UNITED NATIONS ENVIRONMENT PROGRAMME INTERNATIONAL LABOUR ORGANISATION WORLD HEALTH ORGANIZATION INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 186 ETHYLBENZENE 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. First draft prepared by Dr P. Lundberg (National Institute of Occupational Health, Sweden), Dr M. Crookes (Building Research Establishment, United Kingdom), and Dr S. Dobson and Mr P. Howe (Institute of Terrestrial Ecology, Monks Wood, United Kingdom) Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals. World Health Organization Geneva, 1996 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), and the World Health Organization (WHO). 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. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing in Publication Data Ethylbenzene (Environmental health criteria ; 186) 1.Ethylbenzene - toxicity 2.Benzene derivatives 3.Environmental exposure I.Series ISBN 92 4 157186 1 (NLM Classification: QV 633) ISSN 0250-863X 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 to the text, plans for new editions, and reprints and translations already available. (c) World Health Organization 1996 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. 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 ETHYLBENZENE 1. SUMMARY 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS 2.1. Identity 2.2. Physical and chemical properties 2.3. Conversion factors 2.4. Analytical methods 2.4.1. Ethylbenzene in air 2.4.2. Ethylbenzene in water 2.4.3. Ethylbenzene in biological material 2.4.4. Metabolites of ethylbenzene in urine 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Natural occurrence 3.2. Anthropogenic sources 3.2.1. Production processes 3.2.2. Production levels 3.2.3. Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1. Transport and distribution between media 4.1.1. Air 4.1.2. Water 4.1.3. Soil 4.1.4. Sediment 4.2. Transformation 4.2.1. Biodegradation 220.127.116.11 Aerobic degradation 18.104.22.168 Anaerobic degradation 4.2.2. Abiotic degradation 22.214.171.124 Photolysis 126.96.36.199 Photo-oxidation 188.8.131.52 Hydrolysis 4.2.3. Bioaccumulation 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1. Environmental levels 5.1.1. Air 5.1.2. Surface water and sediment 5.1.3. Groundwater 5.1.4. Urban run-off, effluent and landfill leachate 5.1.5. Soil 5.1.6. Biota 5.2. General population exposure 5.2.1. Environmental sources 5.2.2. Food 5.2.3. Drinking-water 5.3. Occupational exposure during manufacture, formulation or use 5.3.1. Biological monitoring 6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1. Absorption 6.1.1. Skin absorption 6.1.2. Absorption via inhalation 6.1.3. Absorption after oral intake 6.2. Distribution 6.3. Metabolic transformation 6.4. Elimination and excretion 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1. Single exposure 7.2. Short-term exposure 7.3. Long-term exposure 7.3.1. Oral exposure 7.3.2. Inhalation exposure 7.4. Skin and eye irritation, sensitization 7.5. Reproductive toxicity, embryotoxicity and teratogenicity 7.6. Mutagenicity and related end-points 7.7. Carcinogenicity 7.8. Other special studies 7.9. Factors modifying toxicity 8. EFFECTS ON HUMANS 8.1. Volunteer studies 8.2. Occupational exposure 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1. Microorganisms 9.2. Aquatic organisms 9.3. Terrestrial organisms 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of human health risks 10.2. Evaluation of effects on the environment 11. CONCLUSIONS 12. FURTHER RESEARCH 13. PREVIOUS EVALUATION BY INTERNATIONAL BODIES REFERENCES RESUME RESUMEN NOTE TO READERS OF THE CRITERIA MONOGRAPHS Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda. * * * A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111). * * * This publication was made possible by grant number 5 U01 ES02617-15 from the National Institute of Environmental Health Sciences, National Institutes of Health, USA, and by financial support from the European Commission. Environmental Health Criteria PREAMBLE Objectives In 1973 the WHO Environmental Health Criteria Programme was initiated with the following objectives: (i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits; (ii) to identify new or potential pollutants; (iii) to identify gaps in knowledge concerning the health effects of pollutants; (iv) to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparable results. The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976 and since that time an ever-increasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth. Since its inauguration the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals. The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently the work became an integral part of the International Programme on Chemical Safety (IPCS), a cooperative programme of UNEP, ILO and WHO. In this manner, with the strong support of the new 14 partners, the importance of occupational health and environmental effects was fully recognized. The EHC monographs have become widely established, used and recognized throughout the world. The recommendations of the 1992 UN Conference on Environment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals. Scope The criteria monographs are intended to provide critical reviews on the effect on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents. As such, they include and review studies that are of direct relevance for the evaluation. However, they do not describe every study carried out. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. Both published and unpublished reports are considered and it is incumbent on the authors to assess all the articles cited in the references. Preference is always given to published data. Unpublished data are only used when relevant published data are absent or when they are pivotal to the risk assessment. A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this information can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Preparation of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World Health Organization). In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Helsinki Declaration. The EHC monographs are intended to assist national and international authorities in making risk assessments and subsequent risk management decisions. They represent a thorough evaluation of risks and are not, in any sense, recommendations for regulation or standard setting. These latter are the exclusive purview of national and regional governments. Content The layout of EHC monographs for chemicals is outlined below. * Summary - a review of the salient facts and the risk evaluation of the chemical * Identity - physical and chemical properties, analytical methods * Sources of exposure * Environmental transport, distribution and transformation * Environmental levels and human exposure * Kinetics and metabolism in laboratory animals and humans * Effects on laboratory mammals and in vitro test systems * Effects on humans * Effects on other organisms in the laboratory and field * Evaluation of human health risks and effects on the environment * Conclusions and recommendations for protection of human health and the environment * Further research * Previous evaluations by international bodies, e.g., IARC, JECFA, JMPR Selection of chemicals Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation. Such meetings have been held in: Ispra, Italy, 1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North Carolina, USA, 1995. The selection of chemicals has been based on the following criteria: the existence of scientific evidence that the substance presents a hazard to human health and/or the environment; the possible use, persistence, accumulation or degradation of the substance shows that there may be significant human or environmental exposure; the size and nature of populations at risk (both human and other species) and risks for environment; international concern, i.e. the substance is of major interest to several countries; adequate data on the hazards are available. If an EHC monograph is proposed for a chemical not on the priority list, the IPCS Secretariat consults with the Cooperating Organizations and all the Participating Institutions before embarking on the preparation of the monograph. Procedures The order of procedures that result in the publication of an EHC monograph is shown in the flow chart. A designated staff member of IPCS, responsible for the scientific quality of the document, serves as Responsible Officer (RO). The IPCS Editor is responsible for layout and language. The first draft, prepared by consultants or, more usually, staff from an IPCS Participating Institution, is based initially on data provided from the International Register of Potentially Toxic Chemicals, and reference data bases such as Medline and Toxline. The draft document, when received by the RO, may require an initial review by a small panel of experts to determine its scientific quality and objectivity. Once the RO finds the document acceptable as a first draft, it is distributed, in its unedited form, to well over 150 EHC contact points throughout the world who are asked to comment on its completeness and accuracy and, where necessary, provide additional material. The contact points, usually designated by governments, may be Participating Institutions, IPCS Focal Points, or individual scientists known for their particular expertise. Generally some four months are allowed before the comments are considered by the RO and author(s). A second draft incorporating comments received and approved by the Director, IPCS, is then distributed to Task Group members, who carry out the peer review, at least six weeks before their meeting. The Task Group members serve as individual scientists, not as representatives of any organization, government or industry. Their function is to evaluate the accuracy, significance and relevance of the information in the document and to assess the health and environmental risks from exposure to the chemical. A summary and recommendations for further research and improved safety aspects are also required. The composition of the Task Group is dictated by the range of expertise required for the subject of the meeting and by the need for a balanced geographical distribution. The three cooperating organizations of the IPCS recognize the important role played by nongovernmental organizations. Representatives from relevant national and international associations may be invited to join the Task Group as observers. While observers may provide a valuable contribution to the process, they can only speak at the invitation of the Chairperson. Observers do not participate in the final evaluation of the chemical; this is the sole responsibility of the Task Group members. When the Task Group considers it to be appropriate, it may meet in camera. All individuals who as authors, consultants or advisers participate in the preparation of the EHC monograph must, in addition to serving in their personal capacity as scientists, inform the RO if at any time a conflict of interest, whether actual or potential, could be perceived in their work. They are required to sign a conflict of interest statement. Such a procedure ensures the transparency and probity of the process. When the Task Group has completed its review and the RO is satisfied as to the scientific correctness and completeness of the document, it then goes for language editing, reference checking, and preparation of camera-ready copy. After approval by the Director, IPCS, the monograph is submitted to the WHO Office of Publications for printing. At this time a copy of the final draft is sent to the Chairperson and Rapporteur of the Task Group to check for any errors. It is accepted that the following criteria should initiate the updating of an EHC monograph: new data are available that would substantially change the evaluation; there is public concern for health or environmental effects of the agent because of greater exposure; an appreciable time period has elapsed since the last evaluation. All Participating Institutions are informed, through the EHC progress report, of the authors and institutions proposed for the drafting of the documents. A comprehensive file of all comments received on drafts of each EHC monograph is maintained and is available on request. The Chairpersons of Task Groups are briefed before each meeting on their role and responsibility in ensuring that these rules are followed. WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ETHYLBENZENE Members Dr D. Anderson, BIBRA Toxicology International, Carshalton, Surrey, United Kingdom Dr A. Bobra, Environment Canada, Orleans, Ontario, Canada Dr K. Hatfield, Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health, Cincinnati, Ohio, USA Mr L. Heiskanen, Environmental Health Assessment and Criteria Section, Chemical Safety Unit, Department of Human Services and Health, Canberra, Australia Mr P. Howe, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom (Co-rapporteur) Dr You-xin Liang, Department of Occupational Health, Shanghai Medical University, Shanghai, China Professor M. Lotti, Institute of Occupational Medicine, University of Padua, Padua, Italy (Chairman) Dr P. Lundberg, Department of Toxicology, National Institute of Occupational Health, Solna, Sweden (Co-rapporteur) Dr Vesa Riihimaki, Institute of Occupational Health, Helsinki, Finland Dr Leif Simonsen, National Institute of Occupational Health, Copenhagen, Denmark Representatives of other Organizations Dr P. Montuschi, Institute of Pharmacology, Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy (representing the International Union of Pharmacology) Secretariat Dr B.H. Chen, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary) IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ETHYLBENZENE A WHO Task Group on Environmental Health Criteria for Ethylbenzene met at the British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom, from 27 February to 2 March 1995. Dr D. Anderson opened the meeting and welcomed the participants on behalf of the host institute. Dr B.H. Chen, IPCS, welcomed the participants on behalf of the Director, IPCS, and the three IPCS cooperating organizations (UNEP/ILO/WHO). The Task Group reviewed and revised the draft criteria monograph and made an evaluation of the risks for human health and the environment from exposure to ethylbenzene. Dr P. Lundberg, National Institute of Occupational Health, Sweden, Dr M. Crookes, Building Research Establishment, United Kingdom and Dr S. Dobson and Mr P. Howe, Institute of Terrestrial Ecology, Monks Wood, United Kingdom, prepared the first draft of this monograph. The second draft was prepared by Dr Lundberg and Mr Howe, incorporating comments received following the circulation of the first draft to the IPCS Contact Points for Environmental Health Criteria monographs. Dr S. Soliman, College of Agriculture & Veterinary Medicine, Saudi Arabia, contributed to the final text of the document. Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS Central Unit, were responsible for the overall scientific content and technical editing, respectively. The efforts of all who helped in the preparation and finalization of the document are gratefully acknowledged. * * * Financial support for this Task Group was provided by the United Kingdom Department of Health as part of its contributions to the IPCS. ABBREVIATIONS FID flame ionization detection GC gas chromatography MS mass spectrometry PID photoionization detection VOC volatile organic compound 1. SUMMARY Ethylbenzene is an aromatic hydrocarbon manufactured by alkylation from benzene and ethylene. The estimated yearly production in the USA is about 5 million tonnes, and in 1983 it was approximately 3 million tonnes in western Europe. Ethylbenzene is a colourless liquid with a sweet gasoline-like odour. It is mainly used for the production of styrene. It is also used in technical xylene as a solvent in paints and lacquers and in the rubber and chemical manufacturing industries. It is found in crude oils, refined petroleum products and combustion products. Ethylbenzene is a non-persistent chemical, being degraded primarily by photo-oxidation and biodegradation. Volatilization to the atmosphere is rapid. The photo-oxidation reaction of ethylbenzene in the atmosphere may contribute to photochemical smog formation. The log octanol-water partition coefficient is 3.13, indicating a potential for bioaccumulation. However, the limited evidence available shows that ethylbenzene bioconcentration factors are low for fish and molluscs. Elimination from aquatic organisms appears to be rapid. Ethylbenzene levels in air at rural sites are generally less than 2 µg/m3. Mean levels of ethylbenzene ranging from 0.74 to 100 µg/m3 have been measured at urban sites. The levels of ethylbenzene found in surface waters are generally less than 0.1 µg/litre in non-industrial areas. In industrial and urban areas ethylbenzene concentrations of up to 15 µg/litre have been reported. Ethylbenzene levels in sediments are generally less than 0.5 µg/kg, although levels between 1 and 5 µg/kg have been found in sediments from heavily industrialized areas. Concentrations in uncontaminated groundwater are generally less than 0.1 µg/litre, but are much higher in contaminated groundwater. The acute toxicity of ethylbenzene to algae, aquatic invertebrates and fish is moderate. The lowest acute toxicity values are 4.6 mg/litre for the alga Selenastrum capricornutum (72-h EC50 based on growth inhibition), 1.8 mg/litre for Daphnia magna (48-h LC50) and 4.2 mg/litre for rainbow trout (96-h LC50). No information is available regarding chronic exposure of aquatic organisms to ethylbenzene. There is limited information regarding the toxicity of ethylbenzene to bacteria and earthworms. There are no data for terrestrial plants, birds or wild mammals. Human exposure to ethylbenzene occurs mainly by inhalation; 40-60% of inhaled ethylbenzene is retained in the lung. Ethylbenzene is extensively metabolized, mainly to mandelic and phenylglyoxylic acids. These urinary metabolites can be used to monitor human exposures. Ethylbenzene has low acute and chronic toxicity for both animals and humans. It is toxic to the central nervous system and is an irritant of mucous membranes and the eyes. The threshold for these effects in humans after short single exposures was estimated to be about 430-860 mg/m3 (100-200 ppm). Inhalation of ethylbenzene for 13 weeks by rats and mice at concentrations up to 4300 mg/m3 (1000 ppm) did not lead to histopathological lesions. The no-observed-effect level, based on increased liver weight in rats, was 2150 mg/m3 (500 ppm). Ethylbenzene is an inducer of liver microsomal enzymes. It is not mutagenic or teratogenic in rats and rabbits. No information is available on reproductive toxicity or carcinogenicity of ethylbenzene. A guidance value of 22 mg/m3 (5 ppm) has been calculated from animal studies. The estimated exposure of the general population (even in the worst case situation) is below this guidance value. Long-term occupational exposure to ethylbenzene concentrations estimated to be of this order of magnitude did not cause adverse health effects in workers. 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS 2.1 Identity Empirical formula: C8H10 Chemical structure: Chemical name: Ethylbenzene Synonyms: Phenylethane, EB, Ethylbenzol Relative molecular mass: 106.16 CAS registry number: 100-41-4 RTECS registry number: DA 07000000 EEC number: 601-023-00-4 2.2 Physical and chemical properties Some physical and chemical properties of ethylbenzene are given in Table 1. The solubility of ethylbenzene in water is 152 mg/litre at 20°C and 101.3 kPa (DEC, 1992) and 138 mg/litre at 15°C (Heilbron et al., 1946). Ethylbenzene is soluble in ethanol, diethylether and most other organic solvents (ECETOC, 1986; DEC, 1992). At room temperature ethylbenzene is a colourless liquid with a sweet, gasoline-like odour (Windholz, 1983). The odour threshold concentration in air is about 2 mg/m3 and in water about 0.1 mg/litre (temperature not stated) (Anon, 1987; DEC, 1992). Ethylbenzene floats on water and, because of its significant vapour pressure and low water solubility, it will disperse in the atmosphere (ECETOC, 1986). Table 1. Some physical and chemical properties of ethylbenzenea Physical state (20°C; 101.3 kPa) liquid Colour colourless Boiling point (°C) (101.3 kPa) 136.2 Melting point (°C) -94.95 Density (25°C; g/cm3) 0.866 Vapour pressure (kPa at 20°C) 1.24 Flash point (°C) 12.8 15 23 Refractive index (15°C, D line) 1.49857 Saturation % in air (20°C; 101.3 kPa) 1.2 Explosion limits (20°C; 101.3 kPa) 1-7.8 Log octanol/water partition coefficient (Log Kow) 3.13 Henry's Law Constant (Pa m3/mol) 887 Log Sorption Partition Coefficient (Log Koc) 1.98-3.04 Water Solubility (20°C; 101.3 kPa; mg/L) 152 a From: Heilbron et al. (1946); Sax (1979); Verschueren (1983); Ullman (1983); Anon (1987); Weast (1988); ATSDR (1990); Cavender (1993); DEC (1992); Mackay et al. (1992) 2.3 Conversion factors 1 ppm = 4.3 mg/m3 at 20°C and 101.3 kPa 1 mg/m3 = 0.23 ppm at 20°C and 101.3 kPa 2.4 Analytical methods 2.4.1 Ethylbenzene in air Ethylbenzene in air can be analysed according to NIOSH (1984). The air is sampled on a solid sorbent (coconut shell charcoal) and desorbed with carbon disulfide. Aliquots are analysed by gas chromatography (GC) with flame ionization detection (FID). With a desorption volume of 0.5 ml, 2.17-8.62 mg can be measured. The detection limit is about 0.1 mg/m3 for a 10-litre sample. Other volatile organic solvents are possible interferences (NIOSH, 1984). To avoid the use of carbon disulfide, sampling on montmorillonite clays (minerals consisting of a three-layer aluminosilicate lattice) and thermal desorption have been used (Harper & Purnell, 1990). This method has not, however, yet been fully evaluated under actual sampling conditions in the field. A method using photoionization detection (PID) for GC, instead of FID, has been described. PID is one to two orders of magnitude more sensitive to most aromatics than is FID (Hester & Meyer, 1979). In an evaluation of sampling and analytical methods for monitoring several volatile organic compounds in air, sampling in a stainless steel canister was shown to be the best. Using cryogenic pre-concentration followed by gas-liquid chromatography (GLC) equipped with a selective detector, ethylbenzene could be analysed at the ppb level (Jayanty, 1989). The sensitivity of the GC/FID method for analysing ethylbenzene and other volatile organic compounds can be improved by using wide bore capillary columns (0.4-0.75 mm internal diameter). By this means, ethylbenzene can be separated from the C8 isomers even in complex mixtures (Frank et al., 1990). Several kinds of Bentones with structures similar to that of Bentone 34 have been tested and compared for the purpose of improving the resolution of ethylbenzene and xylene isomers by GC. Bentone SD-3 was found to have higher selectivity toward these close-boiling compounds than the well-known stationary phase Bentone 34 (Zlatkis & Jiao, 1991). Ultraviolet-spectrometry has also been used for analysis (Yamamoto & Cook, 1968). Commercial detection tubes are available with a detection range of 132.3-1764.0 mg/m3 (DEC, 1992) and of 4.41-220 µg (Gentry & Walsh, 1987). 2.4.2 Ethylbenzene in water Determination of ethylbenzene in water has been performed by using the "head-space" technique coupled to GLC, in combination with mass spectrometry (MS) or infrared detection (Rosen et al., 1963; Burnham et al., 1972; Kleopfer & Fairless, 1972; Grob, 1973). A purge-and-trap method has been developed for determination of four pollutants, including ethylbenzene, in aqueous samples. Water samples are purged at 50°C with helium and the analytes are trapped on Tenax GC. The trap is thermally desorbed directly into a gas chromatograph equipped with FID. The method is laboratory validated for the range of 20-500 ppb using a 5 g aqueous sample (Warner & Beasley, 1984). Zhang & Pawliszyn (1993) developed a headspace solid phase microextraction technique to determine ethylbenzene and other volatile organic compounds (VOC) in water. The detection limit was found to be at the ng/litre level. 2.4.3 Ethylbenzene in biological material The head-space technique can also be used for measurements of ethylbenzene in blood. The detection limit has been reported to be 0.01 mg/litre (Radzikowska-Kintzi & Jakubowski, 1981). The head-space methodology must, however, be optimized specifically for blood rather than using parameters derived from head-space experiments with aqueous media (Dills et al., 1991). An analytical method has been developed that enables the determination of ethylbenzene and other volatile organic compounds in 10 ml of blood samples at the ng/litre level. The method depends on purge-and-trap GC/MS and shows excellent reproducibility and recovery even at ultra-trace levels (Ashley et al., 1992). A method for analysing ethylbenzene in subcutaneous fat was described by Wolff et al. (1977). Fat biopsies are obtained by using a 30 cm3 silanized glass syringe and a size 16 G needle. The fat globules are washed from the syringe and needle by saline. The fat- saline suspension is frozen and thawed to 0°C prior to analysis. Fat globules are weighed and aliquots of CS2 are added. The solution is analysed by GC with dual flame ionization detectors. A method for the determination of ethylbenzene and other alkylbenzenes in plant foliage was developed by Keymeulen et al. (1991). Using a gas chromatograph-quadrupole mass spectrometer in the selected-ion monitoring mode, calibration graphs and detection limits for these hydrocarbons were determined. Extraction was performed with dichloromethane and the optimum extraction time was found to be 6 h. Murray & Lockhart (1981) prepared fish muscle for analysis by extraction with dichloromethane and clean up on a florisil column. Samples were analysed using GC with a FID. A detection limit of 5 µg/g was achieved with 98-102% recovery. A procedure to identify and quantify ethylbenzene in fish samples by GC/MS using a fused-silica capillary column (FSCC) and vacuum extraction has been developed (Hiatt 1981, 1983; Dreisch & Munson 1983). Improved resolution and detection limits at the ng/g level have been achieved with this technique. 2.4.4 Metabolites of ethylbenzene in urine One of the biomarkers of human exposure to ethylbenzene is the urinary concentration of mandelic acid. Mandelic acid is also a metabolite of styrene. Methods to monitor mandelic acid in urine were initially developed in order to evaluate exposure to styrene. In the GC method, mandelic acid is determined after extraction from urine by diethyl ether (Engström & Rantanen, 1974; Gromiec & Piotrowski, 1984). The detection limit for mandelic acid by this method was 1.0 mg/litre. Gas chromato-graphic methods require derivatization of the acid with diazomethane or silyl reagent before analysis. This is not necessary for the HPLC or the ITP methods (Sollenberg, 1991). Urinary samples extracted by diethyl ether can also be determined by isotachophoresis (ITP) with a detection limit of 0.04 mmol/litre (Sollenberg, 1991). This method is comparable to a high-performance liquid chromatographic (HPLC) method first described in 1977, with a detection limit of 0.01 mmol/litre (Ogata et al., 1977; Sollenberg, 1991). Determination of another major metabolite of ethylbenzene, phenylglyoxylic acid, in the urine of occupationally exposed people has been carried out by HPLC methods. The limit of determination is 0.1 mg/litre (Inoue et al., 1995). HPLC and ITP techniques can also be used for the simultaneous determination of mandelic and phenylglyoxylic acids in the urine of rats (Sollenberg et al., 1985). GC methods have been developed for analysis of other metabolic products of ethylbenzene. Simultaneous determination of several minor metabolites in urine from man and rats (e.g., acetophenone, 1-phenylethanol, omega-hydroxyacetophenone, 4-ethylphenol, 2,4-dimethylphenol and 3-methylbenzylalcohol) can be achieved with one method (Engström, 1984a). 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Natural occurrence Ethylbenzene is present in crude oil (Wiesenburg et al., 1981). 3.2 Anthropogenic sources Ethylbenzene is present in refined products (Korte & Boedefeld, 1978). It is produced by incomplete combustion of natural materials, making it a component of forest fires and cigarette smoke. 3.2.1 Production processes About 90% of all ethylbenzene used in the chemical industry is produced via the classic Friedel-Crafts alkylation of benzene with ethylene using soluble aluminium chloride catalyst. These liquid-phase processes generally involve ethyl chloride or occasionally hydrogen chloride as a catalyst promoter. In a variation on this method, dry benzene plus ethylene, catalyst and promoter are fed continuously to the alkylation reactor (Lewis et al., 1983; Fishbein, 1985). Other procedures which have been employed to a much lesser extent for the preparation of ethylbenzene include fractionation of petroleum and ultra-fractionation from a mixed xylene stream (Seader, 1982; Fishbein, 1985). It is not, however, economical to isolate ethylbenzene from the catalytic raffinate (Fishbein, 1985; ECETOC, 1986). An interesting approach for the preparation of ethylbenzene has been developed by Levesque & Dao (1989). In this method the alkylation of benzene to produce ethylbenzene was performed successfully using an aqueous solution of ethanol of concentration similar to a fermentation broth. 3.2.2 Production levels In the USA, the production of ethylbenzene in 1982 and 1983 was 3.0 and 3.6 million tonnes, respectively (Webber, 1984). According to Fishbein (1985), the annual capacity for the production of ethylbenzene was estimated to be about 4.6 million tonnes in the USA in 1983. In 1986, production in the USA was reported to be approximately 4.1 million tonnes (US ITC, 1987). The estimated annual production for ethylbenzene was 5.3 and 5.1 million tonnes for 1993 and 1992, respectively, in the USA. Ethylbenzene was the 19th in 1993 and the 18th in 1992 chemical out of the top 50 chemicals in the USA (US Chemical Industry, 1994). In 1983 the production of ethylbenzene in western Europe was around 3 million tonnes (ECETOC, 1986). 