Dimethyl sulfate (EHC 48, 1985)

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 48

DIMETHYL SULFATE

This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.

Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization

World Health Orgnization
Geneva, 1985

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHYL SULFATE

1. SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

1.1. Summary
1.1.1. Analytical methods
1.1.2. Sources in the environment and occupational
exposure
1.1.3. Experimental animal studies, metabolism,
mutagenicity, and carcinogenicity
1.1.4. Human toxicity and carcinogenicity
1.2. Recommendations for further research
1.2.1. Analytical methods
1.2.2. Sources in the environment
1.2.3. Occupational exposure
1.2.4. Experimental animal studies

2. PROPERTIES AND ANALYTICAL METHODS

2.1. Identity
2.2. Physical and chemical properties
2.3. Analytical methods

3. SOURCES IN THE ENVIRONMENT

3.1. Natural occurrence
3.2. Production levels, processes, and uses
3.2.1. World production
3.2.2. Production processes
3.2.3. Uses
3.3. Disposal of wastes

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental levels
5.2. Occupational exposure

6. KINETICS AND METABOLISM

7. EFFECTS ON EXPERIMENTAL ANIMALS AND OTHER ORGANISMS IN THE
ENVIRONMENT

7.1. Acute effects
7.2. Chronic toxicity and carcinogenicity
7.2.1. Transplacental carcinogenicity
7.3. Mutagenicity and genetic effects
7.4. Reproductive effects, embryotoxicity, and teratogenicity

8. EFFECTS ON MAN

8.1. Toxicity
8.2. Carcinogenicity

9. EVALUATION OF HEALTH RISKS FOR MAN AND EFFECTS ON THE
ENVIRONMENT FROM EXPOSURE TO DIMETHYL SULFATE

REFERENCES

WHO TASK GROUP ON DIMETHYL SULFATE

Members

Dr N. Aldridge, Medical Research Council, Carshalton, Surrey,
United Kingdom (Chairman)

Dr M. Berlin, Monitoring and Assessment Research Centre,
University of London, London, United Kingdom

Dr J. Cavanagh, Institute of Neurology, London, United
Kingdom (Vice-Chairman)

Dr K. Hashimoto, Department of Hygiene, School of Medicine,
Kanazawa University, Ishikawa, Japan

Dr D.G. Hatton, US Food and Drug Administration, Department of
Health and Human Services, Washington DC, USA

Dr M. Ikeda, Department of Environmental Health, Tohoku
University School of Medicine, Sendai, Japan (Rapporteur)

Dr A. Massoud, Ain Shams University, Cairo, Egypt

Dr P.K. Ray, Industrial Toxicology Research Centre, Lucknow,
India

Dr I.V. Sanotsky, Research Institute of Industrial Hygiene
and Occupational Diseases, USSR Academy of Medical
Sciences, Moscow, USSR

Dr P. Shubik, Oxford University, Oxford, United Kingdom

Dr H.A. Tilson, Laboratory of Behavioral and Neurological
Toxicology, NIEHS, Research Triangle Park, North Carolina,
USA

Representatives from Other Organizations

Mr S. Batt, Monitoring and Assessment Research Centre,
University of London, London, United Kingdom

Dr L. Shukar, Monitoring and Assessment Research Centre,
University of London, London, United Kingdom

Mr J.D. Wilbourn, International Agency for Research on Cancer,
Unit of Carcinogen Identification and Evaluation, Lyons,
France

Secretariat

Dr M. Draper, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland (Secretary)

Ms A. Sunden, International Register of Potentially Toxic
Chemicals, Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA DOCUMENTS

While every effort has been made to present information in the
criteria documents as accurately as possible without unduly
delaying their publication, mistakes might have occurred and are
likely to occur in the future. In the interest of all users of the
environmental health criteria documents, readers are kindly
requested to communicate any errors found to the Manager of the
International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland, in order that they may be
included in corrigenda, which will appear in subsequent volumes.

In addition, experts in any particular field dealt with in the
criteria documents are kindly requested to make available to the
WHO Secretariat any important published information that may have
inadvertently been omitted and which may change the evaluation of
health risks from exposure to the environmental agent under
examination, so that the information may be considered in the event
of updating and re-evaluation of the conclusions contained in the
criteria documents.

* * *

A detailed data profile and a legal file can be obtained from
the International Register of Potentially Toxic Chemicals, Palais
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 -
085850).

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHYL SULFATE

Following the recommendations of the United Nations Conference
on the Human Environment held in Stockholm in 1972, and in response
to a number of World Health Assembly Resolutions (WHA23.60,
WHA24.47, WHA25.58, WHA26.68), and the recommendation of the
Governing Council of the United Nations Environment Programme,
(UNEP/GC/10, 3 July 1973), a programme on the integrated assessment
of the health effects of environmental pollution was initiated in
1973. The programme, known as the WHO Environmental Health
Criteria Programme, has been implemented with the support of the
Environment Fund of the United Nations Environment Programme. In
1980, the Environmental Health Criteria Programme was incorporated
into the International Programme on Chemical Safety (IPCS). The
result of the Environmental Health Criteria Programme is a series
of criteria documents.

A WHO Task Group on Environmental Health Criteria for Dimethyl
Sulfate was held at the British Industries Biological Research
Association (BIBRA), in Carshalton, Surrey, United Kingdom, from
5-7 December, 1984. Dr E.M.B. Smith, IPCS, opened the meeting on
behalf of the Director-General. The Task Group reviewed and
revised the draft criteria document and made an evaluation of the
risks to human health and the environment from exposure to dimethyl
sulfate.

The initial draft was prepared by DR M. BERLIN with the
assistance of DR L. SHUKAR and MR S. BATT of the MONITORING AND
ASSESSMENT RESEARCH CENTRE (MARC) London, United Kingdom.

The efforts of all who helped in the preparation and
finalization of the document are gratefully acknowledged.

* * *

Partial financial support for the publication of this criteria
document was kindly provided by the United States Department of
Health and Human Services, through a contract from the National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina, USA - a WHO Collaborating Centre for Environmental
Health Effects. The UK Department of Health and Social Security
generously supported the costs of printing.

Conversion factor:

1 ppm dimethyl sulfate (in air) = 5.24 mg/m³ (Verschueren,
1977).

1. SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

1.1. Summary

1.1.1. Analytical methods

Dimethyl sulfate (DMS) is a very slightly odorous, oily liquid.
It is used extensively as an alkylating agent.

Sensitive analytical techniques have been developed to
determine low levels of DMS in air. Procedures used include gas-
or liquid-chromatography (GC or LC), in the latter case of a
derivative, followed by an appropriate method of detection, such as
mass spectrometry (MS) or a flame ionization detector (FID) for GC,
and ultraviolet (UV) or visible (VIS) spectrometry for LC. The
lowest reported detection limit for a GC procedure is 0.026 mg/m³
(0.005 ppm) for a 1 litre sample and, for LC, a detection limit of
0.05 mg/m³ (0.01 ppm) has been obtained. Several methods are
reported to have the necessary sensitivity and selectivity to
determine DMS at or below current occupational exposure limits.

1.1.2. Sources in the environment and occupational exposure

Although the amount of DMS, processed world-wide as an
intermediate in many industrial processes, is of the order of
millions of kilograms per year, there is little information on
sources and occurrence in the environment. There are no reported
natural sources of DMS, but it may be present in the environment
because of industrial processes. For example, though no specific
incidents have been found, DMS may be present in some industrial
waste, and it has recently been discovered to be formed during the
combustion of sulfur-containing fossil fuels. The acute toxic
effects of DMS are well known and, since it is a potential human
carcinogen, efforts have been made to minimize occupational
exposure, for example, by the use of enclosed systems in processes
using DMS.

1.1.3. Experimental animal studies, metabolism, mutagenicity, and
carcinogenicity

DMS is rapidly cleared from the bloodstream of the rat
following intraveous (iv) administration, being undetectable after
only 5 min: As DMS has a half-life of 4.5 h in pH 7 buffered
aqueous solution, it is assumed that it is rapidly metabolized in
the organs that it reaches first. DMS is an alkylating agent and,
as with other closely-related compounds, it causes changes in
nucleic acids; a single dose of [¹⁴C]-DMS at 80 mg/kg body weight
in rats gave rise to 7-methylguanine.

DNA damage, mutations, chromosomal anomalies, and other genetic
alterations have been induced by DMS in several short-term tests.

