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Published in: International Archives of Occupational and Environmental Health 8/2018

Open Access 01-11-2018 | Original Article

Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014

Authors: Nadin Ulrich, Daniel Bury, Holger M. Koch, Maria Rüther, Till Weber, Heiko-Udo Käfferlein, Tobias Weiss, Thomas Brüning, Marike Kolossa-Gehring

Published in: International Archives of Occupational and Environmental Health | Issue 8/2018

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Abstract

Purpose

The aim of this study was to get a first overview of the exposure to the solvents and reproductive toxicants N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP) in Germany. NMP and NEP metabolite concentrations were determined in 540 24-h urine samples of the German Environmental Specimen Bank collected from 1991 to 2014. With these data we were able to investigate NMP/NEP exposures over time and to evaluate associated risks.

Methods

NMP metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) and NEP metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) were determined by stable isotope dilution analysis using solid phase extraction followed by derivatization (silylation) and GC–EI–MS/MS.

Results

We were able to quantify 5-HNMP and 2-HMSI in 98.0 and 99.6% and 5-HNEP and 2-HESI in 34.8 and 75.7% of the samples. Metabolite concentrations were rather steady over the timeframe investigated, even for NEP which has been introduced as an NMP substitute only in the last decade. Calculated median daily intakes in 2014 were 2.7 µg/kg bw/day for NMP and 1.1 µg/kg bw/day for NEP. For the combined risk assessment of NMP and NEP exposure, the hazard index based on the human biomonitoring assessment I values (HBM I values) was less than 0.1.

