n-Butanol (CAS No. 71-36-3) JACC No. 41 ISSN-0773-6339-41 Brussels, December 2003 n-Butanol (CAS No. 71-36-3) ECETOC JACC No. 41 © Copyright - ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals 4 Avenue E. Van Nieuwenhuyse (Bte 6), B-1160 Brussels, Belgium. All rights reserved. No part of this publication may be reproduced, copied, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the copyright holder. Applications to reproduce, store, copy or translate should be made to the Secretary General. ECETOC welcomes such applications. Reference to the document, its title and summary may be copied or abstracted in data retrieval systems without subsequent reference. The content of this document has been prepared and reviewed by experts on behalf of ECETOC with all possible care and from the available scientific information. It is provided for information only. ECETOC cannot accept any responsibility or liability and does not provide a warranty for any use or interpretation of the material contained in the publication. ECETOC JACC No. 41 n-Butanol (CAS No. 71-36-3) n-Butanol (CAS No. 71-36-3) CONTENTS EXECUTIVE SUMMARY 1 THE ECETOC SCHEME FOR THE JOINT ASSESSMENT OF COMMODITY CHEMICALS 2 1. SUMMARY AND CONCLUSIONS 3 2. IDENTTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 5 2.1 Identify 5 2.2 EU classification and labelling 5 2.3 Physical and chemical properties 6 2.4 Conversion factors 8 2.5 Analytical methods 9 2.5.1 In workplace air 9 2.5.2 In environmental media 9 2.5.3 In biological media 9 3. PRODUCTION, STORAGE, TRANSPORT AND USE 11 3.1 Production 11 3.2 Storage 11 3.3 Transport 11 3.4 Use 12 4. ENVIRONMENTAL DISTRIBUTION AND TRANSFORMATION 13 4.1 Emissions 13 4.1.1 Natural sources 13 4.1.2 Emissions during production and use 13 4.2 Environmental distribution 14 4.3 Environmental fate and biotransformation 15 4.3.1 Atmospheric fate 15 4.3.2 Aquatic fate 15 4.3.3 Terrestrial fate 15 4.3.4 Biodegradation 15 4.3.5 Bioaccumulation 16 4.3.6 Summary and evaluation 16 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 17 5.1 Environmental levels 17 5.1.1 Air 17 5.1.2 Water 17 5.2 Human exposure levels and hygiene standards 18 5.2.1 Non-occupational exposure 18 5.2.2 Occupational exposure 18 5.2.3 Hygiene standards 20 ECETOC JACC No. 41 n-Butanol (CAS No. 71-36-3) 5.2.4 RfC, RfD and IDLH values 20 5.2.5 Summary 21 6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 22 6.1 Micro-organisms 22 6.2 Aquatic organisms 23 6.3 Terrestrial organisms 24 6.4 Summary and evaluation 24 7. KINETICS AND METABOLISM 25 7.1 Absorption and excretion 25 7.1.1 Humans 25 7.1.2 Animals 26 7.2 Distribution and metabolism 32 7.2.1 In vivo data 32 7.2.2 In vitro data 33 7.3 Evaluation 35 8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 37 8.1 Acute toxicity 37 8.1.1 Oral 37 8.1.2 Dermal 38 8.1.3 nhalation 38 8.1.4 Other routes 39 8.1.5 Summary 39 8.2 Skin, respiratory tract and eye irritation, sensitisation 39 8.2.1 Skin irritation 39 8.2.2 Eye irritation 40 8.2.3 Respiratory tract irritation 42 8.2.4 Sensitisation 42 8.2.5 Evaluation 42 8.3 Repeated dose toxicity 43 8.3.1 Oral 43 8.3.2 Dermal 44 8.3.3 Inhalation 44 8.3.4 Summary and evaluation 45 8.4 Genotoxicity 46 8.4.1 In vitro studies 46 8.4.2 In vivo studies 47 8.4.3 Evaluation 48 8.5 Chronic toxicity and carcinogenicity 48 8.6 Reproductive toxicity 48 8.6.1 Developmental toxicity 48 8.6.2 Fertility and effects on reproductive organs 51 8.6.3 Summary and evaluation 51 8.7 Neurotoxicity 52 ECETOC JACC No. 41 n-Butanol (CAS No. 71-36-3) 9. OTHER CONSIDERATIONS AND SUPPORTIVE DATA ON n-BUTYL ACETATE 53 9.1 Metabolism 53 9.1.1 Formation of nBA 53 9.2 Repeated dose toxicity 54 9.3 Reproductive toxicity 56 9.3.1 Developmental toxicity 56 9.3.2 Fertility and effects on reproductive organs 57 9.4 Neurotoxicity 58 10. EFFECTS ON HUMANS 61 10.1 Acute and subchronic toxicity 61 10.1.1 Acute toxicity 61 10.1.2 Short- and long-term exposure 61 10.1.3 Evaluation 63 10.2 Eye and respiratory irritation 63 10.2.1 Epidemiological studies 63 10.2.2 Studies with volunteers / controlled clinical studies 64 10.2.3 Evaluation 65 11. HAZARD ASSESSMENT 66 12. FIRST AID AND SAFE HANDLING ADVICE 70 12.1 First aid and medical treatment 70 12.1.1 Skin and eye injuries 70 12.1.2 lnhalation 70 12.1.3 Ingestion 70 12.2 Safe handling 70 12.2.1 Safety at work 70 12.2.2 Storage safety 70 12.2.3 Fire safety and