## 1 Introduction
However, even trace concentrations have shown that they might have direct toxicity towards individual aquatic organisms [12; 13; 14; 15]. Concerning drinking water, several risk assessments studies indicate that very low concentrations of pharmaceuticals are very unlikely to pose any risks to human health. Still, there are knowledge gaps in assessing the risks that are associated with long term, low-level exposures to pharmaceuticals and possible combined effects of chemical mixtures. The investigation of possible additive or synergistic effects of mixtures would be necessary for an accurate exposure assessment in order to determine whether there are any potential risks to human health, while considering sensitive subpopulations [16; 17]. Because of these challenging questions, PhACs in the environment are reported in thousands of publications during the last decades and reviewed by many authors, demonstrating an increasing concern about them [18; 19; 20; 21; 22; 23; 24; 25; 26; 27]. Efforts have been made to improve the knowledge and data available on sources of PhACs, and how pollution occurs to identify targeted and effective control options. The determination of these compounds in the various environmental matrices, such as water (wastewater, surface water, groundwater, and water for human consumption), soils, sediments, and biota, has grown and is subject to increasingly demanding legislative requirements (in the order of ug/L or ng/L, or ng/g for solid matrices). In water policy, Directive 2013/39/EU refers for the first time to the contamination of water and soil by pharmaceutical waste as an environmental problem [28]. In Europe, to ensure the monitoring of compounds subject to possible hazards, such as emerging pollutants, and to guarantee a quality database to identify/prioritize substances, this directive identifies a set of priority substances in a watch list subject to update. The watch list mechanism was established to require the temporary monitoring of other substances for which evidence suggested a possible risk to or via the environment, in order to inform the selection of additional priority substances. The watch list should contain a maximum of 10 substances or groups of substances, indicating the matrices to be monitored as well as possible methods of analysis that do not involve high costs. Relative to PhACs, this first watch list includes a non-steroidal anti-inflammatory drug (diclofenac) and the hormones 17-\(\beta\)-estradiol (E2) and 17-\(\alpha\)-ethinyl estradiol (EE2) to determine the concentration levels that facilitate the application of appropriate measures given the risk that these substances represent. Two other PhACs, carbamazepine and sulfamethoxazole, are also being studied for possible inclusion in this list. The first watch list was adopted in the Decision 2015/495/EU of 20 March 2015 [29] and it includes seven PhACs: two natural hormones (E2 and estrone (E1)), one synthetic hormone (EE2), one nonsteroidal anti-inflammatory drugs (diclofenac), and three macrolide antibiotics (erythromycin, clarithromycin, and azithromycin). This directive was repealing by Decision 2018/840/EU [30] of 5 June 2018 and the substances mentioned above (EE2, E2, E1, azithromycin, clarithromycin, and erythromycin) were included, together with two other antibiotics, amoxicillin and ciprofloxacin. The Commission removed the diclofenac from the watch list due to the sufficient high-quality monitoring data available for diclofenac [30]. The inclusion of amoxicillin and ciprofloxacin is consistent with the European One Health Action Plan against Antimicrobial Resistance (AMR), which supports the use of the watch list to \"improve knowledge of the occurrence and spread of antimicrobials in the environment\" [31]. All of the evaluations and decisions were supported by the occurrence studies of these contaminants in the aquatic environment, where the high-quality data on their concentrations (quality of the analytical results) were essential.