Role of ranitidine in N-nitrosodimethylamine formation during chloramination of competing micropollutants

Journal Pre-proof Role of ranitidine in N-nitrosodimethylamine formation during chloramination of competing micropollutants

Mingizem Gashaw Seid, Jaeshik Chung, Jaewan Choe, Kangwoo Cho, Seok Won Hong PII:

S0048-9697(20)37687-7

DOI:

https://doi.org/10.1016/j.scitotenv.2020.144156

Reference:

STOTEN 144156

To appear in:

Science of the Total Environment

Received date:

3 September 2020

Revised date:

24 November 2020

Accepted date:

26 November 2020

Please cite this article as: M.G. Seid, J. Chung, J. Choe, et al., Role of ranitidine in N-nitrosodimethylamine formation during chloramination of competing micropollutants, Science of the Total Environment (2020), https://doi.org/10.1016/j.scitotenv.2020.144156

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© 2020 Published by Elsevier.

Journal Pre-proof

Role of ranitidine in N-nitrosodimethylamine formation during chloramination of competing micropollutants

a

of

Mingizem Gashaw Seida,b, Jaeshik Chungb, Jaewan Choec, Kangwoo Chod,e**, Seok Won Honga,b*

Division of Energy and Environment Technology, KIST-School, University of Science and

Water Cycle Research Center, Korea Institute of Science and Technology, Seoul 136-791, Republic

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b

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Technology, Seoul 02792, Republic of Korea

Department of Civil Engineering, Gwangju University, Gwangju 61743, Republic of South

d

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Korea

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c

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of Korea

Division of Environmental Science and Engineering, Pohang University of Science and Technology

e

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(POSTECH), Pohang 37673, Republic of Korea Institute for Convergence Research and Education in Advanced Technology (I-CREATE), Yonsei

University, Incheon 406-840, Republic of Korea

*Corresponding author (S.W. Hong). Tel.: +8229585844; Fax: +822 958 5839; E-mail address: [email protected] **Co-corresponding author (K. Cho).

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Journal Pre-proof Tel.: +82542792289; Fax: +82542798299; E-mail address: [email protected] Abstract Ranitidine (RNT) is a widely known precursor of N-nitrosodimethylamine (NDMA) as evinced by the self-catalytic formation of NDMA during chloramination. In the present study, the NDMA formation potentials (NDMA-FP) of 26 micropollutants were assessed, particularly when mixed with RNT. 11 compounds were identified as individual precursors, including trimebutine and cimetidine, which exhibited substantial NDMA-FP, with up to 10% molar yield. In addition, nitrosamines, other than

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NDMA, namely N-nitrosodiethylamine and N-nitrosomethylamine, were observed from diethylamine-

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containing precursors, such as metoclopramide. In a 1:1 mixture of RNT and a competitor, the change

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in NDMA-FP was mostly comparable (within 20% deviation), while antagonistic interactions were observed for competitors, such as diethylhydroxylamine. The scattered overall NDMA-FP should be

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considered as a product of competition among the precursors for core substrates and intermediates for

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NDMA formation. The co-existence of either trimebutine or metoclopramide with RNT led to an exceptionally synergetic NDMA generation. Degradation kinetics and chlorination/nitrosation

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experiments combined with mass spectroscopy analyses indicated that RNT would accelerate both the initial chlorination and nitrosation of trimebutine and metoclopramide, leading to N-nitroso

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complexes, which have well-understood NDMA formation pathways, i.e., amination with subsequent aminyl radical generation. This work demonstrates a wide array of precursors with NDMA-FP, suggesting that nitrosamine formation is potentially underestimated in field environments.

Keywords: Chloramination; Formation potential; Nitrosation; Precursor mixture; Reaction pathway

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Journal Pre-proof 1. Introduction

Pharmaceuticals and personal care products (PPCPs) are a growing source of concern for the environment because of their widespread production and potential to transform into more dynamic products during water disinfection processes. In particular,

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chloramination of PPCP compounds with amine moieties could generate carcinogenic

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nitrosamines, such as N-nitrosodimethylamine (NDMA; Bond et al., 2017; Sgroi et al.,

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2018; Shen and Andrews, 2010). Ranitidine (RNT), a class of N,N-dimethyl-α-arylamines,

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has been observed to exhibit the highest NDMA molar yields following chloramination

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(Huang et al., 2018; Sgroi et al., 2018) and its potential contributions to the observed

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NDMA levels in surface water have been investigated extensively.

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A significant body of literature has proposed the following concurrent reactions between monochloramine (NH2Cl) and RNT (Huang and Shah, 2018; Liu et al., 2014; Le Roux et al., 2012a): (i) nucleophilic substitution of the dimethylamine (DMA) moiety of RNT to form a dimethylhydrazine-type intermediate (amination), and (ii) electrophilic chlorine transfer to form chlorinated intermediates (chlorination). The former reaction has been reported to generate nitrosating agents, such as NO2Cl and NO+ (Liu et al., 2014),

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Journal Pre-proof leading to self-catalytic NDMA generation from RNT. Evidence presented by Spahr et al. (2017) showed that N-peroxy radicals (from uptake of O2 by aminyl radicals) are also key intermediates for nitrosation. Conversely, the chlorinated organic amine compounds (specifically on the DMA group in terms of chlorammonium species) have been claimed to have chlorination potential, even greater than those of free chlorine (Choi and

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Valentine, 2003) and inorganic chloramines, for co-existing organic compounds (Shah et

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al., 2011). Recently, in particular, an enhanced formation of trihalomethanes and

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haloacetic acids have been observed during chlorination of organic contaminants in the

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presence of RNT (Huang and Shah, 2018). Such findings have suggested that RNT

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intervenes in the chlorination and nitrosation of other coexisting precursors, which has

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rarely been interrogated previously.