extinguishers 71 12.2.4 Protection against fire and explosion 71 12.3 Management of spillage and waste 71 13. BIBLIOGRAPHY 72 13.1 Databases consulted 72 13.2 References quoted 72 13.3 References not quoted 90 APPENDIX A: ABBREVIATIONS 108 APPENDIX B: CRITERIA FOR RELIABILITY CATEGORIES 109 MEMBERS OF THE TASK FORCE 110 MEMBERS OF THE SCIENTIFIC COMMITTEE 111 ECETOC JACC No. 41 n-Butanol (CAS No. 71-36-3) ECETOC JACC No. 41 n-Butanol (CAS No. 71-36-3) EXECUTIVE SUMMARY This report has been produced as part of the ECETOC Joint Assessment of Commodity Chemicals (JACC) programme. It presents a critical evaluation of the toxicity and ecotoxicity data of n-butanol (nBA). Since the last comprehensive review of nBA by IPCS a in 1987, new data have become available. A hazard/risk assessment will be required under current OECD/EU schemes b,c. nBA is a colourless liquid that is primarily used as an intermediate in the manufacture of other chemicals, and in solvent applications. If nBA is released into the environment (airborne), a major part will be distributed to the water compartment. nBA is rapidly degraded in air and water; little accumulation in soil, biota, sediment or suspended matter is anticipated. nBA has a low order of toxicity at all trophic levels. nBA is readily absorbed through the lungs of humans and laboratory animals and can also penetrate the skin. Following absorption, nBA is rapidly metabolised, ultimately to CO2, with small amounts being eliminated in urine as glucuronide and sulphate conjugates. When administered in single doses to laboratory animals by gavage, inhalation or application to the skin, nBA exhibits a low order of toxicity. Available information on the effects of nBA following repeated exposure is supplemented in this report by data on n-butyl acetate, an ester that hydrolyses to form nBA and acetic acid within minutes of entering systemic circulation. The typical effect of high doses of nBA following single or repeated exposure is a transient, depression (narcosis) of the central nervous system, which is commonly seen with other short chain alkyl alcohols. Specific neurotoxicity is not observed. Specific target organs and selective toxicity have not been identified. nBA is not genotoxic and there is no concern for carcinogenic potential. nBA showed some foetotoxicity in laboratory animals at high concentrations that were toxic to the mother, but is devoid of selective developmental toxicity. Male or female fertility is not adversely affected, as shown by studies with n-butyl acetate. Earlier reports describing neurotoxicity and hearing loss in workers exposed to nBA have not been substantiated. In humans, nBA is slightly to moderately irritant to the skin on prolonged contact, and moderately irritant to the eyes. a IPCS Environmental Health Criteria Documents [http://www.who.int/pcs/ra_site/ehc.html] b OECD Existing Chemicals Programme [http://www1.oecd.org/ehs/hazard.htm] c EU Existing Chemicals Work Area [http://ecb.ei.jrc.it/existing-chemicals/] 1 ECETOC JACC No. 41 n-Butanol (CAS No. 71-36-3) THE ECETOC SCHEME FOR THE JOINT ASSESSMENT OF COMMODITY CHEMICALS This report has been produced by an ECETOC Task Force as part of the Joint Assessment of Commodity Chemicals (JACC) programme for preparing critical reviews of the toxicology and ecotoxicology of selected existing industrial chemicals. In the programme, commodity chemicals (i.e. those produced in large tonnage by several companies and having widespread and multiple uses) are jointly reviewed by experts from a number of companies with knowledge of the chemical. It should be noted that in a JACC review only the chemical itself is considered; products in which it appears as an impurity are not normally taken into account. This report presents a critical evaluation of the toxicology, ecotoxicology and physico-chemical properties of n-butanol (nBA; CAS No. 71-36-3). This information is supplemented by toxicological data on n-butyl acetate, which is rapidly hydrolysed in vivo to nBA and acetic acid. Where relevant, the Task Force has assigned a Code of Reliability (CoR) a to (eco)toxicological studies to reflect the degree of confidence that can be placed on the reported results. The criteria used to assess and categorise reliability are included in Appendix B. a A list of special abbreaviations is given at Appendix A 2 ECETOC JACC No. 41 n-Butanol (CAS No.