Conclusions

Based on the investigated subpopulation of the German population, individual and combined NMP and NEP exposures were within acceptable ranges in the investigated timeframe. Sources of NEP exposure in the 90s and 00s remain elusive.
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Literature
go back to reference Åkesson B, Carnerup MA, Jönsson BAG (1997) Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metab Dispos 25:267–269 Åkesson B, Carnerup MA, Jönsson BAG (1997) Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metab Dispos 25:267–269
go back to reference Åkesson B, Carnerup MA, Jönsson BAG (2004) Evaluation of exposure biomarkers from percutaneous absorption of N-methyl-2-pyrrolidone. Scand J Work Environ Health 30:306–312CrossRef Åkesson B, Carnerup MA, Jönsson BAG (2004) Evaluation of exposure biomarkers from percutaneous absorption of N-methyl-2-pyrrolidone. Scand J Work Environ Health 30:306–312CrossRef
go back to reference Apel P, Angerer J, Wilhelm M, Kolossa-Gehring M (2017) New HBM values for emerging substances, inventory of reference and HBM values in force, and working principles of the German Human Biomonitoring Commission 220. Int J Hyg Environ Health (2 Pt A):152–166CrossRef Apel P, Angerer J, Wilhelm M, Kolossa-Gehring M (2017) New HBM values for emerging substances, inventory of reference and HBM values in force, and working principles of the German Human Biomonitoring Commission 220. Int J Hyg Environ Health (2 Pt A):152–166CrossRef
go back to reference Bader M, Wrbitzky R, Blaszkewicz M, Schäper M, van Thriel C (2008) Human volunteer study on the inhalational and dermal absorption of N-methyl-2-pyrrolidone (NMP) from the vapour phase. Arch Toxicol 82:13–20CrossRef Bader M, Wrbitzky R, Blaszkewicz M, Schäper M, van Thriel C (2008) Human volunteer study on the inhalational and dermal absorption of N-methyl-2-pyrrolidone (NMP) from the vapour phase. Arch Toxicol 82:13–20CrossRef
go back to reference Bader M, Wrbitzky R, Blaszkewicz M, van Thriel C (2007) Human experimental exposure study on the uptake and urinary elimination of N-methyl-2-pyrrolidone (NMP) during simulated workplace conditions. Arch Toxicol 8:335–346CrossRef Bader M, Wrbitzky R, Blaszkewicz M, van Thriel C (2007) Human experimental exposure study on the uptake and urinary elimination of N-methyl-2-pyrrolidone (NMP) during simulated workplace conditions. Arch Toxicol 8:335–346CrossRef
go back to reference Becker K, Conrad A, Kirsch N, Kolossa-Gehring M, Schulz C, Seiwert M, Seifert B (2007) German Environmental Survey (GerES): human biomonitoring as a tool to identify exposure pathways. Int J Hyg Environ Health 210: 267–269CrossRef Becker K, Conrad A, Kirsch N, Kolossa-Gehring M, Schulz C, Seiwert M, Seifert B (2007) German Environmental Survey (GerES): human biomonitoring as a tool to identify exposure pathways. Int J Hyg Environ Health 210: 267–269CrossRef
go back to reference Bekanntmachung des Umweltbundesamtes (2015) Stoffmonographie für N-Methyl-2-pyrrolidon (NMP) und “Human-Biomonitoring"-Werte für die Metaboliten 5-Hydroxy-NMP und 2-Hydroxy-N-methylsuccinimid im Urin von Erwachsenen und Kindern. Stellungnahme der Kommission “Human-Biomonitoring” des Umweltbundesamtes 58. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 10:1175–1191 Bekanntmachung des Umweltbundesamtes (2015) Stoffmonographie für N-Methyl-2-pyrrolidon (NMP) und “Human-Biomonitoring"-Werte für die Metaboliten 5-Hydroxy-NMP und 2-Hydroxy-N-methylsuccinimid im Urin von Erwachsenen und Kindern. Stellungnahme der Kommission “Human-Biomonitoring” des Umweltbundesamtes 58. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 10:1175–1191
go back to reference Commission Regulation (EU) No 317/2014 of 27 March 2014 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annex XVII (CMR substances). Off J Eur Union L 93, 28.3.2014, pp. 24–27 Commission Regulation (EU) No 317/2014 of 27 March 2014 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annex XVII (CMR substances). Off J Eur Union L 93, 28.3.2014, pp. 24–27
go back to reference Commission Regulation (EC) No 790/2009 of 10 August 2009 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures. Off J Eur Union L 235, 05.09.2009, pp. 1–439 Commission Regulation (EC) No 790/2009 of 10 August 2009 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures. Off J Eur Union L 235, 05.09.2009, pp. 1–439
go back to reference Commission Regulation (EU) No 944/2013 of 2 October 2013 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures. Off J Eur Union L 261, 03.10.2013, pp. 5–22 Commission Regulation (EU) No 944/2013 of 2 October 2013 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures. Off J Eur Union L 261, 03.10.2013, pp. 5–22