DMS was shown to be carcinogenic in rats after inhalation, over
15 months, of concentrations down to 3 mg/m³. This induced
tumours, principally in the nasal cavity and air passages. There

was limited evidence of transplacental carcinogenicity in rats
following a single iv injection of 20 mg/kg body weight on day 15
of pregnancy. The rapid disappearance of DMS from the bloodstream
and the low level of alkylation of nucleic acids appear to be
closely connected with the low level of carcinogenicity detected in
animals treated intravenously.

The Task Group concluded that the data were insufficient to
deduce complete dose-response relationships for DMS in animal
studies. However, in considering the safety of manufacturing and
handling DMS, it should be noted that a concentration of 3 mg/m³
induced respiratory tract tumours in animals.

1.1.4. Human toxicity and carcinogenicity

DMS is highly toxic for man, particularly for the respiratory
tract, and relatively short-term exposure (10 min) to 500 mg/m³ may
be fatal.

There are numerous reports on the effects of occupational
exposure, but these are confined to reports of acute and subacute
effects. A particular characteristic of the acute effects of DMS
is a delay between exposure and the onset of effects, particularly
pulmonary and laryngeal oedema. This can be of practical
significance, since the presence of DMS, which is almost odourless,
can go undetected. DMS can gain entry through the skin as well as
the respiratory route; eye lesions have been of particular note.
Levels exceeding approximately 5 mg/m³ (1 ppm) are sufficient to
cause eye irritation, often the earliest symptom of acute over-
exposure to DMS. Systemic effects in acute exposure result from
severe cytotoxicity affecting the vital organs.

The available clinical or epidemiological evidence is
insufficient to indicate whether or not DMS is a human carcinogen.
Although, in some countries, it is not regulated as a carcinogen,
it is described by the IARC (1982) as a chemical that is "probably
carcinogenic to humans". DMS should therefore be assumed to be a
potential human carcinogen, and all efforts should be made to
reduce exposure to a minimum.

1.2. Recommendations for Further Research

1.2.1. Analytical methods

At present, several methods for determining DMS are available.
There is, however, a need to compare the accuracy of the different
techniques used. More sensitive techniques will be required to
monitor environmental contamination by DMS.

1.2.2. Sources in the environment

There are few reports concerning the possible formation of DMS,
either in the environment or as a by-product or contaminant of
industrial processes. Recent discoveries of the presence of DMS in
flue lines and air-borne particulate matter from coal- and oil-

fired power plants indicate that further investigation into other
possible industrial sources, especially waste disposal, is
justified. Further work is required on the persistence and effects
of DMS in the environment under different climatic conditions.

1.2.3. Occupational exposure

Long-term monitoring of workers who have been occupationally
exposed to DMS should be continued, and methods for biological
monitoring should be developed. These may include the
determination of methylated purines in urine (for recent exposure),
methylated proteins in blood, chromosome aberrations in blood
cells, and cytological examination of sputum.

1.2.4. Experimental animal studies

It is of particular importance that more studies should be
carried out to establish dose-response relationships for the
development of respiratory-tract and other malignancies.

Because DMS adheres to air-borne particulate matter, studies of
the influence of this on its carcinogenic potential and toxicity
are required.

Other studies are desirable on the toxicity of DMS, especially
in relation to acute and chronic effects on the air passages and
the lung.

The Task Group considers that all studies with DMS should be
undertaken with circumspection, because it is possible that it is a
human carcinogen.

2. PROPERTIES AND ANALYTICAL METHODS

2.1. Identity

Chemical structure:

CH₃-O O
\ /
S
/ \
CH₃-O O

Molecular formula: C₂H₆O₄S

CAS chemical name: sulfuric acid, dimethyl ester

IUPAC name: dimethyl sulfate

Common synonyms: dimethyl ester, dimethyl monosulfate,
methyl sulfate

CAS registry number: 77-78-1

Relative molecular mass: 126.13

2.2. Physical and Chemical Properties

The physical properties of dimethyl sulfate (DMS), which is a
colourless, oily liquid, are summarized in Table 1.

Commercial DMS may contain trace amounts of sulfuric acid.

Most reports state that DMS is odourless, though some claim
that it has a slight onion-like odour. The vapour pressure of DMS
at 20 °C would result in a saturated vapour concentration in air of
3720 mg/m³ (710 ppm) (Du Pont, 1981). It is miscible with many
polar organic solvents and aromatic hydrocarbons, but is only
sparingly soluble in aliphatic hydrocarbons and water. DMS is
hydrolysed slowly in moist air or cold water, and more rapidly in
warm water or acidic solutions. Initial hydrolytic products are
monomethyl sulfate and methanol; complete conversion to sulfuric
acid occurs more slowly (Robertson & Sugamori, 1966). DMS forms
salts of monomethyl sulfate on hydrolysis in aqueous alkaline
solutions (Du Pont, 1981). It reacts explosively with concentrated
aqueous ammonia (Lindlar, 1963). DMS is a strong methylating agent
that reacts with active hydrogen and alkali salts to form
substituted oxygen, nitrogen, and sulfur compounds (Du Pont, 1981).

Table 1. Physical properties of dimethyl sulfate^a
--------------------------------------------------------------
Relative molecular mass 126.13

Boiling point 188 °C (with decomposition)
(at 101 kPa (760 mm Hg))

Melting point -32 °C

Flash point 83 °C

Vapour density (air = 1.00) 4.35

Specific gravity (liquid density) 1.33
(at 20 - 24 °C)

Vapour pressure (at 25 °C) 0.106 kPa (0.8 mm Hg)

Water solubility 28 kg/m³ (2.8 g/100 ml)
(with hydrolysis)

Refractive index (at 20 °C) 1.3874

Log Po/w -4.26
--------------------------------------------------------------
^a From: Browning (1965), Rading et al. (1977), Verschueren
(1977), Hoffman (1980), and Du Pont (1981).

2.3. Analytical Methods

Occupational atmospheric exposure limits have been set at low
levels (i.e., 0.05 - 5.0 mg/m³), necessitating the development of
sensitive analytical methods to monitor exposure. Measurement of
low atmospheric concentrations generally requires considerable
concentration of the contaminant from the ambient atmosphere. This
is usually achieved by adsorption on an inert surface in a sampling
tube, though DMS has also been collected by bubbling air through a
solution, such as pyridine, in which DMS reacts to form a salt
(Tomczyk & Bajerska, 1973), or aqueous alkali in which DMS
decomposes to form methanol (Tada, 1977). Sensitive analytical
techniques are necessary to measure small amounts of DMS in
concentrated air samples, which may also contain a large number of
other contaminants.

Concentration of DMS on an inert material in a sample tube
facilitates storage; however, particular care must be taken, since
DMS is highly reactive and may react with other material adsorbed
at the same time, or with impurities in the adsorbing material.
Samples are best stored at low temperatures, and when very low
levels of DMS are being assessed, scrupulous purification of the
adsorbing medium and sample tube is essential (Ellgehausen, 1975).
Tests have shown that DMS can be stored, without loss, on silica
gel sample tubes for at least 5 h (Du Pont, 1981). Samples can
also be stored in the form of stable derivatives (Eatough et al.,
1981).

A degree of selectivity in the determination of DMS may be
introduced by derivatization (Feigl & Goldstein, 1957; Tada, 1977),
though this adds an extra step to the analysis, and spurious
results may be obtained when other compounds in the sample can
react with the derivatizing agent. For example, other alkylating
agents can interfere in procedures that involve alkylation by DMS
to form coloured derivatives (Tomczyk & Bajerska, 1973). DMS has
been determined in biological fluids (Swann, 1968) by reaction with
4- p-nitrobenzylpyridine according to the method of Epstein et al.
(1955). Selectivity can be further enhanced by derivatization
followed by chromatographic separation, as in the case of the
reaction of DMS with 4-nitrophenoxide to form 4-nitroanisole. This
has been separated and quantified by reversed-phase, high-
performance liquid chromatography (HPLC) with ultraviolet (UV)
detection (Williams, 1982), GC with electron capture (EC) detection
(Du Pont, 1981), and thin-layer chromatography (TLC) with
colorimetric detection (Keller, 1974, 1982).

Most gas chromatographic (GC) methods involve determination of
DMS directly; the method of Du Pont (1981) is an exception. The
general procedure entails concentration of DMS on an adsorption
medium in a sample tube, followed by desorption, either thermally
or by liquid extraction, which in turn is followed by GC separation
of the desorbed material and subsequent detection. Selectivity is
achieved according to both chromatographic separation and the type
of detector used. Flame photometric detection (FPD), being sulfur-
specific, is more selective than flame ionization detection (FID),
though both have been used. Mass spectrometric (MS) detection is
probably more selective still, and has also been used to confirm
the identity of DMS peaks, already determined using other
detectors, by comparison of retention times with DMS standards.
Ellgehausen (1975) has developed a sensitive GC/MS technique and
also a fully-automated GC method for the routine repetitive
determination of DMS, suitable for industrial monitoring (1977).

