Metabolic Fate, Mode-of-Action Considerations, and Benchmark-Dose Risk Assessment of the Natural Monoterpene β-Myrcene
- 1Private University in the Principality of Liechtenstein (UFL), Dorfstrasse 24, 9495 Triesen, Liechtenstein
- 2Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weissenburger Strasse 3, 76187 Karlsruhe, Germany
Abstract
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 provides no indication of DNA reactivity. Separately, a threshold-based dose–response approach was adopted as a pragmatic default assumption, consistent with EFSA and JECFA practice, rather than as an inferred 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. Doses administered on five days per week were converted to time-weighted average daily doses before modeling. The 1000 mg/kg dose group was excluded from modeling because survival at that dose indicated that the maximum tolerated dose had been exceeded. 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 18.2 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 0.18 mg/kg b.w./day, equivalent to 180 µg/kg b.w./day. At estimated flavoring intakes of 3–138 µg/kg b.w./day, the ratio of the ADI to the estimated intake, which is not a margin of exposure in the EFSA sense, ranged from approximately 60 to 1.3. This comparison covers flavoring use alone and does not include other dietary or non-dietary sources of β-myrcene. Conclusions: Thus, an ADI of 0.18 mg/kg b.w./day can be proposed for β-myrcene. Estimated flavoring intakes remain below this value; however, the threshold assumption introduces additional uncertainty, and the margin at the upper exposure estimate is limited to approximately 1.3.
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BibTeX
@article{behnelippert2026metabolic,
title = {{Metabolic Fate, Mode-of-Action Considerations, and Benchmark-Dose Risk Assessment of the Natural Monoterpene β-Myrcene}},
author = {Sascha Behne–Lippert and Dirk W. Lachenmeier},
journal = {Metabolites},
year = {2026},
month = oct,
doi = {10.3390/metabo16110834},
url = {https://www.mdpi.com/2218-1989/16/11/834},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metabolic Fate, Mode-of-Action Considerations, and Benchmark-Dose Risk Assessment of the Natural Monoterpene β-Myrcene
AU - Sascha Behne–Lippert
AU - Dirk W. Lachenmeier
PY - 2026
DA - 2026/10/30
JO - Metabolites
DO - 10.3390/metabo16110834
UR - https://www.mdpi.com/2218-1989/16/11/834
AB - 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 provides no indication of DNA reactivity. Separately, a threshold-based dose–response approach was adopted as a pragmatic default assumption, consistent with EFSA and JECFA practice, rather than as an inferred 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. Doses administered on five days per week were converted to time-weighted average daily doses before modeling. The 1000 mg/kg dose group was excluded from modeling because survival at that dose indicated that the maximum tolerated dose had been exceeded. 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 18.2 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 0.18 mg/kg b.w./day, equivalent to 180 µg/kg b.w./day. At estimated flavoring intakes of 3–138 µg/kg b.w./day, the ratio of the ADI to the estimated intake, which is not a margin of exposure in the EFSA sense, ranged from approximately 60 to 1.3. This comparison covers flavoring use alone and does not include other dietary or non-dietary sources of β-myrcene. Conclusions: Thus, an ADI of 0.18 mg/kg b.w./day can be proposed for β-myrcene. Estimated flavoring intakes remain below this value; however, the threshold assumption introduces additional uncertainty, and the margin at the upper exposure estimate is limited to approximately 1.3.
SN - 2218-1989
ER -