
1993)
with
repeated
exposure
is
used
for
AEGL­
1
derivation.
It
is
supported
by
the
data
from
Schlögel
(
1972)
with
more
pronounced
effects
in
rats
after
6­
hour
exposure
to
0.5
ppm.
It
was
tried
to
get
additional
information
by
several
ways
concerning
the
study
by
Frame
et
al.
(
1993),
reported
only
as
an
abstract,
however
without
success
to
date.
Because
the
conducting
laboratory
(
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
DuPont
Company)
is
well
known
and
judged
as
trustworthy,
this
study
was
used
for
the
derivation
despite
the
limited
reporting.

As
discussed
in
Section
4.3.1
and
4.3.2
no
major
differences
in
toxicokinetics
and
toxicodynamics
(
irritating
effects)
between
species
are
expected
after
exposure
to
dimethyl
sulfate.
However,
some
species
are
shown
to
be
moderately
more
susceptible
than
others.
The
interspecies
factor
is
reduced
to
3
because
the
critical
study
is
with
repeated
exposure.
No
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects.
Hence,
the
uncertainty
factor
to
account
for
susceptible
subpopulations
may
also
be
reduced
to
3,
leading
to
an
overall
uncertainty
factor
of
10.

The
experimental
derived
exposure
values
were
scaled
to
AEGL
time
frames
using
the
equation
Cn
x
t
=
k
(
Ten
Berge
et
al.
1986).
As
demonstrated
in
Section
4.3.3
LC
50
values
derived
in
rats
and
mice
support
the
equation
C2
x
t
=
k.
Thus,
the
value
of
n
=
2
in
the
exponential
function
was
used
for
extrapolation
from
the
6­
hour
exposure
to
30
minutes,
1
hour,
4
hour,
and
8
hour.
Because
extrapolation
from
6
hours
to
short
durations
of
less
than
30
minutes
leads
to
very
high
uncertainty,
the
values
for
10
minutes
are
set
equal
to
the
values
for
30
minutes.

TABLE
8.
AEGL­
1
Values
for
Dimethyl
Sulfate
*)

10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
0.035
ppm
(
0.18
mg/
m3)
0.035
ppm
(
0.18
mg/
m3)
0.024
ppm
(
0.12
mg/
m3)
0.012
ppm
(
0.062
mg/
m3)
0.0087
ppm
(
0.045
mg/
m3)

*)
Relevant
skin
uptake
and
sensitizing
properties
of
dimethyl
sulfate
can
not
be
excluded.
Dimethyl
sulfate
is
a
methylating
and
mutagenic
substance,
classified
as
suspected
human
carcinogen
(
A2:
ACGIH,
1991;
2A:
IARC,
1999;
Carc.
Cat.
2,
R45:
BAuA,
2001).
Dimethyl
Sulfate
Proposed
1:
#/
2003
42
6.
DATA
ANALYSIS
FOR
AEGL­
2
6.1.
Summary
of
Human
Data
Relevant
to
AEGL­
2
There
are
no
scientific
human
data
to
be
used
for
derivation
of
an
AEGL­
2.
Some
suggestions
of
relevant
effect
concentrations
or
thresholds
are
reported
in
the
literature,
but
they
are
not
supported
by
study
reports.
Roßmann
and
Grill
(
1952)
assumed
from
animal
non­
lethal
3­
hour
exposure
to
1.35
ppm
dimethyl
sulfate
vapor
to
cause
severe
symptoms
on
eyes
(
conjunctivitis,
keratitis)
and
respiratory
tract
(
cough,
bronchospasm,
dyspnea)
by
extrapolation.
Wang
et
al.
(
1988)
reported
that
the
observed
moderate
irritative
reactions
on
eyes
and
the
upper
respiratory
tract,
without
abnormal
breathing
sounds
in
19
persons,
occur
at
concentrations
in
excess
of
1
ppm
for
a
10­
minute
exposure
duration.

6.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
2
Schlögel
(
1972)
conducted
investigations
on
inhalation
exposure
to
dimethyl
sulfate
in
rats,
mice,
and
golden
hamster
in
a
study
with
repeated
exposure.
The
lowest
exposure
concentration
of
0.5
ppm
for
6
hours
led
to
changes
in
behavior
within
some
animals
of
all
species
already
after
20
minutes
(
ruffled
fur;
closed
or
half­
closed
eyes).
Following
exposure,
the
animals
developed
breathing
problems
(
they
coughed
and
sneezed
occasionally,
and
breathed
sometimes
similar
to
asthmatics).
After
exposure
to
2
ppm
dimethyl
sulfate
for
6
hours
additionally
conjunctivitis
with
sensitivity
to
light
were
reported.
All
described
effects
occurred
already
after
first
exposure
as
reported
in
personal
communication
(
Schlögel
2003).
A
higher
incidence
of
inflammation
of
the
lungs
was
observed
after
repeated
exposure
to
0.5
and
2
ppm.

At
0.7
and
1.5
ppm
Frame
et
al.
(
1993,
abstract
publication)
observed
dimethyl
sulfate­
related
lesions
(
erosion,
ulceration
and
atrophy
of
respiratory
and
olfactory
epithelial)
in
rats
repeatedly
exposed
for
6­
hours
nose­
only
(
10
exposures).
Effects
increased
in
severity
with
higher
exposure
concentration.

At
0.7
or
1.5
ppm
dimethyl
sulfate
(
nose­
only
exposure
for
6
hours/
day,
10
exposures),
but
not
at
0.1
ppm
pregnant
Crl:
CD7BR
rats
(
25
animals)
revealed
a
significant
reduced
body
weight
gain
between
day
7
and
day
16
of
gestation
(
72
%
of
the
controls
at
0.7
ppm,
30
%
at
1.5
ppm)
(
Alvarez
et
al.
1997).

