Over the last twenty-five years it has become evident that exposure to several phthalates can have adverse effects on human health, such as endocrine disruption. This led to a series of EU regulations that resulted in a decrease in the production volumes of the restricted phthalates and an increased production of substitutes. The current study describes the impact of regulations and changes in production and use of phthalates and their substitutes on internal exposure patterns in two European populations since the beginning of the 2000'ies. Using harmonised data from young adults in Denmark (Danish Young Men Study, n = 1,063, spot urine) and Germany (Environmental Specimen Bank, n = 878, 24-h urine) with repeated cross-sectional design (3-11 cycles per biomarker) we applied Locally Estimated Scatterplot Smoothing (LOESS) and Generalized Linear Models (GLMs) to estimate time trends and the role of covariates on the trend (e.g. age, BMI). Time trends of daily excretion (mikrog/24h) are comparable between the two samples for the regulated (DEHP, BBzP, DiNP, DnBP, DiBP, DiDP/DPHP) as well as the non-regulated substances (DMP, DEP, DINCH, DEHTP) although the rate of change differ for some of the compounds. GLM results indicate that the daily excretion of the most regulated phthalates has decreased over time (DEHP yearly about 12-16%, BBzP 5%, DnBP 0.3-17%, and DiBP 4-12%). Interestingly, also the non-regulated phthalates DMP and DEP decreased by 6-18% per year. In sharp contrast, the phthalate substitutes DINCH and DEHTP show very steep annual increases (~10-68% and ~100%, respectively) between 2009 and 2017. We did not find an effect of age, sex, BMI, or education on the time trend. The present study provides comparable insights into how exposure to phthalates and two of their substitutes have changed over the last two decades in Germany and Denmark. © 2022 The Authors
Metabolites of di-(2-ethylhexyl) terephthalate (DEHTP), a substitute for ortho-based phthalate plasticisers like di-(2-ethylhexyl) phthalate (DEHP), were analysed in 2112 first-morning void urine samples from children and adolescents aged 3-17 years, participating in the population representative German Environmental Survey on Children and Adolescents, GerES V 2014-2017. The major metabolite 5cx-MEPTP was detected in all urine samples with a geometric mean (GM) of 7.39 (my)g/L, with highest levels in the mg/L range. The GM for the other metabolites were 0.55 (my)g/L for 5OH-MEHTP, 0.54 (my)g/L for 5oxo-MEHTP and below the limit of quantification (LOQ) for 2cx-MMHTP. As already observed for other plasticisers and their substitutes, the youngest children (3-5 years) had 2-2.5-fold higher urinary DEHTP metabolite levels compared to 14-17 years old adolescents. High urinary levels of DEHTP metabolites were associated with high DEHTP concentrations in house dust. None of the samples analysed exceeded the toxicologically derived German human biomonitoring guidance value (HBM-I-Value) of 1.8 mg/L for 5cx-MEPTP. Comparison with DEHTP levels reported in other HBM studies worldwide confirmed a widespread exposure of children, adolescents and adults, with considerably higher exposures (2.6-7 fold) reported in the United States. In GerES V, exposure data for 12 different phthalates and the phthalate substitute DINCH were generated as well. Together with the data for DEHTP presented in this manuscript, GerES V allows a current and comprehensive overview on the concurrent exposure of German children and adolescents to common plasticisers. Further evaluation of aggregate exposure characteristics shall support efforts to reduce chemical hazard burden from plasticisers in Germany and beyond. © 2020 The Author(s).