Based on the aforementioned knowledge on RNT, the main purpose of this study was to investigate the nitrosamine (mostly NDMA) formation potential from its precursors, either individually or in mixtures, in the presence of RNT during chloramination. 26 micropollutants were chosen as competing precursors, for which the formation potential of one half of these micropollutants has not been previously

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Journal Pre-proof addressed. Our selection criteria for the precursors included (a) viability of sub-structural amine moieties and functionalities for the NDMA formation (Bond et al., 2017; Dai et al., 2015; Shen and Andrews, 2010), (b) essential and most prescribed/dispensed medicine (Fuentes et al., 2018), (c) highly consumed but potentially hazardous compounds with limited data on nitrosamine formation (Besse and Garric, 2008), and (d) frequently

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detected micropollutants in surface water (Sim et al., 2011). For competing precursors

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with potentially synergetic effects with RNT-generating NDMA, we further investigated

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the reaction mechanisms based on kinetic experiments and tandem mass spectrometry

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2. Material and Methods

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analyses.

2.1. Estimation of Nitrosamine Formation Potential

A list of reagents and chemicals used in this research is provided in Supporting Information (SI, Text-S1). Selected model precursors, namely metamfepramone (MFP), orphenadrine (OPA), venlafaxine (VLX), loperamide (LPA), DMA, lincomycin (LCM),

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Journal Pre-proof amoxicillin (AMX), cimetidine (CMT), tetramethylammonium chloride (TMAC), polydiallyldimethylammonium chloride (PolyDADMAC), diethylamine (DEA), metoclopramide (MCP), famotidine (FMT), tetramethyl-1,3-propanediamine (TMPA), diclofenac (DIC), promethazine (PMZ), nizatidine (NZT), carbamazepine (CBZ), cetyltrimethylammonium chloride (CMAC), sulfamethoxazole (SMX), iopromide (IOP),

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triethylamine (TEA), triethanolamine (TELA), dimethylformamide (DMF),

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diethylhydroxylamine (DEHA), and trimebutine (TMB) were all analytical grade (Sigma-

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Aldrich, ACROS organics, and AK Scientific). For most of the targeted pharmaceuticals,

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the measured maximum environmental concentrations ranged from 0.1 ng L-1 to >105 μg

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L-1 (Cardoso et al., 2014; Kostich et al., 2014; Sim et al., 2011; Kasprzyk-Hordern et al., 2008). Surface water and sewage treatment effluent concentrations of MCP ranged from

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17 to 76 ng L-1, while limited data has been noted for TMB (Besse and Garric, 2008; Nakada et al., 2007). RNT was detected in various water streams in the range of 10– 105 ng L-1 (Cardoso et al., 2014; Sim et al., 2011; Kasprzyk-Hordern et al., 2008). Considering elevated precursor concentrations in a specific environmental matrix, such as wastewater-impacted and brine waters in zero-liquid discharge facilities, the initial

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Journal Pre-proof precursor concentrations used in this study were some orders of magnitude greater than the measured concentrations in source waters. Moreover, higher substrate concentrations facilitate kinetic and analytical procedures. It has to be noted that NDMA-FP has been shown to insignificantly vary with the initial concentration of most tertiary amine

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precursors, including RNT (Hinneh et al., 2019; Seid et al., 2018).

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Throughout the study, a 0.1 L gas-tight amber bottle filled with 10 mM

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phosphate buffer (pH adjusted to 7.8) served as a reactor and was placed in a black box

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to prevent photolysis. The NDMA formation potential (NDMA-FP) of the selected

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precursors (Fig. 1) during chloramination was assessed according to a protocol reported

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in our previous study (Seid et al., 2018). Briefly, 0.2 or 5 mM of preformed NH2Cl was

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added to the precursor (10 µM, 10 mg L-1 for PolyDADMAC) for reaction up to 24 h. The NDMA-FPs of binary mixtures were examined with 10 µM co-existing compounds, with 10 µM RNT as the default. Surface water samples were collected from the Han river (Seoul, Republic of Korea), whose pH and temperature were 7.7 and 23.2 °C, respectively. Average dissolved oxygen (DO), bromide, total nitrogen, and dissolved organic carbon (DOC) concentrations were 8.6, 0.19, 2.3, and 2.74 mg L-1, respectively. Microcystis

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Journal Pre-proof aeruginosa was cultivated in BG11 media at 22 °C in tube flasks under irradiation with cool fluorescent light (F32T8, Philips) for 10 days (with a 12:12-hour light and dark cycle photoperiod). Algal-containing water samples were prepared by adding a Microcystis

aeruginosa cell density of approximately 2.9 × 106 cells mL-1 to tap water. The selected precursor was then spiked to the surface and algal-containing water for further

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chloramination studies. Then, the samples collected during the chloramination

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experiments were quenched with 0.1 M sodium thiosulfate and filtered through a

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0.45 µm pore membrane filter prior to further analyses. The molar yields were calculated

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as the ratios of the produced [NDMA] to the (sum of) the decayed [precursors] (SI, Text-

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S2). For selected (DEA-containing) precursors, formation of N-nitrosodiethanolamine

also quantified.