3.2.3 Uses About 95% of ethylbenzene produced is employed for the production of styrene. Ethylbenzene is a constituent (15-20%) of commercial xylene ("mixed xylenes"), and hence used as a component of solvents, as a diluent in paints and lacquers, and as a solvent in the rubber and chemical manufacturing industries. Ethylbenzene ("mixed xylenes") can also be added to motor fuels. A typical ethylbenzene content of a reformate is about 4% (by volume) (Fishbein, 1985). 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1 Transport and distribution between media The majority of ethylbenzene released into the environment passes directly into the atmosphere or into surface water. 4.1.1 Air It can be predicted from physico-chemical properties that, when ethylbenzene is released into air, the major part remains in the atmosphere and only small amounts are found in water, soil and sediment. If it is assumed that all ethylbenzene is continuously released to the atmosphere, the Level III generic fugacity model consisting of homogeneous compartments of air, water, soil and sediment predicts that over 99% of ethylbenzene would be distributed in the atmosphere at steady state. Ethylbenzene discharged to the atmosphere has very little potential for entering other media. Precipitation from the atmosphere can occur. The key processes determining overall fate are reaction in the air and advection (Mackay et al., 1992). Ethylbenzene has a low water solubility (152 mg/litre at 20°C) and a relatively high vapour pressure (1.24 kPa at 20°C). This means that only a very small proportion of ethylbenzene in the atmosphere is likely to be removed by precipitation. This is shown by the fact that it has been detected only at low levels in rain water samples (see section 5, Table 3). Ethylbenzene may adsorb to atmospheric particulates and be removed along with the particles by precipitation or dry deposition. 4.1.2 Water Transport and distribution of a substance in the aquatic environment are dependent on its solubility, movement of the water, exchanges at the air-water interfaces, adsorption to sediment and particulate matter, and bioconcentration in aquatic organisms. The residence time in water is also dependent upon the type of environmental conditions encountered, such as temperature, wind speed, currents, ice cover, etc. For ethylbenzene, the half-life at 20°C in a river 1 m deep, flowing at 1 m/sec and with a wind velocity of 3 m/sec, calculated according to the method described by Thomas (1982) for high volatility compounds, is 3.1 h. The half-lives in a marine mesocosm were 20 days at 8-16°C in the spring, 2.1 days at 20-22°C in the summer and 13 days at 3-7°C in the winter (Wakeham et al., 1983). Volatilization was a dominant factor. The increased turnover time during summer was also probably due to biodegradation. The seasonal variations between winter and spring may have largely been due to changes in hydrodynamic conditions as a result of changes in wind-driven turbulence. If it is assumed that ethylbenzene is continuously released only into the water compartment, the Level III generic fugacity model predicts that approximately 93% of ethylbenzene would be distributed into the water at steady state, 4.5% into the atmosphere, 2.5% into the sediment and 1% into the soil. The key processes determining overall fate are reaction in water and evaporation (Mackay et al., 1992). It has been estimated (Callahan, 1979) from a computed Henry's Law constant of 6.44 × 10-3 atmos.m3.mol-1 that the volatility of ethylbenzene from water will be very similar to that of toluene (Henry's Law constant = 6.68 × 10-3 atmos.m3.mol-1). Thus, ethylbenzene can be expected to have a half-life for volatilization from still water at a depth of 1 m of about 5 to 6 h (Mackay & Leinonen, 1975). A measured value of the Henry's Law constant of 8.43 × 10-3 atmos.m3.mol-1 (Mackay et al., 1979) supports this estimate. 4.1.3 Soil If it is assumed that ethylbenzene is only released to the soil compartment, the Level III generic fugacity model indicates that approximately 1% of ethylbenzene should be distributed into water, 4.9% into the atmosphere, 94.7% into the soil and >1% into the sediment. The soil acts only as a reservoir. The soil concentration is controlled almost entirely by the rate at which it can evaporate (Mackay et al., 1992). In a study by Jaynes & Boyd (1991), the sorption isotherms of ethylbenzene and some other volatile organic compounds on organo-clays indicated that sorption occurred by partition interactions with the hexadecyltrimethylammonium (HDTMA)-derived organic phase. Mineral-charge effects on sorption of ethylbenzene were evident. Greater sorption of ethylbenzene and other alkylbenzenes by high- charge HDTMA clays was attributed to the ability of the large basal spacings to accommodate larger solute molecules (Jaynes & Boyd, 1991). Several studies of soil-water partitioning for ethylbenzene have been reported. In one study a value of 1.01 (log value) was found for the soil-water partition coefficient (Kp) for a soil of 4.02 (± 0.06)% organic carbon content (Vowles & Mantoura, 1987). Pussemier et al. (1990) reported a soil organic carbon-water partition coefficient (Koc) of 2.41 (log value). Roy & Griffin (1985) estimated log Koc values of 2.60 and 2.87 derived from equations using solubility and Kow data, respectively. The soil organic matter-water partition coefficient (Kom) was measured as 1.98 (log value) for a soil containing 1.9% organic matter (Chiou et al., 1983). Lee et al. (1989) reported log Kom values ranging from 1.73 to 1.97 for untreated soil and from 2.37 to 3.23 for soil treated with organic cations. It is likely that ethylbenzene will be adsorbed to soil to some extent. Roy & Griffin (1985) predicted that ethylbenzene would have low mobility in water-saturated soil, based on the predicted Koc values. However, Howard (1989) stated that the range of soil-water partition coefficients suggests that ethylbenzene is adsorbed moderately by soil and will probably leach through soil. The presence of ethylbenzene in bank infiltrate water suggests that there is a high probability of it leaching through soil. Other factors influencing the movement of ethylbenzene through soil to groundwater include soil type, soil porosity, amount of rainfall, depth of groundwater and extent of degradation. The competitive adsorption of ethylbenzene and water on bentonite was studied by Rhue et al. (1989) using a technique that allowed the amount of adsorbed water and the alkylbenzene to be measured independently. Results indicated that ethylbenzene adsorption on the clay was not affected by water at relative humidities near 0.23 but was reduced significantly at values near 0.5. Laboratory studies indicate that volatilization of ethylbenzene occurs rapidly from sludge-treated soil (100% removal of an initial concentration of 50 mg/kg occurred within 6 days) (Water Pollution Control, 1989). It has been reported that sorption isotherms of ethylbenzene and some other nonionic organic compounds by maize (Zea mays) residues and soil are linear. Sorption coefficients of the corn residues were from 35 to 60 times greater than for surface soil (1.9% organic matter), demonstrating the high sorptive capability of these residues (Boyd et al., 1990). Annable et al. (1993) studied the reduction of gasoline component (including ethylbenzene) leaching potential by soil venting. Results from columns vented for different periods of time showed vented soil to be effective at reducing constituent concentrations in leachate ultimately to about 1 µg/litre. Clapp et al. (1994) compared the performance of activated sludge (AS) and fixed-film processes with biological aerated filter (BAF) fermenters for removal of priority pollutants, including ethylbenzene. They found that the AS and BAF fermenters achieved comparable VOC removal, and stripping rates were slightly higher for the AS fermenters; degradation rates were slightly higher for the BAF fermenters. 4.1.4 Sediment The physical-chemical properties of ethylbenzene indicate that only small amounts should be found in sediment. 4.2 Transformation 4.2.1 Biodegradation 184.108.40.206 Aerobic degradation Ethylbenzene has been shown to be biodegradable in aquatic systems. In simulations of spring and summer conditions in a coastal bay, half-lives of 20 days and 2.1 days, respectively, were obtained for ethylbenzene. Both volatilization and biodegradation were responsible for removal (Wakeham et al., 1983). The reduction in half-life in the summer was thought to represent an increase in microbial degradation. An adaptation period was found to be important for microbial degradation to take place. It was concluded that microbial degradation becomes important under warm conditions, with high biological activity, for the removal of ethylbenzene from the aquatic environment. Howard (1991) report a half-life for aqueous biodegradation, in an unacclimated system, of 3 to 10 days. In an inherent biodegradability test (OECD 302 C), ethylbenzene was degraded by 81 to 126% biological oxygen demand (BOD) in 2 weeks (CITI, 1992). In another biodegradability test, ECETOC (1986) reported that the BOD of ethylbenzene was determined after 6, 9 and 20 days and that biodegradation corresponding to 32, 36 and 45% of the theoretical oxygen demand (TOD) was found. Pitter & Chudoba (1990) reported a BOD5/TOD ratio of 0.29 for ethylbenzene. Ethylbenzene, as part of the water-soluble fraction of gas oil, has been shown to be degraded to 1-phenylethanol by the autochthonous microflora of clean groundwater. After an initial lag phase of 3 to 4 days, complete disappearance of ethylbenzene (from an initial concentration of 45 µg/litre) occurred within 12 days at 10°C (Kappeler & Wuhrmann, 1978a,b). Ethylbenzene was shown to be removed in core samples from an area that had been previously contaminated with unleaded gasoline. Complete degradation occurred within three weeks on incubation of ethylbenzene in core samples that had previously had hydrogen peroxide added, whereas a small amount of ethylbenzene remained after three weeks in the previously gasoline-contaminated and uncontaminated core samples (Thomas et al., 1990). In static experiments, where ethylbenzene was incubated in the dark for 7 days with settled domestic wastewater as microbial inoculum, followed by 3 weekly subcultures from the medium, ethylbenzene was shown to be 100% degraded within 7 days in the initial inoculum and the three subsequent subcultures when the initial ethylbenzene concentration was 5 mg/litre. At an initial ethylbenzene concentration of 10 mg/litre, 69% degradation of ethylbenzene occurred within 7 days in the initial culture, rising to 100% degradation within 7 days in the third subculture, indicating that gradual adaptation was needed for degradation of the higher concentration (Tabak et al., 1981). Soil bacteria have been shown to be capable of using ethylbenzene as a sole carbon source. Microbial oxidative degradation has been shown to proceed via hydroxylation of the aromatic ring to give 2,3-dihydroxy-1-ethylbenzene (Gibson et al., 1973). A similar intermediate has been postulated in the degradation of ethylbenzene by Pseudomonas sp. NCIB 10643 cultures. The 2,3-dihydroxy intermediate was suggested to undergo further degradation by meta cleavage of the aromatic ring (Smith & Ratledge, 1989). Nocardia tartaricans has been shown to be capable of converting ethylbenzene to 1-phenylethanol and acetophenone in a shake flask culture using hexadecane as the source of carbon and energy (Cox & Goldsmith, 1979). Bestetti & Galli (1984) showed that Pseudomonas fluorescens can utilize ethylbenzene as sole carbon source. Degradation appeared to occur by meta cleavage of the ring, with formation of the semi- aldehyde. Utkin et al. (1991) have also recently shown that a species of Pseudomonas is capable of growing on ethylbenzene as the sole source of carbon. Products observed included 1-phenylethanol, 2-phenylethanol, phenylacetate, salicylate, 2-hydroxyphenylacetate and mandelate. 220.127.116.11 Anaerobic degradation In a study to simulate the anaerobic degradation of landfill leachate on aquifer material that was known to support methanogenesis, no significant degradation of ethylbenzene was observed over the first 20 weeks of the experiment. However after 40 weeks the concentration of ethylbenzene was found to be 26% of the original value, and after 120 weeks the concentration was < 1% of the original value (Wilson et al., 1986). Ethylbenzene, at a concentration of 500 mg/litre, was not found to be metabolized by or toxic to enriched methane-producing cultures (Chou et al., 1978). Ethylbenzene has been shown to undergo anaerobic degradation by aquifer microorganisms under denitrifying conditions in the presence of nitrate. A lag period of around 30 days was observed before biodegradation of ethylbenzene occurred, but total removal of ethylbenzene occurred within the 56-day test period. Using aquifer material that had been previously contaminated with jet fuel, little degradation of ethylbenzene occurred over the 180-day test period, but this was enhanced by addition of nitrate (Hutchins et al., 1991a,b). Kuhn et al. (1988) also studied the degradation of ethylbenzene under denitrifying conditions using nitrate as the sole electron acceptor. In their experiment an aquifer column was used which was capable of degrading m-xylene. The concentration of ethylbenzene was only slightly reduced during passage through the column, and the authors concluded that microbial mineralization of ethylbenzene was unlikely under denitrifying conditions. However, they did point out that the experiment was only carried out for 6 days. A longer experimental period might have allowed another microbial population to grow within the column that could have been capable of degrading ethylbenzene. Ethylbenzene, as a component of crude oil contamination of anoxic groundwater, has been found to be degraded in the anoxic region, but the rate of disappearance was found to increase significantly in the more oxygenated parts of the aquifer (Cozzarelli et al., 1990). 4.2.2 Abiotic degradation 18.104.22.168 Photolysis Ethylbenzene does not absorb UV-visible radiation appreciably at wavelengths longer than 290 nm. This means that it is unlikely to be directly photolysed in the troposphere or in solution, as the earth's ozone layer absorbs radiation at wavelengths less than 290 nm (Crookes & Howe, 1992). Mabey et al. (1982) stated that direct photolysis of ethylbenzene is not environmentally significant. 