The European Initiative HBM4EU aimed to further establish human biomonitoring across Europe as an important tool for determining population exposure to chemicals and as part of health-related risk assessments, thus making it applicable for policy advice. Not only should analytical methods and survey design be harmonized and quality assured, but also the evaluation of human biomonitoring data. For the health-related interpretation of the data within HBM4EU, a strategy for deriving health-based human biomonitoring guidance values (HBM-GVs) for both the general population and workers was agreed on. On this basis, HBM-GVs for exposure biomarkers of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), phthalates (diethyl hexyl phthalate (DEHP), di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butyl benzyl phthalate (BBzP), and bis-(2-propylheptyl) phthalate (DPHP)), bisphenols A and S, pyrethroids (deltamethrin and cyfluthrin), solvents (1-methyl-2-pyrrolidone (NMP), 1-ethylpyrrolidin-2-one (NEP), N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC)), the heavy metal cadmium and the mycotoxin deoxynivalenol (DON) were developed and assigned a level of confidence. The approach to HBM-GV derivations, results, and limitations in data interpretation with special focus on the pyrethroids are presented in this paper. © 2023 The Authors
Kasper-Sonnenberg, Monika; Koch, Holger M.; Apel, Petra; Rüther, Maria; Pälmke, Claudia; Brüning, Thomas; Kolossa-Gehring, Marike International Journal of Hygiene and Environmental Health (2019), online 1. August 2019 DINCH (cyclohexane-1,2-dicarboxylic acid-diisononyl ester) is a phthalate plasticizer substitute introduced into the market in 2002. It is increasingly used especially in the production of toys, food contact materials and medical devices. In this measurement campaign on 24-h urine samples of young adults (20–29 years) from the German Environmental Specimen Bank (ESB) collected in 2010, 2011, 2013, 2015 and 2017 (in total 300 samples, 60 samples/year) we analyzed three specific, oxidized DINCH metabolites (OH-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester; cx-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(carboxy-isooctyl) ester, oxo-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester). We merged these data with earlier data of the ESB from the years 1999-2012 and are now able to report levels and time trends of internal DINCH exposure from 1999 to 2017. After first detections of the major oxidized DINCH metabolite OH-MINCH in 2006 (6.7%) detection rates rapidly increased to 43.3% in 2009, 80% in 2010 and 98.3% in 2011 and 2012. From the year 2013 on we could detect OH-MINCH in every urine sample analyzed. The median concentrations of OH-MINCH rapidly increased from 0.15 μg/L in 2010 to twice the concentration in 2011 (0.31 μg/L) with further increases in 2013 (0.37 μg/L), 2015 (0.59 μg/L) and 2017 (0.70 μg/L). Similar increases, albeit at lower detection rates and concentration levels, could be observed for cx-MINCH and oxo-MINCH. All metabolites strongly correlate with each other. For the ESB study population, DINCH exposures are still far below health based guidance values such as the German Human Biomonitoring Value (HBM-I; 4,500 μg/L for the sum of OH-MINCH and cx-MINCH) or the tolerable daily intake (TDI) of EFSA (1 mg/kg bw/d). The median daily DINCH intake (DI) calculated for 2017 was 0.23 μg/kg bw/d, thus 4,310-times lower than the TDI. The maximum DI calculated for one individual in 2012 (42.60 μg/kg bw/d) was a factor of more than 20 below the TDI. The ongoing increase in DINCH exposure needs to be closely monitored in the future, including populations with potentially higher exposures such as children. This close monitoring will enable timely exposure and risk reduction measures if exposures reached critical levels, or if new toxicological data lead to lower health based guidance values. DINCH belongs to the European Human Biomonitoring Initiative (HBM4EU) priority substances for which policy relevant questions still have to be answered. doi: 10.1016/j.ijheh.2019.07.011
Schütze, André; Kolossa-Gehring, Marike; Apel, Petra; Brüning, Thomas; Koch, Holger M. International Journal of Hygiene and Environmental Health (2013), online 16. August 2013 DINCH (diisononylcyclohexane-1,2-dicarboxylate) was introduced into the world market in 2002 as a non-aromatic plasticizer and phthalate substitute. We analyzed 300 urine samples (24 h voids) of the German Environmental Specimen Bank (ESB for Human tissues, ESB Hum) for specific DINCH metabolites by on-line HPLC-MS/MS with isotope dilution quantification. Urine samples of the ESB Hum were from the years 1999, 2003, 2006, 2009 and 2012, chosen to investigate the appearance and a possible trend of DINCH exposure since its market introduction. No DINCH metabolites were detected in the 1999 and 2003 samples. From 2006 on, the percentage of samples with DINCH metabolites above the LOQ increased significantly over the years (7% in 2006, 43% in 2009 and 98% in 2012). The cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester (OH-MINCH) was the predominant metabolite. Median (and 95th percentile) concentrations (in μg/L) increased from <LOQ (0.09) in 2006, to <LOQ (1.02) in 2009 to 0.39 (2.09) in 2012. All oxidized DINCH metabolites (OH-MINCH, cx-MINCH, oxo-MINCH) correlated strongly among each other (ρ>0.75, p < 0.001). The median (95th percentile) DINCH intake in 2012 was calculated to be 0.14 (1.07) μg/kg body weight/day which is considerably below daily intakes currently deemed tolerable. DINCH is regarded to have a preferred toxicological profile over certain anti-androgenic phthalates. The continuation of DINCH measurements in the ESB Hum and other human biomonitoring studies like the German Environmental Survey (GerES) allows tracking the development of DINCH body burdens, the distribution of exposure levels and daily intakes, providing basic data for future toxicological assessment and further epidemiological studies. doi:10.1016/j.ijheh.2013.08.004