The results obtained from the determination of DMS by two
different methods have been compared (Lunsford & Fey, 1979). The
procedures used were: (a) collection of DMS by passing the air
sample through a Porapak P sorbent tube, followed by desorption
with diethyl ether and analysis of an ether aliquot by GC using
electrolytic conductivity detection in the oxidative mode; and (b)
collection of DMS on Tenax-GC absorbent, followed by methylation of
4-nitrophenol with the collected DMS, and determination of the
resulting 4-nitroanisole by HPLC. Concentrations which were
determined to be 1.8, 4.35, and 24.5 µg/litre by method (a) were
determined by method (b) to be 3.18, 7.18, and 20.4 µg/litre,
respectively. The inconsistency of these results and the lack of
other published reports on the comparability of methods used to
determine DMS are indications for further studies in this area.

Some analytical methods for the determination of DMS are
summarized in Table 2. Occupational exposure limits are near the
limits of detection using current techniques. In some cases, it is
possible to lower the detection limit by taking larger air samples
or, particularly in the case of HPLC, by injecting larger samples.

Gas detector tubes are available. However, some of these, although
useful for quickly assessing DMS levels in situations where
poisoning may occur, and for detecting leaks or spills that might
otherwise go unrecognized, are not sufficiently sensitive for the
routine monitoring of occupational exposure (Du Pont, 1981).

For such a toxic substance, more sensitive techniques need to
be developed.
Table 2. Analytical methods
-----------------------------------------------------------------------------------------
Method Detection limit Comments Reference
-----------------------------------------------------------------------------------------
1) GC-MS 0.05 mg/m³ (0.01 ppm) sampling device readily Ellgehausen
Thermal elution for 1 litre air sample portable; suitable for air (1975)
from collection monitoring in workplace
tube

2) GC-FPD not given fully automated system, Ellgehausen
Thermal elution suitable for
atmospheric (1977)
from Tenax monitoring in workplace
adsorption tubes

3) GC-electrolytic 1.57 - 52 mg/m³ (0.3 - thermal desorption Lunsford
conductivity, 10 ppm) for 0.75 litre techniques permit (1978);
detector oxidative air sample, 1.05 - 15.7 replicate analyses; Lunsford &
mode;S-specific mg/m³(0.2 - 3 ppm) for halogen-, sulfur-, and Fey (1979)
detector desorption TWA 12 litre air sample, nitrogen-containing
thermally or by with solvent desorption; compounds have retention
extraction with 0.026 mg/m³ (0.005 ppm) time comparable to DMS
diethyl ether for 12 litre air sample
with thermal desorption

4) GC-FID not given analysis of neutral/basic Lee et al.
GC-FPD airborne particles and (1980)
GC-MS coal fly ash
Particulate
sample collected
on acid-washed
quartz fibre
filters

5) GC-FID 0.2 mg/m³ (0.04 ppm) FPD found to be more Gilland &
GC-FPD for 20 litre air sample selective (S-specific) and Bright
Desorption with = 2 µg/ml in more sensitive than FID; (1980)
acetone solution this degree of sensitivity
is achieved by injecting
large samples necessitat-
ing venting of solvent in
order to protect detector
---------------------------------------------------------------------------------------------------------

Table 2. (contd.)
-----------------------------------------------------------------------------------------
Method Detection limit Comments Reference
-----------------------------------------------------------------------------------------
6) GC-EC 0.026 - 26.2 mg/m³ determination of Du Pont
Derivative (0.005 - 5 ppm) derivative not DMS (1981)
4-nitroanisole for 1 litre directly; suitable for
DMS desorption air sample, lower limit personal air sampling;
from silica gel, = 25 x 10^-9 g/5 ml detection limits can be
sample tube solution lowered by reducing or
with saturated attenuation or taking
solution of sodium larger air samples;
4-nitrophenoxide moisture pick up by silica
in acetone gel can lead toerroneous
results

7) GC-FID 0.26 mg/m³ (0.05 ppm) Sidhu
Desorption from for 20 litre air sample (1981)
silica gel sample
collection tube
with distilled
water

8) GC-FPD 0.04 mg/m³ (0.008 ppm) Keller
Adsorption on for 100 litre air sample (1982)
silica

9) TLC-colorimetric 0.05 mg/m³ (0.01 ppm) requires large sample Keller
Derivative for 500 litre air volume using sampling rate (1974,
4-nitroanisole sample; 0.1 mg/m³ (0.02 of 3 - 4 litre/min; takes 1982)
ppm) for 100 litre air 2 - 2.5 h for 500 litre
sample sample; no sophisticated
instrumentation required

10) Spectrophoto- 0.15 mg/m³ (0.03 ppm) requires 10 litre air Tomczyk &
metric (VIS) (484 for 50 litre air sample sample to establish Bajerska
nm) Derivative whether DMS contamination (1973)
glutaconicaldehyde exceeds permissible
dianil DMS concentration (1 mg/m³);
absorbed by not suitable for personal
reaction with monitoring because pyridine
pyridine used for DMS trap;
interference from other
compounds forming pyridine
salts, e.g., chlorinated
hydrocarbons

11) Spectrophotometric 2.6 mg/m³ (0.5 ppm) methanol and formaldehyde Tada (1977)
(VIS) (580 nm) for 10 litre air sample may interfere
Derivative from = 3 µg/ml in solution
formaldehyde and
chromotropic acid
DMS absorbed by
reaction with
NaOH(aq)
-----------------------------------------------------------------------------------------

13) Infra-red spectro- 0.1 mg/m³ (0.02 ppm) can be determined on site Foxboro/
scopy (9.9 µm or (20 m cell) or short-term storage Wilks (1978)
8.3 µm) (Miran-1A possible in Saran plastic
general purpose bags; acetone and organic
gas analyser) solvents with S-O-C or S=O
bonds may interfere

14) Ion chromatography not given analysis of acidic air- Eatough et
Derivative methyl- borne particles; methyl- al. (1981)
amine Particulate amine formed by sweeping
sample collected sample with ammonia gas;
on acid-washed derivatization with
quartz filter ammonia allows
determination of DMS in
acidic sample in which
artifactual formation of
DMS leads to spurious
results if DMS measured
directly; derivatization
also permits convenient
storage of otherwise
unstable samples

15) Dräger tubes 0.026 - 0.26 mg/m³ suitable for rapid deter- Leichnitz
Derivative N- (0.005 - 0.05 ppm) mination of DMS where (1983)
methyl-4-( p- for 200 strokes of poisoning may occur, and
nitrobenzylidine)- the gas detector routine monitoring for
1,4-dihydro- pump leaks and spills; colour
pyridine change to blue, range of
concentrations determined
by 4 colour comparison
layers; range of measure-
ment can be extended up to
3 mg/m³ (0.6 ppm) by
reducing the number of gas
detector pump strokes;
other organic alkylating
agents also indicated but
give different colour
reactions, e.g., chloro-
formates and phosgene give
yellow/orange indication
-----------------------------------------------------------------------------------------
3. SOURCES IN THE ENVIRONMENT

3.1. Natural Occurrence

DMS has not been identified as a natural product in the
environment, but its presence as a result of combustion processes
cannot be ruled out (sections 4 and 5).

3.2. Production Levels, Processes, and Uses

3.2.1. World production

Although world production figures for DMS are not available, an
estimate of 340 tonnes/year for the production of DMS in the USA,
based on the maximum capacity for the manufacturing process for
DMS, was made by NIOSH (1979), using data from Fuchs (1969).
However, according to Karstadt & Bobal (1982), the USA production
in 1977 may have been as much as 45 000 tonnes, and the National
Toxicology Program (1983) reported domestic production of
approximately 22 000 tonne/year. The annual capacity in western
Europe at the beginning of 1983 was estimated to be at least 31 000
tonne/year (SRI International, 1983) and, at the beginning of 1984,
as 24 000 tonnes/year in 3 countries (SRI International, 1984).

3.2.2. Production processes

DMS is manufactured in a continuous process that involves the
concurrent bubbling of gaseous dimethyl ether into the bottom of an
aluminium tower and the introduction of liquid sulfur trioxide at
the top. The tower fills with the reaction products (96 - 97% DMS,
sulfuric acid, and monomethyl sulfate), which are continuously
withdrawn and purified by vacuum distillation over sodium sulfate
(NIOSH, 1979).