At
10
ppm
Hein
(
1969)
reported
lacrimation
and
salivation
during
an
1­
hour
exposure,
and
corneal
injuries
several
hours
after
cessation
of
exposure
in
guinea
pigs,
but
not
in
rats
and
mice.
However
closed
eyes
and
cleaning
reflexes
were
observed
within
all
species
at
this
concentration.
Occasionally
hemorrhage
lung
zones,
pulmonary
congestion,
emphysema,
and
edema
as
well
as
enlargement
and
blue­
red
discoloration
of
livers
were
observed.
At
histopathology
extension
and
demucosation
of
trachea
and
bronchi
was
observed.
Dimethyl
Sulfate
Proposed
1:
#/
2003
43
6.3.
Derivation
of
AEGL­
2
Breathing
problems
and
asthmatic­
like
breathing
sounds
observed
at
0.5
ppm
at
6­
hour
exposure
after
first
exposure
in
a
repeated
study
in
rats,
mice,
and
golden
hamster
by
Schlögel
(
1972)
are
relevant
effects
for
the
derivation
of
the
AEGL­
2.
Above
this
value
irreversible
lesions
must
be
expected,
what
is
supported
by
injuries
of
respiratory
and
olfactory
epithelial
(
erosion,
ulceration
and
atrophy)
observed
by
Frame
et
al.
(
1993)
at
0.7
ppm
after
repeated
6­
hour
exposure
(
10
exposures).

Effects
(
ruffled
fur,
eye
lid
closure)
observed
already
after
20­
minute
exposure
to
0.5
ppm
are
of
questionable
relevance
for
health
risk
assessments
in
humans.
The
author
was
not
able
to
exclude
some
experimental
influence
caused
by
air
circulation
(
personal
communication,
Schlögel
2003),
however
closed
eyes
and
eye
troubles
were
reported
by
other
authors
at
higher
concentration
with
experimental
animals
(
Flury
1931;
Hein
1969),
as
well
as
in
human
lethal
and
non­
lethal
case
studies
(
Weber
1902;
Strothmann
1929;
Thiess
and
Goldmann
1967;
Savic
1971;
Roux
et
al.
1977;
Zhao
1989;
Testud
et
al.
1999).
Eye
effects
were
not
reported
in
repeated
exposure
studies
with
similar
exposure
concentrations
as
by
Schlögel
(
Frame
et
al.
1993;
Alvarez
et
al.
1997).
Moreover,
the
effect
size
is
judged
to
below
AEGL­
2
level,
therefore
the
well
established
effects
seen
at
0.5
ppm
after
6
hours
are
used
as
a
starting
point
for
AEGL­
2
derivation.

AEGL­
2
values
are
based
on
the
effect
concentrations
in
rats,
mice,
and
golden
hamsters
following
a
6­
hour
exposure
to
0.5
ppm
investigated
by
Schlögel
(
1972).
As
verified
in
personal
communication
(
Schlögel
2003)
effects
observed
after
6­
hour
exposure
to
0.5
ppm
are
reversible
within
a
few
hours.

As
discussed
in
Section
4.3.1
and
4.3.2
no
major
differences
in
toxicokinetics
and
toxicodynamics
(
irritating
effects)
between
species
are
expected
after
exposure
to
dimethyl
sulfate.
However,
some
species
are
shown
to
be
moderately
more
susceptible
than
others.
Therefore,
the
interspecies
factor
is
reduced
to
3.
No
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects.
Hence,
the
uncertainty
factor
to
account
for
susceptible
subpopulations
may
also
be
reduced
to
3,
leading
to
an
overall
uncertainty
factor
of
10.

The
experimental
derived
exposure
values
were
scaled
to
AEGL
time
frames
using
the
equation
Cn
x
t
=
k
(
Ten
Berge
et
al.
1986).
As
demonstrated
in
Section
4.3.3
LC
50
values
derived
in
rats
and
mice
support
the
equation
C2
x
t
=
k.
Thus,
the
value
of
n
=
2
in
the
exponential
function
was
used
for
extrapolation
from
the
6­
hour
exposure
to
30
minutes,
1
hour,
4
hour,
and
8
hour.
Because
extrapolation
from
6
hours
to
short
durations
of
less
than
30
minutes
leads
to
very
high
uncertainty,
the
values
for
10
minutes
are
set
equal
to
the
values
for
30
minutes.

The
derived
AEGL­
2
values
are
assumed
to
be
appropriate
to
avoid
relevant
cell
damage
in
respiratory
tract,
which
may
contribute
to
cell
replication
and
may
be
viewed
as
a
risk
factor
for
development
of
malignant
effects.
Dimethyl
Sulfate
Proposed
1:
#/
2003
44
TABLE
9.
AEGL­
2
Values
for
Dimethyl
Sulfate
*)

10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
0.17
ppm
(
0.88
mg/
m3)
0.17
ppm
(
0.88
mg/
m3)
0.12
ppm
(
0.62
mg/
m3)
0.061
ppm
(
0.32
mg/
m3)
0.043
ppm
(
0.22
mg/
m3)

*)
Relevant
skin
uptake
and
sensitizing
properties
of
dimethyl
sulfate
can
not
be
excluded.
Dimethyl
sulfate
is
a
methylating
and
mutagenic
substance,
classified
as
suspected
human
carcinogen
(
A2:
ACGIH,
1991;
2A:
IARC,
1999;
Carc.
Cat.
2,
R45:
BAuA,
2001).
Dimethyl
Sulfate
Proposed
1:
#/
2003
45
7.
DATA
ANALYSIS
FOR
AEGL­
3
7.1.
Summary
of
Human
Data
Relevant
to
AEGL­
3
No
adequate
human
experiences
are
available
to
derive
AEGL­
3
values.

Two
calculations
for
assumed
human
lethal
concentrations
of
dimethyl
sulfate
were
reported
by
Roßmann
and
Grill
(
1952)
(
5.4
ppm,
3
hours)
and
Wang
et
al.
(
1988)
(
97
ppm,
10
minutes)
based
on
data
from
animal
studies
and
exposure
modeling.
However
for
none
of
the
reported
case
studies
measurements
of
concentrations
were
conducted.

7.2.
Summary
of
Animal
Data
Relevant
to
AEGL­
3
As
presented
in
Section
Species
Variability
(
Section
4.3.1)
guinea
pigs
and
hamsters
are
the
most
susceptible
species
against
vapors
of
dimethyl
sulfate.
A
LC
50
value
for
guinea
pigs
of
32
ppm
was
derived
for
an
1­
hour
exposure
(
Hein
1969).
Hamsters
reveal
a
LC
50
of
56
ppm
(
Hein
1969).
Compared
to
this,
LC
50
values
for
rats
range
from
64
ppm
(
Hein
1969)
to
100
ppm
(
DuPont
1971)
for
an
1­
hour
exposure
period.
For
a
4­
hour
exposure
of
rats
a
LC
50
value
of
32
ppm
was
reported
by
Kennedy
and
Graepel
(
1991).
At
10
ppm
disease
process
that
lasted
several
days
but
no
lethality
was
reported
by
Hein
(
1969)
in
rats
and
guinea
pigs
for
an
1­
hour
exposure,
however
1/
20
mice
died
at
this
concentration
as
well
as
at
42
ppm.
The
highest
LC
0
for
rats
have
been
49
ppm
(
Hein
1969)
and
58
ppm
(
DuPont
1971)
for
an
1­
h
exposure,
and
15
ppm
(
Smyth
1956)
for
a
4­
h
exposure.
In
mice
no
lethality
was
seen
at
49
ppm
at
the
highest
for
an
1­
h
exposure,
and
in
guinea
pigs
at
10
ppm
at
the
highest,
also
for
an
1­
h
exposure
(
Hein
1969).

