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The Toxicology of Glycol Ethers and Its Relevance to Man (Fourth Edition) Volume I

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The Toxicology of Glycol Ethers and Its Relevance to Man (Fourth Edition) Volume I The Toxicology of Glycol Ethers and its Relevance to Man (Fourth Edition) Volume I Technical Report No. 95 ISSN-0773-8072-95 Brussels, February 2005 The Toxicology of Glycol Ethers and its Relevance to Man ECETOC TECHNICAL REPORT No. 95 © Copyright – ECETOC AISBL 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 TR No. 95 The Toxicology of Glycol Ethers and its Relevance to Man The Toxicology of Glycol Ethers and its Relevance to Man CONTENTS - VOLUMES I AND II EXECUTIVE SUMMARY 1 SUMMARY AND CONCLUSIONS 3 Recommendations for further work 13 1. INTRODUCTION 14 1.1 Conversion factors and physico-chemical properties 14 1.2 Production and use 14 1.2.1 Manufacture of ethylene-series glycol ethers 14 1.2.2 Manufacture of propylene-series glycol ethers 15 1.2.3 Uses 15 2. TOXICOLOGICAL OVERVIEW 17 2.1 Acute toxicity 17 2.2 Irritation and sensitisation 18 2.3 Repeated-dose toxicity 19 2.3.1 Effects on the haematopoietic system and the peripheral blood 19 2.3.2 Testes 21 2.3.3 Kidney 22 2.3.4 Liver 22 2.3.5 Lymphatic tissue and immunotoxicity 23 2.3.6 Neurological effects 24 2.4 Genotoxicity and cell transformation 24 2.4.1 Evaluation 25 2.5 Chronic toxicity and carcinogenicity 25 2.5.1 Evaluation 27 2.6 Reproductive and edevelopmental toxicity 27 2.6.1 Evaluation 28 2.7 Absorption, distribution, metabolism and elimination 28 2.7.1 Absorption and distribution 28 2.7.2 Metabolism and elimination 29 2.7.3 Summary and conclusions 34 2.8 Cardiac sensitisation 35 2.9 Neurotoxicity 35 3. HUMAN EXPOSURE AND HEALTH EFFECTS 37 3.1 Human exposure 37 3.1.1 Human volunteer studies 37 3.1.2 Consumer exposure 41 3.1.3 Occupational exposure 42 ECETOC TR No. 95 The Toxicology of Glycol Ethers and its Relevance to Man 3.1.4 Measurement methods 56 3.2 Health effects 59 3.2.1 Haematological effects 60 3.2.2 Behavioural and neurological effects 62 3.2.3 Reproductive effects 63 3.2.4 Other effects, including poisoning 67 3.3 Occupational exposure limit values 72 4. SUBSTANCE PROFILES (VOLUME II/CD) 73 4.1 Substance profile: EGME 4.2 Substance profile: EGMEA 4.3 Substance profile: EGDME 4.4 Substance profile: DEGME 4.5 Substance profile: DEGDME 4.6 Substance profile: TEGME 4.7 Substance profile: TEGDME 4.8 Substance profile: MAA 4.9 Substance profile: EGEE 4.10 Substance profile: EGEEA 4.11 Substance profile: EGDEE 4.12 Substance profile: DEGEE 4.13 Substance profile: DEGEEA 4.14 Substance profile: DEGDEE 4.15 Substance profile: TEGEE 4.16 Substance profile: EGiPE 4.17 Substance profile: EGiPEA 4.18 Substance profile: EGnPE 4.19 Substance profile: EGnPEA 4.20 Substance profile: EGPhE 4.21 Substance profile: EGBE 4.22 Substance profile: EGBEA 4.23 Substance profile: DEGBE 4.24 Substance profile: DEGBEA 4.25 Substance profile: TEGBE 4.26 Substance profile: EGHE 4.27 Substance profile: DEGHE 4.28 Substance profile: 2PG1ME 4.29 Substance profile: 2PG1MEA 4.30 Substance profile: 1PG2ME 4.31 Substance profile: 1PG2MEA 4.32 Substance profile: DPGME 4.33 Substance profile: TPGME 4.34 Substance profile: 2PG1EE 4.35 Substance profile: 2PG1EEA 4.36 Substance profile: DPGEE 4.37 Substance profile: PGPE 4.38 Substance profile: DPGPE ECETOC TR No. 95 The Toxicology of Glycol Ethers and its Relevance to Man 4.39 Substance profile: 2PG1PhE 4.40 Substance profile: 2PG1BE 4.41 Substance profile: DPGBE 4.42 Substance profile: TPGBE 4.43 Substance profile: PGTBE 4.44 Substance profile: DPGTBE 5. BIBLIOGRAPHY 74 5.1 Databases consulted 74 5.2 References quoted 74 5.3 References not quoted 159 APPENDIX A: SPECIAL ABBREVIATIONS 170 APPENDIX B: CONVERSION FACTORS FOR VAPOUR CONCENTRATIONS IN AIR 173 APPENDIX C: OCCUPATIONAL EXPOSURE LIMIT VALUES 174 MEMBERS OF THE TASK FORCE 194 MEMBERS OF THE SCIENTIFIC COMMITTEE 196 ECETOC TR No. 95 The Toxicology of Glycol Ethers and its Relevance to Man EXECUTIVE SUMMARY This report provides an update of an earlier ECETOC review a of a number of important ethylene and propylene glycol mono-ethers and di-ethers (glymes). It includes substantial new information concerning the human health consequences of exposure to this class of chemicals. The report presents toxicity data profiles for each individual compound. Glycol mono-ethers are liquids that combine the solubility characteristics of ethers and alcohols since both functional groups are present. As a result, they are widely used in solvent applications, including formulations such as paints, inks and cleaning