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In vitro exposure to the next-geenration plasticizer DINCH: cytotoxicyy and genotoxicity assessment in human cells
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Abstract(s)
The chemical Di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH) has been applied since 2002 as a non-aromatic plasticizer and a substitute for unsafe phthalates. This non-regulated chemical is a potential carcinogen to humans using (Q)SAR approaches, thus its increasing presence in human households and body is a major concern. Although in humans DINCH is rapidly metabolized and excreted a continuously exposure may lead to adverse health effects, e.g. in occupational environments [1].
Recently, this substance was included in a priority group by the Human Biomonitoring for Europe Initiative (HBM4EU), meaning that human exposure and effects need evaluation. Several in vivo studies revealed that DINCH did not induce toxicity, at low concentrations, although was able to activate phase I and II liver enzymes and triggered cell proliferation in liver, kidney and thyroid glands. In contrast, nephrotoxicity was reported as a critical endpoint at high exposure concentrations [2]. Therefore, this work aimed to investigate DINCH hazardous potential thereby adding information to the limited knowledge about its biological effects. The study comprised a short and longer exposure of human liver cells (HepG2) to a range of concentrations
(1-500 μg/mL). Cytotoxicity was determined by the MTT assay. Potential DNA lesions were evaluated by the comet assay 3h or 24h after exposure, while the clastogenic and aneugenic effects were determined using the cytokinesis-block micronucleus assay following 6h and 48h of exposure, including in the presence of exogenous liver metabolic enzymes (S9 mix). The results indicate that DINCH treatment did not induce
cytotoxicity in HepG2 cells for the tested concentrations. Neither it was able to induce DNA lesions or chromosomal damage. Moreover, the plasticizer did not cause oxidative DNA damage, as measured using modified comet assay. In conclusion, the next-generation plasticizer DINCH did not cause cytotoxicity and genotoxicity in HepG2 cells. Furthermore, the results reported for genotoxicity are in line with the ones reported by Anses report [3] and in ECHA database. However, recent in vitro studies showed that DINCH is cytotoxic at 100 μg/mL after a 7-day period exposure of L929 murine cells [4]. Given the reported nephrotoxicity, the current analysis focuses on the potential in vitro toxic outcomes using human kidney (HK-2) cells.[1] H.M. Koch, et. al., Archives of Toxicology 87(5), 799-806 (2013).
[2] V.S. Bhat, et. al., Journal of Toxicology and Environmental Health 17(2), 63-94 (2014).
[3] Avis de l'Anses n°2015-RE-0003 relatif à une analyse de la meilleure option de gestion des risques
pour le DINCH ® (1,2-cyclohexanedicarboxylic acid, diisononyl ester, n° CAS 166412-78-8).
https://www.anses.fr/fr/system/files/REACH2015re0003.pdf.
[4] T. Eljezi, et. al., Chemosphere 173, 452-459 (2017).
Description
Keywords
Di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH) Genotoxicity Testing Human Liver and Kidney Cells Cytotoxicity Micronucleus Assay S9 fraction Comet Assay Genotoxicidade Ambiental