Studies
with
"
sublethal"
concentrations
in
rats
(
34
ppm),
mice
(
48
ppm)
and
golden
hamsters
(
20
ppm)
for
an
1­
hour
exposure
(
4x
per
year)
revealed
severe
dyspnea
and
breathing
problems
within
all
species
4
hours
after
cessation
of
exposure,
that
aggravated
the
following
2
days
(
Schlögel
1972).
A
recovery
was
observed
not
until
one
week
after
exposure.
Isolated
lethality
was
reported
after
1st
exposure,
especially
in
rats
and
hamsters,
as
can
be
derived
from
the
supplied
figures.
However,
no
figures
were
given
for
the
unexposed
control
group.

7.3.
Derivation
of
AEGL­
3
The
most
qualified
study
to
derive
a
lethal
concentrations
below
LC
100
is
the
study
from
Hein
(
1969).
In
this
experiment,
after
1­
hour
exposure
most
species
showed
no
lethality
after
10
ppm.
Only
with
mice
there
was
an
incidence
of
lethal
effect
in
1/
20
animals
after
exposure
to
10
ppm.
However,
there
was
no
clear
dose
response
with
no
lethality
after
49
ppm
in
mice.
The
highest
non­
lethal
concentration
of
49
ppm
(
rats,
1­
h
exposure)
was
used
for
the
derivation
of
the
AEGL­
3
values.
Accuracy
of
the
derived
LC
0
in
hamster
by
Hein
(
1969)
was
largely
confirmed
by
BMCL
calculations:
Dimethyl
Sulfate
Proposed
1:
#/
2003
46
Rat
BMCL
05
32
ppm
(
log
Probit)
Mouse
BMCL
05
44
ppm
(
log
Probit)
Guinea
Pig
BMCL
05
5.8
ppm
(
Quantal
Quadratic)
Hamster
BMC
01
12.6
ppm
(
Multistage)

The
study
bei
Hein
(
1969)
was
chosen
due
to
the
comprehensively
reported
effects
and
the
long
follow­
up
observation
period
of
3
weeks.
This
LC
0
is
further
supported
by
the
LC
0
of
58
ppm
derived
from
a
study
by
DuPont
(
1971),
which
is
however
less
extensive
reported.

As
discussed
in
Section
4.3.1
and
4.3.2
no
major
differences
in
toxicokinetics
and
toxicodynamics
(
irritating
effects)
between
species
are
expected
after
exposure
to
dimethyl
sulfate.
However,
some
species
are
shown
to
be
moderately
more
susceptible
than
others.
The
rat
as
the
species
used
for
the
derivation
of
the
AEGL­
3
values
is
less
susceptible
as
for
example
the
guinea
pig.
Because
not
the
most
susceptible
species
was
used,
an
interspecies
factor
of
10
was
applied.
No
large
differences
in
susceptibility
between
individuals
are
expected
for
lethality.
Hence,
the
uncertainty
factor
to
account
for
susceptible
subpopulations
may
be
reduced
to
3,
leading
to
an
overall
uncertainty
factor
of
30,
which
is
applied
on
the
highest
valid
LC
0
of
49
ppm
(
rats,
1­
h
exposure)
received
in
the
study
from
Hein
(
1969).

The
experimental
derived
exposure
values
were
scaled
to
AEGL
time
frames
using
the
equation
Cn
x
t
=
k
(
Ten
Berge
et
al.
1986).
As
demonstrated
in
Section
4.3.3
LC
50
values
derived
in
rats
and
mice
support
the
equation
C2
x
t
=
k.
Thus,
the
value
of
n
=
2
in
the
exponential
function
was
used
for
extrapolation
from
the
1­
hour
exposure
to
all
durations.

TABLE
10.
AEGL­
3
Values
for
Dimethyl
Sulfate
*)

10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
4.0
ppm
(
21
mg/
m3)
2.3
ppm
(
12
mg/
m3)
1.6
ppm
(
8.3
mg/
m3)
0.82
ppm
(
4.3
mg/
m3)
0.58
ppm
(
3.0
mg/
m3)

*)
Relevant
skin
uptake
and
sensitizing
properties
of
dimethyl
sulfate
can
not
be
excluded.
Dimethyl
sulfate
is
a
methylating
and
mutagenic
substance,
classified
as
suspected
human
carcinogen
(
A2:
ACGIH,
1991;
2A:
IARC,
1999;
Carc.
Cat.
2,
R45:
BAuA,
2001).
Dimethyl
Sulfate
Proposed
1:
#/
2003
47
8.
SUMMARY
OF
AEGLS
8.1.
AEGL
Values
and
Toxicity
Endpoints
The
derived
AEGL
values
for
various
levels
of
effects
and
duration
of
exposure
are
summarized
in
Table
11.
The
AEGL­
1
value
is
based
on
nasal
cell
proliferation
in
rats
(
Frame
et
al.
1993).
The
AEGL­
2
value
is
based
on
breathing
problems
observed
in
different
species
(
rat,
mouse,
hamster)
(
Schlögel
1972).
The
AEGL­
3
values
is
based
on
emphysema
and
edema
of
the
lung,
observed
in
rats,
mice,
hamsters,
and
guinea
pigs,
that
can
result
in
lethality
(
Hein
1969;
DuPont
1971)
.