3.2.3. Uses

The major use of DMS is as an alkyating agent, and it has been
employed extensively in both industry (Fishbein et al., 1970;
Fishbein, 1977; NIOSH, 1979; Du Pont, 1981) and the laboratory
(Fieser & Fieser, 1967; Funazo et al., 1982). DMS is used, for
example, for the alkylation of phenols and amines, important
intermediates in the dye, pharmaceutical, and perfumery industries
(NIOSH, 1979). In the pharmaceutical industry, DMS has been used
in the manufacture of antipyretics (Dzhezhev & Tsvetkov, 1970) and
anticholinergic agents (IARC, 1974; Fishbein, 1977). It has been
suggested that, except when it is being used specifically to
prepare quaternary ammonium methosulfate salts, DMS, as an
alkylating agent, could potentially be replaced by a methyl halide
such as methyl chloride (Darr, 1977). However, this would require
the use of specialized equipment to handle gaseous reactions, which
may not be practical for many processes. DMS has been used in many
other industrial processes including the extraction of aromatic
hydrocarbons, where it is used as a solvent (Browning, 1965), and
in combination with boron compounds in the stabilization of sulfur

trioxide (Fuchs, 1969). It is also used as a sulfating and
sulfonating agent (Gilbert, 1965; Du Pont, 1981) and has served as
a war gas (Browning, 1965).

3.3. Disposal of Wastes

It has been suggested that waste products from industry may
contain DMS (Khvoles & Korobko, 1977). However, DMS can be
decomposed, prior to disposal. The two principal methods
recommended for the disposal of DMS include: dilution with water
and neutralization (Dzhezhev & Tsvetkov, 1970; Du Pont, 1981), and
incineration (Ottinger et al., 1973; Du Pont, 1981). Dilution
should preferably be to less than 1%, as this reduces the dangers
of accumulation of toxic quantities and hydrolyses DMS to sulfuric
acid and methanol (Ottinger et al., 1973). As the resulting
solution is corrosive, it must be neutralized, and this may be
achieved using caustic soda, soda ash, or lime (Du Pont, 1981).
This is an exothermic reaction, and cooling or further dilution may
be necessary. Ottinger et al. (1973) suggest that DMS is best
disposed of by incineration preceded, where possible, by dilution
and neutralization. Incineration equipment should include
efficient oxides of sulfur-scrubbing devices, and must expose the
waste material to sufficient heat to ensure complete combustion to
carbon dioxide, water vapour, and sulfur dioxide. Direct
incineration of concentrated DMS is considered to be acceptable for
small quantities only, because of the danger of exposure to
vapourized but unburned DMS (Ottinger et al., 1973). Small
quantities have been disposed of by pouring onto vermiculite,
sodium biocarbonate, or a sand-soda mix (90 - 10) and burning in
an open incinerator with scrap wood and paper (Du Pont, 1981). DMS
can also be atomized and burned in a suitable combustion chamber.
Alternatively, adsorption on vermiculite, dry sand, or similar
material followed by disposal in a secure landfill can be used for
the disposal of DMS (NIOSH/OSHA, 1978).

Recommendations for the containment and neutralization of DMS
spills include covering the spill area with dilute (2 - 5%) caustic
soda, dilute (2 - 5%) ammonia solution, wetted soda ash (Du Pont,
1981), or with lime which, being a dry powder, will absorb the
liquid and contain the spill (May & Baker, 1973). After a suitable
period (Du Pont (1981) recommend 24 h), the material can either be
washed away with copious quantities of water, if circumstances
permit, or be collected for disposal. Protective clothing should
be worn when cleaning up spills. Dilute ammonia scattered around
the spill area will neutralize DMS vapour (May & Baker, 1973).
Hydrolysis of DMS is almost instantaneous in aqueous ammonia;
however, concentrated ammonia should not be used for neutralization
since it can react explosively with DMS (Lindlar, 1963).

The combustion of sulfur-containing fossil fuels has been
reported to cause atmospheric contamination by DMS adsorbed on
particulate matter (Lee et al., 1980; Eatough et al., 1981).

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

Despite the fact that DMS has been used extensively in industry
for more than 60 years (IARC, 1974), there have been no reports of
environmental contamination by DMS, until recently. The half-life
of DMS (0.1 - 1 M) in pH 7 2.5 mM phosphate buffer solution is
reported to be only about 4.5 h, and even this is catalysed by any
reactive species, such as sulfur nucleophiles, that are present
(Swann, 1968). A shorter half-life of 40 min has been described in
pH 7.4 phosphate buffer (concentration unspecified) at 20 °C; there
was even more rapid hydroysis at 37.5 °C, when the half-life was
reduced to 7.5 min (Druckrey et al., 1966). Therefore, any DMS,
for example, in waste streams from industrial processes, is likely
to be hydrolysed. Aqueous hydrolysis of DMS appears to be the main
route of breakdown, initially yielding monomethyl sulfate and
methanol. Monomethyl sulfate is only very slowly hydrolysed to
sulfuric acid, under similar conditions (Robertson & Sugamori,
1966). Lee et al. (1980) and Eatough et al. (1981) have reported
atmospheric contamination with DMS absorbed on particulate matter
from both coal- and oil-fired power plants. However, when samples
were left at room temperature for 4 days or more, no DMS was found.
The breakdown products of DMS vary, depending on the temperature
and humidity. At a temperature of 20 - 23 °C and relative humidity
of 70 - 80%, the predominant products were sulfuric acid and sulfur
dioxide, whereas at a high humidity (99 - 100%) and elevated
temperature (43 - 45 °), methanol vapour predominated (Dzhezhev &
Tsvetkov, 1970). Any DMS in the atmosphere is likely to wash out
in rain and hydrolyse, and it is probable that oxidation by HO.
radical to form sulfuric acid, formaldehyde, carbon monoxide, and
carbon dioxide would only occur very slowly (Radding et al., 1977).

DMS is strongly lipophobic and is not expected to bioaccumulate
(Radding et al., 1977).

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental Levels

Studies on the formation and stability of DMS from the
combustion of sulfur-containing fossil fuels (Lee et al., 1980;
Eatough et al., 1981) are the only environmental studies available.

Lee et al. (1980) and Eatough et al. (1981) measured levels of
DMS and monomethyl sulfate (MMS) in particulate matter in the flue
lines and the plumes of both coal- and oil-fired power plants.
Techniques have been developed to determine the concentrations of
DMS and MMS in acidic, basic, or neutral particulate matter. DMS
levels of 93 - 328 mg/kg (0.74 - 2.6 µmol/g) were found in
particulate matter (coal fly ash) from the flue line of a small
coal-fired heating plant with a collection temperature of about
110 °C. The amounts of DMS in airborne particulate matter,
collected 125 m from the stack at the same site, varied with the
length of time of the sampling procedure; a DMS concentration of
43 mg/kg (0.34 µmol/g) particulate matter was found in a 5-day
sample. Although the total amount of DMS was less in the plume
particulate sample than in the flue-line sample, the ratio of DMS
to total sulfur was 30 times greater in the former (Eatough,
personal communication, 1984). Lee et al. (1980) identified
concentrations of MMS of 22 - 830 mg/kg (0.2 -7.4 µmol/g) in the
flue line, downstream from the electrostatic precipitator of a
larger coal-fired power plant.

In studies carried out to compare levels of DMS and MMS found
in large coal- and oil-fired power plants, only MMS was found in
flue particulate matter collected after the electrostatic
precipitator. The collection temperature was almost 150 °C. In
both plants, DMS and monomethyl sulfate were found in plume
particulate matter measured at 3 km from the coal-fired process and
at 12 km from the oil-fired process. Though, at both sites, the
ratio of monomethyl sulfate to total sulfur was only slightly
greater in the plume sample than in the flue-line sample, the ratio
of DMS to total sulfur was greatly increased in the plume sample at
the smaller coal-fired site. Eatough et al. (1983) showed that the
ratio of DMS to total sulfur does, in fact, increase with
increasing plume transport time. The oil-fired power plant had
higher DMS and MMS levels in airborne particulate matter, relative
to total sulfur, than either of the 2 coal-fired plants, even
though samples were taken at a greater distance from the stack.
However, the measured levels are not directly comparable, because
of differences in environmental conditions at the 3 sites.

DMS is known to decompose at, or above, its boiling point; it
is therefore assumed to be formed downstream of the combustion
chamber. No DMS has been found in hopper ash, presumably because,
at this stage, temperatures are still too high (Eatough, personal
communication, 1984). The effect of temperature was also
demonstrated by the absence of DMS in particulate matter in flue
lines, when the temperature was 150 °C, and its presence in the
flue line at a temperature of 110 °C.

