Estragole in Herbal Medicinal Products – time for action?

Introduction In its public statement (PS) of 2005 on the use of Estragole in Herbal Medicinal Products (HMP) the EMEA Herbal Medicinal Products Working Party (HMPC), in regard of interspecies differences in metabolic activation, a probably non-linear dose response curve at low doses and the low doses and short treatment duration typically found in medicinal use of relevant herbal products, did not see the necessity of a limitation [1].

Results, Discussion With reference to newly published data, the HMPC issued a revised PS in March 2022. However, the available data did still not allow to derive a health-based guidance value (HBGV) by application of established approaches. Therefore, the HMPC imposed a limit only for the use of estragole-containing products in the pediatric population as well as in pregnancy and lactation. For all other products applicants viz marketing authorization holders must assess possibilities to reduce the estragole content/intake to a “practically achievable” level [2]. In its draft revised Community monographs on Foeniculum vulgare fruit (var. vulgare and var. dulcis, respectively), the HMPC proposes to reduce daily doses to the minimum for which a traditional use has been demonstrated [3]. While this may appear a moderate and “practicable” approach to some, it would be a grave and immature intervention, given that important stipulations of the HMPC Public Statement, i.e., provision for food background exposure to estragole and less-than-lifetime exposure, have not been considered [4]. Given as well, that a current EFSA assessment of the safety of Foeniculum vulgare (infusion) will be finalised by May 2025. It is expected that this opinion will include information on the level of estragole exposure via food [5]. The discussion in the scientific community [6] [7] [8] and ongoing research [9] highlight important data gaps for estragole.

Conclusion Open toxicological questions and the dynamic of current research call for reservation and commensuration when deriving regulatory measures from the HMPC public statement.

AcknowledgementMany thanks for fruitful discussions to D. Schrenk and J. Fahrer, University of Kaiserslautern and to O. Kelber, Steigerwald Arzneimittelwerk GmbH, Darmstadt.

 

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• References

• 1 EMEA Herbal Medicinal Products Committee (HMPC). Public Statement on the use of herbal medicinal products containing estragole. EMEA/HMPC/137212/2005
• 2 EMA Committee on Herbal Medicinal Products (HMPC). Public statement on the use of herbal medicinal products containing estragole. EMA/HMPC/137212/2005 Rev 1
• 3 Committee on Herbal Medicinal Products (HMPC). European Union herbal monograph on Foeniculum vulgare Miller subsp. vulgare var. vulgare, fructus Draft – Revision July 2022 EMEA/HMPC/372841/2016
• 4 ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk - Step 5 (EMA/CHMP/ICH/83812/2013). European Medicines Agency, Committee for Human Medicinal Products, 25 August 2015
• 5 European Commission. Commission request for a scientific opinion on the safety of bitter and sweet fennel. SANTE/E1/FN/ml (2022)5598643, Brussels 19/07/2022
• 6 Eisenreich A. et al. Foods 2021; 10: 2139
• 7 Davidsen JM. et al. Food Chem Toxicol 2023; 175: 113646
• 8 Schulte-Hubbert R. et al. Toxicology 2020; 444: 152566
• 9 Ackermann G et al. German Pharmacology and Toxicology Summit GPTS, Session 1, Poster P035, 03-07-2023

Publication History

Article published online:
14 June 2023