TABLE
11.
Summary
of
AEGL
Values
Classification
Exposure
Duration
10­
minute
30­
minute
1­
hour
4­
hour
8­
hour
AEGL­
1
(
Nondisabling)
0.035
ppm
(
0.18
mg/
m3)
0.035
ppm
(
0.18
mg/
m3)
0.024
ppm
(
0.12
mg/
m3)
0.012
ppm
(
0.062
mg/
m3)
0.0087
ppm
(
0.045
mg/
m3)

AEGL­
2
(
Disabling)
0.17
ppm
(
0.88
mg/
m3)
0.17
ppm
(
0.88
mg/
m3)
0.12
ppm
(
0.62
mg/
m3)
0.061
ppm
(
0.32
mg/
m3)
0.043
ppm
(
0.22
mg/
m3)

AEGL­
3
(
Lethal)
4.0
ppm
(
21
mg/
m3)
2.3
ppm
(
12
mg/
m3)
1.6
ppm
(
8.3
mg/
m3)
0.82
ppm
(
4.3
mg/
m3)
0.58
ppm
(
3.0
mg/
m3)

*)
Relevant
skin
uptake
and
sensitizing
properties
of
dimethyl
sulfate
can
not
be
excluded.
Dimethyl
sulfate
is
a
methylating
and
mutagenic
substance,
classified
as
suspected
human
carcinogen
(
A2:
ACGIH,
1991;
2A:
IARC,
1999;
Carc.
Cat.
2,
R45:
BAuA,
2001).

An
useful
presentation
to
evaluate
the
derived
AEGL
values
in
context
of
the
existing
empirical
effect
concentration
is
presented
in
Figure
2.
For
this
plot,
the
toxic
responses
are
placed
into
severity
categories
according
to
the
AEGL
levels:
no
effect,
discomfort,
disabling,
some
lethality,
lethality
(
100
%).
For
humans,
the
only
available
indication
of
an
adverse
effect,
i.
e.
irritative
symptoms
of
the
eyes
at
1
ppm
for
a
10
minute
exposure,
which
is
however
based
on
an
assumption
by
Wang
et
al.
(
1988),
was
used
to
better
categorize
the
animal
data.

These
comparisons
with
available
experimental
data
indicate,
that
the
derived
AEGL
values
are
protective
for
humans
at
any
of
the
3
levels
of
severity.
Dimethyl
Sulfate
Proposed
1:
#/
2003
48
Figure
2:
Category
Plot
of
Toxicity
Data
compared
to
AEGL
Values
8.2.
Comparison
with
Other
Standards
and
Guidelines
Cartlidge
et
al.
(
1996)
proposed
a
MEL
(
maximum
exposure
limit)
of
0.05
ppm
(
0.26
mg/
m3)
for
occupational
exposure
(
8­
hour
TWA)
for
the
UK
Health
and
Safety
Executive
(
HSE).
Additionally,
a
precautionary
"
Sk"
skin
notation
was
considered
to
be
necessary
due
to
the
absorption
of
dimethyl
sulfate
through
skin.

German
guidance
concentrations
(
TRK)
for
dimethyl
sulfate
production
were
regulated
with
0.02
ppm
(
0.1
mg/
m3)
and
0.04
ppm
(
0.2
mg/
m3)
for
dimethyl
sulfate
use,
not
based
on
toxicological
consideration.

In
Denmark
the
occupational
limit
value
for
dimethyl
sulfate
is
0.01
ppm
(
0.05
mg/
m3)
(
Cartlidge
et
al.
1996).
Dimethyl
Sulfate
Proposed
1:
#/
2003
49
The
U.
S.
ACHPPM
(
1999)
derived
1­
hour
MAG­
values
(
Military
Air
Guidelines)
of
0.3
ppm
(
minimal
effects
level),
1
ppm
(
significant
effects
level)
and
7
ppm
(
severe
effects
level).
An
1
­
14
day
MAG
with
skin
notation
of
0.01
ppm
is
proposed
for
no
significant
health
effects
in
the
deployed
population
for
continuous
exposure
(
24
hours
to
14
days
in
duration).
Data
base
for
derivation
of
MAG­
values
are
existing
values,
however
no
guideline
for
dimethyl
sulfate
is
specified.

ECB
(
2002)
calculated
a
theoretical
Health­
based
Occupational
Reference
Value
(
HBORV)
of
0.1
mg/
m3
(
0.02
ppm)
based
on
a
fictive
NOAEL
of
9
mg/
m3
from
a
semichronic
inhalation
study
or
a
NOAEL
of
0.9
mg/
m3
from
a
chronic
inhalation
study.
However
it
is
remarked,
that
it
cannot
be
excluded,
that
systemic
effects
occur
even
at
0.02
ppm
by
comparison
of
these
fictive
NOAEL
´
s
with
available
toxicological
data
from
Frame
et
al.
(
1993),
Alvarez
et
al.
(
1997),
and
Schlögel
(
1972).

TABLE
12.
Existent
Standards
and
Guidelines
for
Dimethyl
Sulfate
Guideline
Exposure
Duration
10
minute
30
minute
1
hour
4
hour
8
hour
AEGL­
1
0.035
ppm
0.035
ppm
0.024
ppm
0.012
ppm
0.0087
ppm
AEGL­
2
0.17
ppm
0.17
ppm
0.12
ppm
0.061
ppm
0.043
ppm
AEGL­
3
4.0
ppm
2.3
ppm
1.6
ppm
0.82
ppm
0.58
ppm
ERPG­
1
(
AIHA)
a
­

