**1. Introduction**

Myristicin (CAS N◦: 607-91-0; IUPAC name: 4-methoxy-6-prop-2-enyl-1,3-benzodioxole), elemicin (CAS N◦: 487-11-6; IUPAC name: 1,2,3-trimethoxy-5-prop-2-enylbenzene), safrole (CAS N◦: 94-59-7; IUPAC name: 5-prop-2-enyl-1,3-benzodioxole), and methyleugenol (CAS N◦: 93-15-2; IUPAC name: 1,2-dimethoxy-4-prop-2-enylbenzene) are secondary plant metabolites belonging to the group of alkenylbenzenes (Figure 1). Such derivatives may particularly be found in Umbelliferae (anise, star anise, fennel, sweet fennel, and parsley), Myristicaceae (nutmeg and mace), Labiatae (sweet and exotic basil), and Compositae (tarragon).

**Figure 1.** Structural formulas of methyleugenol, elemicin, safrole, and myristicin.

Several alkenylbenzene derivatives are known toxicants. For example, safrole and methyleugenol were classified by the International Agency for Research on Cancer (IARC)

**Citation:** Götz, M.E.; Sachse, B.; Schäfer, B.; Eisenreich, A. Myristicin and Elemicin: Potentially Toxic Alkenylbenzenes in Food. *Foods* **2022**, *11*, 1988. https://doi.org/10.3390/ foods11131988

Academic Editor: Isabel Sierra Alonso

Received: 31 May 2022 Accepted: 1 July 2022 Published: 5 July 2022

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as "possibly carcinogenic to humans" (Group 2B) [1,2]. Moreover, the Scientific Committee on Food (SCF) of the European Commission (EC) considered safrole and methyleugenol as genotoxic carcinogens and suggested restrictions for their use in foods [3,4]. In consequence, the EC prohibited the addition of safrole and methyleugenol as pure flavoring substances to food and established maximum levels for these substances–when naturally present–for certain flavored foodstuffs, such as soups and sauces or non-alcoholic beverages (Regulation (EC) No 1334/2008). In contrast to safrole and methyleugenol, the structurally closely related alkenylbenzenes myristicin and elemicin were not assessed by international expert bodies in a comparable manner until now (Figure 1). This is probably due to the lack of reliable data regarding genotoxicity, carcinogenicity, and other toxic effects.

It is assumed that the toxicity of safrole and methyleugenol is mainly caused by metabolic activation at the allylic side chain, namely 1- -hydroxylation and subsequent sulfonation to the resulting allylic sulfate esters. These intermediates are instable and may subsequently react with cellular nucleophiles including DNA and proteins [5]. The relevance of further metabolites, e.g., quinone methides or other so far unknown reactive intermediates possibly involved in hepatotoxic effects are far less clear.

Paying attention to the chemical structure, it may be noted that the less intensively studied derivatives, myristicin and elemicin, each bear just one additional methoxy substituent at the benzene core as compared to safrole and methyleugenol, respectively (Figure 1). The allylic side chain is a common feature of all the four alkenylbenzenes discussed here. Metabolic differences with respect to the allylic side chain, the suspected site of metabolic activation leading to toxicity, are expected to be marginal. However, oxidative demethylenation of myristicin and oxidative demethylation of elemicin at the benzene core are not entirely comparable to similar reactions on safrole and methyleugenol. Consequently, the resulting patterns of urinary benzyl metabolites that could be detected in rats [6,7] and in humans [8] following elemicin and nutmeg ingestion, respectively, are different from those formed from safrole and methyleugenol in rodents.

Nevertheless, for all the four compounds, the toxic principle that is assumed to lead to toxification is the 1- -hydroxylation and subsequent sulfonation to the resulting allylic sulfate esters [5].

Intake of myristicin, elemicin, safrole, and methyleugenol is presumed to occur mainly from the consumption of spices and essential oils made thereof [9,10]. High levels may also be present in plant-based food supplements (PFS) as well as in various processed flavored foods such as sauces, baked goods, and beverages, such as cola-flavored softdrinks [5,10–13].

Taken together, the toxicological relevance of alkenylbenzene occurrence, especially for less intensively investigated members such as myristicin and elemicin, is still under discussion.

In this review, we summarize and discuss the current knowledge regarding occurrence, toxicokinetics, and the toxicity of myristicin vs. safrole, as well as elemicin vs. methyleugenol. Moreover, we highlight data gaps currently impeding the assessment of the adverse health effects of these substances.

#### **2. Occurrence of Myristicin and Elemicin**

The occurrence of the alkenylbenzenes safrole and methyleugenol in plants used as foods was described in detail elsewhere [5]. Beside this, aromatic plants, as well as powders, extracts, or essential oils made thereof can also serve as sources for myristicin and elemicin, which are described here.

Of note, when interpreting occurrence data, it should always be kept in mind that the chemical constituents of culinary spices, including alkenylbenzenes, are widely dependent not only on species but also on environmental factors such as geographic location, seasonal variation, and harvest time. Furthermore, the analytical method–especially the extraction procedure–may also affect the obtained occurrence data [14–16]. In the following part, as well as in Table 1, we will present relevant examples of (culinary) plants and their essential oils containing myristicin and elemicin.
