Environmental Health Criteria 163 CHLOROFORM Please note that the layout and pagination of this web version are not identical with the printed version. Chloroform (EHC 163, 1994) INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 163 CHLOROFORM 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. J. de Fouw National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands. Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization World Health Orgnization Geneva, 1994 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals. WHO Library Cataloguing in Publication Data Chloroform. Page 1 of 119 Chloroform (EHC 163, 1994) (Environmental health criteria ; 163) 1.Chloroform - adverse effects I.Series ISBN 92 4 157163 2 (NLM Classification: QV 81) 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 1994 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 CHLOROFORM 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. Sampling and analysis in air 2.4.1.1 Direct measurement 2.4.1.2 Adsorption-liquid desorption 2.4.1.3 Adsorption-thermal desorption 2.4.1.4 Cold trap-heating 2.4.2. Sampling and analysis in water 2.4.3. Sampling and analysis in biological samples 2.4.3.1 Blood and tissues 2.4.3.2 Urine 2.4.3.3 Fish 2.4.4. Sampling and analysis in soil gas 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE Page 2 of 119 Chloroform (EHC 163, 1994) 3.1. Natural occurrence 3.2. Anthropogenic sources 3.2.1. Production 3.2.1.1 Direct production levels and processes 3.2.1.2 Indirect production 3.2.1.3 Emissions from direct production and use 3.2.1.4 Emissions from indirect production 3.2.2. Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1. Transport and distribution between media 4.1.1. Transport 4.1.2. Distribution 4.1.3. Removal from the atmosphere 4.2. Biotic degradation 4.3. Bioaccumulation 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1. Environmental levels 5.1.1. Ambient air 5.1.2. Indoor air 5.1.3. Water 5.1.3.1 Sea water 5.1.3.2 Rivers and lakes 5.1.3.3 Rain water 5.1.3.4 Waste water 5.1.3.5 Ground water 5.1.3.6 Drinking-water 5.1.4. Soil 5.1.5. Foodstuffs 5.2. General population exposure 5.2.1. Outdoor air 5.2.2. Indoor air 5.2.3. Drinking-water 5.2.4. Foodstuffs 5.3. Occupational exposure during manufacture, formulation or use 6. KINETICS IN LABORATORY ANIMALS AND HUMANS 6.1. Pharmacokinetics 6.1.1. Absorption 6.1.1.1 Oral 6.1.1.2 Dermal 6.1.1.3 Inhalation 6.1.2. Distribution 6.1.3. Elimination and fate 6.1.4. Physiologically based pharmacokinetic modelling for chloroform 6.2. Biotransformation and covalent binding of metabolites 6.3. Human studies 6.3.1. Uptake 6.3.1.1 Oral 6.3.1.2 Dermal 6.3.1.3 Inhalation 6.3.2. Distribution 6.3.3. Elimination 6.3.4. Biotransformation 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS Page 3 of 119 Chloroform (EHC 163, 1994) 7.1. Single exposure 7.1.1. Lethality 7.1.2. Non-lethal effects 7.1.2.1 Oral exposure 7.1.2.2 Subcutaneous and intraperitoneal exposure 7.1.2.3 Inhalation exposure 7.1.2.4 Dermal exposure 7.2. Short-term exposure 7.2.1. Oral exposure 7.2.1.1 Mice 7.2.1.2 Rats 7.2.2. Inhalation exposure 7.3. Long-term exposure 7.4. Skin and eye irritation 7.5. Reproductive toxicity, embryotoxicity and teratogenicity 7.5.1. Reproduction 7.5.2. Embryotoxicity and teratogenicity 7.5.2.1 Oral exposure 7.5.2.2 Inhalation exposure 7.6. Mutagenicity and related end-points 7.7. Carcinogenicity 7.7.1. Mice 7.7.2. Rats 7.7.3. Dogs 7.7.4. Studies on initiating-promoting activity 7.7.4.1 Mice 7.7.4.2 Rats 7.8. In vitro studies 7.9. Factors modifying toxicity; toxicity of metabolites 8. EFFECTS ON HUMANS 8.1. Acute non-lethal effects 8.2. Epidemiology 8.2.1. Occupational exposure 8.2.2. General exposure 8.3. Abuse and addiction 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1. Freshwater organisms 9.1.1. Short-term toxicity 9.1.2. Long-term toxicity 9.2. Marine organisms 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of human health risks 10.1.1. Exposure 10.1.2. Health effects 10.1.3. Approaches to risk assessment 10.1.3.1 Non-neoplastic effects 10.1.3.2 Neoplastic effects 10.2. Evaluation of effects in the environment 11. FURTHER RESEARCH 12. PREVIOUS EVALUATION BY INTERNATIONAL BODIES Page 4 of 119 Chloroform (EHC 163, 1994) REFERENCES RESUME RESUMEN WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROFORM Members Dr M.W. Anders, Department of Pharmacology, University of Rochester, Rochester, New York, USA Dr D.Anderson, British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom Dr R.J. Bull, Washington State University, College of Pharmacy, Pullman, Washington, USA Dr C.D. Carrington, Food and Drug Administration, Washington DC, USA Dr M. Crookes, Environment Section, Building Research Establishment, Garston, Watford, United Kingdom Dr E. Elovaara, Institute of Occupational Health, Department of Industrial Hygiene and Toxicology, Helsinki, Finland Dr J. de Fouw, Toxicology Advisory Centre, National Institute of Public Health and Environmental Protection (RIVM), Bilthoven, the Netherlands (Rapporteur) Dr M.E. Meek, Environmental Health Directorate, Health Protection Branch, Health and Welfare, Ottawa, Canada (Chairperson) Dr R. Pegram, Environmental Toxicology Division, Health Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA Dr S.A. Soliman, Department of Pesticide Chemistry, College of Agriculture and Veterinary Medicine, King Saud University-Al-Qasseem, Bureidah, Saudi Arabia (Vice-Chairman) Dr L. Vittozzi, Istituto Superiore di Sanità, Laboratorio di Tossicologia, Comparata ed Ecotossicologia, Rome, Italy (Vice-Chairman) Dr P.P. Yao, Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Beijing, China Representatives of other Organizations Dr B. Butterworth, International Life Sciences Institute, Risk Science Institute, Washington DC, USA Secretariat Dr B.H. Chen, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary) Dr P.G. Jenkins, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland Page 5 of 119 Chloroform (EHC 163, 1994) Dr C. Partensky, International Agency for Research on Cancer, Lyon, France 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 kindly 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 FOR CHLOROFORM A WHO Task Group on Environmental Health Criteria for Chloroform met in Geneva from 15 to 19 November 1993.