ERPG­
2
(
AIHA)
0.2
ppm
ERPG­
3
(
AIHA)
1
ppm
EEGL
(
NRC)
b
PEL­
TWA
(
OSHA)
c
0.1
ppm
PEL­
STEL
(
OSHA)
d
IDLH
(
NIOSH)
7
ppm
REL­
TWA
(
NIOSH)
f
0.1
ppm
REL­
STEL
(
NIOSH)
g
TLV­
TWA
(
ACGIH)
h
0.1
ppm
"
skin"
notation
TLV­
STEL
(
ACGIH)
i
Dimethyl
Sulfate
Proposed
1:
#/
2003
10
minute
30
minute
1
hour
4
hour
8
hour
50
MAK
(
Germany)
j
MAK
Pe
a
k
Li
m
i
t
(
Germany)
k
MAC
(
The
Netherlands)
l
0.1
OEL
(
Denmark)
0.01
HBORV
0.02
aERPG
(
Emergency
Response
Planning
Guidelines,
American
Industrial
Hygiene
Association
(
AIHA
1994)
The
ERPG­
1
is
the
maximum
airborne
concentration
below
which
it
is
believed
nearly
all
individuals
could
be
exposed
for
up
to
one
hour
without
experiencing
other
than
mild,
transient
adverse
health
effects
or
without
perceiving
a
clearly
defined
objectionable
odor.
An
ERPG­
1
for
dimethyl
sulfate
was
not
derived.
The
ERPG­
2
is
the
maximum
airborne
concentration
below
which
it
is
believed
nearly
all
individuals
could
be
exposed
for
up
to
one
hour
without
experiencing
or
developing
irreversible
or
other
serious
health
effects
or
symptoms
that
could
impair
an
individual=
s
ability
to
take
protection
action.
The
ERPG­
2
for
dimethyl
sulfate
is
based
on
experiences
in
humans.
The
ERPG­
3
is
the
maximum
airborne
concentration
below
which
it
is
believed
nearly
all
individuals
could
be
exposed
for
up
to
one
hour
without
experiencing
or
developing
life­
threatening
health
effects.
The
ERPG­
3
for
dimethyl
sulfate
is
based
on
experiences
in
humans
(
lethal
intoxication
after
intake
of
28
mg
(
calculated)).
bEEGL
(
Emergency
Exposure
Guidance
Levels,
National
Research
Council
The
EEGL
is
the
concentration
of
contaminants
that
can
cause
discomfort
or
other
evidence
of
irritation
or
intoxication
in
or
around
the
workplace,
but
avoids
death,
other
severe
acute
effects
and
long­
term
or
chronic
injury.
An
EEGL
for
dimethyl
sulfate
was
not
derived.
cOSHA
PEL­
TWA
(
Occupational
Health
and
Safety
Administration,
Permissible
Exposure
Limits
­
Time
Weighted
Average)
(
OSHA
1998)
is
defined
analogous
to
the
ACGIH­
TLV­
TWA,
but
is
for
exposures
of
no
more
than
10
hours/
day,
40
hours/
week.
dOSHA
PEL­
STEL
(
Permissible
Exposure
Limits
­
Short
Term
Exposure
Limit)
(
OSHA
1989)
is
defined
analogous
to
the
ACGIH­
TLV­
STEL.
eIDLH
(
Immediately
Dangerous
to
Life
and
Health,
National
Institute
of
Occupational
Safety
and
Health)
(
NIOSH
1996)
represents
the
maximum
concentration
from
which
one
could
escape
within
30
minutes
without
any
escape­
impairing
symptoms,
or
any
irreversible
health
effects.
The
IDLH
for
dimethyl
sulfate
is
based
on
acute
inhalation
toxicity
data
in
humans.
fNIOSH
REL­
TWA
(
National
Institute
of
Occupational
Safety
and
Health,
Recommended
Exposure
Limits
­
Time
Weighted
Average)
(
NIOSH
1996)
is
defined
analogous
to
the
ACGIH­
TLV­
TWA.
gNIOSH
REL­
STEL
(
Recommended
Exposure
Limits
­
Short
Term
Exposure
Limit)
(
NIOSH
1996)
is
defined
analogous
to
the
ACGIH
TLV­
STEL.
hACGIH
TLV­
TWA
(
American
Conference
of
Governmental
Industrial
Hygienists,
Threshold
Limit
Value
­
Time
Weighted
Average)
(
ACGIH
1991)
is
the
time­
weighted
average
concentration
for
a
normal
8­
hour
workday
and
a
40­
hour
workweek,
to
which
nearly
all
workers
may
be
repeatedly
exposed,
day
after
day,
without
adverse
effect.
iACGIH
TLV­
STEL
(
Threshold
Limit
Value
­
Short
Term
Exposure
Limit)
(
ACGIH
1991)
Dimethyl
Sulfate
Proposed
1:
#/
2003
51
is
defined
as
a
15­
minute
TWA
exposure
which
should
not
be
exceeded
at
any
time
during
the
workday
even
if
the
8­
hour
TWA
is
within
the
TLV­
TWA.
Exposures
above
the
TLV­
TWA
up
to
the
STEL
should
not
be
longer
than
15
minutes
and
should
not
occur
more
than
4
times
per
day.
There
should
be
at
least
60
minutes
between
successive
exposures
in
this
range.
jMAK
(
Maximale
Arbeitsplatzkonzentration
[
Maximum
Workplace
Concentration])
(
Deutsche
Forschungsgemeinschaft
[
German
Research
Association]
2000)
is
defined
analogous
to
the
ACGIH­
TLV­
TWA.
The
MAK
Commission
classified
dimethyl
sulfate
as
category
A2
carcinogen,
therefore
no
MAK
was
derived.
kMAK
Spitzenbegrenzung
(
Peak
Limit
[
give
category])
(
German
Research
Association
2000)
constitutes
the
maximum
average
concentration
to
which
workers
can
be
exposed
for
a
period
up
to
30
minutes
with
no
more
than
2
exposure
periods
per
work
shift;
total
exposure
may
not
exceed
8­
hour
MAK
The
MAK
Commission
classified
dimethyl
sulfate
as
category
A2
carcinogen,
therefore
no
MAK
peak
limit
was
derived.
lMAC
(
Maximaal
Aanvaaarde
Concentratie
[
Maximal
Accepted
Concentration])
(
SDU
Uitgevers
[
under
the
auspices
of
the
Ministry
of
Social
Affairs
and
Employment],
The
Hague,
The
Netherlands
2000)
is
defined
analogous
to
the
ACGIH­
TLV­
TWA.
Dimethyl
Sulfate
Proposed
1:
#/
2003
52
9.
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Dimethyl
Sulfate
Proposed
1:
#/
2003
58
APPENDIX
A:
Derivation
of
AEGL
Values
Dimethyl
Sulfate
Proposed
1:
#/
2003
59
Derivation
of
AEGL­
1
Key
Study:
Frame
et
al.
(
1993;
abstract
publication)

Toxicity
endpoint:
Altered
nasal
cell
proliferation
from
repeated
exposure
to
0.1
ppm
for
6
hours
(
10
exposures).