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(NDELA), N-nitrosodiethylamine (NDEA), and N-nitrosomethylethylamine (NMEA) was

2.2. Analysis

Total chlorine and NH2Cl were quantified according to the standard method 4500-Cl G (APHA, 1998). DO, bromide ion, total nitrogen, and DOC concentrations were

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Journal Pre-proof measured using a YSI 5100 oxygen meter (YSI, Yellow Springs, OH, USA), an automatic ion chromatograph (DIONEX, ICS-1000, USA), and total organic carbon analyzer (TOC-5000, Shimadzu, Japan), respectively. A high-performance liquid chromatography (HPLC, 1260 infinity Quaternary LC VL, Agilent Technologies, USA) system was used to monitor the concentrations of pharmaceuticals, aliphatic amines, alkyl quaternary compounds, and

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NDELA, according to the methods described in SI, Text-S3 (Larson and Pfeiffer, 1983;

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Seid et al., 2018; Yu et al., 2016). Other nitrosamine compounds of interest (NDMA,

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NDEA, and NMEA) were monitored via gas chromatography coupled to low-resolution mass

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spectrometry (GC-LRMS, 6890N GC system, Agilent Technologies, USA), in accordance with

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the methodology of Kim et al. (2013). Identification of reaction pathways for the selected samples were based on an ultraperformance liquid chromatography-quadrupole-time of

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flight-high resolution mass spectrometry system (UPLC-Q-TOF-HRMS, ACQUITY UPLC, Waters Corp., USA). Details of the methods are described in SI, Text-S3. Unless described otherwise, all analyses were conducted using deionized (DI) water from a Milli-Q purification system (Millipore, Bedford, MA, USA) with a conductivity lower than 14.4 μS cm-1.

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Journal Pre-proof

3. Results and Discussion

3.1.

NDMA-FP of Individual Precursor upon Chloramination

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Fig. 2 illustrates the molar yields of NDMA from each precursor (initial

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concentration of 10 µM). The conversion (consumption) of the precursors was greater

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than 80% within 24 h, excluding DEHA, TE(L)A, IOP, CMAC, PolyDADMAC, and TMAC (Fig.

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S1). In a control sample with only NH2Cl, the auto-decomposition was lower than 10%, while the consumed fraction of NH2Cl was as high as 88% (NZT), depending on the

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reactivities with precursors and degradation intermediates. Therefore, [NH2Cl] was always

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in excess of the precursor throughout the experiments. RNT exhibited the highest NDMA yield among the tested precursors, and the NDMA-FP value (averaged to 49.3%) was consistent with the range reported in literature (Table S1), validating the reliability of our NDMA-FP protocol. CMT had the second highest NDMA yield (9.3%), while TMPA, MFP, OPA, TMB, NZT and PMZ had values between 3 and 7%. Two secondary amine moieties in the CMT structure might be responsible for the observed NDMA-FP values (Huang et

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Journal Pre-proof al., 2018). To the best of our knowledge, this is the first study to report a notable NDMA-FP value for CMT. The NDMA-FPs of DEA, DMA, DMF, LPA, and VLX were lower than 3%, while negligible NDMA generation was observed for the other precursors, which is consistent with the findings of previous studies (Table S1) under analogous conditions (Bond et al., 2017; Gan et al., 2015; Hinneh et al., 2019; Mamo et al., 2016;

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Park et al., 2009; Piazzoli et al., 2018; Shen and Andrews, 2010; West et al., 2016). The

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molar yields of NDEA were significant only for the DEA-containing precursors, DEA and

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TEA, with measured values of 0.43 and 0.10%, respectively. The obtained results are also

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similar to values reported in the literature (Mitch and Sedlak, 2004; West et al., 2016). In

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the case of MCP, 0.60, 1.2, and 0.49% molar yields of NDEA, NDMA, and NMEA were observed, respectively. The NDMA formation from MCP is likely associated with its

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deethylated fragment, although the yield in this study was lower than the reported values from in vitro and in vivo studies (Brambilla and Martelli, 2007). Although NDELA concentrations were always under the detection limits of the present study, potential NDELA generation was suggested upon chloramination of TELA-containing gray water (Dai et al., 2015).

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Journal Pre-proof A significant body of literature has evaluated NDMA formation upon chloramination in terms of a structure–activity relationship, where the molar yield could be assessed based on the stability of carbocations and/or electronic properties (partial charge, acidity) of DMA-N functionality (Bond et al., 2017; Liu et al., 2014; Le Roux et al., 2012a; Selbes et al., 2012). So far, no sole descriptor could fully account for the largely

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variable NDMA-FP values, leading to a need for comprehensive analyses. For aliphatic

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amine and amide (Figs. 1A and 2A), relatively high stability of the carbocation enables

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TMPA to exhibit the highest NDMA yields from DMA moieties (well-known NDMA

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precursor) at both ends (Liu et al., 2014). In comparison, sluggish reactions with NH2Cl

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were observed in the case of DEHA, TEA, and TELA (conversion: 13–28%, Fig. S1).

