Photocatalytic degradation of 4-amino-6-chlorobenzene-1,3- disulfonamide stable hydrolysis product of hydrochlorothiazide: Detection of intermediates and their toxicity * Sanja J. Armakovi  c a , Stevan Armakovi  c b , Dragana D.  Cetojevi  c-Simin c , Filip  Sibul a , Biljana F. Abramovi  c a, * a University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg D. Obradovi ca 3, 21000 Novi Sad, Serbia b University of Novi Sad, Faculty of Sciences, Department of Physics, Trg Dositeja Obradovi ca 4, 21000 Novi Sad, Serbia c University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Dr Goldmana 4, 21204 Sremska Kamenica, Serbia article info Article history: Received 27 April 2017 Received in revised form 20 July 2017 Accepted 26 August 2017 Available online xxx Keywords: Diuretic Degradation Study of intermediates Toxicity Computational analysis abstract In this work we have investigated in details the process of degradation of the 4-amino-6-chlorobenzene- 1,3-disulfonamide (ABSA), stable hydrolysis product of frequently used pharmaceutical hydrochlorothi- azide (HCTZ), as one of the most ubiquitous contaminants in the sewage water. The study encompassed investigation of degradation by hydrolysis, photolysis, and photocatalysis employing commercially available TiO 2 Degussa P25 catalyst. The process of direct photolysis and photocatalytic degradation were investigated under different type of lights. Detailed insights into the reactive properties of HCTZ and ABSA have been obtained by density functional theory calculations and molecular dynamics simulations. Specifically, preference of HCTZ towards hydrolysis was confirmed experimentally and explained using computational study. Results obtained in this study indicate very limited efficiency of hydrolytic and photolytic degradation in the case of ABSA, while photocatalytic degradation demonstrated great po- tential. Namely, after 240 min of photocatalytic degradation, 65% of ABSA was mineralizated in water/ TiO 2 suspension under SSI, while the nitrogen was predominantly present as NH þ 4 . Reaction in- termediates were studied and a number of them were detected using LC-ESI-MS/MS. This study also involves toxicity assessment of HCTZ, ABSA, and their mixtures formed during the degradation processes towards mammalian cell lines (rat hepatoma, H-4-II-E, human colon adenocarcinoma, HT-29, and human fetal lung, MRC-5). Toxicity assessments showed that intermediates formed during the process of pho- tocatalysis exerted only mild cell growth effects in selected cell lines, while direct photolysis did not affect cell growth. © 2017 Elsevier Ltd. All rights reserved. 1. Introduction Diuretic, 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide-1,1-dioxide (hydrochlorothiazide, HCTZ) is frequently used for the treatment of hypertension, congestive heart insuffi- ciency, renal tubular acidosis, prevention of rock formation in kidneys, sometimes even for treatment of hypercalciuria (Brigante et al., 2005; Mahajan et al., 2012). O'Grady et al. (1999) have reported that HCTZ does not metabolize completely and at least 62.6% of the oral dose is eliminated by the kidney unchanged within 24 h. Thieme et al. (2001) had reported that hydrolysis process already starts in urine. HCTZ is one the most ubiquitous contaminants in the sewage (Radjenovi c et al., 2009; Estrada-Arriaga et al., 2016) and river waters (L opez-Serna et al., 2013). Petrovi c et al. (2014) were detected HCTZ in Novi Sad (Serbia) in drinking water, the Danube River, canal water and municipal waste water in concentration from 24 to 1070 ng/L. A common property observed for thiazides is hydrolysis in aqueous media. In the case of HCTZ hydrolysis only one of degra- dation product was identified e 4-amino-6-chlorobenzene-1,3- * This paper has been recommended for acceptance by Dr. Harmon Sarah Michele. * Corresponding author. E-mail address: biljana.abramovic@dh.uns.ac.rs (B.F. Abramovi c). Contents lists available at ScienceDirect Environmental Pollution journal homepage: www.elsevier.com/locate/envpol https://doi.org/10.1016/j.envpol.2017.08.090 0269-7491/© 2017 Elsevier Ltd. All rights reserved. Environmental Pollution xxx (2017) 1e9 Please cite this article in press as: Armakovi c, S.J., et al., Photocatalytic degradation of 4-amino-6-chlorobenzene-1,3-disulfonamide stable hydrolysis product of hydrochlorothiazide: Detection of intermediates and their toxicity, Environmental Pollution (2017), https://doi.org/ 10.1016/j.envpol.2017.08.090