22.214.171.124 Photo-oxidation Atmospheric oxidation of ethylbenzene is rapid and proceeds via free-radical chain processes. The most important oxidant is the hydroxyl radical, but ethylbenzene is also reactive with other species found in the atmosphere, such as alkoxy radicals, peroxy radicals, ozone and nitrogen oxides. Estimates for the half-life of ethylbenzene in the atmosphere have been made from smog chamber experiments and from knowledge of the reaction rate constant for reaction with hydroxyl radicals. Atkinson (1985) reviewed the available hydroxyl radical reaction rate constant data and recommended a kOH value of 7.5 × 10-12 molecule-1.cm3.sec-1 at 25°C for reaction with ethylbenzene. A study by Callahan (1979) produced an atmospheric half-life of around 15 h for ethylbenzene. Another report gave a figure of 51% loss of ethylbenzene due to reaction with hydroxyl radicals in one day (12 sunlight hours) (Singh et al., 1981, 1983). An atmospheric lifetime of 14 sunlight hours has been quoted based on a value of kOH (Singh et al., 1986). An important point when considering these data is that the half-life calculated depends on several factors, including temperature and also the actual concentration of hydroxyl radicals in the atmosphere. It is known that the concentration of hydroxyl radicals depends greatly on the amount of sunlight available; thus a typical figure is around 2 × 106 molecules/cm3 in summer months, falling by a factor of approximately 2 in winter months (Singh et al., 1986). At night the concentration of hydroxyl radicals is negligible. Even so, it can be seen that ethylbenzene is removed from the atmosphere quite readily by reaction with hydroxyl radicals. It is also possible that ethylbenzene will be removed from aquatic systems by similar types of reactions, as hydroxyl radicals are known to exist in aquatic systems. 126.96.36.199 Hydrolysis It is considered unlikely that ethylbenzene will hydrolyse under typical conditions found in the environment. 4.2.3 Bioaccumulation Ethylbenzene has an octanol-water partition coefficient of 3.13 (log value), which indicates that bioaccumulation of ethylbenzene could take place. Using this partition coefficient, an estimated bioconcentration factor (BCF) of 2.16 (log value) can be calculated (Bysshe, 1982). In goldfish, a measured BCF of 1.19 (log value) has been reported (Ogata et al., 1984). No details of exposure concentrations or length of exposure were given. When the manila clam (Tapes semidecussata) was exposed to ethylbenzene at a concentration of 0.08 mg/litre in water containing other petroleum hydrocarbons, the concentration found in the tissue was 0.37 mg/kg after 8 days. Depuration occurred rapidly after exposure ceased, tissue concentrations being below the limit of detection (< 0.13 mg/kg) after 15 days (Nunes & Benville, 1979). The low measured BCF values indicate that biomagnification of ethylbenzene through the aquatic food chain is unlikely. No aquatic food chain magnification was predicted from the model calculations and empirical observations by Thomann (1989). 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels 5.1.1 Air Measured levels of ethylbenzene in air are presented in Table 2. Mean levels of ethylbenzene ranging from 0.74 to 100 µg/m3 have been measured at urban sites. Industrial releases and vehicle emissions are the principal sources of ethylbenzene. Levels found at rural sites are generally < 2 µg/m3. Ethylbenzene levels for indoor air are included in section 5.2.1. 5.1.2 Surface water and sediment The levels of ethylbenzene found in surface water are shown in Table 3. These are generally less than 0.1 µg/litre in non-industrial areas. In industrial and urban areas ethylbenzene concentrations of up to 15 µg/litre have been reported. In 1985, 21 water samples and 21 bottom sediment samples were collected at 7 sites in Japan and were analysed for the presence of ethylbenzene. None of the water samples contained ethylbenzene; 3 of the sediment samples from one site contained ethylbenzene concentrations of 0.9 to 2.7 µg/kg dry weight. The detection limit was 0.02 µg/litre for water and 0.8 µg/kg dry weight for bottom sediment. In 1986, ethylbenzene was detected in 7 out of 133 samples of surface water at 5 out of 46 sites (0.03-1.1 µg/litre) and in 28 out of 120 samples of bottom sediment at 15 out of 40 sites (0.5-28 µg/kg dry weight). The detection limit was 0.03 µg/litre for water and 0.5 µg/kg dry weight for sediment (EAJ, 1989). Staples et al. (1985) reviewed the US EPA's STORET water quality database and reported that median levels of ethylbenzene in ambient surface water were less than 5.0 µg/litre between 1980 and 1982. Ethylbenzene was detected in 10% of the 1101 samples collected during this period. The median ethylbenzene concentration in sediment was 5.0 µg/kg dry weight, the compound being detected in 11% of the 350 samples. In a study of the Tees Estuary, United Kingdom, levels of ethylbenzene between 1 and 5 µg/kg were found in river sediment from a heavily industrialized area (Whitby et al., 1982). Table 2. Concentrations of ethylbenzene in air Sampling source Concentration (µg/m3) References Rural 0.23-1.6 (range of means) Petersson (1982), Clark et al. (1984b), Jüttner (1988), Lanzerstorfer & Puxbaum (1990), Kawata & Fujeda (1993) Urban 0.74-100 (range of means) Grob & Grob (1971), Bos et al. (1977), Louw et al. (1977), Singh et (maximum value, 360) al. (1981; 1982; 1986), Nelson & Quigley (1982), Harkov et al. (1983), De Bortoli et al. (1984), Clark et al. (1984a), Guicherit & Schulting (1985), Jonsson et al. (1985), Hunt et al. (1986), Bruckmann et al. (1988), Lanzerstorfer & Puxbaum (1990), Chan et al. (1991a), Derwent (personal communication to the IPCS, 1991), Industrial/residential site 22.0 (annual mean) Bruckmann et al. (1988) near a rubber factory Industrial site near 10.8 (annual mean) Bruckmann et al. (1988) refineries producing lubricating oil Industrial site 94 (mean) Kroneld (1989) near automotive 52 (< 1.6 km away) Sexton & Westberg (1980) painting plant 11.5 (6.4 km away) 5 (17.6 km away) Near to car plant 86 Petersson (1982) 27.8 (1 km away) Road tunnels 2.1-48.2 Bos et al. (1977), Hampton et al. (1983), Dannecker et al. (1990) Motorway 147 (mean) Thorburn & Colenutt (1979) Table 3. Concentrations of ethylbenzene in water Sampling source Concentration Reference (µg/litre)a Surface waters Non-industrial river sites < 0.1 Waggott (1981), McFall et al. (1985), SAC (1989) Industrial/urban river sites 1.9-15 Gomez-Belinchon et al. (1991) (range of means) Estuary (industrial area) ND-1.8 Whitby et al. (1982) Seawater 0.0018-0.026 Gschwend et al. (1982), Gomez-Belinchon (range of means) et al. (1991) Sea near offshore oil 0.07 Sauer (1981) platform Rainwater 0.0006-0.009 Kawamura & Kaplan (1983), Pankow et al. (1984) Groundwater Uncontaminated NDb-0.07 Kenrick et al. (1985) Contaminated 30-2000 Tester & Harker (1981), Van Duijvenbooden & Kooper (1981), Stuermer et al. (1982), Rao et al. (1985) Water-table at a solvent up to 28 000 Cline & Viste (1985) recovery facility Table 3. (Cont'd) Sampling source Concentration Reference (µg/litre)a Effluent Effluent from wastewater/ NDc-14 Kennicutt et al. (1984); Namkung & Rittmann sewage treatment works (1987); Feiler et al. (1979); Michael et al. (1991); Gossett et al. (1983) Landfill leachate 1.7-2310 Först et al. (1984); Reinhard et al. (1984); Van Duijvenbooden & Kooper (1981); Cline & Viste (1985) a ND = not detected b detection limit = 0.01 µg/litre c detection limit not stated A sludge characterization study for a slip containing wastewater sludge situated in Baltimore Harbour, USA, was performed. The slip contained an estimated 14 100 m3 of sludge, which averaged 20% solids (by weight). Organic compounds were found to be the primary constituents in the sludge, the highest concentrations being represented by benzene, ethylbenzene, toluene and xylenes (Mott & Romanow, 1991/1992). 5.1.3 Groundwater The levels of ethylbenzene in groundwater are summarized in Table 3. Ethylbenzene levels in uncontaminated groundwater are generally < 0.1 µg/litre. However, much higher levels have been reported for groundwater contaminated via waste disposal, fuel spillage and industrial facilities. At a solvent recovery facility, ethylbenzene concentrations of up to 28 000 µg/litre were measured. Lesage et al. (1990) detected ethylbenzene in 3% of anoxic groundwater samples at a concentration of 2 µg/litre. Goodenkauf & Atkinson (1986) analysed 63 wells and detected ethylbenzene in only one at a concentration of 0.99 µg/litre; the detection limit was 0.5 µg/litre. Ethylbenzene was found in 3 out of 466 groundwater samples collected in the USA in 1982. The maximum concentration was 1.1 µg/litre and the detection limit 0.5 µg/litre (Cotruvo, 1985). 5.1.4 Urban run-off, effluent and landfill leachate The levels of ethylbenzene in effluent from wastewater/sewage treatment plants and landfill leachate are summarized in Table 3. When Perry et al. (1979) analysed a range of industrial effluent samples, 19 contained < 10 µg/litre, 4 contained 10-100 µg/litre and 2 contained > 100 µg/litre. Staples et al. (1985) reported that ethylbenzene was detected in 7.4% of 1368 industrial effluent samples collected between 1980 and 1983, the median concentration being less than 3.0 µg/litre. Cole et al. (1984) detected ethylbenzene in 4% of urban run-off samples. Concentrations ranged from 1-2 µg/litre; however, no detection limits were stated. 5.1.5 Soil ATSDR (1990) reported that ethylbenzene was detected in 9.22% soil samples from 1177 sites. The geometric mean of these samples was 697 µg/kg. 5.1.6 Biota Several species of aquatic organisms have been analysed for ethylbenzene (Table 4). Table 4. Levels of ethylbenzene in aquatic species (Gossett et al., 1983) Species Ethylbenzene level µg/kg wet weight Pacific sanddab (Citharichthys xanthostigma) (liver) <0.3 scorpion fish (Scorpaena guttata) (liver) <0.3 Dover sole (Microstomus pacificus) (liver) 0.3 white croaker (Genyonemus lineatus) (liver) 4 shrimp (muscle) <0.3 invertebrate (whole body) <0.3 NOTE: No detection limits were stated; organisms were collected from an area near to the discharge zone of a waste treatment plant; ethylbenzene levels of 14 µg/litre in effluent and 0.5 µg/kg (dryweight) in sediment were measured in the area at the time of sampling. In 1986, ethylbenzene was detected in 43 out of 138 fish samples at 16 out of 42 sites in Japan, the concentrations ranging from 1.0 to 9.8 µg/kg wet weight. The detection limit was 1 µg/kg wet weight (EAJ, 1989). Staples et al. (1985) reviewed the US EPA's STORET water quality database and reported that ethylbenzene was not detected in 97 biota samples (detection limit, 0.025 mg/kg wet weight). Lockhart et al. (1992) reported data on ethylbenzene levels in freshwater fish sampled in the Canadian Arctic in 1985 and 1986. Mean ethylbenzene concentrations ranged from 2.45 to 49.6 µg/kg in muscle tissue and from 1.81 to 46.3 µg/kg in liver tissue for burbot. In whitefish muscle tissue samples, mean ethylbenzene concentrations ranged from 7.46 to 104 µg/kg. 5.2 General population exposure 5.2.1 Environmental sources The magnitude of natural releases into the environment has not been established. Although ethylbenzene is ubiquitous in rural and urban atmospheres, levels in urban areas are elevated due to vehicular and industrial emissions. Ethylbenzene was not detectable in some rural samples, while those taken on busy urban streets contained levels up to 99 µg/m3 (23.1 ppb) (ATSDR, 1990). The Environmental Protection Agency (USA) conducted a study of ethylbenzene levels in public access buildings and found that concentration, which was 387 µg/m3 (90 ppb) at the time construction was completed, declined to 39 µg/m3 (9 ppb) following several months of occupation of the building. This indicated that building materials and/or finishings, such as paints, carpets and adhesives, were likely sources of emissions (Pellizzari et al., 1984). Subsequent emission studies using inhalation chambers revealed that ethylbenzene was emitted from glued carpet at a mean level of 6.4 (± 3.2) µg/m3, corresponding to an emission rate of 77 (± 39) ng/min per m2 (Wallace et al., 1987c). Hodgson et al. (1991) studied the emissions of volatile organic compounds in a new office building over a period of 14 months. Ethylbenzene levels in the building ranged from 7.0 to 11.8 µg/m3, as compared to 1.8 µg/m3 in the outdoor air. The authors suggested that motor vehicles in the underground carpark of the building were one of the major sources of ethylbenzene, but this area was not specifically monitored. Wallace et al. (1987a,b) monitored ethylbenzene in breathing-zone air, exhaled air and ambient air samples taken from some of the home backyards of 400 residents of an industrial/chemical manufacturing area (the cities of Bayonne and Elizabeth, New Jersey, USA). Median levels of ethylbenzene ranged from 4.6 to 7.1 µg/m3 for breathing- zone air, 1.3 to 2.9 µg/m3 for exhaled air and 2.2 to 4.0 µg/m3 for backyard air. Personal air monitoring conducted at home yielded high ethylbenzene levels, believed to be due to the presence of the chemical in tobacco smoke. The maximum geometric mean ethylbenzene exposure of people living in homes with smokers (13 µg/m3) was approximately 1.5 times the geometric mean of people living in homes without smokers (8 µg/m3). Wallace et al. (1987a) found the geometric mean level of ethylbenzene in the expired air of smokers (n=200) to be 2 to 3 times higher than in that of non-smokers (n=322). Wallace et al. (1987a) estimated that the total amount of ethylbenzene in the mainstream smoke of a single cigarette, containing 16 mg of tar and nicotine, was 8 µg. In another study, the blood concentration of ethylbenzene was measured in 13 non-smokers and 14 cigarette smokers, all living in an urban area. The concentration of ethylbenzene in blood ranged from 175 to 2284 ng/litre and 378 to 2697 ng/litre, respectively (Hajimiragha et al., 1989). Fellin & Otson (1993) monitored indoor air for ethylbenzene in 754 randomly selected Canadian residences in 1986. Mean ethylbenzene concentrations were 6.46 µg/m3 in winter, 8.15 µg/m3 in spring, 4.35 µg/m3 in summer and 13.97 µg/m3 in autumn. Wallace et al. (1989) carried out a study on seven volunteers who performed 25 common activities thought to increase personal exposure to volatile organic compounds during a 3-month period. Monitoring personal, indoor and outdoor air levels, as well as exhaled breath, revealed that painting and using a carburettor cleaner resulted in an 80-fold increase in ethylbenzene exposure. Combustion sources (including cigarette smoke), gasoline vapours and consumer products containing ethylbenzene increased exposures by up to 6 times over the background level. Chan et al. (1991b) studied exposure of commuters in Boston, USA to ethylbenzene. These individuals spent 1.3 to 1.7 h per day (5% to 7% of the day) commuting and this contributed 10-20% of their total daily ethylbenzene exposure. The results showed that the highest exposures were associated with commuting by car (5.8 µg/m3) and that the use of car heaters resulted in even higher in-vehicle levels of ethylbenzene. Heater use resulted in a passenger compartment mean ethylbenzene level of 8 µg/m3, whereas non-use resulted in 3.7 µg/m3. The authors postulated that heaters can increase influx of both the vehicle's own exhaust and general roadway exhaust. Coal-fired power stations have been found to emit ethylbenzene along with other volatile organic compounds (Garcia, 1992). Bevan et al. (1991) monitored exposure to vehicle emissions while commuting by bicycle on urban roads in Southampton, United Kingdom and compared it with ethylbenzene exposure for a typical suburban area. Mean ethylbenzene levels on urban roads were 30.3 µg/m3 compared with 15.1 µg/m3 for suburban areas. The authors reported that 2 metres from the exhaust of a stationary idling vehicle the mean ethylbenzene level was 137 µg/m3. Ashley et al. (1994) analysed the blood ethylbenzene concentration of 631 non-occupationally exposed people in the USA. The mean and median levels were 0.11 and 0.06 µg/litre, respectively, and the detection limit was 0.02 µg/litre. Kawai et al. (1992) evaluated urinalysis and blood analysis as means of detecting human exposure to ethylbenzene and some other volatile organic compounds, using 143 exposed and 20 non-exposed workers. They found that both solvent concentration in blood and metabolite concentration in urine correlated significantly with the concentration of the solvent in air. Pellizzari et al. (1982) analysed volatile organic compounds in human milk samples taken from lactating women living in urban areas of the USA and found ethylbenzene in all eight samples. Ethylbenzene has also been detected in human axillary volatiles (Labows et al., 1979). However, both these studies were based solely on qualitative scans of the mass spectra peaks from GC/MS analysis; no detection limits were stated. 