5.2. Occupational Exposure

Despite the extensive use of DMS (for example, in 1976, 4200
workers were estimated to be exposed annually in the USA) (NIOSH,
1979), with more recent estimates ranging from 1250 to 3900
(National Toxicology Program, 1983)), there are surprisingly few
published reports on actual occupational exposure levels. In 1973,
air concentrations of DMS at 9 potential leakage points in 2 sites
handling DMS in the USA were reported to vary from less than
1 mg/m³ (0.2 ppm) to more than 5.24 mg/m³ (1 ppm) (the lower and
upper limits of detection of the Miran 1 infra-red analyser used).
Concentrations of about 5 mg/m³ or slightly higher were commonly
found. Since techniques for handling DMS have improved over the
years, past exposures would almost certainly have been higher
(ACGIH, 1980). In a later study, carried out at 1 of the 2 sites,
peak air concentrations were reported to be 1 - 1.6 mg/m³ (0.2 -
0.3 ppm). The average level found during the filling of drums for
the transport of DMS was 0.42 mg/m³ (0.08 ppm), and this was the
highest of the site samples. The operator might spend a full 8-h
shift filling drums. However, the drum filling operation is
intermittent, depending on customer requirements, and the operator
should be wearing full protective clothing, including goggles,
overalls, apron, gloves, and rubber boots. Average air
concentrations of 0.005 mg DMS/m³ (0.001 ppm) or less were found in
the control room, where the operator in charge of the manufacturing
process spent the most time and which was separated from the
building containing the manufacturing process (Olguin & Morgan,
1976).

In a survey at another DMS-manufacturing site, DMS
concentrations in excess of a recommended maximum permissible
concentration (0.36 mg/m³) were found in 53% of 48 samples of air
in the vicinity of the DMS production process, and in 70% of
samples of air in the vicinity of the purification process.
Possible emission sources of DMS included non-hermetically sealed
apparatus, the opening of reactors to take samples or to reduce
pressure, and manholes in the floor intended for the drainage of
spilt chemicals. An air concentration of 12.3 mg DMS/m³ was found
near a manhole. The same survey also revealed DMS contamination of
workers' skin and clothes, as well as contamination of equipment
surfaces (2 - 3.5 mg/dm²) and workers' gas masks (0.5 - 1.2 mg/dm²)
(Molodkina et al., 1979). Ellgehausen (1975) reported DMS
concentrations of 0.25 - 0.3 mg/m³ in the neighbourhood of a
defective flange in a plant during a DMS reaction process.

Dzhezhev & Tsvetkov (1970) suggested that accidents and fires
in plants producing or using DMS might be caused by excessive
heating of the reagent.

No information is available on the possible confounding effects
of particulate matter in air in the analytical procedures.

Occupational exposure is most likely to be through inhalation
of DMS, either in the gaseous phase or adsorbed on particulate
matter. However, there are several reports in the literature of
toxic effects resulting from skin contamination through spills,
though, in such cases, inhalation of fumes might be a contributory
factor (Weber, 1902; Balazs, 1934; Littler & McConnell, 1955).

In addition to possible exposure to DMS, when handling the
compound directly, it has been reported by one chemical company
that DMS was identified as an impurity in one of its products, a
mixture of sulfonated methyl esters. The risk of exposure to DMS
is believed to be limited to workers processing the product in an
open reaction vessel^a.

A recommended threshold limit value/time-weighted average
(TLV/TWA) for dimethyl sulfate in workroom air is 0.5 mg/m³ (ACGIH,
1984). Recommended occupational exposure levels for various
countries are shown in Table 3.

-------------------------------------------------------------------
^a US EPA (1982) Status report 8EHQ -0482-0442.

Table 3. Occupational exposure levels for various countries^a
--------------------------------------------------------------------------
Country Exposure limit Category of Comments
(ppm) (mg/m³) limit
--------------------------------------------------------------------------
Australia^b 0.1 0.5 TWA^b Suspected to be of
carcinogenic pot-
ential for man

Brazil^a 0.08 0.4 for 48 h
per week

Czechoslovakia^a Suspected carcino-
genic substance

Denmark^c 0.01 0.05 Suspected to be of
carcinogenic pot-
ential for man

Finland^d 0.01 0.05 STEL^l
(15 min)

Germany, Democratic 5 average
Republic of^e 5 short-term

Germany, Federal 0.1 TRK^m Carcinogenic
Republic of^a (in manufacture)
0.2 TRK^m (in use) Working material -
proved in experi-
mental animal
studies

Hungary^e 5 MACⁿ - TWA^k

Italy^e 0.01 0.05 TWA^k Carcinogenic (Rec-
ommendation pre-
pared by the Ital-
ian Association of
Industrial Hygien-
ists and the Ital-
ian Society of In-
dustrial Medicine
for approval in
1978 by the Min-
istry of Labour)

Japan^a 0.1 0.5 MACⁿ

Netherlands^f 0.1 0.5 MACⁿ - C^o

Poland^e 1 C^o

Romania^e 3 average
8 max
--------------------------------------------------------------------------

Table 3. (contd.)
--------------------------------------------------------------------------
Country Exposure limit Category of Comments
(ppm) (mg/m³) limit
--------------------------------------------------------------------------
Sweden^a Carcinogenic sub-
stance; it may be
manufactured,
used, and handled
only after permis-
sion has been
granted by the
labour inspectorate

Switzerland^g 0.04 0.2 TWA^k Regarded as a
0.02 0.1 in production carcinogenic sub-
stance

United Kingdom^h 0.1 0.5 TWA^k
0.1 0.5 STEL^l

USA
(a) OSHA^a 1 5 PEL^p - TWA^k

(b) ACGIHⁱ 0.1 0.5 TLV^g - TWA^k Suspected to be of
carcinogenic pot-
ential for man

USSR^j 0.1 MACⁿ
--------------------------------------------------------------------------
^a From: ILO (1980) and IRPTC (1983).
^b From: Australia National Health and Medical Council (1982).
^c From: Arbejdstilsynet (1981).
^d From: Arbetarskyddsstyrelsen (1982).
^e From: ILO (1980).
^f From: Arbeidsinspectie (1981).
^g From: SUVA (1980).
^h From: UK Health and Safety Executive (1984).
ⁱ From: ACGIH (1984).
^j From: Centre of International Projects (in press).
^k TWA = Time-weighted average.
^l STEL = Short-term exposure limit.
^m TRK = Technische Richtkonzentrationen (Technical Guiding
Concentration).
ⁿ MAC = Maximum allowable concentration.
^o C = Ceiling value.
^p PEL = Permissible exposure limit.
^q TLV = Threshold limit value.

Note: Occupational exposure levels and limits are derived in
different ways, possibly using different data and expressed
and applied in accordance with national practices. These
aspects should be taken into account when making
comparisons.

6. KINETICS AND METABOLISM

DMS can be absorbed via the dermal, respiratory, and oral
routes.

Swann (1968) studied the rate of disappearance of DMS from the
blood of the rat following a single iv injection of 75 mg/kg body
weight in 0.5 ml of 0.1 M sodium citrate buffer (pH 7.4). There
was a rapid fall in the concentration of DMS in the blood of the
rat to 1/6 of the amount that would be expected if the compound had
been evenly distributed in the body water. No detectable DMS was
found, 5 min after the injection. In a separate iv study, Swann &
Magee (1968) found that the lung and the brain exhibited a much
higher degree of nucleic acid alkylation than the liver and kidney.
Since the first 2 organs receive a relatively larger proportion of
the cardiac output, it was proposed that DMS does not equilibrate
throughout the body but breaks down in the organs that it
penetrates first. The in vivo breakdown of DMS was considerably
faster than expected, in view of the 4.5-h half-life of the
compound in 2.5 mM pH 7 phosphate buffer. However, this may be
because of its high reactivity with cellular constituents.
Ghiringhelli et al. (1957) found a maximum level of methanol of
18.7 mg/litre in blood samples taken from 5 guinea-pigs, at
intervals, following an 18-min inhalation exposure to air
containing DMS at a concentration of 393 mg/m³ (75 ppm). During
the first 2 days following exposure, 0.064 - 0.156 mg methanol per
day was excreted in the urine; if all the DMS inhaled had been
absorbed and hydrolysed, a maximum of 0.9 mg methanol would have
been found.