Nagorka, Regine; Koschorreck, Jan Environmental Pollution 262 (2020), 114237; online 20. Februar 2020 Plasticizers are marketed in high volumes and Di(2-ethylhexyl) phthalate (DEHP) is frequently detected in the environment and human populations. Industry had largely relied on DEHP until regulation started to restrict its marketing in 1999 due to environmental and human health concerns. The aim of this study was to obtain spatial-temporal trends for DEHP and its substitutes in German rivers. We have investigated suspended particulate matter (SPM) samples from the German Environmental Specimen Bank (ESB) for the presence of 23 plasticizers, i.e. 17 phthalates and 6 non-phthalates. The samples were collected in the last 10 years at 13 sites in large river basins in Germany such as the Rhine, Elbe and Danube. A decrease in DEHP concentrations was observed at all sampling sites between the mid-2000s and 2017. The maximum concentration for DEHP was determined in 2006 in samples from Rehlingen/Saar (6720 ng/g dry weight (dw)). By 2017, the DEHP concentration in Rehlingen had dropped to 2080 ng/g dw. Currently, Diisononyl phthalate (DINP) is the plasticizer with the highest levels in the SPM samples (maximum value 4150 ng/g dw in Rehlingen/Saar). Our results show that novel plasticizers such as Diisononylcyclohexane-1,2-dicarboxylate (DINCH) spread rapidly in surface waters after their market introduction. We have found several plasticizers of emerging concern in the environmental samples, the further use of which is currently under review under the EU chemicals regulation (REACH, registration, evaluation, authorisation and restriction of chemicals). In particular for Di(2-propylheptyl) phthalate (DPHP) a significant increase in concentration was observed at almost all sites between the mid-2000s and 2017, for example in Prossen/Elbe from 24 ng/g dw (2005) to 1380 ng/g dw (2017). doi: 10.1016/j.envpol.2020.114237
Hexamoll DINCH 1 2-Cyclohexandicarbonsäuredi-isononylester   DINCH Formel: C26H48O4 CAS-Nummer: 166412-78-8 Erläuterung: Wichtiger Phthalatersatzstoff
Phthalates are mainly used as plasticizers for polyvinyl chloride (PVC). Exposure to several phthalates is associated with different adverse effects most prominently on the development of reproductive functions. The HBM4EU Aligned Studies (2014-2021) have investigated current European exposure to ten phthalates (DEP, BBzP, DiBP, DnBP, DCHP, DnPeP, DEHP, DiNP, DiDP, DnOP) and the substitute DINCH to answer the open policy relevant questions which were defined by HBM4EU partner countries and EU institutions as the starting point of the programme. The exposure dataset includes ~5,600 children (6-11 years) and adolescents (12-18 years) from up to 12 countries per age group and covering the North, East, South and West European regions. Study data from participating studies were harmonised with respect to sample size and selection of participants, selection of biomarkers, and quality and comparability of analytical results to provide a comparable perspective of European exposure. Phthalate and DINCH exposure were deduced from urinary excretions of metabolites, where concentrations were expressed as their key descriptor geometric mean (GM) and 95th percentile (P95). This study aims at reporting current exposure levels and differences in these between European studies and regions, as well as comparisons to human biomonitoring guidance values (HBM-GVs). GMs for children were highest for total-DEHP metabolites (33.6 mikrog/L), MiBP (26.6 mikrog/L), and MEP (24.4 mikrog/L) and lowest for total-DiDP metabolites (1.91 mikrog/L) and total-DINCH metabolites (3.57 mikrog/L). In adolescents highest GMs were found for MEP (43.3 mikrog/L), total-DEHP metabolites (28.8 mikrog/L), and MiBP (25.6 mikrog/L) and lowest for total-DiDP metabolites (= 2.02 mikrog/L) and total-DINCH metabolites (2.51 mikrog/L). In addition, GMs and P95 stratified by European region, sex, household education level, and degree of urbanization are presented. Differences in average biomarker concentrations between sampling sites (data collections) ranged from factor 2 to 9. Compared to the European average, children in the sampling sites OCC (Denmark), InAirQ (Hungary), and SPECIMEn (The Netherlands) had the lowest concentrations across all metabolites and ESTEBAN (France), NAC II (Italy), and CROME (Greece) the highest. For adolescents, comparably higher metabolite concentrations were found in NEB II (Norway), PCB cohort (Slovakia), and ESTEBAN (France), and lower concentrations in POLAES (Poland), FLEHS IV (Belgium), and GerES V-sub (Germany). Multivariate analyses (Survey Generalized Linear Models) indicate compound-specific differences in average metabolite concentrations between the four European regions. Comparison of individual levels with HBM-GVs revealed highest rates of exceedances for DnBP and DiBP, with up to 3 and 5%, respectively, in children and adolescents. No exceedances were observed for DEP and DINCH. With our results we provide current, detailed, and comparable data on exposure to phthalates in children and - for the first time - in adolescents, and - for the first time - on DINCH in children and adolescents of all four regions of Europe which are particularly suited to inform exposure and risk assessment and answer open policy relevant questions. © 2023 The Authors.