5.2.2 Food Ethylbenzene has been detected in several types of dried legumes. Levels of between 0 and 11 µg/kg (mean 5 µg/kg) in beans, 13 µg/kg in split peas and 5 µg/kg in lentils were measured (Lovegren et al., 1979). Although ethylbenzene has been detected in the skin of roasted guinea hens (at a level of 2 µg/kg) by Noleau & Toulemonde (1988), the authors did not state whether the source of the ethylbenzene was directly from the skin or the cooking process. 5.2.3 Drinking-water Otson et al. (1982) found that ethylbenzene levels in Canadian treated potable water ranged from <1 to 10 µg/litre. Westrick et al. (1984) reported that ethylbenzene was detected in 8 out of 945 samples of finished (undefined) water from groundwater supplies. The levels ranged from 0.74 to 12 µg/litre. Coleman et al. (1984) analysed drinking-water from Cincinnati, USA and found an ethylbenzene level of 0.036 µg/litre. Durst & Laperle (1990) studied the migration of ethylbenzene from polystyrene containers into stored deionized water. The water samples were stored for up to 90 days at temperatures ranging from 24 to 66°C. Migration of ethylbenzene increased with time and storage temperature. The levels in the water samples ranged from 16 µg/litre on day 1 to 41 µg/litre at 24°C, 48 µg/litre at 38°C and 107 µg/litre at 52°C. Ethylbenzene levels of up to 209 µg/litre were detected on day 8 at 66°C. 5.3 Occupational exposure during manufacture, formulation or use Occupational exposure to ethylbenzene alone is rare. Simultaneous exposure to other organic solvents usually occurs. The following ethylbenzene exposure levels have been reported from various occupational settings: exposure to gasoline, mean concentration of less than 0.08 mg/m3 (Rappaport et al., 1987); exposure to jet fuel, mean concentrations of 0.02 mg/m3 (4 h) and 0.07 mg/m3 (15 min) and maximum concentrations of 1.3 mg/m3 (4 h) and 8.0 mg/m3 (15 min) (Holm et al., 1987); exposure in petroleum and chemical factories, mean concentration of 7.7 mg/m3 (Inoue et al., 1995); exposure while varnishing vehicles, average concentration of 17 mg/m3 (Angerer & Wulf, 1985); exposure during paint-rolling and brushing, maximum concentration of 3.2 mg/m3 (Verhoeff et al., 1988); exposure in a petroleum company and a pharmaceutical factory, concentration range of 0.05-23 mg/m3 (Lu & Zhen, 1989). During painting operations, ethylbenzene and some other volatile organic compounds were detected in the working atmosphere at concentrations ranging from 0.1 to 69.1 ppm (Vincent et al., 1994). 5.3.1 Biological monitoring Determination of mandelic acid in urine has been recommended as a biomarker of exposure to ethylbenzene. In studies by Bardodej & Bardodejová (1970) and by Gromieck & Piotrowski (1984), exposure to ethylbenzene at 430 mg/m3 (100 ppm) for 8 h resulted in 13 mmol/litre and 7.8 mmol/litre, respectively, of mandelic acid in the end-of-exposure urine samples. A value of 1.5 g mandelic acid per g creatinine (about 10 mmol/litre) in the post-shift urine has been proposed as a Biological Exposure Index (ACGIH, 1985-1986). In specific analysis (e.g., by gas chromatography), the urinary level of mandelic acid is negligible (less than 0.2 mmol/litre) in the general population. However, certain drugs may be metabolized to mandelic acid (Aitio et al., 1994). Monitoring of personal exposure has shown that low ethylbenzene concentrations of approximately 8.6 mg/m3 (2 ppm) correlate significantly (correlation coefficients of 0.6-0.7) with urinary phenylglyoxylic acid concentration, suggesting that measurements of this acid in the urine could be used for biomonitoring (Inoue et al., 1995). 6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1 Absorption 6.1.1 Skin absorption One human subject was exposed for 2 h to ethylbenzene vapour at concentrations ranging from 650 to 1300 mg/m3 in an exposure chamber. The exposed skin accounted for 90-95% of the total skin area. Clean breathing air was provided by means of a gas-tight respirator. The mandelic acid concentration in urine, before, during and up to 6 h after exposure, was within physiological limits (approximately 2.7 mg/litre). The authors concluded that the skin is not a relevant route of entry into the body for ethylbenzene vapours (Gromiec & Piotrowski, 1984). The possible absorption of liquid ethylbenzene across human sin has also been studied (Dutkiewicz & Tyras, 1967). Ethylbenzene (0.2 ml=174 mg) was applied in a watch glass tightly fixed on the forearm. The exposed skin area was 17.3 cm2. After 10-15 min the contents of the watch glass space was extracted with ethanol and the recovered amount of ethylbenzene determined spectrophotometrically. On the basis of the quantity of ethylbenzene not recovered, the mean absorption rate for seven people was calculated to be 28 mg/cm2 per hour (range 22-33 mg cm2 per hour). The penetration rate of ethylbenzene through excised rat skin has been determined in a penetration chamber. One ml of ethylbenzene was applied to 2.55 cm2 skin. After a 6-h application period, the penetration rate was found to be about 0.99 nmoles/cm2 per min (6 µg/cm2 per hour (Tsuruta, 1982). Percutaneous absorption of ethylbenzene has been studied in hairless mice (11 animals) (Susten et al., 1990). 14C-ring-labelled ethylbenzene (in a volume of 5 µl) was injected into a chamber glued onto the back skin (0.8 cm2), and the animals were housed in metabolism cages for 4 h. During that period exhaled breath samples were collected. At the end of 4 h, the animals were killed and the absorbed dose was measured in the excreta and carcass. A total of 95.2 (± 1)% of the nominal dose was recovered. The absorption rate was calculated to be 0.037 (± 0.0315) mg/cm2 per min (2.2 ± 1.9 mg/cm2 per hour). Dermal absorption of volatile organic chemicals from aqueous solutions has been studied in male Fischer-344 rats. For 24 h the rats were exposed (3.1 cm2 dorsal shaved skin) to 2 ml (in a glass exposure cell) of one-third saturated, two-thirds saturated, or a fully saturated solution of ethylbenzene. Blood samples were obtained at 0, 0.5, 1, 2, 4, 8, 12 and 24 h. The peak blood level (exposure to neat ethylbenzene) was 5.6 mg/litre. The level reached a maximum within 4 h and then either remained at about the same level for the duration of the exposure or decreased. The blood levels were directly related to the exposure concentrations (Morgan et al., 1991). The data concerning skin permeability of ethylbenzene in humans (Dutkievicz and Tyras, 1967) is not consistent with the animal data. The reliability of the estimated fluxes of ethylbenzene through human skin must be questioned because they are many times higher than the measured fluxes through rat skin, whereas from studies of in vitro percutaneous absorption it is known that rat skin is more permeable than human skin (mean ratio about 3) for several chemicals (Barber et al., 1992). 6.1.2 Absorption via inhalation When volunteers (number not given) were exposed to 99, 185, 198 or 365 mg/m3 (23, 43, 46 or 85 ppm) ethylbenzene for 8 h, 64% of the inhaled ethylbenzene was taken up by the respiratory tract (Bardodej & Bardodejova, 1966). In another study, six volunteers were exposed under controlled conditions for 8 h to 18, 34, 80, 150 or 200 mg/m3. The retention of ethylbenzene in the lungs (difference in concentration between inhaled and exhaled air) was 49% (± 5%) independent of the exposure concentration (Gromiec & Piotrowski, 1984). When volunteers were exposed to 430 mg/m3 or 870 mg/m3 of "industrial xylene" (containing 40% ethylbenzene and 60% xylenes) for 2 h, about 60% was taken up, independent of concentration. If the workload increased during exposure, the retention dropped to 50% (Ĺstrand et al., 1978). In a study by Chin et al. (1980a), rats (male, Harlan-Wistar) were exposed to 14C-labelled ethylbenzene at a concentration of 1000 mg/m3 for 6 h. Assuming a ventilation rate of 100 ml/min, each rat had an estimated intake of 36 mg ethylbenzene, of which 44% was absorbed. 6.1.3 Absorption after oral intake Toxicity studies in various animal species show indirectly that ethylbenzene is absorbed after oral administration (Wolf et al., 1956, NTP, 1992). Moreover, in one study, ethylbenzene appeared to be rapidly and well absorbed from the gastro-intestinal tract since more than 80% of the administered radioactively labelled compound was recovered in urine within 48 h (Climie et al., 1983). 6.2 Distribution When volunteers (n=12) were exposed for 2 h to 100 or 200 ppm "industrial xylene", the amount of ethylbenzene taken up correlated with the amount of body fat ("industrial xylene" consisted of 40.4% ethylbenzene, 49.4% m-xylene, 8.8% o-xylene and 1.4% p-xylene). The concentration of ethylbenzene ranged from 4 to 8 mg/kg in subcutaneous adipose tissue 30 min after exposure. There was, however, a negative correlation between the concentration in the adipose tissue and the estimated relative amount of fat (Engström & Bjurström, 1978). The ethylbenzene concentration in the subcutaneous fat of workers in a styrene polymerization plant was less than 0.8 mg/kg. The level of exposure to ethylbenzene was reported to be below 17 mg/m3 (4 ppm). The 25 workers were exposed to a variety of other chemicals as well (Wolff et al., 1977). When rats were exposed to 1000 mg/m3 14C-ring-labelled ethylbenzene for 6 h, 0.2% of this radioactivity was found 42 h later in the tissues, mainly in the liver, gastrointestinal tract, fat and the carcass (Chin et al., 1980a). In a study by Engström et al., (1985), male Wistar rats (n = 20) were exposed to 215, 1290 or 2580 mg ethylbenzene/m3 (50, 300 or 600 ppm) for 6 h/day, and 5 days/week for up to 16 weeks. The concentration of ethylbenzene in perirenal fat was measured in weeks 2, 5 and 9. There were no consistent changes in ethylbenzene levels during the course of exposure. After 16 weeks the amount of ethylbenzene in perirenal fat was 8.5, 167.7 and 262.2 mg/kg fat at the three exposure levels, respectively. 6.3 Metabolic transformation Metabolic pathways of ethylbenzene based on urinary metabolites have been proposed for humans (Fig. 1) and for rats (Fig. 2). The main metabolic pathway is oxidation of the side chain, both in humans and in animals. However, it has been demonstrated that there are both qualitative and quantitative inter-species differences in the metabolites produced (Engström et al., 1984; Engström 1984b). In humans, the main metabolites of ethylbenzene are mandelic and phenylglyoxylic acids. In several animal species the metabolic transformation continues to benzoic acid, leading to excretion of hippuric acid after conjugation with glycine. This conjugate is generally one of the main urinary metabolites, together with mandelic acid, in rats and dogs (Chin et al., 1980b). Hydroxylation of the aromatic nucleus is a minor pathway. In the rabbit this phenolic pathway accounts for less than 2% of the ethylbenzene absorbed (Kiese & Lenk, 1974). Ethylbenzene is metabolized by the microsomal cytochrome P-450 enzyme system. Although specific isozymes have not been unequivocally identified, enzyme induction studies suggest that CYP2B1/2, CYP1A1/2 and CYP2E1 may be involved (see section 7.8). Four male volunteers were exposed to 655 mg/m3 (150 ppm) ethylbenzene for 4 h and urine was collected for 24 h. Mandelic acid (71.5%) and phenylglyoxylic acid (19.1%) were the main metabolites, but smaller amounts of 1-phenylethanol, p-hydroxyacetophenone, m-hydroxyacetophenone, 1-phenyl-1,2-ethandiol, 4-ethylphenol, omega-hydroxyacetophenone and acetophenone were also found. Ring oxidation accounted for 4.0%. Simultaneous exposure to 150 ppm m-xylene did not alter the urinary metabolite pattern, but it delayed excretion and decreased the amounts of metabolites excreted (Engström et al., 1984). Mandelic acid (64%) and phenylglyoxylic aid (25%) were found to be the main urinary excretion products in volunteers after an 8-h exposure to 99-365 mg/m3 (23-85 ppm) ethylbenzene (Bardodej & Bardodejová, 1970). When two volunteers were exposed by inhalation to 430 mg/m3 (100 ppm) ethylbenzene for 4 h, most of the mandelic acid was excreted as the R-enantiomer (Drummond et al., 1989). In a study by Korn et al. (1992), urinary samples from workers exposed to ethylbenzene, toluene and xylenes were analysed. The average urinary concentration of phenylglyoxylic acid was 50.1 mg/litre. The concentration of mandelic acids was 135.2 mg/litre, of which 127.8 mg/litre was R-mandelic acid and 7.3 mg/litre was S-mandelic acid. The R/S ratio was independent of the air concentration of ethylbenzene, which varied between 6.4 and 142 mg/m3 (1.5 and 33 ppm). Four female histology laboratory assistants were exposed to a mixture of xylenes (75%) and ethylbenzene (25%). The air concentration of the solvent was 160-179 mg/m3, and the concentration of ethylbenzene in blood collected at the end of the working day was reported to be 0.5 to 0.8 mg/litre. The 24-h excretion of 2-ethylphenol in urine varied between 4.4 and 6.0 mg corresponding to 1 to 1.5% of the retained ethylbenzene (Angerer & Lehnert, 1979). The findings by Angerer & Lehnert (1979) that ethylbenzene is metabolized to 2-ethylphenol could not be verified by Engström et al. (1984). Male Wistar rats (6 per group) were exposed for 6 h to ethylbenzene at 1290 or 2580 mg/m3 (300 or 600 ppm). The urine was collected for 48 h from the onset of exposure. Altogether, 14 different metabolites from ethylbenzene were identified. The main metabolites were 1-phenylethanol, mandelic acid and benzoic acid, each of which accounted for about 25%. Only 13% (low dose) and 6% (high dose) of the estimated absorbed doses were eliminated during the 6-h exposure. Over the 48-h period, the corresponding values were 83% and 59%, respectively. The metabolic pattern was similar, irrespective of the exposure level (Engström, 1984b). In another study, male Wistar rats (20 per group) were exposed to 215, 1290 or 2580 mg ethylbenzene/m3 (50, 300 or 600 ppm) for 6 h/day, 5 days/week, for up to 16 weeks. Urinary excretion of some of the metabolites was measured in weeks 2, 5 and 9. A significant dose-related percentage decrease of phenylglyoxylic acid and hippuric acid plus benzoic acid was found. A corresponding increase of 1-phenylethanol and omega-hydroxyacetophenone excretion was also noted. The total amount of metabolites in urine collected during the 24 h after onset of exposure remained, however, constant at each exposure level throughout the study (Engström et al., 1985). When a single oral dose of 318 mg ethylbenzene/kg body weight was administered to rabbits, the main urinary metabolites found were hippuric acid and methylphenylglucuronic acid, which together represented 60-70% of the dose, while mandelic acid and phenaceturic acid were minor metabolites (El Masry et al., 1956). It has been established in in vivo studies that experimental animals convert ethylbenzene mainly to the R-enantiomer of mandelic acid (Drummond et al., 1990). In an in vitro study it was found that ethylbenzene is hydroxylated by cytochrome P-450cam (from Escherichera coli) almost exclusively at the secondary ethyl carbon with about a 2:1 ratio of R:S products (Filipovic et al., 1992). The rates of metabolism of ethylbenzene have been studied in vitro in rabbit liver and lung. Organs from five female animals were used, but details of the experimental procedures were not reported. For the liver (mean weight 76 g) the rate of metabolism was 453 nmol/g tissue per 10 min (34.4 µmol per liver per 10 min or 11.7 nmol per nmol cytochrome P-450 per 10 min). The corresponding figures for lung (mean weight 7.7 g), were 680 nmol, 5.3µmol and 200.1 nmol, respectively. Thus, lung tissue may significantly contribute to the body clearance of ethylbenzene in rabbits (Sato & Nakajima, 1987). 