Scientific review on the link between the narcotic effects of solvents and (developmental) neurotoxicity Final report Prepared for ECHA Contract Number : ECA.6677-E3 DMG de Groot Cerespark 1, 5844AE Stevensbeek, NL March 2017 Scientific Review (Final Report, R1): OECD TG 443, Organic Solvents, DNT triggers 14 March 2017 Scientific review on the link between the narcotic effects of solvents and (developmental) neurotoxicity Contract Number: ECA.6677-E3 March 2017 Final Report Prepared for the European Chemicals Agency (ECHA) by DMG de Groot PhD, ERT Cerespark 1, 5844AE Stevensbeek, NL Tel: +31 644 163 121 Email: [email protected] Document Change Record Report Version Date Change details Outline 31 Augustus 2016 Draft Final report V1 30 September 2016 Prepared in light of ECHA comments discussed (by teleconference) 25-08-2016; 09-09-2016 Draft Final report R1 02 October 2016 Finetuning (referenceslist; tables) Draft Final report R2 25 October 2016 Revised in light of (written) ECHA comments Draft Final report R3 22 November 2016 Revised in light of ECHA comments discussed (by teleconference) 10-11-2016 Final report V1 09 January 2017 Completed in light of (written) ECHA comments Final report R1 14 March 2017 Finetuning (executive summary; chapter numbering) in light of ECHA comments discussed (by teleconference) 02-03-2017 Disclaimer The views and propositions expressed herein are, unless otherwise stated, those of DMG de Groot and do not necessarily represent any official view of ECHA. DMG de Groot PhD, ERT i Scientific Review (Final Report, R1): OECD TG 443, Organic Solvents, DNT triggers 14 March 2017 Table of Contents Document Change Record ..…………………………………………………………………………………………..…………..….….. i Disclaimer ..…………………………………………………………………………………………..…………………………………..….….. i Table of Contents ………………………………………………………………………………………..………………………………...... ii Glossary ………………………………………………………………………………………………………………………..…………..….… vi Executive summary …………………………………………………………………………………………………..…………………... viii 1 INTRODUCTION .................................................................................................................. 1 1.1 Introduction .............................................................................................................................. 1 1.2 Organic solvents ................................................................................................................ 2 1.2.1 How are organic solvents defined in this review? …………………………………………………………….…… 2 1.2.2 Solvent properties: volatility, lipophilicity and small molecule size …………………..…………..……… 3 1.2.3 Narcotic effects of organic solvents …………………………………………………….…………..….………...….… 3 1.2.4 How are ‘narcosis’, ‘anesthesia’ and ‘narcotic organic solvents’ defined in this review?.......... 4 1.2.5 On the mechanism(s) of narcotic/neurologic effects of narcotic organic solvents ….…….....…… 5 1.2.6 Solvents: usage and exposure ………………………………………………………………………………….………..… 6 1.3 Narcotic organic solvents and (developmental) neurotoxicity …………………………………...….… 7 1.3.1 Research on Organic Solvents and (developmental) Neurotoxicity ……………………………….…...… 7 2 METHODS ………………………………………………………………………………………………………………..……. 10 2.1 Selection, grouping and evaluation of narcotic organic solvents ………………………………..….. 10 2.1.1 Selection of narcotic organic solvents (harmonized classification as STOT SE 3: H336) and developmental neurotoxicity (Annexes 4, 5, 6) …………………………………….…….…..… 10 2.1.2 Grouping of selected narcotic organic solvents classified as STOT SE 3: H336 (Annex 7) …………………………………………………………………………………………………………….….… 10 3 RESULTS ……………………………………………………………………………………………………..…………….…… 12 3.1 Presentation of grouping, narcosis and neurotoxicity of selected narcotic organic solvents ………………………………………..………………………………………………………………....… 12 3.1.1 Narcotic effects and/or (developmental) neurotoxicity of selected and grouped narcotic organic solvents (harmonized classification as STOT SE 3: H336) (Table 1) ………………...….…... 12 3.2 Evaluation of grouping, narcosis and neurotoxicity of selected narcotic organic solvents …..…………………………………………………………………………………………………….….. 15 3.2.1 Narcosis and/or neurotoxicity of selected organic solvents: main grouping (Table 1) ….…..… 15 DMG de Groot PhD, ERT ii Scientific Review (Final Report, R1): OECD TG 443, Organic Solvents, DNT triggers 14 March 2017 3.2.2 Neurologic effects of the organic solvents presented in Table 1: individual results ………....…. 15 3.2.3 Summary / Conclusions on grouping of the narcotic organic solvents, the narcosis and neurotoxicity …………………………………………………………………………………………....…… 17 4. DISCUSSION ……………………………………………………………………………………………………………....…. 18 4.1 Grouping of the selected solvents based on chemical structure and polarity ……………...…. 