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The NDMA-FP from aromatic precursors (Figs. 1B and 2B) are remarkably influenced by their reactivity with chloramine, DMA-N acidity, and/or geometric features of the adjacent structure. The reaction between IOP and chloramine (Wendel et al., 2014) was insignificant, as illustrated in Fig. S1. Branched amines with a C2 linker attached to the core oxygen or nitrogen atom (OPA) generated more NDMA than branched amines with carbonyl functionalities (LPA), due to higher stability of the leaving group (Bond et

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Journal Pre-proof al., 2017; Selbes et al., 2012). The NDMA-FP could also be related with the pKa of DMAN; specifically, the range between 6.5 and 8.5 has been observed to be optimal for the nitrosamine formation from the selected precursors (Bond et al., 2017). In the present study, MFP with a pKa of 7.78 had NDMA-FP values far greater than weakly acidic (such as DIC with pKa of 4.15) or basic precursors (VLX and MCP with pKa of 8.9 and 10.3,

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respectively). Nevertheless, LPA and TMB with comparable pKa values (8.6 and 8.2,

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respectively) showed substantially different molar yields (0.8 and 4.0%, respectively; Table

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S2). The presence of electron withdrawing groups on DMA-N, the bond distance of the

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DMA moiety from adjacent aromatic structures, and the stability of carbocation would

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influence the NDMA-FP (Bond et al., 2017; Selbes et al., 2012; Shen and Andrews, 2010). In case of free or polymer-bound quaternary alkylamines (Figs. 1C and 2C), the

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conversion during the 24 h reaction was only in the 30–65% range. In addition, precursors with positive partial charges on the DMA-N could be degraded to tertiary/secondary amines with relatively low NDMA yields (Park et al., 2009). The accessibility of a lone pair on N would influence the stability of carbocations during chloramination; the observed NDMA-FP values of CMAC, PolyDADMAC, and TMAC (with

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Journal Pre-proof partial charge of 0.329), were considerably smaller than those of RNT and DMA, with negatively charged DMA-N (Table S2).

In the case of sulfur-containing precursors (Figs. 1D and 2D), relatively facile reactions were noted (Deborde and von Gunten, 2008), as illustrated in Fig. S1, and the

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NDMA-FP is likely to depend on the nature of the S group (adjacent to amine moiety)

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and the distance between the amine and the hetero-functional linkers. For instance,

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precursors containing aromatic sulfonamides, methyl sulfide, and β-lactams are less

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susceptible to hydrolysis with weaker leaving groups than phenothiazine, with an alkyl

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linker (PMZ), resulting in negligible NDMA formation from AMX, SMX, and LCM.

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Excluding FMT, 5-membered heterocycles with thioether (NZT, CMT, and RNT) formed

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more NDMA than other sulfur-containing precursors. As previously demonstrated, amines with β-aromatic substituents are prone to nucleophilic substitution to initiate active NDMA generation (Le Roux et al., 2012a; Selbes et al., 2012). Nonetheless, RNT and NZT with analogous structures showed far different NDMA molar yields, most likely because the electron donating heteroatom in furan-2-ylmethylium (O in RNT) allowed the formation of more stable carbocation than in thiazol-4-ylmethylium (N and S in NZT)

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Journal Pre-proof cations (Shen and Andrews, 2010). The NDMA-FP from FMT was insignificant due to electron-withdrawing sulfonyl functionalities (Bond et al., 2017; Selbes et al., 2012).

3.2.

NDMA-FP of Precursors in Mixture with RNT

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In this study, the NDMA-FP was evaluated with RNT and added competing

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precursor (10 + 10 µM mixture). The residual [precursors] in mixture almost completely

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matched the sum of [precursor] in individual experiments. Furthermore, excluding DEHA,

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DO is considerably in excess per available [precursor] (Figs. S1 and S2), so that the [DO] or [NH2Cl] would not limit the precursor degradation and oxygenation. The control

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sample (20 µM RNT only) had an NDMA-FP of 59.7%, which was moderately higher than

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that of the 10 µM RNT sample in Fig. 2. As illustrated in Fig. 3, the observed ultimate [NDMA] from precursor mixture samples were mostly comparable (within 20% deviation) to the sum of individual NDMA generation from RNT and the competitor. Analogous data in Figs. 2 and 3 were reproduced under an elevated [NH2Cl]0 of 5 mM (Fig. S3) to corroborate that the NDMA generation was marginally affected by the increase of [NH2Cl]0 from 0.2 to 5 mM. Therefore, part of the subsequent experiments was

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Journal Pre-proof performed at [NH2Cl]0 = 5 mM for amenable data collection under the accelerated kinetics.