go back to reference Conrad A, Schröter-Kermani C, Hoppe HW, Rüther M, Pieper S, Kolossa-Gehring M (2017) Glyphosate in German adults—time trend (2001 to 2015) of human exposure to a widely used herbicide. International Journal of Hygiene and Environmental Health (220), pp. 8–16CrossRef Conrad A, Schröter-Kermani C, Hoppe HW, Rüther M, Pieper S, Kolossa-Gehring M (2017) Glyphosate in German adults—time trend (2001 to 2015) of human exposure to a widely used herbicide. International Journal of Hygiene and Environmental Health (220), pp. 8–16CrossRef
go back to reference ECHA (2011) Annex 1 Background document to the Opinion proposing harmonised classification and labelling at Community level of N-ethyl-2-pyrrolidone (NEP). ECHA/RAC/CLH-O-0000002192-83-01/A1, checked on 8/28/2016 ECHA (2011) Annex 1 Background document to the Opinion proposing harmonised classification and labelling at Community level of N-ethyl-2-pyrrolidone (NEP). ECHA/RAC/CLH-O-0000002192-83-01/A1, checked on 8/28/2016
go back to reference ECHA (2013) Annex XV restriction report proposal for a restriction—NMP, checked on 8/28/2016 ECHA (2013) Annex XV restriction report proposal for a restriction—NMP, checked on 8/28/2016
go back to reference Fink JK (2011) Chapter 9: Poly(vinylpyrrolidone). In: Handbook of engineering and specialty thermoplastics, Volume 2: water soluble polymers. Wiley, Hoboken, Salem Fink JK (2011) Chapter 9: Poly(vinylpyrrolidone). In: Handbook of engineering and specialty thermoplastics, Volume 2: water soluble polymers. Wiley, Hoboken, Salem
go back to reference Koch HM, Bader M, Weiss T, Koslitz S, Schütze A, Kafferlein H-U, Brüning T (2014) Metabolism and elimination of N-ethyl-2-pyrrolidone (NEP) in human males after oral dosage. Arc Toxicol 88:893–899CrossRef Koch HM, Bader M, Weiss T, Koslitz S, Schütze A, Kafferlein H-U, Brüning T (2014) Metabolism and elimination of N-ethyl-2-pyrrolidone (NEP) in human males after oral dosage. Arc Toxicol 88:893–899CrossRef
go back to reference Koch HM, Kolossa-Gehring M, Schröter-Kermani C, Angerer J, Brüning T (2012) Bisphenol A in 24 h urine and plasma samples of the German Environmental Specimen Bank from 1995 to 2009: a retrospective exposure evaluation. J Expo Sci Environ Epidemiol 22:610–616CrossRef Koch HM, Kolossa-Gehring M, Schröter-Kermani C, Angerer J, Brüning T (2012) Bisphenol A in 24 h urine and plasma samples of the German Environmental Specimen Bank from 1995 to 2009: a retrospective exposure evaluation. J Expo Sci Environ Epidemiol 22:610–616CrossRef
go back to reference Koch HM, Rüther M, Schütze A, Conrad A, Pälmke C, Apel P, Brüning T, Kolossa-Gehring M (2017) Phthalate metabolites in 24-h urine samples of the German Environmental Specimen Bank (ESB) from 1988 to 2015 and a comparison with US NHANES data from 1999 to 2012. Int J Hyg Environ Health 220:130–141CrossRef Koch HM, Rüther M, Schütze A, Conrad A, Pälmke C, Apel P, Brüning T, Kolossa-Gehring M (2017) Phthalate metabolites in 24-h urine samples of the German Environmental Specimen Bank (ESB) from 1988 to 2015 and a comparison with US NHANES data from 1999 to 2012. Int J Hyg Environ Health 220:130–141CrossRef
go back to reference Kolossa-Gehring M, Becker K, Conrad A, Schröter-Kermani C, Schulz C, Seiwert M (2012) Environmental surveys, specimen bank and health related environmental monitoring in Germany. Int J Hyg Environ Health 215: 120–126CrossRef Kolossa-Gehring M, Becker K, Conrad A, Schröter-Kermani C, Schulz C, Seiwert M (2012) Environmental surveys, specimen bank and health related environmental monitoring in Germany. Int J Hyg Environ Health 215: 120–126CrossRef
go back to reference Kolossa-Gehring M, Fiddicke U, Leng G, Angerer J, Wolz B (2017) New human biomonitoring methods for chemicals of concern—the German approach to enhance relevance. Int J Hyg Environ Health 220:103–112CrossRef Kolossa-Gehring M, Fiddicke U, Leng G, Angerer J, Wolz B (2017) New human biomonitoring methods for chemicals of concern—the German approach to enhance relevance. Int J Hyg Environ Health 220:103–112CrossRef
go back to reference Kortenkamp A, Faust M (2010) Combined exposures to anti-androgenic chemicals: steps towards cumulative risk assessment. Int J Androl 2: 463–474CrossRef Kortenkamp A, Faust M (2010) Combined exposures to anti-androgenic chemicals: steps towards cumulative risk assessment. Int J Androl 2: 463–474CrossRef