Time
scaling:
C2
x
t
for
extrapolation
to
30
minutes,
1
hour,
4
hours,
8
hours
k
=
0.12
ppm2
x
360
min
=
3.6
ppm2
x
min
The
10­
min
AEGL­
1
was
set
at
the
same
concentration
as
the
30­
min
AEGL­
1
Uncertainty
factors:
3
for
interspecies
variability
3
for
intraspecies
variability
Combined
uncertainty
factor
of
10
Modifying
factor:
None
Calculations:

10­
minute
AEGL­
1
10­
min
AEGL­
1
=
30­
min
AEGL­
1
=
0.035
ppm
(
0.18
mg/
m3)

30­
minute
AEGL­
1
C2
x
30
min
=
3.6
ppm2
x
min
C
=
0.35
ppm
30­
min
AEGL­
1
=
0.35
ppm/
10
=
0.035
ppm
(
0.18
mg/
m3)

1­
hour
AEGL­
1
C2
x
60
min
=
3.6
ppm2
x
min
C
=
0.24
ppm
1­
hour
AEGL­
1
=
0.24
ppm/
10
=
0.024
ppm
(
0.12
mg/
m3)

4­
hour
AEGL­
1
C2
x
240
min
=
3.6
ppm2
x
min
C
=
0.12
ppm
4­
hour
AEGL­
1
=
0.12
ppm
/
10
=
0.012
ppm
(
0.062
mg/
m3)

8­
hour
AEGL­
1
C2
x
480
min
=
3.6
ppm2
x
min
C
=
0.087
ppm
8­
hour
AEGL­
1
=
0.087
ppm/
10
=
0.0087
ppm
(
0.045
mg/
m3)
Dimethyl
Sulfate
Proposed
1:
#/
2003
60
Derivation
of
AEGL­
2
Key
Studies:
Schlögel
(
1972)

Toxicity
endpoints:
Breathing
difficulties
and
asthmatic­
like
breathing
sounds
at
0.5
ppm
for
6
hours.

Time
scaling
C2
x
t
for
extrapolation
to
30
minutes,
1
hour,
4
hours,
8
hours
k
=
0.52
ppm2
x
360
min
=
90
ppm2
x
min
The
10­
min
AEGL­
2
was
set
at
the
same
concentration
as
the
30­
min
AEGL­
2.

Uncertainty
factors:
3
for
interspecies
variability
3
for
intraspecies
variability
Combined
uncertainty
factor
of
10
Modifying
factor:
None
Calculations:

10­
minute
AEGL­
2
10­
min
AEGL­
2
=
30­
min
AEGL­
2
=
0.17
ppm
(
0.88
mg/
m3)

30­
minute
AEGL­
2
C2
x
30
min
=
90
ppm2
x
min
C
=
1.7
ppm
30­
min
AEGL­
2
=
1.7
ppm/
10
=
0.17
ppm
(
0.88
mg/
m3)

1­
hour
AEGL­
2
C2
x
60
min
=
90
ppm2
x
min
C
=
1.2
ppm
AEGL­
2
=
1.2
ppm/
10
=
0.12
ppm
(
0.62
mg/
m3)

4­
hour
AEGL­
2
C2
x
240
min
=
90
ppm2
x
min
C
=
0.61
ppm
AEGL­
2
=
0.61
ppm/
10
=
0.061
ppm
(
0.32
mg/
m3)

8­
hour
AEGL­
2
C2
x
480
min
=
90
ppm2
x
min
C
=
0.43
ppm
AEGL­
2
=
0.43
ppm/
10
=
0.043
ppm
(
0.22
mg/
m3)
Dimethyl
Sulfate
Proposed
1:
#/
2003
61
Derivation
of
AEGL­
3
Key
Studies:
Hein
(
1969)

Toxicity
endpoint:
LC
0
of
49
ppm
for
1­
hour
exposure
in
rats.
Calculation
of
BMCL
05
gained
32
ppm.

Time
scaling
C2
x
t
for
extrapolation
to
10
minutes,
30
minutes,
4
hours,
8
hours
k
=
492
ppm2
x
60
min
=
144060
ppm2
x
min
Uncertainty
factors:
10
for
interspecies
variability
3
for
intraspecies
variability
Combined
uncertainty
factor
of
30
Modifying
factor:
None
10­
minute
AEGL­
3
C2
x
10
min
=
144060
ppm2
x
min
C
=
120
ppm
10­
min
AEGL­
3
=
120
ppm/
30
=
4.0
ppm
(
21
mg/
m3)

30­
minute
AEGL­
3
C2
x
30
min
=
144060
ppm2
x
min
C
=
69
ppm
30­
min
AEGL­
3
=
69
ppm/
30
=
2.3
ppm
(
12
mg/
m3)

1­
hour
AEGL­
3
C
=
49
ppm
1­
hour
AEGL­
3
=
49
ppm/
30
=
1.6
ppm
(
8.3
mg/
m3)

4­
hour
AEGL­
3
C2
x
240
min
=
144060
ppm2
x
min
C
=
24.6
ppm
4­
hour
AEGL­
3
=
24.6
ppm/
30
=
0.82
ppm
(
4.3
mg/
m3)

8­
hour
AEGL­
3
C2
x
480
min
=
144060
ppm2
x
min
C
=
17.4
ppm
8­
hour
AEGL­
3
=
17.4
ppm/
30
=
0.58
ppm
(
3.0
mg/
m3)
Dimethyl
Sulfate
Proposed
1:
#/
2003
62
APPENDIX
B:
Carcinogenicity
Assessment
Dimethyl
Sulfate
Proposed
1:
#/
2003
63
Cancer
Assessment
for
Dimethyl
Sulfate
Based
on
a
carcinogenic
study
conducted
by
Schlögel
(
1972)
calculations
to
elucidate
doseresponse
relationship
were
conducted
using
the
ppm­
hour
factor.
Schögel
exposed
rats,
mice
and
golden
hamsters
to
0.5
ppm,
2
ppm
and
to
a
sublethal
dose
(
rats
34
ppm,
mice
48
ppm,
golden
hamsters
20
ppm).
The
incidences
of
benign
and
malignant
tumors
of
respiratory
tract,
eyes
and
related
organs
were
determined.
An
increased
incidence
of
nose
and
lungs
was
observed
following
dimethyl
sulfate
exposure.
This
study
shows
a
limited
quality
concerning
number
of
animals,
dose
levels,
and
exposure
duration,
however
there
is
no
other
suitable
study
for
derivation
of
a
quantitative
risk
figure.

Calculation
of
dose­
response
relationship
0.5
ppm
group
The
animals
were
exposed
for
about
15
month,
twice
a
week,
however
higher
concentration
and
frequence
of
exposure
were
conducted
for
the
first
weeks
(
about
1
month).
No
statement
can
be
made
on
the
exact
concentration
and
duration
(
personal
communication).
Therefore
a
ppm­
hour
calculation
results
in
at
least
420
ppm­
hour,
if
0.5
ppm
were
used
for
the
whole
duration:
1.
month
(
5
6­
hour
exposures
/
week)
=
20
exposures
=
120
hours
2.
­
15­
month
(
2
6­
hour
exposures
/
week)
=
120
exposures
=
720
hours
ppm­
hour
factor
=
720
hours
x
0.5
ppm
=
420
Cancer
incidence
for
all
animals
=
5.2
%

2
ppm
group
All
animals
were
exposed
for
about
15
month
with
constant
dimethyl
sulfate­
concentration.
1.
­
15­
month
(
1
6­
hour
exposure
every
two
weeks)
=
32
exposures
=
192
hours
ppm­
hour
factor
=
192
hours
x
2
ppm
=
384
Cancer
incidence
for
all
animals
=
13.5
%

sublethal
group
All
animals
were
exposed
4
times
within
a
year.
4
exposures
(
1
exposure
every
3
month
for
1
hour)
=
4
hours
ppm­
hour
factor
for
rats
=
4
hours
x
34
ppm
=
136
ppm­
hour
factor
for
mice
=
4
hours
x
48
ppm
=
192
ppm­
hour
factor
for
golden
hamsters
=
4
hours
x
20
ppm
=
80
Cancer
incidence
for
rats
=
3.1
%
No
tumors
were
observed
in
mice
and
golden
hamster.