When Swann & Magee (1968) administered a single iv dose
(80 mg/kg body weight) of [¹⁴C]-DMS to 6 male Wistar rats, and
sacrificed the animals after 4 h, radioactivity was detected in
7-methylguanine in the lung, brain, liver, and kidney. However,
the levels of the compound were extremely low and, in all organs,
well below the levels detected in studies in which
dimethylnitrosamine and N-methyl- N-nitrosourea, amongst other
compounds, were administered. Using these data, Lutz (1979)
calculated a covalent binding index (CBI) of 37, 4 h after iv dose,
for DMS in rat liver. Comparable CBI values in rat liver for
dimethylnitrosamine and N-methyl- N-nitrosourea, also calculated
from Swann & Magee's data, were 7100 (5 h after an intraperitoneal
(ip) dose) and 400 (4 h after an iv or oral dose), respectively.

CBI = damage to DNA = µmol chemical/mol nucleotides
dose mmol chemical/kg body weight

Löfroth et al. (1974) showed that 7-methylguanine and small
quantities of 1-methyladenine and 3-methyladenine could be detected
in the urine of mice exposed to DMS via inhalation. In two
separate studies, 4 male NMRI mice were exposed to average [³H]-DMS
concentrations of 16.3 mg/m³ or 0.32 mg/m³ for 135 min and 60 min,
respectively (maximum concentration approximately 4 times higher).
The total amount of methylated purines found in the urine in 2
consecutive 24-h periods was about 0.15 - 0.3% of the total dose,

and, in each case, the major product isolated was 7-methylguanine.
For example, at the higher DMS concentration, following a total
estimated dose of 9.25 MBq (250 µCi), 7.62 MBq (206 µCi) were
excreted in the urine, of which 10.55 x 10^-3 MBq (285 nCi) were
associated with 7-methylguanine, 21 nCi with 3-methyladenine, and
14 nCi with 1-methyladenine.

DMS is an S_N2-type alkylating agent that reacts predominantly
with the nucleophilic N-7 of guanine and forms comparatively small
amounts of other DNA adducts, which may be more critical products
with respect to carcinogenicity.

To conclude, after iv administration, DMS is rapidly
metabolized in the organs that it reaches first, and alkylates
nucleic acids in vivo. No urinary metabolites other than low
levels of methanol have been reported.

7. EFFECTS ON EXPERIMENTAL ANIMALS AND OTHER ORGANISMS IN THE
ENVIRONMENT

7.1. Acute Effects

Data on the acute toxicity of DMS in several animal species are
summarized in Table 4. DMS is an extremely potent toxic agent. In
a review of DMS toxicity, Fassett (1963) reported eye and
respiratory tract irritation and CNS effects in animals, similar to
those reported in human beings. Rats exposed through oral,
subcutaneous (sc), and iv routes to DMS at the LD₅₀ developed
periodically-recurring cramps about 30 min after dosing, followed
by clinical deterioration, shallow respiration, with death
occurring after 10 - 24 h. Oral dosing caused severe necrosis in
the forestomach and stomach (Druckrey et al., 1966). Other signs
included skin burns, coughing, dyspnoea, cyanosis, convulsions, and
coma preceding death (Browning, 1965). A latent period frequently
occurred before the onset of symptoms.

No rigorous attempts to establish dose-response relationships
for acute toxicity have been reported for any animal species.
Several species have been observed for the effects of short-term
inhalation of DMS. However, it is difficult to compare the results
of different studies as some were designed to observe the effects
of a given dose, others report only lethal doses, and while some
studies were designed to determine median lethal concentrations,
the duration of exposure was not the same in each case.
Pathological findings in animals following inhalation exposure to
DMS are similar to those observed in human beings. Batsura et al.
(1980) exposed rats to an LC₅₀ level of DMS of 45 mg/m³ for 4 h.
Groups of animals were sacrificed immediately following exposure
and at intervals thereafter. Following a 4-h exposure to DMS, the
rats were dyspnoeic with cyanosis of the mucosae, hyperaemia of the
lungs, and haemorrhages in the internal organs. Some animals had a
nasal discharge. Histological and electron microscopic examination
of lung tissue revealed haemorrhage and coagulated proteins in the
alveoli. After a latent period of 5 - 6 h, accumulation of
oedematous fluid in the air spaces developed progressively over
24 - 48 h.

Ghiringhelli et al. (1957) observed congestion of the
kidneys, spleen, liver, and lungs in the mouse, guinea-pig,
and rat following inhalation of DMS at 390 mg/m³ (75 ppm) for
17, 24, and 26 min, respectively. Histological examination
showed marked pulmonary emphysema and peribronchitis. In the
mouse, there was fatty degeneration with necrotic areas in the
liver. In rats, following oral, sc, and iv administration of
DMS, Druckrey et al. (1966) reported haemorrhagic pulmonary
oedema, hepatic congestion, and intestinal bleeding.

Table 4. Acute animal toxicity
------------------------------------------------------------------------------------------
Animal Route of Effects Dose Reference
administration
------------------------------------------------------------------------------------------
Cat inhalation death after 917 mg/m³ (175 ppm), Flury & Zernick (1931)
several days 11 min

Cat inhalation death after 408 mg/m³ (78 ppm), Flury & Zernick (1931)
1.5 weeks 11 min

Cat inhalation death after 102 mg/m³ (19.5 ppm), Flury & Zernick (1931)
1.5 weeks 11 min

Guinea-pig inhalation death 393 mg/m³ (75 ppm), Ghiringhelli et al.
24-min LC₅₀ (1957)

Guinea-pig inhalation death 167 mg/m³ (32 ppm), Verschueren (1977)
60-min LC₅₀

Monkey inhalation death after 133 mg/m³ (25.5 ppm), Flury & Zernick (1931)
3 days 40 min

Monkey inhalation extremely ill 67 mg/m³ (12.8 ppm), Flury & Zernick (1931)
after 6 h; 20 min
recovery in
4 weeks

Mouse inhalation death 513 mg/m³ (98 ppm), Verschueren (1977)
60-min LC₅₀

Mouse inhalation death 393 mg/m³ (75 ppm), Ghiringhelli et al.
17-min LC₅₀ (1957)

Mouse inhalation death 280 mg/m³, 4-h LC₅₀ Molodkina et al. (1979)

Rat inhalation death 393 mg/m³ (75 ppm), Ghiringhelli et al.
26-min LC₅₀ (1957)

Rat inhalation death 335 mg/m³ (64 ppm), Verschueren (1977)
60-min LC₅₀

Rat inhalation 5/6 deaths 157 mg/m³ (30 ppm), Smyth et al. (1951)
4 h

Rat inhalation no deaths 78 mg/m³ (15 ppm), Smyth (1956)
4 h

Rat inhalation death 45 mg/m³, 4-h LC₅₀ Batsura et al. (1980)

Rat inhalation death 45 mg/m³, 4-h LC₅₀ Molodkina et al. (1979)
------------------------------------------------------------------------------------------

Rabbit oral death in 2 h 250 mg/kg Weber (1902)

Rabbit oral death within 50 mg/kg Weber (1902)
17 h

Rat oral death 440 mg/kg LD₅₀ Smyth et al. (1951)

Rat oral death 440 mg/kg LD₅₀ Druckery et al. (1966)

Rat gavage death 205 mg/kg LD₅₀ Molodkina et al. (1979)

Mouse gavage death 140 mg/kg LD₅₀ Molodkina et al. (1979)

Rabbit subcutaneous death in 300 mg/kg Weber (1902)
45 min

Rabbit subcutaneous death in 2 h 53 mg/kg Weber (1902)

Rat subcutaneous death 100 mg/kg LD₅₀ Druckrey et al. (1966)

Rat intravenous death 90 mg/kg LD₅₀ Druckrey et al. (1970)

Rat intravenous death 40 mg/kg LD₅₀ Druckrey et al. (1966)

Rat intravenous coma and 2 x LD₅₀ Druckrey et al. (1966)
death

Mouse intraperitoneal death 61 mg/kg LC₅₀ Fischer et al. (1975)

Rabbit skin death after 5 ml Weber (1902)
22 h

Mouse skin 50% mortality tail immersed twice Molodkina et al. (1979)
in DMS

Bluegill aquatic death 7.5 g/m³ (7.5 ppm), Dawson et al. (1977)
sunfish 96-h LC₅₀
(Lepomis
machro-
chirus)
------------------------------------------------------------------------------------------

Table 4. (contd.)
------------------------------------------------------------------------------------------
Animal Route of Effects Dose Reference
administration
------------------------------------------------------------------------------------------
Tidewater aquatic death 15 g/m³ (15 ppm), Dawson et al. (1977)
silverside 96-h LC₅₀
(Menidia
beryllina)
---------------------------------------------------------------------------------------------------------
7.2. Chronic Toxicity and Carcinogenicity