go back to reference Koslitz S, Meier S, Schindler BK, Weiss T, Koch HM, Brüning T, Käfferlein HU (2014) Biomonitoring of N-ethyl-2-pyrrolidone in automobile varnishers. Toxicol Lett 231:142–146CrossRef Koslitz S, Meier S, Schindler BK, Weiss T, Koch HM, Brüning T, Käfferlein HU (2014) Biomonitoring of N-ethyl-2-pyrrolidone in automobile varnishers. Toxicol Lett 231:142–146CrossRef
go back to reference Lermen D, Schmitt D, Bartel-Steinbach M, Schröter-Kermani C, Kolossa-Gehring M, von Briesen H, Zimmermann H (2014) A new approach to standardize multicenter studies: mobile lab technology for the German Environmental Specimen Bank. PLoS ONE 9(8), e105401CrossRef Lermen D, Schmitt D, Bartel-Steinbach M, Schröter-Kermani C, Kolossa-Gehring M, von Briesen H, Zimmermann H (2014) A new approach to standardize multicenter studies: mobile lab technology for the German Environmental Specimen Bank. PLoS ONE 9(8), e105401CrossRef
go back to reference Meier S, Schindler BK, Koslitz S, Koch HM, Weiss T, Käfferlein HU, Brüning T (2013) Biomonitoring of exposure to N-methyl-2-pyrrolidone in workers of the automobile industry. Ann Occup Hyg 57:766–773 Meier S, Schindler BK, Koslitz S, Koch HM, Weiss T, Käfferlein HU, Brüning T (2013) Biomonitoring of exposure to N-methyl-2-pyrrolidone in workers of the automobile industry. Ann Occup Hyg 57:766–773
go back to reference Moos RK, Koch HM, Angerer J, Apel P, Schröter-Kermani C, Brüning T, Kolossa-Gehring M (2015) Parabens in 24 h urine samples of the German Environmental Specimen Bank from 1995 to 2012. Int J Hyg Environ Health 218:666–674CrossRef Moos RK, Koch HM, Angerer J, Apel P, Schröter-Kermani C, Brüning T, Kolossa-Gehring M (2015) Parabens in 24 h urine samples of the German Environmental Specimen Bank from 1995 to 2012. Int J Hyg Environ Health 218:666–674CrossRef
go back to reference Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. Off J Eur Union L 353, 31.12.2008, pp. 1–1355 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. Off J Eur Union L 353, 31.12.2008, pp. 1–1355
go back to reference Saillenfait AM, Gallissot F, Langonné I, Sabaté JP (2002) Developmental toxicity of N-methyl-2-pyrrolidone administered orally to rats. Food Chem Toxicol 40:1705–1712CrossRef Saillenfait AM, Gallissot F, Langonné I, Sabaté JP (2002) Developmental toxicity of N-methyl-2-pyrrolidone administered orally to rats. Food Chem Toxicol 40:1705–1712CrossRef
go back to reference Saillenfait AM, Gallissot F, Morel G (2003) Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation exposure. Food Chem Toxicol 41(4):583–588CrossRef Saillenfait AM, Gallissot F, Morel G (2003) Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation exposure. Food Chem Toxicol 41(4):583–588CrossRef
go back to reference Saillenfait AM, Gallissot F, Sabate JP (2007b) Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats. J Appli Toxicol 27:491–497CrossRef Saillenfait AM, Gallissot F, Sabate JP (2007b) Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats. J Appli Toxicol 27:491–497CrossRef
go back to reference Saillenfait AM, Sabaté JP, Gallissot F (2007a) Comparative developmental toxicities of the three major metabolites of N-methyl-2-pyrrolidone after oral administration in rats. J Appl Toxicol 27(6):571–581CrossRef Saillenfait AM, Sabaté JP, Gallissot F (2007a) Comparative developmental toxicities of the three major metabolites of N-methyl-2-pyrrolidone after oral administration in rats. J Appl Toxicol 27(6):571–581CrossRef
go back to reference Schindler BK, Koslitz S, Meier S, Belov VN, Koch HM, Weiss T et al (2012) Quantification of four major metabolites of embryotoxic N-methyl- and N-ethyl-2-pyrrolidone in human urine by cooled-injection gas chromatography and isotope dilution mass spectrometry. Anal Chem 84: 3787–3794CrossRef Schindler BK, Koslitz S, Meier S, Belov VN, Koch HM, Weiss T et al (2012) Quantification of four major metabolites of embryotoxic N-methyl- and N-ethyl-2-pyrrolidone in human urine by cooled-injection gas chromatography and isotope dilution mass spectrometry. Anal Chem 84: 3787–3794CrossRef
go back to reference Schröter-Kermani C, Müller J, Jürling H, Conrad A, Schulte C (2013) Retrospective monitoring of perfluorocarboxylates and perfluorosulfonates in human plasma archived by the German Environmental Specimen Bank. Int J Hyg Environ Health 216:633–640CrossRef Schröter-Kermani C, Müller J, Jürling H, Conrad A, Schulte C (2013) Retrospective monitoring of perfluorocarboxylates and perfluorosulfonates in human plasma archived by the German Environmental Specimen Bank. Int J Hyg Environ Health 216:633–640CrossRef