The
highest
ppm­
hour
factor
results
from
the
0.5
ppm
group,
but
the
highest
cancer
incidence
for
treatment
related
tumors
was
found
in
the
2
ppm
group.
Therefore
no
dose­
response
relationship
can
be
drawn.
At
this
concentration,
as
well
as
at
0.5
ppm
cytotoxicity
of
respiration
tract
was
observed.
Dimethyl
Sulfate
Proposed
1:
#/
2003
64
Unit
risk
calculations
As
reported
in
Section
3.8.,
ECB
(
2002)
conducted
a
carcinogenic
risk
estimation
for
dimethyl
sulfate
based
on
the
results
from
Schlögel
(
1972).
The
2
ppm
dosage
scheme
resulted
in
the
highest
incidence
of
malignant
tumors
and
was
therefore
used
for
risk
assessment.

Calculations
gained
a
carcinogenic
activity
attributable
to
the
exposure
to
the
substance
per
unit
concentration
(
expressed
per
mg/
m3),
expressed
as
I
conc.

I
conc
=
(
6/
27
­
0/
36)
/
(
10.5
x
456/
728
x
613/
728
x
6/
24
x
1/
14)
=
2.2
(
mg/
m3)­
1
I
conc
carcinogenic
activity
attributable
to
the
exposure
to
the
substance
per
unit
concentration
(
expressed
per
mg/
m3)
I
e
6/
27
(
incidences
of
malignant
tumors
in
exposed
male
and
female
animals)
I
c
0/
36
(
incidences
of
malignant
tumors
in
control
male
and
female
animals)
C
10.5
(
concentration
in
experiment
in
mg/
m3)
X
po
15
month,
456
days
(
exposure
period)
X
pe
613
days
(
mean
survival
time
found
in
the
exposure
group)
L
728
days
(
mean
survival
time
found
in
the
control
group)

Calculation:
To
calculate
a
concentration
of
dimethyl
sulfate
that
would
cause
a
theoretical
excess
cancer
risk
of
10­
4
the
risk
is
divided
by
the
1­
day
carcinogenic
activity:

dose
=
1x10­
4
/
2.2
(
mg/
m3)­
1
=
0.045
µ
g/
m3
To
convert
a
75­
year
exposure
to
a
24­
hour
exposure,
the
concentration
is
multiplied
by
the
number
of
days
in
75
years:

24­
hour
exposure
concentration
=
0.045
µ
g/
m3
x
27375
=
1232
µ
g/
m3
To
convert
to
an
8­
hour
exposure
an
inhalation
volume
of
10
m3
for
occupational
exposure
and
20
m3
for
24­
hour
is
used:

8­
hour
exposure
=
1232
µ
g/
m3
x
20/
10
=
2464
µ
g/
m3
To
adjust
for
uncertainties
in
assessing
potential
cancer
risks
under
short­
term
exposures
the
8­
hour
exposure
is
divided
by
an
adjustment
factor
of
6
(
see
NAC
2000):

2464
µ
g/
m3
/
6
=
411
µ
g/
m3
(
0.079
ppm)

Corresponding,
calculations
for
10­
5
and
10­
6
risk
levels
are
conducted:

10­
5
risk
level
=
41
µ
g/
m3
(
8­
hour
exposure)
10­
6
risk
level
=
4.1
µ
g/
m3
(
8­
hour
exposure)
Dimethyl
Sulfate
Proposed
1:
#/
2003
65
Due
to
the
missing
dose­
effect
relationship
calculations
on
carcinogenic
risk
levels
are
uncertain.
Dimethyl
sulfate
reveals
the
potential
to
react
with
nucleophilic
groups
of
nucleic
acids
and
therefore
acts
as
a
directly
genotoxic
agent
(
Löfroth
et
al.
1974;
Mathison
et
al.
1995;
Swann
and
McGee
1968).
However,
the
observed
cancer
incidence
in
the
study
conducted
by
Schlögel
(
1972)
may
have
been
influenced
by
cytotoxic
effects
(
irritant
effects
in
target
tissues)
as
seen
at
the
exposure
concentration.

Concluding
remark:
The
10­
4
risk
level
is
above
AEGL­
2
for
8­
hour
exposure.
Dimethyl
Sulfate
Proposed
1:
#/
2003
66
APPENDIX
C:
Derivation
Summary
for
Acute
Exposure
Guideline
Levels
for
Dimethyl
Sulfate
Dimethyl
Sulfate
Proposed
1:
#/
2003
67
AEGL­
1
Values
10
min
30
min
1
h
4
h
8
h
0.035
ppm
0.035
ppm
0.024
ppm
0.012
ppm
0.0087
ppm
Reference:
Frame,
S.
R.,
Panepinto,
A.
S.,
Bogdanffy,
M.
S.,
1993.
Effects
of
inhalation
exposure
to
dimethyl
sulfate
on
nasal
epithelial
cell
proliferation.
The
Toxicologist,
13,
389.

Test
Species/
Strain/
Sex/
Number:
rats;
number
not
indicated;
sex
not
specified
Exposure
Route/
Concentration/
Durations:
inhalation
(
nose­
only);
0,
0.1,
0.7,
or
1.5
ppm
for
6
h/
d,
2
wk
(
10
exposures)

Effects:
All
concentrations:
Nasal
epithelial
cell
proliferation.
Severity
of
this
lesions
decreased
from
anterior
to
posterior
regions.
Hypertrophy,
hyperplasia,
and
squamous
metaplasia
were
restricted
to
respiratory
epithelium.
For
0.1
ppm
these
effects
were
described
as
slight.
0.7,
1.5
ppm:
Dose­
dependent
lesions
of
respiratory
and
olfactory
epithelium
(
erosion,
ulceration,
atrophy)

Endpoint/
Concentration/
Rationale:
6­
h
exposure
to
0.1
ppm
resulted
in
changes
in
nasal
epithelial
cell
proliferation
(
decreased
labeling
index
for
respiratory
epithelium;
increased
labeling
index
for
olfactory
epithelium)

Uncertainty
Factors/
Rationale:
Total
uncertainty
factor:
10
Interspecies:
3
­
little
species
variability
is
observed
at
lethal
and
non­
lethal
endpoints
Intraspecies:
3
­
no
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects.

