Mucolytic Drugs Ambroxol and Bromhexine: Transformation under Aqueous Chlorination Conditions.

Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso-substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure.

Cocamidopropyl betaine - a potential source of nitrogen-containing disinfection by-products in pool water.

Water treatment for most public pools involves disinfection with active chlorine leading to the formation of disinfection by-products (DBPs). Among them, nitrogen-containing compounds (N-DBPs) having increased toxicity and adverse effects on human health are of the greatest concern. Being the major component of various body washers for swimmers, cocamidopropyl betaine (CAPB) represents a potential and still underestimated anthropogenic precursor of N-DBPs in pool water. The purpose of this study was to investigate CAPB transformation pathways and mechanisms under the aqueous chlorination conditions. High-performance liquid and two-dimensional gas chromatography hyphenated with high-resolution mass spectrometry were used for the search and tentative identification of the primary and final CAPB transformation products. A wide range of DBPs containing up to five chlorine atoms including these in combination with hydroxyl and additional carbonyl groups has been revealed in model chlorination experiments for the first time. The proposed mechanism of their formation involves nucleophilic substitution of the secondary amide hydrogen atom at the first stage with subsequent free radical and electrophilic addition reactions resulting in non-selective introduction of halogen atoms and hydroxyl groups in the alkyl chain. The deep transformation products include short-chain chlorinated hydrocarbons and their oxidation products as well as dimethylcarbamoyl chloride possessing high toxicity and carcinogenic properties. Targeted analysis of real swimming pool water samples confirmed the results of model experiments enabling semi-quantitative determination of CAPB (0.8 µg L-1) and 18 primary DBPs, including 10 chlorine-containing compounds with the total concentration of 0.1 µg L-1. Among them, monochloro (50%) and hydroxydichloro (25%) derivatives predominate. The toxicity and health of the main DBPs has been estimated using QSAR/QSTR approach. Thus, the possibility of formation of new classes of potentially toxic chlorine-containing DBPs associated with the widespread use of detergents and cosmetics was shown.

Antiviral drug Umifenovir (Arbidol) in municipal wastewater during the COVID-19 pandemic: Estimated levels and transformation.

An indole derivative umifenovir (Arbidol) is one of the most widely used antiviral drugs for the prevention and treatment of COVID-19 and some other viral infections. The purpose of the present study was to shed light on the transformation processes of umifenovir in municipal wastewater, including disinfection with active chlorine, as well as to assess the levels of the antiviral drug and its metabolites entering and accumulating in natural reservoirs under conditions of the SARS-CoV-2 pandemic. The combination of high-performance liquid chromatography with electrospray ionization high-resolution mass-spectrometry and inductively coupled plasma mass spectrometry was used for tentative identification and quantification of umifenovir and its transformation products in model reaction mixtures and real samples of wastewater, river water, biological sludge and bottom sediments taken at the wastewater treatment plant in Arkhangelsk, a large cultural and industrial center at the Russian North. Laboratory experiments allowed identifying fifteen bromine-containing transformation products, forming at the initial stages of the chlorination and fourteen classic volatile and semi volatile disinfection by-products with bromoform as the dominant one. Chlorinated derivatives are only the minor disinfection by-products forming by substitution of alkylamine group in the aromatic ring. The schemes of umifenovir transformation in reactions with dissolved oxygen and sodium hypochlorite are proposed. Two established primary transformation products formed by oxidation of the thioether group to sulfoxide and elimination of thiophenol were detected in noticeable concentrations in the wastewater together with their precursor. The level of umifenovir reached 1.3 mg kg-1 in the sludge and municipal wastewater treat contained 1 µg L-1 of that drug, while its removal during biological wastewater treatment was about 40%. Pronounced accumulation of umifenovir and its transformation products in biological sludge and bottom sediments of natural reservoirs may be a source of the future secondary pollution of the environment.

Identification of novel disinfection byproducts in pool water: Chlorination of the algaecide benzalkonium chloride.

The maintenance of public swimming pools requires numerous technological steps. One of the most important issues involves microbiological safety. Benzalkonium chloride (BAC) encompasses homologous alkylbenzyldimethylammonium chlorides with various alkyl chains, in particular C12 and C14, and is known as a popular algaecide for keeping water clean. In addition to BAC, NaOCl and UV-irradiation are also used to treat pool water as additional technological steps. Therefore, BAC itself can become a precursor of disinfection byproducts (DBPs). High-performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS), with accurate mass measurements, has allowed the discovery of several groups of DBPs that are related to BAC in public pool water in Arkhangelsk (Russia). These DBPs include numerous isomeric monochlorinated derivatives ([C21H37ClN]+ and [C23H41ClN]+), hydroxyl derivatives ([C21H38NO]+ and [C23H42NO]), carbonyl ([C21H36NO]+ and [C23H40NO]+), and dicarbonyl derivatives ([C21H34NO2]+ and [C23H38NO2]+). In addition, chlorinated alcohols, ketones and ketoalcohols of BAC were also detected, including [C21H35ClNO]+, [C21H37ClNO]+ and [C21H35ClNO2]+ for BAC-12; and [C23H39ClNO]+, [C23H41ClNO]+ and [C23H39ClNO2]+ for BAC-14. MS/MS allowed reliable elucidation of the structures of novel DBPs, proving that chlorination starts via radical substitution in the long aliphatic chains of BAC. UV-irradiation dramatically accelerates the reaction completely destroying the original compounds in less than an hour, while the array of the intermediate products remains the same as in the dark. The formation of other DBPs proceeds due to further reactions of these primary products. The concentrations of novel DBPs in pool water reach µg L-1 levels. These conclusions were proved by conducting model reactions of BAC with NaOCl.