go back to reference Schütze A, Gries W, Kolossa-Gehring M, Apel P, Schröter-Kermani C, Fiddicke U et al (2015) Bis-(2-propylheptyl)phthalate (DPHP) metabolites emerging in 24 h urine samples from the German Environmental Specimen Bank (1999–2012). Int J Hyg Environ Health 218:559–563CrossRef Schütze A, Gries W, Kolossa-Gehring M, Apel P, Schröter-Kermani C, Fiddicke U et al (2015) Bis-(2-propylheptyl)phthalate (DPHP) metabolites emerging in 24 h urine samples from the German Environmental Specimen Bank (1999–2012). Int J Hyg Environ Health 218:559–563CrossRef
go back to reference Schütze A, Kolossa-Gehring M, Apel P, Brüning T, Koch HM (2014) Entering markets and bodies: increasing levels of the novel plasticizer Hexamoll® DINCH® in 24 h urine samples from the German Environmental Specimen Bank. Int J Hyg Environ Health 217:421–426CrossRef Schütze A, Kolossa-Gehring M, Apel P, Brüning T, Koch HM (2014) Entering markets and bodies: increasing levels of the novel plasticizer Hexamoll® DINCH® in 24 h urine samples from the German Environmental Specimen Bank. Int J Hyg Environ Health 217:421–426CrossRef
go back to reference Stellungnahme der Kommission “Humanbiomonitoring” des Umweltbundesamtes (2015) Stoffmonographie für N-ethyl-2-pyrrolidon (NEP) und Human-Biomonitoring (HBM)-Werte für die Metaboliten 5-Hydroxy-NEP (5-HNEP) und 2-Hydroxy-N-ethylsuccinimid (2-HESI) im Urin: Stellungnahme der Kommission Human-Biomonitoring des Umweltbundesamtes 58. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 9:1041–1052 Stellungnahme der Kommission “Humanbiomonitoring” des Umweltbundesamtes (2015) Stoffmonographie für N-ethyl-2-pyrrolidon (NEP) und Human-Biomonitoring (HBM)-Werte für die Metaboliten 5-Hydroxy-NEP (5-HNEP) und 2-Hydroxy-N-ethylsuccinimid (2-HESI) im Urin: Stellungnahme der Kommission Human-Biomonitoring des Umweltbundesamtes 58. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 9:1041–1052
go back to reference Søeborg T, Frederiksen H, Andersson AM (2012) Cumulative risk assessment of phthalate exposure of Danish children and adolescents using the hazard index approach 35. Int J Androl 3:245–252CrossRef Søeborg T, Frederiksen H, Andersson AM (2012) Cumulative risk assessment of phthalate exposure of Danish children and adolescents using the hazard index approach 35. Int J Androl 3:245–252CrossRef
go back to reference Teuschler LK, Hertzberg RC (1995) Current and future risk assessment guidelines, policy, and methods development for chemical mixtures. Toxicology 105(2–3):137–144CrossRef Teuschler LK, Hertzberg RC (1995) Current and future risk assessment guidelines, policy, and methods development for chemical mixtures. Toxicology 105(2–3):137–144CrossRef
go back to reference US-Patent US 7,994,350 B2. Applied for by Schmidtke, Versch H, Simon R, Ott S, Drews K, Mollner R, S. (inventors); BASF. App. no. US 12/299,544 US-Patent US 7,994,350 B2. Applied for by Schmidtke, Versch H, Simon R, Ott S, Drews K, Mollner R, S. (inventors); BASF. App. no. US 12/299,544
go back to reference WO-Patent WO/2006/023118A1. Applied for by Kahn, A.P. (inventors); Lyondell Chemical Technology, L.P.. Patent no. PCT/US2005/023869 WO-Patent WO/2006/023118A1. Applied for by Kahn, A.P. (inventors); Lyondell Chemical Technology, L.P.. Patent no. PCT/US2005/023869
go back to reference WO-Patent WO/2005/090447. Applied for by Ott, K., Pinkos, R., Nickel, H., Andreae, M., Rossbacher, R., Eisenbarth, P., Huttenloch, O. (inventors); BASF Aktiengesellschaft, Ludwigshafen/Germany. Patent no. PCT/EP2005/002681 WO-Patent WO/2005/090447. Applied for by Ott, K., Pinkos, R., Nickel, H., Andreae, M., Rossbacher, R., Eisenbarth, P., Huttenloch, O. (inventors); BASF Aktiengesellschaft, Ludwigshafen/Germany. Patent no. PCT/EP2005/002681
go back to reference Wiesmüller GA, Eckard R, Dobler L, Günsel A, Oganowski M, Schröter-Kermani C et al (2007) The Environmental Specimen Bank for Human Tissues as part of the German Environmental Specimen Bank. Int J Hyg Environ Health 210:299–305CrossRef Wiesmüller GA, Eckard R, Dobler L, Günsel A, Oganowski M, Schröter-Kermani C et al (2007) The Environmental Specimen Bank for Human Tissues as part of the German Environmental Specimen Bank. Int J Hyg Environ Health 210:299–305CrossRef
Metadata
Title
Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014
Authors
Nadin Ulrich
Daniel Bury
Holger M. Koch
Maria Rüther
Till Weber
Heiko-Udo Käfferlein
Tobias Weiss
Thomas Brüning
Marike Kolossa-Gehring
Publication date
01-11-2018
Publisher
Springer Berlin Heidelberg
Published in
International Archives of Occupational and Environmental Health / Issue 8/2018
Print ISSN: 0340-0131
Electronic ISSN: 1432-1246
DOI
https://doi.org/10.1007/s00420-018-1347-y

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