18 4.1.1 Narcosis and neurotoxicity of grouped organic solvents based on chemical structure .…….... 18 4.1.2 Narcosis and neurotoxicity of grouped organic solvents: polarity ranking …………………….…… 18 4.2 Evaluation of potential target molecules for narcosis and/or neurotoxicity ………………..…. 19 4.2.1 Narcotic/neurologic effects following acute exposure to organic solvents …………………..…..… 19 4.2.2 Narcotic/neurologic effects following sub-chronic /chronic (low-level) exposure to organic solvents ………………………………………………………………………………………………….…..….….19 4.2.3.1 Excitatory ion channel receptors: NMDA-glutamate receptor ……………………………………..…….. 20 4.2.3.2 Toluene exposure and NMDA-glutamate receptor …………………………………………………..….……… 20 4.2.4.1 Inhibitory ion channel receptors: GABA receptor ………………………………………………………..……… 21 4.2.4.2 Toluene, Propofol, and GABA receptor ………………………………………………………………………….….… 21 4.2.5 Unique behavior of GABAA (NMDA and AMPA) during nervous system development …………. 22 4.2.6 Dopamine and suspected organic solvent-induced neurodegenerative diseases ……….…..…… 23 5. REFERENCES …………………………………………………………………………………………………………………… 25 ANNEX 1 ………………………………………………………………………………………………………………………………...… 43 A1 Solvents: usage and exposure ……………………………………………………………………………….……… 43 ANNEX 2………………………………………………………………………………………………………………………..……….…. 44 A 2 Development of the nervous system ……………………………………………………………………….…..… 44 A2.1 Stem cells, neurons and glial cells …………………………………………………………………………..…………. 44 A2.2 Neurotrophic factors …………………………………………………………………………………..…………………….. 45 A2.3 Stages of brain development ………………………………………………………………………………………….……45 A2.4 Duration and completion of the different developmental processes ………………………….….…… 46 A2.5 Outgrowth of dendrites and axons …………………………………………………………………….………….….. 47 A2.6 Apoptosis / Synapse pruning ……………………………………………………………………………………….…..… 47 ANNEX 3 …………………………………………………………………………………………………………………………………… 48 A3 Considerations for grouping organic solvents for narcosis and neurotoxicity …….…….….… 48 DMG de Groot PhD, ERT iii Scientific Review (Final Report, R1): OECD TG 443, Organic Solvents, DNT triggers 14 March 2017 A3.1 Chemical structure and physical-chemical properties …………………………………………………….. 48 A3.1.1 Substance with strong electrophilic character …………………………………………………………..…….…. 48 A3.1.2 Toxic metabolite ……………………………………………………………………………………………………….…….…. 48 A3.1.3 D-structure of the molecule …………………………………………………………………………………………….…. 49 A3.1.4 The reporting by different sources on the physical-chemical properties of a substance ……… 49 A3.2 Grouping of solvents based on physical-chemical properties …………………………………………. 49 A3.2.1 Example from the literature (McKee et al., 2015) ………………………………………………………………. 49 Blanc page …………………………………………………………………………….……………………………………………………….. 51 ANNEX 4 ……………………………………………………………………………………………………………………………...……. 52 A4.1 Substances registered under REACH with harmonised classification as STOT SE 3: H336 ... 52 A4.1.1 References to Annexes 4, 5, 6 …………………………..………………………………………………………..…..…. 53 A4.1.2 Table with selection of narcotic organic solvents (taken from ECHA dissemination site) ….… 59 ANNEX 5 …………………………………………………………………………………………………………………………….……… 97 A5.1 Articles, reports and other documents searched and studied for this review ……………..….. 97 A5.1.1 Table with Articles, reports and documents (complete references included) ………………………. 98 Blanc page …………………………………………………………………………….…………………………………………………….. 136 ANNEX 6…………………………………………………………………………………………………………………………………… 137 A6.1 Information on developmental neurotoxicity derived from Annexes 4 and 5 ………..…..… 137 A6.1.1 Information on developmental neurotoxicity, derived from Annex 4 ……………………..…..…… 138 A6.1.2 Information on developmental neurotoxicity, derived from Annex 5 …………………….……….… 143 Blanc page …………………………………………………………………………….…………………………………………………….. 174 ANNEX 7 ………………………………………………………………………………………………………………………………….. 175 A7.1 Detailed information on grouping of selected narcotic organic solvents ………..…………….. 175 A7.1.1 Abbreviations to Annex 7 ………………………………………………………………………………..…………..…… 176 DMG de Groot PhD, ERT iv Scientific Review (Final Report, R1): OECD TG 443, Organic Solvents, DNT triggers 14 March 2017 A7.1.2 Table with detailed information on grouping of selected narcotic organic solvents …….…... 177 Blanc page …………………………………………………………………………….…………………………………………………….. 226 ANNEX 8 ………………………………………………………………………………………………………………………………..… 227 A8 Organic solvents and ion channel receptors ……………………………………………………………….… 227 A8.1 Excitatory ion channel receptors ………………………………………………………………………….….…… 227 A8.1.1 NMDA-glutamate receptor ………………………………………………………………………………….…………… 227 A8.2 Inhibitory ion channel receptors ………………………………………………..………………………………… 227 A8.2.1 Gamma aminobutyric acid-A (GABAA ) ………………………………………….……………………..………..…