6.4 Elimination and excretion In humans, ethylbenzene is mainly excreted in the urine as mandelic and phenylglyoxylic acids (Bardodej & Bardodejová, 1970; Ĺstrand et al., 1978; Engström et al., 1984; Gromiec & Piotrowski, 1984). Only up to 5% of retained ethylbenzene is estimated to be exhaled without transformation (Ĺstrand et al., 1978). The elimination half-lives of ethylbenzene in exhaled air and urine have been estimated to be 0.5-3 h and 8 h, respectively (Wolff, 1976). In human volunteers exposed to 100 or 200 ppm "industrial xylene" for 2 h, there was no decline in the concentration of xylenes plus ethylbenzene in the gluteal subcutaneous adipose tissue between 30 min and 22 h after exposure (Engström & Bjurström, 1978). The elimination of mandelic acid has been found to be biphasic, with half-lives of 3.1 and 24.5 h (Gromiec & Piotrowski, 1984). The elimination kinetics for 10 volatile organic compounds, including ethylbenzene, has been studied in human volunteers exposed to a variety of consumer products. Breath samples were collected post-exposure and analysed by GC/MS. The half-lives for the 10 chemicals varied from a few hours to 1-2 days. The authors concluded that volatile organic compounds exhibit relatively short residence times in the body (Pellizzari et al., 1992). Male Harlan-Wistar rats exposed to 14C-ring-labelled ethylbenzene (1000 mg/m3) for 6 h excreted 82% of the radioactivity in the urine, 8.2% in expired air (0.03% as CO2) and 0.7% in faeces. After 42 h, 0.2% remained in the tissues. The remaining 8.3% could not be accounted for (Chin et al., 1980a). 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1 Single exposure Single high exposures to ethylbenzene cause irritation of the mucous membranes and central nervous system effects. The results from single exposure in vivo studies are summarized in Table 5. Table 5. Single exposure of animals to ethylbenzenea Species Route Dose Parameter Reference Rat oral 3.5 g/kg LD50 Wolf et al. (1956) Rat oral 4.7 g/kg LD50 Smyth et al. (1962) Rat inhalation 9.37 g/m3 (2180 ppm) Minimum Molnár et al. (1986) narcotic conc. Rat inhalation 17.2 g/m3 (4000 ppm) 1 h LC10 Smyth et al. (1962) Rat inhalation 17.2 g/m3 (4000 ppm) 4 h LC50 Smyth et al. (1962) Rat inhalation 34.4 g/m3 (8000 ppm) 1 h LC100 Smyth et al. (1962) Rabbit dermal 77.4 g/kg LD50 Smyth et al. (1962) a Additional information is given in the following reviews: DFG (1985), ECETOC (1986). 7.2 Short-term exposure In a short-term study, six male rats (Sprague Dawley) were exposed for 6 h/day during 3 consecutive days to 8.6 g/m3 (2000 ppm) ethylbenzene. The animals were killed 16-18 h after the last exposure. Small increases in dopamine and noradrenaline levels and turnover in various parts of the hypothalamus and the median eminence were reported. Ethylbenzene was also found to produce selective reduction in prolactin and corticosterone secretion and selective increase in dopamine turnover within the dopamine-cholecystokinin-8- immuno-reactive nerve terminals of the nucleus accumbens (posterior part) (Andersson et al., 1981). When eight male rabbits (New Zealand) were exposed 12 h daily for 7 days to 3.22 g/m3 (750 ppm) ethylbenzene, there was a marked (p<0.05) depletion of striatal and tuberoinfundibular dopamine. Such an effect was also caused by intraperitoneal dosing of rabbits (eight per group) with mandelic or phenylglyoxylic acid (4 mmol/kg per day for 3 days) in saline (Romanelli et al., 1986). In a 4-week inhalation study Fischer-344 rats (five of each sex per group) were exposed to ethylbenzene for 6 h/day, 5 days per week, at exposure levels of 0, 426, 1643 or 3363 mg/m3 (0, 99, 382 or 782 ppm). At the two highest exposure levels, sporadic lacrimation and salivation, as well as significantly (p<0.05) increased liver weights, were seen. At the highest exposure level, there was a small increase in leukocyte counts and, in males, a marginal increase in platelet counts (Cragg et al., 1989). In the same study, mice (B6C3F1) of both sexes were similarly exposed. At 1643 and 3363 mg ethylbenzene/m3, females showed significantly (p<0.01) increased absolute and relative liver weights. In males a significantly (p<0.05) increased relative liver-to-brain weight ratio was seen. Male and female rabbits (New Zealand White) were also used in this study. The exposure levels were 0, 1643, 3363 and 6923 mg/m3 (0, 382, 782 and 1610 ppm). At the highest exposure level females gained weight more slowly than controls but neither sex exhibited gross or microscopic organ changes (Cragg et al., 1989). No changes in mortality pattern were seen in the three species. There were no changes in clinical chemistry parameters in rats or rabbits. Mice were not subjected to clinical chemistry or haematological examinations due to the small volume of blood that could be collected. For similar reasons, urinalyses were performed for rats (no change) but not for mice. Rabbits were excluded from urinalysis for logistical reasons. No changes in gross or microscopic pathology were noted in any of over 30 tissues from each of the three species when the animals were exposed at the highest concentration (Cragg et al., 1989). 7.3 Long-term exposure 7.3.1 Oral exposure Matched groups of 10 Wistar female rats were given daily ethylbenzene doses of 0, 13.6, 136, 408 or 680 mg/kg by stomach tube 5 days a week for 6 months. The two highest dosages induced slight increases in liver and kidney weights and slight cloudy swelling of parenchymal liver cells and of the tubular epithelium in the kidney (Wolf et al., 1956). 7.3.2 Inhalation exposure In a 13-week National Toxicology Program study, groups of 10 rats (F-344/N) and 10 mice (B6C3F1) of each sex were exposed for 6 h (plus 10 min to reach 90% of the target chamber concentration) per day, 5 days per week for 92 (female rats), 93 (male rats), 97 (female mice) or 98 (male mice) days, at ethylbenzene concen-trations of 0, 430, 1075, 2150, 3225 or 4300 mg/m3 (0, 100, 250, 500, 750 or 1000 ppm). Blood for clinical chemistry and haematological examination was collected on study days 4 and 23 and again at week 13 from both male and female rats. Dose-related increases in absolute liver weight were seen in both sexes of mice exposed to the two highest dose levels, and the relative kidney weight of female mice exposed to 4300 mg/m3 was greater than that of the controls. Increased absolute and relative liver and kidney weights were seen in male rats exposed to the two highest dose levels. Increased absolute liver and kidney weights were seen in female rats exposed to the three highest dose levels, but no increased relative liver and kidney weights were seen. No chemically related histopathological changes were observed in any rat or mouse tissues. Clinical chemistry results were negative (NTP, 1992). In another study, groups of five male rats (Wistar) were exposed for 6 h/day, 5 days/week to ethylbenzene concentrations of 0, 215, 1290 or 2580 mg/m3 (0, 50, 300 or 600 ppm) and sacrificed after 2, 5, 9 or 16 weeks of exposure. At 2580 mg/m3 liver cells showed a slight proliferation of smooth endoplasmic reticulum, slight degranulation and splitting of rough endoplasmic reticulum, and enlarged mitochondria. At the same dose level, liver microsomal protein, but not cytochrome P-450, concentration was slightly increased. There was also an increase in NADPH-cytochrome c reductase, 7-ethoxycoumarin- O-deethylase and UDPG-transferase activities in the liver. In the kidney only the two latter enzymes showed dose-related increases. Urinary excretion of thioethers was measured to ascertain the generation of electrophilic intermediates during ethylbenzene metabolism. Excretion of thioethers increased in a dose-dependent manner, with some fluctuation over the course of 7 weeks, reaching about eight times the control level at 2580 mg ethylbenzene/m3. However, there was no decrease in hepatic or renal levels of glutathione (GSH), indicating that the cells were able to maintain the intra-cellular homeostasis of GSH during exposure (Elovaara et al., 1985). In inhalation experiments, matched groups of 10-25 male and female Wistar rats, 5-10 guinea-pigs, 1-2 rabbits and 1-2 rhesus monkeys of either sex or both sexes were all exposed 7 h/day, 5 days/week, for up to 6 months. The exposure levels were 0, 1720 and 2580 mg/m3 (0, 400 and 600 ppm) for 186 days, 5375 mg/m3 (1250 ppm) for 214 days (no monkeys) or 9460 mg/m3 (2200 ppm) for 144 days (rats only). Slight effects were seen in rats: increased liver and kidney weights at 1720 mg/m3; increased liver and kidney weights at 2580 mg/m3; and small histopathological changes (cloudy swelling) in liver and kidney at 5375 and 9460 mg/m3 (Wolf et al. 1956). In guinea-pigs and monkeys slightly increased liver weights were noted in the 2580 mg/m3 group only. At the same exposure level, small histopathological effects in the testes, described as degeneration of the germinal epithelium, were seen in rabbits and monkeys. At 5375 mg/m3 a slight growth depression was noted in guinea-pigs. The no-observed-effect level (all four species) was considered to be about 860 mg/m3 (200 ppm) (Wolf et al., 1956). It should be noted, however, that Cragg et al. (1989) found no histopathological effects in the testes of rats and rabbits exposed to up to 3363 mg/m3 (782 ppm) for 4 weeks, and the lack of toxicity was confirmed by NTP (1992). 7.4 Skin and eye irritation, sensitization Inhalation for 3 min of ethylbenzene at a concentration of 4300 mg/m3 caused slight nasal irritation in guinea-pigs, and an 8-min exposure caused eye irritation as well. At 8600 mg/m3 a 1-min exposure was enough to cause both effects (Cavender, 1993). Two drops of undiluted ethylbenzene placed in the eyes of rabbits resulted in slight conjunctival irritation but no effects on the cornea (Wolf et al., 1956). A slight conjunctival irritation with some reversible corneal injury was reported in rabbits in a study by Smyth et al. 1962. Undiluted ethylbenzene has been shown to produce moderate irritation when applied to the uncovered skin of rabbits (Smyth et al., 1962). The application of undiluted ethylbenzene to the ear and to the shaved abdomen of rabbits up to 20 times during a 4-week period resulted in moderate irritation. There was erythema and oedema with superficial necrosis and exfoliation of large patches of skin (Wolf et al., 1956). No animal sensitization studies have been reported. 7.5 Reproductive toxicity, embryotoxicity and teratogenicity In an inhalation study, rats (Wistar or Sprague-Dawley) and rabbits (New Zealand White) were exposed to 430 or 4300 mg/m3 (100 or 1000 ppm) ethylbenzene for 6 to 7 h/day on gestation days 1 to 19 (rats) or 1 to 24 (rabbits). All pregnant animals were sacrificed on the day before term (day 21 for rats, day 30 for rabbits). The rabbits had a significantly (p<0.05) reduced number of live pups per litter at both exposure levels, but the number of implantations per litter and the number of dead or resorbed fetuses per litter did not differ from those of the controls. Maternal toxicity in rats exposed to 4300 mg/m3 was reflected in increased liver, kidney and spleen weights. There was a significant (p<0.05) increase in the incidence of extra ribs in both of the exposed rat groups (Hardin et al., 1981). In a further study, rats (CFY) were exposed to ethylbenzene concentrations of 600, 1200 or 2400 mg/m3 continuously (24 h/day) from day 7 to day 15 of pregnancy. They were then killed on day 21. Mice (CFLP) were exposed for three periods of 4 h per day to 500 mg/m3 on days 6-15 of pregnancy and killed on day 18. Rabbits (New Zealand White) were exposed continuously on days 7-20 of gestation to 500 or 1000 mg/m3 and were killed at day 30. The maternal toxic effects (not specified) in mice and rats were moderate and dose-dependent. In both species ethylbenzene caused skeletal growth retardation, extra ribs and reduced fetal growth rate at the highest concentration. In rabbits, the highest dose concentration caused mild maternal toxic effects (decreased weight gain) and reduction in the number of fetuses due to abortion (Ungváry & Tátrai, 1985). When rats (F-344/N) and mice (B6C3F1) were exposed to ethylbenzene at concentrations of 0, 430, 2150 and 4300 mg/m3 (0, 100, 500 and 1000 ppm), 6 h per day, 5 days per week, for 13 weeks, there were no changes in sperm or vaginal cytology (NTP, 1992). Rat embryos were explanted on day 9 of gestation and cultured in rat serum with added xylene (containing 18% ethylbenzene) at concentrations up to 1.0 ml/litre serum. Dose-dependent retardation of growth and development was seen but there were no observable teratogenic effects (Brown-Woodman et al., 1991). No multigeneration and reproductive studies on ethylbenzene have been reported. 7.6 Mutagenicity and related end-points In a National Toxicology Program study, ethylbenzene was not mutagenic in Salmonella tests and did not induce chromosomal aberrations or sister chromatid exchange in Chinese hamster ovary (CHO) cells in vitro, although it did induce trifluorothymidine resistance in mouse lymphoma cells at the highest concentration tested (80 mg/litre). There was no increase of micronuclei in the peripheral blood of mice exposed to ethylbenzene (NTP, 1992). In several other studies ethylbenzene did not induce point mutations (with or without added metabolic activation system). In addition, it did not cause an increase in the spontaneous recessive-lethal frequency in the Drosophila recessive-lethal test, nor had it any chromosomal effects in vitro (Donner et al., 1980; Florin et al., 1980; Dean et al., 1985). Ethylbenzene had a marginal effect on sister chromatid exchange in human lymphocytes in vitro when a high (10 mmol/litre) concentration was used (Norppa & Vainio, 1983). In addition, in the TK+/- test in mouse lymphoma cells there was a slight effect at a high concentration (80 mg/litre) (McGregor et al., 1988). This study is obviously the same as the one subsequently reported by NTP (1992). No excess of chromosomal aberrations in bone marrow cells was seen in rats after up to 18 weeks of exposure (6 h/day, 5 days/week) to 300 ppm of a xylene mixture containing 18.3% ethylbenzene (Donner et al., 1980). 