Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014
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.
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.
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.
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.
KeywordsHuman biomonitoring N-Methyl-2-pyrrolidone (NMP) N-Ethyl-2-pyrrolidone (NEP) German Environmental Specimen Bank (ESB) Exposure assessment Urinary metabolites
This study was financed by the German Environment Agency (Umweltbundesamt, Grant No. 3714 622006). We would like to acknowledge the teams of the ESB, of the University Hospital Muenster and of Fraunhofer IBMT for their excellent work in acquiring, handling, and storing of human samples for the German ESB. The development of the analytical method and its application in a population study are part of a large-scale 10-year project on the advancement of human biomonitoring in Germany. This project is a cooperation agreed in 2010 between the German Federal Ministry for Environment, Nature Conservation and Nuclear Safety (BMU) and the Verband der Chemischen Industrie e.V. (German Chemical Industry Association—VCI) and is managed by the German Environment Agency (UBA). In this cooperation project the analytical method development is financed by the Chemie Wirtschaftsförderungsgesellschaft mbH while the first application of the novel methodology in a population study is financed by the German Environment Agency. Experts from governmental scientific authorities, industry and science closely accompany and advise the project in selecting substances and developing methods.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Åkesson B, Carnerup MA, Jönsson BAG (1997) Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metab Dispos 25:267–269Google Scholar
- 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 10:1175–1191Google Scholar
- 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. 24–27Google Scholar
- 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. 1–439Google Scholar
- 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. 5–22Google Scholar
- 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 8/28/2016Google Scholar
- ECHA (2013) Annex XV restriction report proposal for a restriction—NMP, checked on 8/28/2016Google Scholar
- ECHA (2016a) https://echa.europa.eu/substance-information/-/substanceinfo/100.011.662. Accessed 17 Aug 2016
- ECHA (2016b) https://echa.europa.eu/substance-information/-/substanceinfo/100.018.409. Accessed 26 Aug 2016
- Fink JK (2011) Chapter 9: Poly(vinylpyrrolidone). In: Handbook of engineering and specialty thermoplastics, Volume 2: water soluble polymers. Wiley, Hoboken, SalemGoogle Scholar
- 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 220:130–141CrossRefGoogle Scholar
- 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 57:766–773Google Scholar
- 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. 1–1355Google Scholar
- 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: 3787–3794CrossRefGoogle Scholar
- 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 9:1041–1052Google Scholar
- 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 12/299,544Google Scholar
- WO-Patent WO/2006/023118A1. Applied for by Kahn, A.P. (inventors); Lyondell Chemical Technology, L.P.. Patent no. PCT/US2005/023869Google Scholar
- 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/EP2005/002681Google Scholar