## 4 Discussion  
The primary objective of the present pilot clinical trial was to evaluate the safety of a newly formulated mouthwash containing cynenol, potassium nitrate and zinc chloride. This objective was confirmed in terms of the lack of adverse events and a good user's tolerability. As secondary objectives this study also evaluated the clinical and microbiological effect of this newly formulated mouth rinse, when compared to a standard control mouth rinse, demonstrating a similar effect (no statistically significant differences were demonstrated). In terms of safety, no adverse events were reported during the study. The subject's perceptions on the assigned mouth rinse used, assessed through self-reported questionnaires, showed statistically significant differences between groups at the 6-week visit in questions 5 and 8, favoring the control group, since users of the experimental mouthwash reported a greater sensation of dry mouth (\(p=0.016\)) and reported a lower score on their overall opinion of the trial mouthwash (\(p=0.022\)), although this opinion improved at 12 weeks (\(p>0.05\)). In 2006, a panel of experts assessed the safety of different ingredients used as cosmetic biocides/preservatives and/or fragrances, including cynenol. They concluded that o-Cymen-5-ol was safe at concentrations up to 0.5% [21]. These data are in line with a previous study (2011) where 17 adverse events were reported, but only one occurred in the experimental group after the use of a toothpaste containing cynenol and zinc chloride and it was considered as not related to the treatment itself [22]. Conversely, in another study, a mild case of lip tingling, associated with the use of a toothpaste containing 0.1% cynenol, 0.6% zinc chloride and sodium fluoride, was reported [23]. In terms of the effect of the tested mouth rinse on gingival health, statistically significant differences between the groups were only observed when evaluating the changes in PII between the baseline and the 12-week visit, with small intragroup changes, but with better results in the control group. These results differ from those observed in previous studies, where the mean PII score in the cynenol and zinc chloride group was 2.05 at 12 weeks, while in the fluoride control toothpaste, it was 2.71 (\(p<0.0001\)) [22]. In another study, evaluating in situ plaque formation with a specific software, differences after 4 days and after 8 days suggested a short-term anti-plaque effect of a 0.10% cynenol mouthwash [24]. The effect on dentin hypersensitivity (Schiff and VAS) showed a trend towards reduction in both groups, but no statistically significant differences between the groups were found. These results, using a formulation with potassium nitrate, are in line with those from a systematic review, reporting the lesser efficacy of potassium, as compared with arginine in a treatment for dentin hypersensitivity [25]. Similarly, a clinical study reported that a control mouth rinse containing 0.2% sodium fluoride reduced hypersensitivity after 2 and 6 weeks of use was equally efficient as the experimental mouthwash containing 3% potassium nitrate and 0.2% sodium fluoride at 2 weeks, although at 6 weeks, significant differences were reported in favor of the experimental group in terms of general sensitivity and response to cold air tests [26]. The impact on tooth staining, a significant side effect of antiseptics, was also evaluated, revealing no statistically significant differences between the groups. While in the experimental group there was a minor increase of 0.4 (SD = 0.3) at 6 weeks and 0.4 (SD = 0.4) at 12 weeks, in the control group, there was a small decrease. In recent years, there has been a growing interest in using plant-based antimicrobial substances, such as cynenol, as alternatives to traditional antiseptics like chlorhexidine and triclosan. This is primarily due to the possibility that these natural compounds may cause fewer side effects.