fluids. Non-solvent applications include uses as anti-icing agents in jet fuel, hydraulic system fluids and as chemical intermediates. The hazard assessment of several glycol ethers can be based on short-term exposure studies because long-term exposure have not lead to more severe or different systemic effects. Glycol ethers have the potential to penetrate the skin (as a liquid or vapour) and this, therefore, represents a potentially significant route of exposure. The majority of glycol ethers are of low acute toxicity; the main effect seen in laboratory animals at high doses is narcosis, typical of many solvents. Some glycol ethers are eye irritants. Overall, numerous studies with glycol ethers show that they do not exhibit genotoxic activity. The results of carcinogenicity studies with glycol ethers are consistent with this lack of genotoxic activity. The systemic toxicity of the ethylene-based glycol ethers is mediated by their metabolism to the corresponding alkoxyacetic acids. Methyl- and ethyl-substituted ethylene glycol ethers can cause bone marrow depression, testicular atrophy, developmental toxicity, and immunotoxicity in animals. It should be noted that methyl- and ethyl-ethers of ethylene glycol are not used in consumer products in Europe. In contrast, the longer chain ethylene glycol ethers (ethylene glycol butyl ether, -propyl ether, -isopropyl ether and -phenyl ether) do not cause any of these effects. Toxicity commonly associated with the longer chain homologues involves red blood cell haemolysis (anaemia), to which humans are resistant. The alkoxyacetic acid metabolites of glycol ethers are responsible for the haemolysis. None of the ethylene-bond effects have been observed for the propylene glycol ethers (α-isomers in commercial products); they are secondary alcohols and cannot be metabolised to their corresponding alkoxypropionic acids. Propylene glycol ethers are dealkylated to propylene glycol and then oxidised. The only change observed with propylene glycol ethers is an adaptive liver response and male rat kidney toxicity, which is not considered relevant to humans. a ECETOC. 1995. The toxicology of glycol ethers and its relevance to man. Technical Report 64. European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels, Belgium [ISSN-0773-8072-64] ECETOC TR No. 95 1 The Toxicology of Glycol Ethers and its Relevance to Man Reports of a number of effects in humans have been associated with glycol ether exposure, such as anaemia, granulocytopenia and leukopenia, increased risk of abortion or reduced sperm count in painters. Many such reports relate to methyl- and ethyl-substituted glycol ethers and are confounded by simultaneous exposures to other chemicals as well as limited information on exposure levels, which do not allow firm conclusions to be made concerning the contribution of glycol ethers to the observed effects. The toxicological findings reported to date indicate that, except for haemolytic anaemia and the liver and kidney effects in long-term studies, the effects seen in animals are also relevant to humans. ECETOC TR No. 95 2 The Toxicology of Glycol Ethers and its Relevance to Man SUMMARY AND CONCLUSIONS Glycol mono-ethers are liquids that combine the solubility characteristics of ethers and alcohols since both functional groups are present in the molecule. They are therefore widely used in solvent applications, including formulations such as paints, inks and cleaning fluids. Non-solvent applications include uses as anti-icing agents in jet fuel, hydraulic system fluids and as chemical intermediates. The majority of glycol ethers are of low acute toxicity. Clinical signs of acute intoxication in animals are consistent with non-specific depression of the central nervous system, which is typical of many solvents. Lethargy and haemoglobinuria have been observed in glycol ethers that produced haemolysis in rodents. Although some glycol ethers are irritant to the eye, most are not, and none are appreciably irritant to the skin on acute exposure. As with other solvents, prolonged or repeated skin exposure may lead to a severe skin irritation. It is recognised that the glycol ether class lacks specific determinants for either genotoxicity or carcinogenicity. Negative results obtained in conventional genotoxicity assays, both in vivo and in vitro, confirm the lack of genotoxic activity for this class of solvents. Some glycol ethers have been tested in life-time studies in rats and mice, including ethylene glycol ethyl ether, ethylene glycol n-butyl ether, diethylene glycol ethyl ether, 2-propylene glycol 1-methyl ether and propylene glycol tert-butyl ether.
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