Antagonistic effects of some co-existing precursors were observed, where the overall NDMA-FP of the mixture had negligible correlations with the NDMA-FP of the

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competing precursor. In particular, a subset of the aliphatic amine/amide (DEHA, TEA,

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TELA) significantly reduced the NDMA formation from RNT. Shen and Andrews, (2010)

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also reported analogous reduction in NDMA-FP from mixtures of pharmaceuticals in

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simulated distribution systems. Considering the low individual NDMA-FP, these

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competitors obviously intervened with the NDMA generation from RNT. The most

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remarkable reduction in NDMA-FP was observed by the addition of DEHA, which is well

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known to scavenge molecular oxygen, a key substrate for nitrosamine generation. This observation concurred with Fig. 4; marginal difference in the molar yield was obtained with or without adding DEHA under N2-purging ([DO] < 1 mg L-1). TEA and TELA would produce cationic intermediates and organic chloramine with imine upon chlor(am)ination (Abia et al., 1998), presumably to deactivate the DMA functionalities of RNT and degradation intermediates. Fig. S2 demonstrates that the consumption of NH2Cl was

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Journal Pre-proof significantly retarded by the added DEHA, TEA, and TELA. In addition, evidence has been presented demonstrating that TE(L)A could facilitate formation of N-nitrosamines other than NDMA (Dai et al., 2015).

Despite the lack of solid evidence in this study, potential interference of RNT with

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NDMA generation from some precursors in group D could be postulated (e.g., AMX). For

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example, Spahr et al., (2017) noted that one equivalent of hydrogen peroxide is

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generated along with two equivalents of NDMA and methyl-furfuryl carbocation during

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chloramination of RNT. The resulting H2O2, as a strong reactive oxygen species, could

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compete with the NH2Cl for electron-rich moieties to reduce the ultimate NDMA-FP from

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the competitors. Consequently, the wide variability in NDMA-FP from the mixed

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precursors should be understood as the result of competing reactions among precursors (and their degradation products) for key intermediates of NDMA formation, including nitrosating agents and organic chloramines (chlorammonium and other N-Cl derivatives).

MCP and TMB brought about considerable increase in NDMA formation in mixtures with RNT (Fig. 3), which drew our primary attention. In addition, the added RNT analogously enhanced the formation of other nitrosamines, such as NDEA and NMEA, in

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Journal Pre-proof the case of MCP (Fig. 5). The synergetic NDMA generations between TMB/MCP and RNT were evaluated in realistic operational conditions in (waste)water treatment ([NH2Cl]0 = 2.5 mg Cl2 L-1) in DI, surface, and algal waters (pH 7.8). Before chloramination (background), no NDMA was detected in DI and algal-containing water samples, while nearly 1.2 nM NDMA was detected in surface water, similar to the concentrations found

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previously (Kim et al., 2013). The average NDMA-FPs concentrations in the chloraminated

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(blank control) DI, surface, and algal-containing water samples were 0.054, 2.2, and

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4.7 nM, respectively (Fig. 6A), showing a good agreement with previous studies (Kim and

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Han, 2011; Ma et al., 2017). When 1 µM RNT was spiked in algal-containing water, higher

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amounts of NDMA were formed in the subsequent chloramination (0.38 µM), while nominally lower values (0.2 µM) were noted in surface water (Fig. 6B). In contrast, both

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water samples caused a considerably higher NDMA formation (ranging from 0.13 to 0.50 µM) from 10 µM TMB or MCP than the DI water (Fig. 6C and 6D). NH2Cl decay (Fig. S4) was evidently more rapid in the presence of DOC. However, a plateau of NDMA concentrations appeared mostly within 10 h, so that chloramine decay was assumed to have a marginal influence on NDMA-FP. Therefore, the difference

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Journal Pre-proof in the NDMA concentration from the selected precursor spiked in the surface water was likely due to the presence of bromide. Recently, it was demonstrated that bromide may deter nitrosating agents from RNT chloramination (Seid et al., 2020), which could ultimately reduce the NDMA formation in the surface water. In contrast, the existence of bromide ions was found to enhance the NDMA formation from both TMB and MCP

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(data not shown), as in the case of Le Roux et al., (2012b) for tertiary amine compounds.

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The higher amount of NDMA formed in the presence of bromide can be explained by

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the formation of dealkylated (such as DMA) and brominated products, leading to a high

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selectivity in the subsequent nucleophilic substitution of the terminal MCP/TMB amine

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on bromochloramines (Le Roux et al., 2012b). Nonetheless, for RNT with a high molar yield, the additional NDMA formation from DMA is negligible (Le Roux et al., 2012a);

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rather competition with terminal amine hindered NDMA formation from RNT (Seid et al., 2020). Furthermore, nitrogen-rich organic compounds released from algal biomass were found to accelerate the NDMA generation from coexisting pharmaceuticals, more distinctly from TMB and MCP. Analogous with chlorinated–aminated RNT (vide infra), chlorammonium species generated from algal compounds (Hua et al., 2017) could be

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Journal Pre-proof responsible for the synergism, facilitating the initial substitution reaction. As illustrated in Fig. 6E and 6F, when 10 µM MCP or TMB was mixed with 1 µM RNT, the ultimate [NDMA] increased by about 13 and 42%, respectively, in all water matrices, when compared to the sums of RNT and MCP or TMB samples. Such observations were astonishing, and demonstrated that MCP and (to an extent) TMB can be effective NDMA

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precursors, with the coexistence of relatively minimal RNT serving as a catalyst. The

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chloramine dosage in realistic scenarios.

