Environmental Health Criteria 48 DIMETHYL SULFATE

Environmental Health Criteria 48

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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

The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals.

ISBN 92 4 154188 1

The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made

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to the text, plans for new editions, and reprints and translations already available.

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The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

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

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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,

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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

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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

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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.

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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

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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

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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

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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 Ref ------1) GC-MS 0.05 mg/m3 (0.01 ppm) sampling device readily Ell Thermal elution for 1 litre air sample portable; suitable for air (19 from collection monitoring in workplace tube

2) GC-FPD not given fully automated system, Ell 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 Lun conductivity, 10 ppm) for 0.75 litre techniques permit (19 detector oxidative air sample, 1.05 - 15.7 replicate analyses; Lun mode;S-specific mg/m3 (0.2 - 3 ppm) for halogen-, sulfur-, and Fey 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 GC-FPD airborne particles and (19 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 Gil GC-FPD for 20 litre air sample selective (S-specific) and Bri Desorption with = 2 µg/ml in more sensitive than FID; (19

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acetone solution this degree of sensitivity is achieved by injecting large samples necessitating venting of solvent in order to protect detector ------

Table 2. (contd.) ------Method Detection limit Comments Ref ------6) GC-EC 0.026 - 26.2 mg/m3 determination of Du Derivative (0.005 - 5 ppm) derivative not DMS (19 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) Sid Desorption from for 20 litre air sample (19 silica gel sample collection tube with distilled water

8) GC-FPD 0.04 mg/m3 (0.008 ppm) Kel Adsorption on for 100 litre air sample (19 silica

9) TLC-colorimetric 0.05 mg/m3 (0.01 ppm) requires large sample Kel Derivative for 500 litre air volume using sampling rate (19 4-nitroanisole sample; 0.1 mg/m3 (0.02 of 3 - 4 litre/min; takes 198 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 Tom metric (VIS) (484 for 50 litre air sample sample to establish Baj nm) Derivative whether DMS contamination (19 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 Tad (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) ------

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Table 2. (contd.) ------Method Detection limit Comments Ref ------12) HPLC - UV (305 nm) 0.05 mg/m3 (0.01 ppm) can lower detection Wil Derivative 4- for 10 litre air sample limit by increasing (19 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 Fox scopy (9.9 µm or (20 m cell) or short-term storage Wil 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- Eat Derivative methyl- borne particles; methyl- al. 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- Lei Derivative N- (0.005 - 0.05 ppm) mination of DMS where (1 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 measurement 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

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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

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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).

Page 14 of 37 Dimethyl sulfate (EHC 48, 1985)

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,

Page 15 of 37 Dimethyl sulfate (EHC 48, 1985)

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

Page 16 of 37 Dimethyl sulfate (EHC 48, 1985)

(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 potential for man

Brazila 0.08 0.4 for 48 h per week

Czechoslovakiaa Suspected carcinogenic substance

Denmarkc 0.01 0.05 Suspected to be of carcinogenic potential 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 experimental animal studies

Hungarye 5 MACn - TWAk

Italye 0.01 0.05 TWAk Carcinogenic (Rec- ommendation prepared 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 ------

Page 17 of 37 Dimethyl sulfate (EHC 48, 1985)

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

Switzerlandg 0.04 0.2 TWAk Regarded as a 0.02 0.1 in production carcinogenic substance

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 potential 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.

Page 18 of 37 Dimethyl sulfate (EHC 48, 1985)

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

Page 19 of 37 Dimethyl sulfate (EHC 48, 1985)

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. 3 (1980) exposed rats to an LC50 level of DMS of 45 mg/m 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 & Zernic several days 11 min

Cat inhalation death after 408 mg/m3 (78 ppm), Flury & Zernic

Page 20 of 37 Dimethyl sulfate (EHC 48, 1985)

1.5 weeks 11 min

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

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

Guinea-pig inhalation death 167 mg/m3 (32 ppm), Verschueren (1 60-min LC50

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

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

Mouse inhalation death 513 mg/m3 (98 ppm), Verschueren (1 60-min LC50

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

3 Mouse inhalation death 280 mg/m , 4-h LC50 Molodkina et al

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

Rat inhalation death 335 mg/m3 (64 ppm), Verschueren (1 60-min LC50

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

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

3 Rat inhalation death 45 mg/m , 4-h LC50 Batsura et al.

3 Rat inhalation death 45 mg/m , 4-h LC50 Molodkina et al ------

Table 4. (contd.) ------Animal Route of Effects Dose Reference administration ------Rat inhalation maximum 2 min Smyth et al. ( 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. (

Page 21 of 37 Dimethyl sulfate (EHC 48, 1985)

Rat oral death 440 mg/kg LD50 Druckery et al

Rat gavage death 205 mg/kg LD50 Molodkina et a

Mouse gavage death 140 mg/kg LD50 Molodkina et a

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

Rat intravenous death 90 mg/kg LD50 Druckrey et al

Rat intravenous death 40 mg/kg LD50 Druckrey et al

Rat intravenous coma and 2 x LD50 Druckrey et al death

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

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

Mouse skin 50% mortality tail immersed twice Molodkina et a in DMS

Bluegill aquatic death 7.5 g/m3 (7.5 ppm), Dawson et al. 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. 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

Page 22 of 37 Dimethyl sulfate (EHC 48, 1985)

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

Page 23 of 37 Dimethyl sulfate (EHC 48, 1985)

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

Page 24 of 37 Dimethyl sulfate (EHC 48, 1985)

(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

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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).

Page 26 of 37 Dimethyl sulfate (EHC 48, 1985)

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)

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