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    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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        ISBN 92 4 154188 1    

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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 sulfatea
--------------------------------------------------------------
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)
-----------------------------------------------------------------------------------------

Table 2.  (contd.)
-----------------------------------------------------------------------------------------
Method                  Detection limit           Comments                    Reference
-----------------------------------------------------------------------------------------
12) HPLC - UV (305 nm)  0.05 mg/m3 (0.01 ppm)     can lower detection         Williams       
    Derivative 4-       for 10 litre air sample   limit by increasing         (1982)
    nitroanisole                                  concentration of solution 
                                                  before injection or by  
                                                  using larger sample loop
                                                    
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 vessela. 

    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 countriesa
--------------------------------------------------------------------------
Country              Exposure limit  Category of       Comments
                     (ppm)  (mg/m3)  limit
--------------------------------------------------------------------------
Australiab           0.1    0.5      TWAb              Suspected to be of
                                                       carcinogenic pot-
                                                       ential for man

Brazila              0.08   0.4      for 48 h 
                                     per week

Czechoslovakiaa                                        Suspected carcino-
                                                       genic substance

Denmarkc             0.01   0.05                       Suspected to be of
                                                       carcinogenic pot-
                                                       ential for man

Finlandd             0.01   0.05     STELl
                                     (15 min)

Germany, Democratic         5        average
Republic ofe                5        short-term

Germany, Federal            0.1      TRKm              Carcinogenic
Republic ofa                         (in manufacture)  
                            0.2      TRKm (in use)     Working material -
                                                       proved in experi-
                                                       mental animal
                                                       studies

Hungarye                    5        MACn - TWAk

Italye               0.01   0.05     TWAk              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)

Japana               0.1    0.5      MACn

Netherlandsf         0.1    0.5      MACn - Co

Polande                     1        Co

Romaniae                    3        average
                            8        max
--------------------------------------------------------------------------

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

Switzerlandg         0.04   0.2      TWAk              Regarded as a
                     0.02   0.1      in production     carcinogenic sub-
                                                       stance

United Kingdomh      0.1    0.5      TWAk
                     0.1    0.5      STELl

USA
 (a) OSHAa           1      5        PELp - TWAk

 (b) ACGIHi          0.1    0.5      TLVg - TWAk       Suspected to be of
                                                       carcinogenic pot-
                                                       ential for man

USSRj                       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 SN2-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)
------------------------------------------------------------------------------------------

Table 4.  (contd.)
------------------------------------------------------------------------------------------
Animal      Route of         Effects        Dose                   Reference
            administration
------------------------------------------------------------------------------------------
Rat         inhalation       maximum        2 min                  Smyth et al. (1951)
                             exposure to  
                             saturated 
                             vapour 
                             pressure for 
                             no deaths

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)