Metabolic Fate, Mode of Action, and Benchmark-Dose Risk Assessment of the Natural Monoterpene β-Myrcene

Background: The acyclic monoterpene β-myrcene (CAS No. 123-35-3) is a food flavoring classified by the International Agency for Research on Cancer (IARC) as “possibly carcinogenic to humans” (Group 2B) based on neoplastic findings in rodents. Its toxicological relevance is closely tied to its metabolic fate: CYP-mediated epoxidation yields reactive intermediates that are rapidly detoxified to diols, and the weight of evidence supports a non-genotoxic, threshold mode of action. This study therefore combined this metabolic understanding with benchmark dose-response (BMD) modeling to derive a health-based guidance value (HBGV). Methods: Tumor-incidence data from the two-year National Toxicology Program (NTP) gavage studies in rats and mice were modeled with BMDS Online version 25.1 from US EPA, following international guidelines. A benchmark response (BMR) of 10% extra risk and a 95% lower confidence limit were applied. Models were evaluated by goodness of fit and Akaike information criterion (AIC). Results: The BMDL₁₀ of 25.4 mg/kg b.w./day for hepatocellular adenoma (including multiple) in male mice was selected as the point of departure (POD). Applying an uncertainty factor of 100 yielded an acceptable daily intake (ADI) of 0.25 mg/kg b.w./day, equivalent to 250 µg/kg b.w./day. At estimated flavoring intakes of 3–138 µg/kg b.w./day, the ADI-to-intake ratio ranged from approximately 83 to 1.8. Conclusion: Thus, an ADI of 0.25 mg/kg b.w./day can be proposed for β-myrcene. Estimated flavoring intakes remain below this value; however, the margin at the upper exposure estimate is limited to approximately 1.8.