Modifying
Factors:
None
Animal
to
Human
Dosimetric
Adjustment:
Not
applied
(
insufficient
data)

Time
Scaling:
C2
x
t
for
extrapolation
to
30
minutes,
1
hour,
4
hours,
8
hours.
The
10­
min
AEGL­
1
was
set
at
the
same
concentration
as
the
30­
min
AEGL­
1
Data
Adequacy:
Although
the
adequacy
of
data
is
limited
due
to
the
publication
as
an
abstract
and
due
to
repeated
exposure,
the
AEGL­
1
values
are
supported
by
additional
observations
of
slight
effects
in
rats
exposed
to
0.5
ppm
for
6
hours
(
Schlögel
1972).
Dimethyl
Sulfate
Proposed
1:
#/
2003
68
AEGL­
2
values
10
min
30
min
1
h
4
h
8
h
0.17
ppm
0.17
ppm
0.12
ppm
0.061
ppm
0.043
ppm
Reference:
Schlögel,
F.
A.,
1972.
Cancerogenität
und
chronische
Toxizität
inhalierten
Dimethylsulfats.
Med.
Inaug.­
Dissertation,
Universität
Würzburg.

Test
Species/
Strain/
Sex/
Number:
Wistar
rats,
NMRI
mice,
Syrian
golden
hamsters;
males
and
females;
10
or
15
animals
Exposure
Route/
Concentration/
Durations:
Inhalation
(
whole­
body);
0,
0.5,
2
ppm;
6
h;
repeated
exposure
Effects:
0.5
ppm:
Changes
in
behavior
within
some
animals
of
all
species
already
after
20
minutes
(
ruffled
fur;
closed
or
halfclosed
eyes).
Following
exposure,
the
animals
developed
breathing
problems
(
cough
and
sneezing).
2
ppm:
Conjunctivitis
with
sensitivity
to
light;
expiration
sounds
similar
to
asthmatics.
All
described
effects
occurred
already
after
first
exposure.

Endpoint/
Concentration/
Rationale:
breathing
problems
following
6­
h
exposure
to
0.5
ppm
Uncertainty
Factors/
Rationale:
Total
uncertainty
factor:
10
Interspecies:
3
­
little
species
variability
is
observed
at
lethal
and
non­
lethal
endpoints
Intraspecies:
3
­
no
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects.

Modifying
Factors:
None
Animal
to
Human
Dosimetric
Adjustment:
Not
applied
(
insufficient
data)

Time
Scaling:
C2
x
t
for
extrapolation
to
30
minutes,
1
hour,
4
hours,
8
hours.
The
10­
min
AEGL­
2
was
set
at
the
same
concentration
as
the
30­
min
AEGL­
2.

Data
Adequacy:
The
study
was
well
conducted
and
was
extensively
reported
(
as
doctoral
thesis).
However,
it
was
conducted
for
investigating
the
carcinogenicity
and
chronic
effects
of
dimethyl
sulfate,
therefore
short­
term
effects
not
reported
in
detail,
but
have
been
inquired
by
the
author.
Concentration
was
regularly
controlled
by
gas
chromatography.
Dimethyl
Sulfate
Proposed
1:
#/
2003
69
AEGL­
3
Values
10
min
30
min
1
h
4
h
8
h
4.0
ppm
2.3
ppm
1.6
ppm
0.82
ppm
0.58
ppm
Reference:
Hein,
N.,
1969.
Zur
Toxicität
von
Dimethylsulfat.
Med.
Inaug.­
Dissertation,
Universität
Würzburg.

Test
Species/
Strain/
Sex/
Number:
5
female
Wistar
rats,
10
or
20
female
NMRI
mice,
5
golden
hamsters,
5
guinea
pigs
(
sex
not
indicated);

Exposure
Route/
Concentration/
Durations:
Inhalation
(
whole­
body);
10,
49,
64,
71,
127
ppm
(
rats),
10,
42,
49,
64,
71,
127
ppm
(
mice),
33,
40,
49,
64,
71,
127
ppm
(
hamster),
10,
33,
40,
71
ppm
(
guinea
pigs);
1
h
Effects:
The
highest
LC0
for
rats
have
been
49
ppm
(
Hein
1969)
and
58
ppm
(
DuPont
1971)
for
an
1­
h
exposure,
and
15
ppm
(
Smyth
1956)
for
a
4­
h
exposure.
Guinea
pigs
have
been
most
susceptible
to
DMA
vapor
(
LC50
of
32
ppm).
49
ppm:
During
exposure
dyspnea
with
inspiratory
stridor
and
lacrimation
were
noticed.
Necropsy
showed
severe
inflation
of
stomach
and
small
intestine
and
occasionally
emphysema
and
edema
of
lungs.

Endpoint/
Concentration/
Rationale:
Pulmonary
congestion
and
severe
inflations
of
GIT
have
been
observed
at
1­
h
exposure
to
49
ppm.

Uncertainty
Factors/
Rationale:
Total
uncertainty
factor:
30
Interspecies:
10
­
little
species
variability
is
observed
at
lethal
and
non­
lethal
endpoints,
but
rats
as
the
species
used
for
the
AEGL­
3
derivation
was
not
the
most
susceptible
one.
Intraspecies:
3
­
no
large
differences
in
susceptibility
between
individuals
are
expected
for
unspecific
irritating
effects.

Modifying
Factors:
None
Animal
to
Human
Dosimetric
Adjustment:
Not
applied
(
insufficient
data)

Time
Scaling:
C2
x
t
for
extrapolation
to
10
minutes,
30
minutes,
4
hours,
8
hours
Data
Adequacy:
The
study
was
well
conducted
and
was
extensively
reported
(
as
doctoral
thesis).
Concentration
was
regularly
controlled
by
gas
chromatography.
A
3­
week
follow­
up
observation
was
used
to
cover
effects
developed
after
a
latency
period.