Comparison of single and divided doses of DMS in rats
(Molodkina et al., 1979) showed a high cumulative toxicity by Lim's
method (Sanotsky & Ulanova, 1983) (cumulative coefficient, 2.71).
When 27 BD rats, approximately 100 days old, were exposed by
inhalation for 1 h, 5 times a week for 19 weeks to DMS at 55 mg/m³
(approximately 10 ppm), several early deaths from inflammation of
the nasal cavity and pneumonia were reported. Of the 15 surviving
animals, 3 developed squamous cell carcinomas of the nasal cavity,
1 developed a glioma of the cerebellum, and 1 a lymphosarcoma of
the thorax with metastases in the lungs. Similarly, of 20 rats
exposed to 16 mg/m³ (approximately 3 ppm), 1 developed a squamous
cell carcinoma of the nasal cavity, 1 an aesthesioneuroepithelioma
of the olfactory nerve, and 1 a malignant neurinoma originating
from the end fibres of the trigeminus. Some early deaths occurred
at this concentration due to the necrotizing effect of DMS in the
nasal passages (Druckrey et al., 1970).

Of 8 BD rats given weekly sc injections of 16 mg DMS/kg body
weight for 49 weeks (average cumulative dose 784 mg/kg), 6
survived, and, of these, 4 developed sarcomas at the site of
injection. Similar sarcomas were seen in 7 out of 11 survivors
from 12 BD rats given weekly sc injections of DMS at 8 mg/kg body
weight (total dosage 466 mg/kg body weight); 1 rat in this group
developed a hepatoma with metastases in the spleen and lung
(Druckrey et al., 1966). A single sc dose of 50 mg/kg body weight
resulted in the induction of local sarcomas in 7 out of 15 BD rats
of which 3 had metastases in the lungs. The incidence of tumours
in the control rats was not reported in these studies, but the oily
vehicle was reported not to have caused local sarcomas at the
injection site in control tests (Druckrey et al., 1970).

Wistar rats, Golden hamsters, and NMRI mice of both sexes were
exposed to calculated average DMS concentrations of 3 mg/m³ (0.59
ppm) and 8.7 mg/m³ (1.66 ppm) by inhalation for 15 months (Schlögel
& Bannasch, 1970; Schlögel, 1972). The low-dose group was exposed
for 6 h, twice weekly, and the high-dose group for 6 h, every 14
days. The study lasted for 30 months. In the high-dose group, the
average life span of the mouse was shortened by 21% and that of the
rat by 60%. Malignant tumours of the nasal cavity and lung were
observed in 10 out of 74 animals in the 8.7 mg/m³ dose group (rat:
6/27 nasal carcinomas, 0/36 in controls; mouse: 3/25 lung
carcinomas, 0/19 in controls; hamster: 1/22 lung carcinomas, 0/15

in controls). Four out of 97 animals in the 3 mg/m³ dose group had
malignant tumours including 1 sarcoma of the thorax (rat: 3/37,
nasal and lung carcinomas; mouse: 1/32, 1 lung carcinoma and 1
sarcoma of the thorax; hamster: 28 animals exposed, no tumours).
Although no malignant tumours of the respiratory tract were found
in 70 control animals, 2 other malignant tumours were reported in
this group. In both exposed groups, the mouse and rat appeared to
be more susceptible to the carcinogenic effects of DMS than the
hamster.

In an inhalation study, Fomenko et al. (1983) exposed groups of
90 female mice (CBAX57Bl/6) to DMS at a concentration of 0.4, 1, or
20 mg/m³ for 4 h per day, 5 days per week. A statistically-
significant increase in lung adenomas was observed only in the
highest-dose group.

Two groups of 12 BD rats, given weekly iv injections of DMS at
2 or 4 mg/kg body weight for 114 weeks (cumulative dose of 228 or
456 mg/kg, respectively), did not develop any tumours (Druckrey et
al., 1970). A similar finding was reported by Swann & Magee
(1968), who injected 9 rats intravenously with 75 - 150 mg DMS/kg
body weight; the frequency of dosing and the duration of the study
were not reported. No carcinomas were demonstrated in 20 ICR/Ha
Swiss mice following dermal application of DMS, 3 times per week at
a dose of 0.1 mg/0.01 ml acetone for 475 days (Van Duuren et al.,
1974).

The lack of tumour formation following iv dosing with DMS is
probably due to its extreme reactivity in vivo (Swann, 1968). DMS
generally induces tumours at the site of contact, that is at the
injection site following sc exposure, and in the respiratory tract
following inhalation. However, Druckrey et al. (1970) did not find
any tumours in the lower respiratory tract or lungs of rats
following inhalation of DMS, but tumours of the nasal cavity were
found. This was attributed to the fact that rats breathe
exclusively through the nose. Schlögel (1972) also found more
nasal cavity carcinomas than lung carcinomas in the rat. In an
inhalation study using higher concentrations (17 and 55 mg/m³),
Druckrey et al. (1970) found that many rats died prematurely from
the necrotizing effects of DMS with inflammation of the nasal
cavity and pneumonia rather than from tumours.

7.2.1. Transplacental carcinogenicity

There is one limited study in which 8 pregnant BD rats were
given a single iv injection of 20 mg DMS/kg body weight on the 15th
day of pregnancy. Among 59 offspring, observed for more than 1
year, 7 developed malignant tumours, including 3 tumours of the
brain (at 466, 732, and 907 days). Other tumours included 1
adenoma of the thyroid, 2 hepatic-cell carcinomas, and 1 carcinoma
of the uterus (Druckrey et al., 1970).

7.3. Mutagenicity and Genetic Effects

The genotoxic effects of DMS have been extensively reviewed
(Hoffman, 1980; IARC, 1982). DNA damage, mutations, chromosomal
anomalies, and other genotoxic effects have been observed in
viruses, prokaryotes, fungi, vascular plants, insects, fish,
mammalian cells in vitro, and in mammals in vivo.

Several assays have demonstrated induction of DNA damage by
DMS. DMS is active in the Escherichia coli Poly A^+/- and Proteus
mirabilis repair assays (Adler et al., 1976; Fluck et al., 1976)
and is an activator of transforming DNKA in Haemophilus influenzae
and Bacillus subtilis, inducing fluorescent indole-requiring
mutations in the latter system (Zamenhof et al., 1956; Bresler et
al., 1968a,b). DMS induced unscheduled DNA synthesis in primary
rat hepatocyte cultures (Probst et al., 1981) and also in human
fibroblasts from normal and xeroderma pigmentosum donors (Cleaver,
1977; Wolff et al., 1977). DMS also caused single-strand breaks in
rat hepatocytes (Sina et al., 1983). It has been demonstrated to
bind covalently with DNA in rats treated in vivo (Swann & Magee,
1968; Löfroth et al., 1974) and to inhibit testicular DNA synthesis
in the mouse (Seiler, 1977).

DMS is mutagenic in bacterial systems including Salmonella
typhimurium in which it is mutagenic without activation in both
forward and reverse mutation assays (Braun et al., 1977; Skopek et
al., 1978) and in a host-mediated assay (Braun et al., 1977). Both
base-pair substitutions and frame-shift mutations have been
reported, though, in the latter case, there is some inconsistency,
since a negative response has also been obtained (Braun et al.,
1977). Mutations have been induced by DMS in animal (Thiry, 1963;
Solyanik et al., 1972) and plant viruses, including tobacco mosaic
virus (Fraenkel-Conrat, 1961; Singer & Fraenkel-Conrat, 1969a,b),
and in fungi, including Neurospora crassa (Kolmark, 1956),
Aspergillus nidulans (Moura Duarte, 1971), and Saccharomyces
cerevisiae (Prakash & Sherman, 1973). Genetic variants in at
least 40 different genera of vascular plants have been obtained
using DMS as a mutagen (Hoffman, 1980). The induction of sex-
linked recessive lethal mutations in Drosophila melanogaster has
been reported (Rapoport, 1947; Alderson, 1964; Vogel & Natarajan,
1979) and DMS has been shown to be mutagenic in Chinese hamster
ovary cells at the HGPRT locus (Couch et al., 1978; Hsie et al.,
1979; Tan et al., 1983) and in Chinese hamster V79 cells, in the
absence of metabolic activation (Newbold et al., 1980).