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synergetic NDMA generation in the mixture could be more substantial under lower

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3.3. Elevated NDMA Formation from MCP/RNT and TMB/RNT Mixture

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3.3.1. Potential Chloramination Pathways of MCP or TMB

In the present study, the possible chloramination pathways of TMB and MCP relevant to NDMA generation were assessed based on GC-LRMS and UPLC-Q-TOF-HRMS analyses (SI, Text-S4–5, Figs. S5–S10). The mechanisms are consistent with the wellunderstood NDMA formation pathways (Le Roux et al., 2012a; Spahr et al., 2017) and could facilitate the prediction of NDMA precursors and their interpretation. Chlorinated

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Journal Pre-proof intermediates of TMB (m/z 422 [387 + Cl]) could be formed by the initial chlorine transfer, presumably to dimethylamino-2-phenylbutyl moiety, to release either DMA, phenyl, or 3,4,5trimethoxybenzoate moiety (Scheme S1). However, simple liberation of DMA could not fully account for the NDMA generation from TMB, which was significantly greater than DMA (Fig. 2). Therefore, m/z 403 [TMB + NH2] was observed

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due to nucleophilic substitution of TMB in NH2Cl, in accordance with literature (Liu et al.,

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2014; Liu and Zhong, 2017). Subsequent uptake of O2 by the hydrazine analogues was

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evinced to produce aminyl and amino-peroxyl radicals (Spahr et al., 2017), whose decay

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could yield the NDMA and deaminated-hydroxylated-fragments, m/z 360 [387– N(CH3)2

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+ OH]. In the case of MCP, the chlorinated intermediates (m/z 335 [299 + Cl]) would lead to the C-C rupture on β-diethylaminoethyl moiety (Scheme S2), to give m/z 227

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[299 – C4H10N] and its analogues as the primary molecular fragments. Resulting (chlorine-substituted) secondary amines, including DMA, DEA, and methylethylamine, would account for the generation of NDMA, NDEA, and NMEA, respectively (Andrzejewski and Nawrocki, 2018). Again, methylethyl- or di(m)ethylhydrazine analogues (via neucleophilic substitution with NH2Cl) and N-peroxyl radicals (MeEtNN-OO•, Me2NN-

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Journal Pre-proof OO•, and Et2NN-OO• via subsequent O2 uptake) were expected to be the core intermediates (Andrzejewski and Nawrocki, 2018; Liu and Zhong, 2017).

3.3.2. Effects of RNT on the Chlor(am)ination and Nitration of MCP and TMB

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TMB and MCP were less reactive towards NH2Cl than RNT, as evinced by the

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observed individual second-order rate constants, 0.35, 0.66, and 6.2 M− 1 s− 1 for MCP,

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TMB, and RNT, respectively (Table S3). The observations are consistent with the previous

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reports (Dodd and Huang, 2007; Spahr et al., 2017) on chloramination of furan and methoxybenzene-containing pharmaceuticals. In the presence of RNT, however, the

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second-order rate constants increased to 0.50 and 2.5 M− 1 s− 1 for MCP and TMB,

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respectively. Therefore, it was reasonable to presume that chlorinated RNT might promote the initial chlorination steps in TMB and MCP. The stronger leaving group of organic chlorammonium than that of chloramine (Huang and Shah, 2018) was further presumed to not only accelerate the precursor degradation, but also generate intermediate amines with stable carbocations for efficient NDMA generation (vide infra). Tertiary amines, such as creatinine (CRT) and trimethylamine (TMA), were also reported

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Journal Pre-proof to form the chlorammonium species and enhance chlorination of methoxybenzenecontaining pharmaceuticals (Shah et al., 2011). To this end, the elevated rates of TMB degradation in the presence of TMA or CRT presented in Table S3 clearly confirm our postulation. Nevertheless, the NDMA-FP of TMB was almost perfectly maintained with the added TMA or CRT (Fig. S11). Accordingly, the copresence of RNT was suspected to

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facilitate the nitrosation of degradation products from TMB and MCP, which would be a

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necessary step for the NDMA generation.

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To support the abovementioned hypothesis, we performed chlorination (with

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5 mM NaOCl at pH 7.8) with subsequent nitrosation (by addition of 5 mM NaNO2 at pH

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4) for RNT, MCP, TMB, and DMA, as reported in the literature (Brambilla and Martelli,

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2007; Zhang et al., 2014). As a result of chlorination, the generation of nitrosating agent (N-peroxyl radical) from RNT was expected to be infeasible, whereas NO+ (via a nitrosyl cation or nitryl chloride) from nitrite ion in acidic environment could provide the nitrosofunctionality (Zeng and Mitch, 2016). Furthermore, earlier studies have shown that chlorine residual could contribute to enhance nitrosation of DMA-N by increasing •NOlike activity and N-peroxyl radicals (Choi and Valentine, 2003; Uppu et al., 1998).

