EMA adopts final Public Statement on Pyrrolizidine Alkaloids

Recommendation

5/6 June 2024

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At the 100th HMPC meeting, held from 5-7 July 2021, EMA´s Committee on Herbal Medicinal Products (HMPC) adopted the final Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination with PAs. The document describes chemical, toxicological, pharmacological and pharmacokinetic properties of PAs and sets out recommendations for oral and cutaneous use of herbal medicinal products containing PAs.

Maximum daily intake of PAs recommended by the HMPC

The HMPC document is an update of the public statement published in 2014, which now includes the considerations of a possible PA contamination by accidentally harvested toxic weeds. In 2016 the HMPC recommended a maximum daily oral intake of PAs of 1.0 µg (previously a limit of 0.35 µg per day had been considered necessary). It is now confirmed:

"Considering the insignificant difference in safety risk associated to the acceptable intakes determined with TD50 and BMDL10 methods, the HMPC agreed that an acceptable intake equivalent to 1 µg/day for an adult can be used as the limit for oral intake of PAs."

Compared to the draft version, the final public statement contains a few editorial changes. In addition, it is stated that PA specifications are no longer considered necessary for essential oils:

"From data provided and supportive investigations, it can be concluded that essential oils with pharmaceutical quality are to be seen as of low concern. […] essential oils of pharmaceutical quality contained in HMPs (either as active ingredient or as excipient) would not need to provide specifications concerning PA content."

Pharmacopoeias

The European Pharmacopoeia contains a new general chapter 2.8.26. Contaminant pyrrolizidine alkaloids (Ph. Eur. Supplement 10.6) which will be implemented on 1 January 2022. Regarding PA limits it states: "Patient exposure to PAs from medicinal products should be as low as possible and must not exceed the maximum daily intake agreed by the competent authority."

Furthermore, the USP is currently working on two new general chapters:

• <1567> Pyrrolizidine Alkaloids
• <567> Analysis of Contaminant Pyrrolizidine Alkaloids (PAs)

The final document EMA/HMPC/893108/2011 Rev. 1 together with an overview of comments received during public consultation is available on the EMA Website.