Chromosomal aberrations have been induced by DMS in a variety
of vascular plants including Vicia faba (Loveless, 1951), wheat
(Shkvarnikov et al., 1965), sunflower (Ploknikov, 1973), and Norway
spruce ( Picea abies L.) (Terasmaa, 1976). A DMS-induced increased
frequency of sister chromatid exchanges has also been reported in
Chinese hamster lung fibroblast cells and in Chinese hamster
diploid cells (Latt et al., 1981; Connell & Medcalf, 1982), and in
cultured human fibroblasts from both normal and xeroderma
pigmentosum donors (Wolff et al., 1977). Sharma (1980) found
chromosomal aberrations in bone marrow cells in 64% of rats treated

with DMS at 0.35 mg/kg body weight compared with 1 - 2% in
controls. Santosy et al. (1982) also observed an increased
frequency of chromosome aberrations in the bone marrow cells of SHK
C57B mice exposed to DMS levels of 0.2 - 20 mg/m³.

DMS has been reported to be negative in dominant lethal tests
in mice (Epstein & Shafner, 1968). In studies by Sanotsky et al.
(1982) and Domshlack (1984), an increased frequency of black or
depigmented spots was observed in the fur of F₁, WR mice following
maternal exposure by inhalation to DMS levels of 1.34 - 26 mg/m³.
Fomenko et al. (1983) studied the mutagenic effects of DMS by
inhalation in Wistar rats and CBWA and WR mice. Groups were
exposed to 0.3, 2.0, and 20 mg/m³. Chromosome aberrations in
lymphocytes were reported at all concentrations.

Genetic effects were observed in fish embryos following
treatment of sperm with DMS (Tsoi, 1969, Tsoi et al., 1974;
Kormilin et al., 1979; Hoffman, 1980), and disturbances in the
nucleoli of oocytes from fish have been reported following exposure
to DMS-contaminated water (Khvoles & Korobko, 1975).

7.4. Reproductive Effects, Embryotoxicity, and Teratogenicity

Sanotsky et al. (1982) and Fomenko et al. (1983) reported that
inhalation of DMS at concentrations of 0.3 or 3 mg/m³ for 1.5 - 4
months did not have any effects on the germ cells or the
spermatogenic epithelium of Wistar rats. In mice and rats,
inhalation of DMS at 0.5 - 20 mg/m³, throughout pregnancy, was
reported to induce pre-implantation losses, and embryotoxic effects
including anomalies of the cardiovascular system (Sanotsky et al.,
1982; Fomenko et al., 1983).

In pregnant WR mice, following inhalation of DMS (0.29 - 26
mg/m³) during days 1 - 13 of pregnancy, there were intrauterine and
early postnatal deaths, and no progeny survived (Domshlack, 1984).

8. EFFECTS ON MAN

8.1. Toxicity

DMS is highly toxic for man. Exposure by inhalation to 500
mg/m³ (97 ppm) for 10 min may be fatal (Deichman & Gerarde, 1969).
Levels exceeding approximately 5.0 mg/m³ (1 ppm) can cause
reddening of the eyes (ACGIH, 1980), often the earliest symptom of
acute over-exposure to DMS. As DMS does not have any
characteristic odour or other properties that might warn of
exposure, it is particularly hazardous. There are reports in the
literature in which apparently minimal exposure has resulted in
severe symptoms. However, despite its extensive use, few cases of
death from either long-term or acute exposure to DMS have been
reported.

Weber (1902) reported 2 cases of fatal occupational poisoning.
In both cases, the primary lesion encountered was in the
respiratory system, with severe damage to the mucosae and lungs and
also renal and cardiac damage. Another case of fatal occupational
poisoning was reported by Moeschlin (1965) in which fumes were
received directly in the face for a few minutes. Despite mild
initial symptoms of a burning sensation in the eyes and nausea,
death from suffocation occurred 11 h after the incident. A
colleague exposed at the same time sought medical attention and,
despite severe symptoms, made a complete recovery. One case of
ingestion of DMS with fatal consequences has been reported (Nida,
1947). After licking the finger to taste DMS, immediate irritation
of the soft palate, constriction of the throat, and increased
salivation ensued, which improved on treatment. However, 24 h
later, there was a sudden onset of oedema of the glottis, and death
occurred. At autopsy, acute corrosion of the upper digestive
tract, oedema of the glottis, and emphysema of the lungs were
found.

There are several reports of non-fatal poisoning following
acute exposure to DMS (Mohlau, 1920; Balazs, 1934; Grçsz, 1937;
Brina, 1946; Tara et al., 1954; Littler & McConnell, 1955; Tara,
1955; Roche et al., 1962; Browning, 1965; Moeschlin, 1965; ACGIH,
1976, 1980; Roux et al., 1977). The severity of the signs and
symptoms reported varied and they were similar to those found in
fatal cases. Immediate manifestations may be non-existent or very
mild, but become increasingly severe after a latent period of
4 - 12 h. Even burns from direct spillage on the skin are delayed
in onset and may still occur despite immediate thorough irrigation
and neutralization (Littler & McConnell, 1955). Corneal ulceration
and severe inflammation of the eyes and eyelids with photophobia
are commonly reported; these symptoms generally resolve
satisfactorily (Tara, 1955; Roche et al., 1962), though
irreversible loss of vision has been reported (Mohlau, 1920; ACGIH,
1976). Irritation of the mucous membranes of the mouth and
respiratory tract may be severe with pulmonary oedema; there may be
hoarseness and oropharyngeal oedema, which persist for several
weeks (Tara, 1955). Genital and mucous membrane lesions have been
reported following direct contact, generally with the vapour.

Systemic effects can include convulsions, delirium, coma,
analgesia, pyrexia, pulmonary oedema, delayed renal and hepatic
failure, and cardiac damage (Littler & McConnell, 1955; Ottinger et
al., 1973). Ivanova et al. (1983) have reported the development of
lung fibrosis following DMS exposure in human beings.

8.2. Carcinogenicity

Druckrey et al. (1966) reported the case of a 47-year-old male
who died from bronchial cancer after 11 years of occupational
exposure to DMS. Three out of 10 co-workers also died from
bronchial cancer. Lung cancer was reported in a chemist exposed by
inhalation to DMS for over 7 years; however, in this case, there
was concomitant exposure to other alkylating agents that were
present at higher concentrations (Bettendorf, 1977). A case of
choroidal melanoma has been reported in a man exposed to DMS for 6
years (Albert & Puliafito, 1977). Pell (1976) studied a group of
145 workers who had been exposed to DMS for various periods between
1932 and 1972. No significant excess in the total number of deaths
in the exposed population was reported and, in particular, no
significant increase in deaths from lung cancer was noted.

Increased chromosome and chromatid aberrations in lymphocytes
have been reported in workers exposed to DMS at concentrations
ranging from 0.2 - 20 mg/m³ (Sanotsky et al., 1982; Katsova &
Pavlenko, 1984).

9. EVALUATION OF HEALTH RISKS FOR MAN AND EFFECTS ON THE
ENVIRONMENT FROM EXPOSURE TO DIMETHYL SULFATE

DMS has been shown to induce genotoxic effects in a number of
test systems, and has been demonstrated to be carcinogenic in
experimental animals. At present, there is insufficient clinical
or epidemiological evidence to indicate whether or not DMS is a
human carcinogen. It is described by the IARC (1982) as a chemical
which is "probably carcinogenic to humans" and, in some countries,
it is regulated as a carcinogen, DMS should be assumed to be a
potential human carcinogen, and exposure to it controlled.

In addition, DMS is acutely toxic, particularly for the lungs
(section 7.1, 8.1). Where possible, all procedures should be
carried out in enclosed systems in conjunction with careful
monitoring of atmospheric DMS levels. Even with good industrial
hygiene, it is important to monitor workers occupationally exposed
to DMS. There are potential procedures such as monitoring
methylated purines in urine (for recent exposure), methylated
proteins in blood, chromosome aberrations in blood cells, and the
monitoring of sputum cytology (for long-term follow-up), but these
need to be further developed and evaluated.

The Task Group considered that data were insufficient to derive
complete dose-response relationships for DMS in animal studies.
However, it should be noted, when considering the safety of
manufacturing and using DMS, that concentrations in the region of
3 mg/m³ have induced respiratory tract tumours in animals (section
7.2). It is possible that DMS may be adsorbed on atmospheric
particulate matter and thus its toxic effects enhanced.

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    See Also:
       Toxicological Abbreviations
       Dimethyl sulfate (HSG 29, 1989)
       Dimethyl sulfate (ICSC)
       Dimethyl Sulfate (IARC Summary & Evaluation, Volume 71, 1999)