## 8 Do Coumarins Have an Impact on Food Safety? As mentioned before, simple coumarins are the most plentiful in wood and aged spirits. The majority of these coumarins are considered not hazardous to human health at the concentrations detected in beverages and edible plants [283]. Nevertheless, studies dealing with a higher dosage of coumarin extracted from natural sources revealed chronic toxic effects, particularly hepatotoxicity [234]. As a result, it is necessary to quantify coumarins, specifically the coumarin, in spirit beverages, using precise and accurate analytical methods (described in Section 5). Clinical studies have shown that coumarin is probably not a carcinogen for humans, which has led to its classification as a Group 3 chemical with only limited toxicity [284]. Previously, coumarin was used in flavours and as a chrome-plating brightener until 1954, when the FDA classified it as a carcinogen and banned its use in foodstuffs [284]. In 1956, in vivo studies revealed that the coumarin incorporated into the diet of rats and dogs caused the initial damage to their liver tissue [285]. Contrary to these findings, the in vivo studies for mutagenic and genotoxic potential suggest that coumarin is not a genotoxic agent, because the dose-response relationships for coumarin-induced toxicity and carcinogenicity are non-linear, with tumour formation occurring only at high doses (>280 mg/kg/day), which are associated with pulmonary and hepatic toxicity [112; 286]. Although the majority of coumarins are not intrinsically toxic, with the exception of coumarin, some derivatives and higher doses may raise concerns related to food safety. Regarding data on food toxicology, which is focused on the study of compounds present in food that can potentially cause adverse effects on consumer health, the Chemical Safety Data Sheets (SDS) and PubChem data available confirm that the most common coumarins found in wood raw material and aged spirit beverages have little harmful effect on human beings (Table 9). The physiological functions and the target organs of the six most prevalent coumarins are influenced by their chemical structure. It is evident that substituent groups (Figure 16) have a notable impact, and even minor differences in structure lead to different actions and varied affinities for biological targets: hydroxyl, methoxy, and glycosidic groups in various positions on the coumarin skeleton. Certain structural modifications during metabolic degradation can result in more toxic metabolites, which is the reason why it is critical to identify and understand the metabolites that can be generated in the human system. Umbelliferone, for example, is a coumarin degradation metabolite that is also a known human metabolite of 7-methoxycumarin and coumarin. Specific tissues or organs may be highly susceptible to the impacts of particular substances due to their physiological activities, high metabolic activity, or exposure. For example, coumarin is predominantly metabolised in the liver through cytochrome P-450. In phase I, metabolic events such as oxidation, reduction, and hydrolysis are used to modify functional groups in order to prepare the substrate for subsequent conjugation reactions in phase II. The cytochrome P-450 enzyme in the liver hydroxylated coumarin and similar compounds [298], and the most prevalent hydroxylation pathways happens at the 3- and 7-positions, to produce 3-hydroxycumarin (3-OHC) and 7-hydroxycumarin (7-OHC), respectively, and for coumarin [299; 300]. The presence of a significant amount of 3-OHC is thought to facilitate the formation of the cytotoxic by-product o-HPA (Figure 15), which could potentially contribute to, or be accountable for, coumarin-induced toxicity. Coumarin demands extra attention when compared to other naturally occurring coumarins, not only because of its lower LD\({}_{50}\) (more toxic), but also because it is commonly found in cinnamon-containing food and drinks.