7.7 Carcinogenicity In a carcinogenicity study, rats (Sprague-Dawley) were exposed to one of several aromatic hydrocarbons, including ethylbenzene. Groups of rats (40 of each sex) were exposed to 500 mg ethylbenzene (in olive oil) per kg body weight by gavage, 4 or 5 days per week for 104 weeks. Results were determined after 141 weeks. The first malignant tumour, a nephroblastoma, was observed after 33 weeks. The total number of malignant tumours was 31 in the 77 animals of the exposed group alive at 33 weeks compared with an incidence of 23 of 94 animals in the control group. The authors concluded that ethylbenzene caused an increase in the incidence of total malignant tumours, although there was no increase in the incidence of any specific type of tumour (Maltoni et al., 1985). It is difficult to draw any firm conclusion from this study because of inadequate reporting. 7.8 Other special studies Ethylbenzene was found to have low acute cytotoxicity in vitro on Ehrlich ascites cells (Holmberg & Malmfors, 1974). The effects of ethylbenzene have been studied in four in vitro test systems: decreased cell growth in Ascites sarcoma BP 8 cells; decreased oxidative metabolism in hamster brown fat cells; cell membrane damage of human embryonic lung fibroblasts; and inhibition of ciliary activity in chicken embryo trachea. On a 0-9 point scale (equivalent to 0-100%) the activity of these four systems scored 4, 6, 8 and 8, respectively (Curvall et al., 1984). The activity of cytochrome CYP2E1 can be monitored in microsomal preparations by p-nitrophenol hydroxylation. When rabbit (white male New Zealand) liver microsomes were treated with up to 0.25 mM ethylbenzene an inhibition of p-nitrophenol hydroxylation was seen (Koop & Laethem, 1992). In a study by Pyykkö et al. (1987), Sprague-Dawley male rats were given ethylbenzene dissolved in corn oil intraperitoneally in a single dose of 5 mmol/kg (530 mg/kg body weight). The rats were killed 24 h later and the livers and lungs removed. In the liver 7-ethoxycoumarin- 0-deethylase (a marker of CYP2B1/2) was induced 4-fold; no induction was found in the lung. Ethylbenzene also induced 7-ethoxyresorufin- 0-deethylase (a marker of CYP1A1/2) both in the liver (4-fold) and the lung (2.5 fold). These findings are common to many aromatic solvents. Alterations in the levels of specific cytochrome P-450 isozymes were measured by Western immunoblotting techniques using rabbit anti-rat polyclonal antibodies for cytochrome CYP1A1, CYP2B1 and CYP2E1 on rat liver microsomes. The rats, male and female Holtzman rats, were given 10 mmoles ethylbenzene per kg body weight for 3 days and killed 24 h after the last injection. Ethylbenzene was shown to induce CYP2B1/2B2 to a greater extent in male rats, while cytochrome CYP2E1 was only induced in female rats. The level of cytochrome CYP1A1 was not affected by ethylbenzene (Sequeira et al., 1992). In another study (Gut et al., 1993), Wistar male rats were exposed in a dynamic inhalation apparatus to 4 mg ethylbenzene/litre air, 20 h per day, for 4 days. The rats were then killed and liver microsomes prepared. By use of Western immunoblotting techniques it was shown that cytochrome CYP2B1 was induced and the cytochrome CYP2E1 levels were decreased. In a sensory irritation test, groups of four male mice (Swiss-Webster) were exposed for 30 min to ethylbenzene at concentrations of 1.76, 3.7, 8.06, 17.07 or 41.45 g/m3 (410, 860, 1875, 3970 or 9640 ppm). The RD50 value, i.e. the concentration necessary to depress the respiratory rate by 50%, was calculated to be 17.46 g/m3 (4060 ppm) (95% confidence interval 10.6-28.6 g/m3; 2480-6660 ppm). The respiratory rate decreased due to sensory irritation of the upper respiratory tract (Damgĺrd Nielsen & Alarie, 1982). In a similar test male mice (Swiss F1) were exposed for about 5 min to different concentrations of ethylbenzene. At least four different concentrations were used and there were six mice for each concentration. In this study the RD50 value was calculated to be 6.16 g/m3 (1432 ppm) (De Ceaurriz et al., 1981). 7.9 Factors modifying toxicity Rats (Sprague-Dawley) were exposed for 2 h to 774 mg/m3 (180 ppm) ethylbenzene. One of two corresponding animals received 20 mmol ethanol/kg body weight in physiological saline intraperitoneally before exposure to ethylbenzene. Ethanol enhanced significantly (1.4 fold) the blood levels of inhaled ethylbenzene (Römer et al., 1986). 8. EFFECTS ON HUMANS 8.1 Volunteer studies A dermal maximization test conducted on 25 volunteers at a concentration of 10% ethylbenzene in petrolatum produced no skin sensitization reaction (ECETOC, 1986). In a review of studies from the 1930s, it was stated that exposure to 21.5 g/m3 (5000 ppm) ethylbenzene for a few seconds gives intolerable irritation of nose, eyes and throat. A few seconds of exposure to 4.3 g/m3 (1000 ppm) initially gives eye irritation which diminishes after a few minutes of exposure (Damgĺrd Nielsen & Alarie, 1982). In a study on ethylbenzene metabolism in man it was incidentally reported that, when the exposure was above the occupational limit value (8 h; 430 mg/m3,100 ppm), complaints of fatigue, sleepiness, headache and irritation of the eyes and respiratory tract were reported (Bardodej & Bardodejová, 1970). Healthy male subjects were exposed to technical xylene (containing 20.7% ethylbenzene) for 2 h with or without a 100-watt workload on an ergometer cycle. The air concentration of technical xylene was 435 or 1300 mg/m3. During work at the higher exposure level, evidence of performance decrement was observed in three of the five performance tests: reaction time addition test (p<0.05), short-term memory (p<0.05) and choice reaction time (p<0.10) (Gamberale et al., 1978). 8.2 Occupational exposure A number of epidemiological studies have been carried out on groups occupationally exposed to mixtures of solvents, including ethylbenzene. In these studies it is difficult to attribute the effects to ethylbenzene or any other single chemical present. Ethylbenzene occurs in mixed xylenes (at up to 30%) and effects of occupational exposure to mixed xylenes are usually presented as effects of xylenes and not of ethylbenzene. A cross-sectional epidemiological study showed no strong evidence of adverse neurobehavioural effects in 105 house painters when compared with 53 workers from various professions (non-painters). The concentration of ethylbenzene at the workplace was up to 12.9 mg/m3 (3 ppm). Other solvents present were ethyl acetate, toluene, butyl acetate, methyl isobutyl ketone and xylene. In two neurobehavioural tests significant differences were found between painters and controls (the tests were "change of personality" and "short-term memory capacity"). In a subgroup of painters with repeated prenarcotic symptoms at the workplace, the differences were more pronounced (Triebig et al., 1988). In a study involving 35 spray painters, employed for between 2 and 26 years, erythrocyte and haemoglobin levels were slightly (but not statistically significantly) lower than those of the controls. The concentration of ethylbenzene was 17.2 mg/m3 (4 ppm) (Angerer & Wulf, 1985). In a medical surveillance report of some 200 ethylbenzene- production workers, mandelic acid concentrations in urine were measured twice a year for 20 years. Mandelic acid concentration in the samples never exceeded 3.25 mmol/litre (=497 mg/litre), and the mean value was 0.20-0.30 mmol/litre. According to the authors, a post-shift urine mandelic acid concentration of 6.25 mmol/litre is equivalent to an air concentration of 200 mg/m3. Therefore, the measured maximum and mean mandelic acid values were considered to be equivalent to air ethylbenzene concentrations of about 86 and 8.6 mg/m3 (20 and 2 ppm), respectively. None of the workers examined over the last 10 years showed any effects on the levels of haemoglobin, leucocytes or platelets, nor did they have a changed haematocrit or alanine aminotransferase activity (Bardodej & Círek, 1988). Minor changes in evoked potential and nerve conduction velocity were found in 22 workers exposed to ethylbenzene at concentrations of 0.43-17.2 mg/m3 (0.1-4 ppm) for 4-20 years. They were also exposed to styrene (about 1.5 ppm) (Lu & Zhen, 1989). 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1 Microorganisms Ethylbenzene has been shown to inhibit the respiration of sewage sludge utilizing biogenic substrates. Two screening tests were used, RIKA and OECD 209. The concentration of ethylbenzene used was at the limit of solubility in the medium (approximately 150 mg/litre), and inhibitions of the respiration rate of 30% (ACCEDE 209) and 100% (RIKA) were observed (Volskay & Grady, 1990). Bringmann & Kühn (1980) studied the effect of ethylbenzene on bacteria. A toxicity threshold of 12 mg/litre for Pseudomonas putida was obtained in a cell multiplication inhibition test. 9.2 Aquatic organisms Numerous acute toxicity tests have been carried out on ethylbenzene. Organisms that have been studied include protozoans (Bringmann & Kühn, 1980), algae (US EPA, 1978; Bringmann & Kühn, 1980; Galassi et al., 1988; Masten et al. 1994), water fleas (LeBlanc, 1980; Bringmann & Kühn, 1982; Abernethy et al., 1986; Galassi et al., 1988; Vigano, 1993), diatoms (US EPA, 1978; Masten et al., 1994), copepods, grass shrimp (Potera, 1975), bay shrimps (Benville & Korn, 1977), mysid shrimps (US EPA, 1978; Masten et al., 1994), Dungeness crabs (Caldwell et al., 1976) and Pacific oysters (LeGore, 1974). Fish that have been studied include rainbow trout (Mayer & Ellersieck, 1986; Galassi et al., 1988), guppy (Pickering & Henderson, 1966; Galassi et al., 1988), bluegill (Pickering & Henderson, 1966; Buccafusco et al., 1981), fathead minnow, goldfish (Pickering & Henderson, 1966), channel catfish (Mayer & Ellersieck, 1986), Atlantic silverside (Masten et al., 1994), striped bass (Benville & Korn, 1977) and sheepshead minnow (US EPA, 1978; Heitmuller et al., 1981). Many of the test results are not comparable, owing to inconsistent exposure conditions, resulting from emulsions, open static systems and systems with large air spaces. Aquatic toxicity results from consistent exposure conditions, which are comparable, are shown in Table 6. No information regarding chronic exposure of aquatic organisms to ethylbenzene has been reported. Table 6. Toxicity of ethylbenzene to aquatic organisms Species Age/size Stat/flowa Temperature Salinity pH Parameterc Concentration Reference (°C) (0/00) (mg/litre)d Alga stat 72-h EC50 4.6 Galassi et al. (1988) (Selenastrum stat 19-21 48-h EC50 7.2 (3.4-15.1) Masten et al. (1994) capricornutum) stat 19-21 96-h EC50 3.6 (1.7-7.6) Masten et al. (1994) Water flea < 24 h statb 24-h LC50 2.2 Galassi et al. (1988) (Daphnia magna) statb 21-25 48-h LC50 2.1e Abernethy et al. (1986) < 24 h statb 48-h LC50 1.81-2.38 Viganň (1993) Diatom (Skeletonema statb 19-21 48-h EC50 7.5 (5.0-11.2) Masten et al. (1994) costatum) statb 19-21 72-h EC50 4.9 (2.4-9.8) Masten et al. (1994) statb 19-21 96-h EC50 7.7 (5.9-10.0) Masten et al. (1994) Mysid shrimp < 24 h flow 24-26 20 8.0 48-h LC50 >5.2 Masten et al. (1994) (Mysidopsis < 24 h flow 24-26 20 8.0 96-h LC50 2.6 (2.0-3.3) Masten et al. (1994) bahia) Rainbow trout stat 96-h LC50 4.2 Galassi et al. (1988) (Oncorhynchus mykiss) Guppy stat 96-h LC50 9.2 Galassi et al. (1988) (Poecilia reticulata) Table 6. (Cont'd) Species Age/size Stat/flowa Temperature Salinity pH Parameterc Concentration Reference (°C) (0/00) (mg/litre)d Atlantic silverside 3-15 mg flow 21-23 20 48-h LC50 6.4 (5.8-7.5) Masten et al. (1994) (Menidia menidia) 3-15 mg flow 21-23 20 96-h LC50 5.1 (4.4-5.7) Masten et al. (1994) a in all cases a closed system was used; stat = static conditions (water unchanged for the duration of the test); flow = flow-through conditions (ethylbenzene concentration in water continously maintained) b air space was eliminated c the EC50 for algae was based on growth inhibition d test concentrations were measured, unless stated otherwise e nominal test concentration; 9.3 Terrestrial organisms An LC50 value of 47 µg per cm2 of contact area was obtained for earthworms exposed to ethylbenzene adsorbed on filter paper in glass vials (Neuhauser et al., 1986). Callahan et al. (1994) reported a 2-day LC50 value of 4.93 µg/kg for Eisenia foetida in a contact toxicity test. No toxicity data on plants, birds and wild mammals have been reported. 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1 Evaluation of human health risks The acute and chronic toxicities of ethylbenzene are low. The toxic effects in humans and animals relate to depression of the central nervous system (CNS) and to irritation of the mucous membranes and eyes. No data concerning carcinogenic or reproductive effects have been reported. Ethylbenzene does not have significant mutagenic properties or teratogenic effects. Exposure to more than 430 mg/m3 (100 ppm) causes symptoms of CNS depression and irritation in humans. A 20-year medical surveillance study of 200 workers showed no indications of effects in routine blood tests. The maximum exposure, estimated from the urinary concentration of mandelic acid, was less than about 86 mg/m3 (20 ppm) and the mean value about 8.6 mg/m3 (2 ppm). In a 13-week animal study, increased liver weight was the only dose-related biological finding in male rats. This was seen at a concentration of 3225 mg/m3 (750 ppm) or more. The definition and aim of the use of a guidance value for the general population have been described by IPCS (1994). On the basis of biological significance criteria cited above, a no-observed-effect level (NOEL) of 2150 mg/m3 (500 ppm) was defined. The no-observed-adverse-effect level would be higher than 4300 mg/m3 (1000 ppm) (highest concentration used), since the increase in liver weight was not associated with any histopathological findings. A NOEL of 2150 mg/m3 (500 ppm) was used as the basis for determining the guidance value. The following uncertainty factors were used: 10 for interspecies variability; 5 for intraspecies variability (effect seen in males only); and 2 for lack of chronic toxicity data. This gives a guidance value of 22 mg/m3 (5 ppm). From the medical surveillance study the NOEL could be estimated to be between 8.6 mg/m3 (2 ppm) (mean value) and 86 mg/m3 (20 ppm) (maximum value). However, since no dose-response relationship was derived, this study is not suitable for the estimation of a guidance value. Furthermore, no effects would be expected at this exposure level, which is almost the same as the guidance value. Humans are exposed to ethylbenzene principally by inhalation, where the substance is rapidly absorbed into the body. Exposure by skin absorption or ingestion may also occur. Ethylbenzene is not considered to bioaccumulate. Table 7 gives the estimated weekly ethylbenzene dose resulting from different types of exposure. A guidance value of 22 mg/m3 (5 ppm) ethylbenzene is approximately equivalent to a weekly ethyl- benzene dose of 2000 mg. This is 100 times higher than the worst exposure situation of the general population. Table 7. Estimated weekly ethylbenzene dose from different types of exposures Type of exposure Reported concentration Weekly total amount Dose mg/week in media inhaled, ingested or smoked General population Inhalation (means)b 0.74-100 µg/m3 140 m3 0.07-10c Ingestion (food) 13 µg/kgd 7 kg 0.1 Drinking- or groundwaterb 0.07-1.1 µg/litree 14 litres 0.01 30.0 µg/litref 0.42 Occupational Inhalation (mean)g 10 mg/m3 300c Inhalation (max)g 100 mg/m3 50 m3 3000c Inhalationh 430 mg/m3 12700c Smokers 8 µg/cigarettei 140 cigarettes/week 1.1 a Based on a breathing rate of 20 m3/day b Values from Tables 2 and 3 c Retention 60% d Lovegren et al. (1979) (highest reported value) e Highest reported values of uncontaminated groundwater f Lowest reported value of contaminated groundwater g Bardodej & Círek (1988) h Corresponds to occupational exposure limits in several countries i Wallace et al. (1987a) A 2-year carcinogenicity study has been performed by the National Toxicology Program (USA) but the results are not yet available. 