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Journal Pre-proof The NDMA yields after chlorination of individual precursors were <0.5% (Fig. 7A), in an order of magnitude comparable with the previous reports (Zhang et al., 2014). Upon nitrosation only, approximately 1.6 and 1.2% NDMA molar yields were noted from RNT and DMA, while NDMA formation occurred from the others was insignificant. In comparison, the yields after chlorination and subsequent nitrosation for RNT, MCP, TMB,

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and DMA increased to 1.3–2.0%. As illustrated in Fig. 7B, the NDMA formation from RNT

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was moderately reduced by the added competitors (MCP, TMB, and DMA) in individual

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chlorination or nitration. Upon combination of chlorination and nitrosation, in

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comparison, the NDMA yield increased significantly in mixtures of RNT+MCP and

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RNT+TMP, as compared to RNT only (20 µM) or RNT+DMA. These results demonstrated that the enhanced NDMA formation in mixtures is attributable to the chlorinating and

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nitrosating agents generated from RNT.

3.3.

3. Proposed Mechanism of the Enhanced NDMA Formation

We further employed tandem mass spectrometry for the mixed RNT/TMB, RNT/MCP (Figs. S12–S14), to elucidate the synergetic NDMA formation mechanisms. First,

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Journal Pre-proof we monitored chlorinated–aminated RNT (Fig. S12), a potent intermediate of NDMA generation from RNT chloramination (NH2Cl/NHCl2; Zhang et al., 2020). The peak of RNTNH-Cl (m/z 364) appeared after 0.5 h of chloramination, with the intensity decreasing gradually over time. In the presence of TMB or MCP, the m/z 364 signal diminished far more quickly than that of the control sample (RNT only). The observations strongly

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suggested that RNT-NH-Cl would be responsible for the augmented NDMA generation

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in the mixture.

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In addition, the chloramination of mixture samples gave evident signals from

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dimethyl amino-phenylbutane from TMB (m/z 174 [387 – C10H12O4]) and N-deethylated

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fragments of MCP (m/z 271 [299 – C2H5]), which would principally mediate nitrosamine

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formation. More importantly, their complexes with RNT-NH-Cl were identified as m/z 538 [387 – C12H18N + RNT-NH-Cl) for TMB (Fig. S13) and m/z 435 [299 – C12H18N + RNT-NHCl] for MCP (Fig. S14), solidifying that RNT-NH-Cl could shift the degradation of intermediate speciation. These fragments were observed only for the mixture samples during the non-target MS analysis, however, further investigations are required for more

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Journal Pre-proof variable situations, along with the interrogation of the core structures of MCP and TMB responsible for the synergism based on computational chemistry techniques.

Consequently, the NDMA formation pathways in the mixture could be proposed as Scheme 1 and S3. Electrophilic substitutions of the RNT-NH-Cl would effectively cut off

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3,4,5-trimethoxybenzoate moiety from TMB and ethyl moiety from MCP in a catalytic

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manner. The resulting amine intermediates are believed to form nitrosamine more

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effectively than the mother compounds for the following reasons. First, a greater electron

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density on N might facilitate the nucleophilic substitution on NH2Cl (amination) and

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subsequent aminyl radical generation. Second, stable carbocations of the principal

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intermediates in mixture would allow the subsequent formation of nitroso-group such as

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m/z 204 for TMB (Fig. S13) and m/z 117 for MCP (Fig. S14) and make liberation of NDMA more amenable (Brambilla and Martelli, 2007; El-Shaheny et al., 2019). The formation of

N-nitroso-compound cations was recently evinced to be an essential step before the release of NDMA (Zhang et al., 2020). As corroborated above, the nitrosation could also be expedited by the N-peroxyl radicals generated from RNT-NH-Cl, such as RNT-NH-OO• and NH2-O-O• (Spahr et al., 2017). In particular, an active role of NH2-O-O• might

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Journal Pre-proof explain the synergism by a relatively small amount of RNT. It is worth mentioning that nitrosation catalyzed by RNT could trigger the generation of other nitrosamines, as in the case of MCP (Fig. 5).

Environmental Significance

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3.4.

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This study demonstrated that the role of RNT to explain the NDMA levels in

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surface water should be understood in terms of inhibitive/synergetic interactions with

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other precursors. Even though the [MCP or TMB] in the present study (10 µM) might be higher than the observed concentrations in environment, the enhanced NDMA formation

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by RNT is expected to occur at lower concentrations.

In addition, our findings should not be undervalued because i) potential synergism of RNT with other amine compounds (either as influent DOC or effluent organic matter) cannot be ruled out, especially in (waste) water treatment processes employing chloramines, ii) elevated concentrations of the precursors are possible under only selected circumstances, such as in reverse osmosis concentrates, which could

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Journal Pre-proof contact chloramines during membrane cleaning. Consequently, the novel insights provided by the present work necessitate the re-examination of a wide range of precursors, for which nitrosamine formation in actual environments could have been

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underestimated.