The production and use of the plasticisers Hexamoll® DINCH (di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate) and DPHP (di-(2-propylheptyl) phthalate) have increased after both chemicals were introduced into the market in the early 2000s as substitutes for restricted high molecular weight phthalates. During the population representative German Environmental Survey (GerES) of Children and Adolescents (GerES V, 2014-2017), we collected urine samples and measured the concentrations of DINCH and DPHP metabolites in 2228 and in a subsample of 516 participants, respectively. We detected DINCH and DPHP metabolites in 100% and 62% of the 3-17 years old children and adolescents, respectively. Geometric means of DINCH metabolites were 2.27 myg/L for OH-MINCH, 0.93 myg/L for oxo-MINCH, 1.14 myg/L for cx-MINCH and 3.47 myg/L for DINCH (Sigma of OH-MINCH + cx-MINCH). Geometric means of DPHP metabolites were 0.30 myg/L for OH-MPHP, 0.32 myg/L for oxo-MPHP and 0.64 myg/L for DPHP (Sigma of OH-MPHP + oxo-MPHP). The 3-5 years old children had almost 3-fold higher DINCH biomarkers levels than adolescents (14-17 years). Higher concentrations of DPHP biomarkers among young children only became apparent after creatinine adjustment. Urinary levels of DINCH but not of DPHP biomarkers were associated with the levels of the respective plasticisers in house dust. When compared to HBM health-based guidance values, we observed no exceedance of the HBM-I value of 1 mg/L for DPHP (Sigma of OH-MPHP + oxo-MPHP). However, 0.04% of the children exceeded the health based guidance value HBM-I of 3 mg/L for DINCH (Sigma of OH-MINCH + cx-MINCH). This finding shows that even a less toxic replacement of restricted chemicals can reach exposures in some individuals, at which, according to current knowledge, health impacts cannot be excluded with sufficient certainty. In conclusion, we provide representative data on DINCH and DPHP exposure of children and adolescents in Germany. Further surveillance is warranted to assess the substitution process of plasticisers, and to advise exposure reduction measures, especially for highly exposed children and adolescents. Providing the results to the European HBM Initiative HBM4EU will support risk assessment and risk management not only in Germany but also in Europe. © 2019 The Authors. Published by Elsevier GmbH
DINCH (cyclohexane-1,2-dicarboxylic acid-diisononyl ester) is a phthalate plasticizer substitute introduced into the market in 2002. It is increasingly used especially in the production of toys, food contact materials and medical devices. In this measurement campaign on 24-h urine samples of young adults (20-29 years) from the German Environmental Specimen Bank (ESB) collected in 2010, 2011, 2013, 2015 and 2017 (in total 300 samples, 60 samples/year) we analyzed three specific, oxidized DINCH metabolites (OH-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester; cx-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(carboxy-isooctyl) ester, oxo-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester). We merged these data with earlier data of the ESB from the years 1999-2012 and are now able to report levels and time trends of internal DINCH exposure from 1999 to 2017. After first detections of the major oxidized DINCH metabolite OH-MINCH in 2006 (6.7%) detection rates rapidly increased to 43.3% in 2009, 80% in 2010 and 98.3% in 2011 and 2012. From the year 2013 on we could detect OH-MINCH in every urine sample analyzed. The median concentrations of OH-MINCH rapidly increased from 0.15 (Mü)g/L in 2010 to twice the concentration in 2011 (0.31 (Mü)g/L) with further increases in 2013 (0.37 (Mü)g/L), 2015 (0.59 (Mü)g/L) and 2017 (0.70 (Mü)g/L). Similar increases, albeit at lower detection rates and concentration levels, could be observed for cx-MINCH and oxo-MINCH. All metabolites strongly correlate with each other. For the ESB study population, DINCH exposures are still far below health based guidance values such as the German Human Biomonitoring Value (HBM-I; 4,500 (Mü)g/L for the sum of OH-MINCH and cx-MINCH) or the tolerable daily intake (TDI) of EFSA (1mg/kg/bw/d). The median daily DINCH intake (DI) calculated for 2017 was 0.23 (Mü)g/kg bw/d, thus 4,310-times lower than the TDI. The maximum DI calculated for one individual in 2012 (42.60 (Mü)g/kg bw/d) was a factor of more than 20 below the TDI. The ongoing increase in DINCH exposure needs to be closely monitored in the future, including populations with potentially higher exposures such as children. This close monitoring will enable timely exposure and risk reduction measures if exposures reached critical levels, or if new toxicological data lead to lower health based guidance values. DINCH belongs to the European Human Biomonitoring Initiative (HBM4EU) priority substances for which policy relevant questions still have to be answered. © 2019 Elsevier GmbH. All rights reserved.
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