10.2 Evaluation of effects on the environment Ethylbenzene is found in air, water, soil, sediment, biota and groundwater. It is released primarily into air and water from various natural and anthropogenic sources. The atmosphere is the major sink for ethylbenzene. Ethylbenzene is rapidly photo-oxidized in the atmosphere and this may contribute to photo-chemical smog formation. In water, the key processes determining overall fate are volatilization and biodegradation. The log octanol/water partition coefficient is 3.13, indicating a potential for bioaccumulation. However, the limited evidence available shows that ethylbenzene bioconcentration factors are low for fish and molluscs. Elimination from aquatic organisms appears to be rapid. Biomagnification through the food chain is unlikely. Mean levels of ethylbenzene in air ranging from 0.74 to 100 µg/m3 have been measured at urban sites. Industrial releases and vehicle emissions are the principal sources of ethylbenzene. Levels found at rural sites are generally <2 µg/m3. The levels of ethylbenzene in surface water are generally less than 0.1 µg/litre in non-industrial areas. In industrial and urban areas ethylbenzene concentrations of up to 15 µg/litre have been reported. Urban run-off, effluent and landfill leachate are sources of local contamination. Ethylbenzene levels in sediment are generally < 0.5 µg/kg. Levels of ethylbenzene between 1 and 5 µg/kg have been found in sediments from heavily industrialized areas. Ethylbenzene levels in uncontaminated groundwater are generally < 0.1 µg/litre. However, much higher levels have been reported for groundwater contaminated via waste disposal, fuel spillage and industrial facilities. Acute toxicity studies on aquatic organisms show ethylbenzene to be of moderate toxicity. The lowest acute toxicity values are 4.6 mg/litre for algae (72-h EC50), 1.8 mg/litre for daphnids (48-h LC50) and 4.2 mg/litre for fish (96-h LC50). There are no chronic toxicity studies on aquatic organisms. There is limited information regarding the toxicity of ethylbenzene to bacteria and earthworms. There are no data for terrestrial plants, birds or wild mammals. On the basis of available data, it is concluded that ethylbenzene is unlikely to be found at levels in the environment that will cause adverse effects on aquatic and terrestrial ecosystems, except in cases of spills or point-source emissions. 11. CONCLUSIONS Ethylbenzene has low toxicity. Its vapour irritates the mucous membranes to a limited extent and causes prenarcotic effects on the central nervous system. With respect to the general population, a tentative guidance value of 22 mg/m3 (5 ppm) for ethylbenzene in inhaled air has been derived, although information on certain important toxicity end-points are unavailable. This value would correspond to a weekly absorbed dose (daily ventilation of 20 m3 with 60% retention) of about 2000 mg. It is at least 200 times higher than the dose received in the most polluted living environment reported. Hence, no harmful effects on the general population would be expected. However, it should be noted that the guidance value of 22 mg/m3 (5 ppm) is about 10 times higher than the odour threshold (about 2.2 mg/m3; 0.5 ppm), and so exposure at that level may cause annoyance. On the other hand, odour detection may be considered to be a safeguard against excessive exposure. Ethylbenzene is a non-persistent chemical and is degraded primarily by photooxidation and biodegradation. Volatilization to the atmosphere is rapid. Photooxidation reactions of ethylbenzene may contribute to photochemical smog formation. Limited evidence suggests that bioaccumulation is low in aquatic organisms. Ethylbenzene is unlikely to cause adverse effects in aquatic or terrestrial ecosystems except in cases of spills or point-source emissions. 12. FURTHER RESEARCH a) To fill the data gaps that currently limit the toxicological evaluation of ethylbenzene, an appropriate rodent carcinogenicity study and a reproductive toxicity study are needed. (The former study has been conducted but the study report has not yet been published.) b) There is little information on the long-term effects of ethylbenzene in humans and, in particular, no dose-response or dose-effect data are at hand. Epidemiological studies of populations occupationally exposed to ethylbenzene should be encouraged. In this context, the use of ethylbenzene metabolites in urine as a marker of exposure can be of special value because the method determines the internal doses that individuals receive via all routes of exposure. Because ethylbenzene is a central nervous system depressant, and because some studies suggest that high doses of the substance or its metabolites may affect the metabolism of some neurotransmitters in the brain, epidemiological studies should address the central nervous system as a potential target organ. Moreover, since ethylbenzene is almost invariably only one of the components in solvent mixtures at the workplace, study designs that address possible interactions between ethylbenzene and other solvents are desirable. c) Further mechanistic studies are needed. 13. PREVIOUS EVALUATION BY INTERNATIONAL BODIES A guideline value of 300 µg/litre for ethylbenzene in drinking-water was recommended by WHO in 1993. 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En 1983, l'Europe occidentale en a produit environ 3 millions de tonnes. Il se présente sous la forme d'un liquide incolore dégageant une odeur douceâtre qui rappelle l'essence. On l'utilise principalement pour la production de styrčne. Ajouté ŕ du xylčne technique, il sert également de solvant pour les peintures et les vernis et on l'emploie aussi dans l'industrie chimique et dans celle du caoutchouc. Il est présent dans le pétrole brut, les produits raffinés dérivés du pétrole et dans leurs produits de combustion. L'éthylbenzčne n'est pas persistant car il se décompose dans l'environnement, principalement par photo-oxydation et par dégradation biologique. Il est possible que la photo-oxydation de l'éthylbenzčne dans l'atmosphčre contribue ŕ la formation du smog photochimique. Le logarithme du coéfficient de partage entre l'octanol et l'eau est égal ŕ 3,13, ce qui indique que le composé se pręte ŕ une bioaccumulation. Cependant, les données limitées dont on dispose montrent que le facteur de bioaccumulation de l'éthylbenzčne est faible pour les mollusques et les poissons. Apparemment, il est vite éliminé par les organismes aquatiques. A la campagne, la concentration d'éthylbenzčne dans l'air est généralement inférieure ŕ 2 µg/m3. Sur des sites urbains, on a trouvé des teneurs moyennes allant de 0,74 ŕ 100 µg/m3. La concentration d'éthylbenzčne présente dans les eaux superficielles est généralement inférieure ŕ 0,1 µg/litre dans les zones non industrialisées. En revanche, dans les zones urbaines ou industrialisées, la concentration peut atteindre 15 µg/litre. Dans les sédiments, la concentration est en général inférieure ŕ 0,5 µg/litre, encore que l'on ait signalé des valeurs comprises entre 1 et 5 µg/litre dans des sédiments provenant de régions fortement industrialisées. Dans les eaux souterraines non contaminées, la concentration est habituellement inférieure ŕ 0,1 µg/litre, mais elle est beaucoup plus élevée dans les eaux contaminées. L'éthylbenzčne présente une toxicité aiguë modérée pour les algues, les invertébrés aquatiques et les poissons. La valeur de la CE50 ŕ 72 h est de 4,6 mg/litre pour l'algue Selenastrum capricornutum, la CL50 ŕ 48 h est de 1,8 mg/litre pour Daphnia magna, et on a une CL50 ŕ 96 h de 4,2 mg/litre pour la truite arc-en-ciel. On ne possčde aucune donnée sur l'exposition chronique des organismes aquatiques ŕ l'éthylbenzčne. En ce qui concerne les bactéries et les lombrics, les données toxicologiques sont limitées. Il n'en n'existe aucune sur les végétaux terrestres, les oiseaux ou les mammifčres sauvages. Chez l'homme, l'exposition ŕ l'éthylbenzčne se produit principalement par inhalation; 40 ŕ 60% du composé sont retenus dans les poumons. L'éthylbenzčne est fortement métabolisé, principalement en acides mandélique et phénylglyoxylique. On peut utiliser les métabolites présents dans les urines pour surveiller l'exposition humaine. Qu'elle soit aiguë ou chronique, la toxicité de l'éthylbenzčne est faible pour l'homme et les animaux. Il exerce des effets toxiques sur le systčme nerveux central et il est irritant pour les muqueuses et les yeux. Le seuil de concentration pour ces effets chez l'homme a été estimé ŕ environ 430-860 mg/m3 (100-200 ppm) lors d'une seule exposition de courte durée. Des rats et des souris ŕ qui on avait fait inhaler pendant 13 semaines de l'éthylbenzčne ŕ des concentrations allant jusqu'ŕ 4300 mg/m3, n'ont présenté aucune lésion histopathologique. La dose sans effet observable (critčre retenu: l'augmentation du poids du foie) a été estimée ŕ 2150 mg/m3 (500 ppm). L'éthylbenzčne stimule les enzymes des microsomes hépatiques. Il n'est ni mutagčne ni tératogčne pour le rat ou le lapin. On ne dispose d'aucune donnée au sujet de ses effets toxiques éventuels sur l'appareil reproducteur ni sur son pouvoir cancérogčne. Une valeur-guide de 22 mg/litre (5 ppm) a été calculée ŕ partir des résultats fournis par les études sur l'animal. On estime que la population générale est exposée ŕ des concentrations inférieures ŕ cette valeur, męme dans les cas les plus graves. On a constaté qu'une exposition de longue durée en milieu professionnel, ŕ des concentration de cet ordre, n'avait aucun effet nocif sur la santé des travailleurs exposés. RESUMEN El etilbenceno es un hidrocarburo aromático que se obtiene por alkilación del benceno y del etileno. La producción estimada en los Estados Unidos de América es de unos cinco millones de toneladas por ańo, y en Europa occidental fue de aproximadamente tres millones de toneladas en 1983. El etilbenceno es un líquido incoloro de olor dulce semejante al de la gasolina. Se utiliza principalmente para la producción de estireno. También se utiliza en el xileno técnico como disolvente de pinturas y lacas, así como en la industria del caucho y en la fabricación de sustancias químicas. Se encuentra en el petróleo crudo, en los productos de petróleo refinados y en productos de combustión. El etilbenceno es una sustancia química no persistente, que se degrada principalmente por fotooxidación y biodegradación. Su volatilización en la atmósfera es rápida. La reacción de foto- oxidación del etilbenceno en la atmósfera puede contribuir a la formación de niebla fotoquímica. El logaritmo del coeficiente de reparto octanol-agua es 3,13, lo que indica posibilidad de bioacumulación. Sin embargo, los limitados indicios disponibles muestran que los factores de bioconcentración del etilbenceno son bajos para peces y moluscos. La eliminación por los organismos acuáticos parece ser rápida. Los niveles de etilbenceno en el aire en puntos rurales son generalmente inferiores a 2 µg/m3. En puntos urbanos se han registrado niveles medios de etilbenceno que oscilan entre 0,74 y 100 µg/m3. Los niveles de etilbenceno detectados en las aguas superficiales son generalmente inferiores a 0,1 µg/litro en zonas no industriales. Se han comunicado concentraciones de etilbenceno de hasta 15 µg/litro en zonas industriales y urbanas. Los niveles de etilbenceno en sedimentos son generalmente inferiores a 0,5 µg/kg, aunque en sedimentos de zonas muy industrializadas se han encontrado niveles de 1 a 5 µg/kg. Las concentraciones en aguas subterráneas no contaminadas son generalmente inferiores a 0,1 µg/litro, pero son mucho más elevadas en aguas subterráneas contaminadas. La toxicidad aguda del etilbenceno para las algas, los invertebrados acuáticos y los peces es moderada. Los valores de toxicidad aguda más bajos son de 4,6 mg/litro para el alga Selenastrum capricornutum (CE50 a las 72 horas, sobre la base de la inhibición del crecimiento), 1,8 mg/litro para Daphnia magna (CL50 a las 48 horas) y 4,2 mg/litro para la trucha irisada (CL50 a las 96 horas). No se dispone de información sobre la exposición crónica de los organismos acuáticos al etilbenceno. Hay información limitada sobre la toxicidad del etilbenceno para las bacterias y para las lombrices. No hay datos relativos a las plantas terrestres, las aves y los mamíferos silvestres. La exposición humana al etilbenceno se produce principalmente por inhalación; el 40-60% del etilbenceno inhalado se retiene en los pulmones. El etilbenceno se metaboliza extensamente, transformándose sobre todo en ácidos mandélico y fenilglioxílico. Estos metabolitos urinarios pueden utilizarse para vigilar la exposición humana. El etilbenceno tiene una toxicidad aguda y crónica baja tanto para los animales como para el hombre. Es tóxico para el sistema nervioso central e irrita las mucosas y los ojos. El umbral para esos efectos en el ser humano después de exposiciones únicas breves se estimó en aproximadamente 430-860 mg/m3 (100-200 ppm). La inhalación de etilbenceno por ratas y ratones durante 13 semanas en concentraciones de hasta 4300 mg/m3 (1000 ppm) no dio lugar a lesiones histopatológicas. El nivel sin efectos observados, sobre la base de un aumento del peso del hígado en las ratas, fue de 2150 mg/m3 (500 ppm). El etilbenceno es un inductor de las enzimas microsómicas hepáticas. No es mutagénico ni teratogénico en ratas y conejos. No se dispone de información sobre la toxicidad reproductiva ni la carcinogenicidad del etilbenceno. Se ha calculado un valor de orientación de 22 mg/m3 (5 ppm) a partir de estudios realizados en animales. La exposición estimada de la población general (incluso en la peor de las situaciones) es inferior a ese valor de orientación. La exposición ocupacional a largo plazo a concentraciones de etilbenceno estimadas en este orden de magnitud no ocasionaron efectos adversos en la salud de los trabajadores.
See Also: Ethylbenzene (CHEMINFO)