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4. Conclusions

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This study investigated nitrosamine formation from RNT and 26 micropollutants upon

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chloramination in individual and mixed conditions. For individual solutions, RNT and MCP exhibited the highest molar yields of NDMA (50–60%) and NDEA/NMEA (~0.6%),

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respectively. This study, for the first time, notes that the NDMA-FP of CMT, MFP, OPA,

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and TMB, is as high as 10%. Partial charge/pKa of amine-N, stability of carbocation, and/or chemical structure linked to amine-N could collectively, but incompletely, influence NDMA formation potential. In precursor mixtures, compounds such as DEHA and TE(L)A reduced the NDMA-FP of RNT by scavenging either O2 or DMA functionalities. Ultimate [NDMA] from mixtures were comparable to the sum of individual NDMA generation (within 20% deviation) for most competing precursors. NDMA

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Journal Pre-proof formation from TMB and MCP was enhanced by copresence with RNT, most probably because of chlorinating intermediates (RNT-NH-Cl) and nitrosating agents (with nitrosofunctionalities) generated from RNT. UPLC-Q-TOF–MS analysis results suggested that the core intermediates of NDMA generation were m/z 174 and m/z 271 for TMB and MCP, respectively. More importantly, UPLC-Q-TOF-MS analysis suggested that their complexes

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with RNT-NH-Cl could alter the intermediate speciation and enhance nitrosamine

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formation. Considering that these micropollutants are present in water sources, their

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concentration should be monitored by water treatment facilities when employing

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chloramination to mitigate NDMA generation. In terms of total nitrosoamines, the

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potential contribution of NDELA, NDEA, and NMEA should also be properly addressed.

Acknowledgments

The experimental work was supported by Korea Environment Industry & Technology Institute (KEITI) through the “Project for developing innovative drinking water and wastewater technologies,” funded by Korea Ministry of Environment (MOE; 2019002710010). This study was also supported by Young Researcher Program (NRF-

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Journal Pre-proof 2019R1C1C1003435) and Basic Research Laboratory (NRF-2018R1A4A1022194) through the National Research Foundation of Korea.

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Journal Pre-proof Figures and Schemes

Fig. 1. Acronyms and chemical structures of interrogated precursors in this study: (A) aliphatic amine and amides, (B) aromatics, (C) free or polymer-bound quaternary alkylamines, and (D) mixed sulfur-containing precursors.

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Fig. 2. Molar yields of NDMA from individual precursors including (A) aliphatic amine

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and amides, (B) aromatics, (C) free or polymer-bound quaternary alkylamines, and (D)

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mixed sulfur-containing precursors ([precursors]0 = 10 µM, [NH2Cl]0 = 0.2 mM, pH = 7.8,

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and reaction duration = 24 h).

Fig. 3. The ultimate [NDMA] from mixture ([precursors]0 = 10 µM + [RNT]0 = 10 µM)

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versus sum of [NDMA] from individual precursors from Fig. 2 ([NH2Cl]0 = 0.2 mM, pH =

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7.8, reaction duration = 24 h). Solids lines indicate symmetry with 20% deviation. [NDMA] from 10 µM RNT is shown as reference.

Fig. 4. Effects of diethylhydroxylamine (DEHA) and N2 purging on molar yields of Nnitrosodimethylamine (NDMA) from ranitidine (RNT) ([RNT]0 = 10 or 20 µM, [DEHA]0 = 10 µM, [NH2Cl]0 = 5 mM, pH 7.8, and reaction duration = 24 h).

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Journal Pre-proof Fig. 5. Molar yields of N-nitrosodiethylamine (NDEA) and N-nitrosomethylethylamine (NMEA) during chloramination of metoclopramide (MCP) with and without ranitidine (RNT) ([RNT]0 = [MCP]0 = 10 µM, [NH2Cl]0 = 5 mM, pH = 7.8, and reaction duration = 24 h). Fig. 6. NDMA generation under a reduced chloramine dose ([NH2Cl]0 = 2.5 mg Cl2 L-1) in DI, surface, and algal waters from (A) non-spiked waters and precursor spiked waters (B)

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RNT (1 µM), (C) MCP (10 µM), (D) TMB (10 µM), and (E and F) mixtures (1 µM RNT +

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10 µM MCP or TMB) after 24 h chloramination at pH = 7.8.

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Fig. 7. Molar yields of NDMA from (I) chlorination, (II) nitrosation, and (III) chlorination

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with sequential nitrosation of (A) individual precursors (10 µM) and (B) mixtures (total

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(24 h) for nitrosation).

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20 µM) ([NaOCl]0 = 5 mM at pH = 7.8 (24 h) for chlorination and [NO2-] = 5 mM at pH 4

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Scheme 1. Proposed NDMA formation pathway during chloramination of TMB in the presence of RNT. (*) indicates chloramination (NH2Cl/NHCl2).

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Journal Pre-proof CRediT author statement

Mingizem Gashaw Seid: Conceptualization, Methodology, Writing- Original draft. Jaeshik Chung: Data curation, Validation. Jaewan Choe: Data curation, Validation. Kangwoo Cho: Supervision, Funding acquisition, Writing- Reviewing and Editing. Seok Won Hon: Supervision, Resources,

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Funding acquisition, Writing- Reviewing and Editing.

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Journal Pre-proof Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may

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Graphical abstract

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Journal Pre-proof Highlights

 Twenty-seven amine-functionalized anthropogenic sources investigated.  Multiple nitrosamines and scattered NDMA formation potential explored.  Metoclopramide and trimebutine, along with ranitidine, promoted NDMA formation.  NDMA formation increased with chlorination followed by nitrosation.

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 Chloraminated fragments were identified by UPLC-Q-TOF-HRMS and (GC)/TOF

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Figure 1

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