1 8 July 2020 2 EMA/HMPC/893108/2011 Rev. 1 3 Committee on Herbal Medicinal Products (HMPC) 1 4 Public statement on the use of herbal medicinal products 5 containing toxic, unsaturated pyrrolizidine alkaloids (PAs) 6 including recommendations regarding contamination of 7 herbal medicinal products with pyrrolizidine alkaloids 8 Draft Draft discussed by Working Party on Community monographs and November 2011 Community list (MLWP) January 2012 March 2012 May 2012 Adopted by Committee on Herbal Medicinal Products (HMPC) for 24 September 2012 release for consultation Start of public consultation 25 October 2012 End of consultation (deadline for comments) 15 February 2013 2nd draft discussed by MLWP March 2013 May 2013 July 2013 Coordination with Safety Working Party July-October 2013 2nd draft adopted by HMPC for release for consultation 17 September 2013 End of consultation (deadline for comments) 15 February 2014 Re-discussion by MLWP of 2nd draft March 2014 October 2014 Adopted by HMPC 24 November 2014 Draft Revision 1 discussed in HMPC November 2019 January 2020 1 In the context of this PS, the term "herbal medicinal products" (HMP) also includes "traditional herbal medicinal products" (THMP). Therefore only the term "herbal medicinal products" or "HMP" is used throughout. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. March 2020 May 2020 July 2020 Draft Revision 1 adopted by HMPC for release for consultation 8 July 2020 Start of public consultation 15 August 2020 End of consultation (deadline for comments). Comments should be 15 November 2020 provided using this template. The completed comments form should be sent to [email protected] 9 Keywords Herbal medicinal products; Traditional herbal medicinal products; HMPC; pyrrolizidine alkaloids 10 Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with pyrrolizidine alkaloids EMA/HMPC/893108/2011 Page 2/39 11 Public statement on the use of herbal medicinal products 12 containing toxic, unsaturated pyrrolizidine alkaloids (PAs) 13 including recommendations regarding contamination of 14 herbal medicinal products with PAs 15 Table of contents 16 1. Introduction (Problem statement) .......................................................... 4 17 1.1. Occurrence of pyrrolizidine alkaloids (PAs) ............................................................. 4 18 1.2. Chemistry and types of PAs ................................................................................. 4 19 1.3. Human exposure to PAs via food .......................................................................... 6 20 1.4. Contamination of herbal medicinal products ........................................................... 9 21 2. Discussion ............................................................................................... 9 22 2.1. Regulatory status and assessment of PAs or PA-containing products .......................... 9 23 2.2. Pharmacokinetics of PAs .................................................................................... 11 24 2.3. Mechanism of toxic action of PAs ........................................................................ 14 25 2.3.1. Single and repeat dose toxicity in animals ......................................................... 15 26 2.3.2. Acute and chronic toxicity in humans ............................................................... 17 27 2.3.3. Genotoxicity and Carcinogenicity of PAs ............................................................ 19 28 3. Conclusions and recommendations ........................................................ 23 29 3.1. Intake limits .................................................................................................... 23 30 3.2. Recommendations ............................................................................................ 24 31 3.3. Quality measures to reduce contamination with PAs .............................................. 26 32 4. Implementation of suitable testing procedures to control PA levels ...... 26 33 4.1. Analytical methods ........................................................................................... 26 34 4.2. Specifications for herbal substances, herbal preparations, HMPs .............................. 27 35 4.3. Implementation of measures to avoid or reduce PA contamination in HMPs ............... 27 36 5. Abbreviations ........................................................................................ 28 37 6. References ............................................................................................ 29 Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with pyrrolizidine alkaloids EMA/HMPC/893108/2011 Page 3/39 38 1. Introduction (Problem statement) 39 It became apparent during assessment of Symphytum officinale (monograph 40 EMEA/HMPC/572844/2009) that the risk assessment of pyrrolizidine alkaloids (PAs) poses considerable 41 difficulties, with several PAs being regarded as both hepatotoxic and carcinogenic. Considering that PAs 42 are natural constituents of a number of plants used for medicinal purposes the HMPC decided to 43 prepare a public statement on the use of herbal preparations containing PAs (EMA 2014). 44 Furthermore, it was increasingly reported that herbal teas including those used as medicines may 45 contain variable amounts of PAs, although the plants used as ingredients are not known to produce 46 PAs (BfR 2013). In the following, based on information from several Member States, it was recognised 47 that there might be a problem of contamination due to PA-containing weeds, which has to be seen 48 primarily as quality-related topic. Several national regulatory authorities addressed the issue of PA 49 contamination in HMPs and also the HMPC prepared a statement to support harmonisation in this 50 regard (EMA 2016). The Public statement on contamination of herbal medicinal products/traditional 51 herbal medicinal products with pyrrolizidine alkaloids (EMA/HMPC/328782/2016) gave transitional 52 recommendations for risk management and quality control. 53 After a 3-years-period, the HMPC decided to reconsider both Public statements (see HMPC meeting 54 report January 2019 - EMA/HMPC/26549/2019) and published Calls for data before re-assessing and 55 concluding on recommendations with respect to the risks associated with the use of herbal medicinal 56 products containing PAs naturally or from contamination. 57 Revision 1 is based on a review of newly available data and the improved evaluation methods. The 58 specific contamination issue and subsequent recommendations for risk management and quality 59 control are now included (see also section 1.4; 1.4; 3.2 and 4). 60 1.1. Occurrence of pyrrolizidine alkaloids (PAs) 61 Pyrrolizidine alkaloids are heterocyclic organic compounds derived from ornithine (Moreira et al. 2018). 62 They occur in nature in more than 6,000 plants (in excess of 300 plant species of up to 13 families, 63 mainly in the families of Boraginaceae (all genera), Asteraceae (tribes Senecioneae and Eupatorieae) 64 and Fabaceae (genus Crotalaria)), representing about 3% of the world’s flowering plants (Prakash et 65 al. 1999, Louisse et al. 2019, He et al. 2019). They are very effective insect-feeding deterrents and 66 consequently have evolved independently on at least four occasions in a number of different plant 67 families (Edgar et al. 2015). More than 350 different PAs, excluding the N-Oxides, were described up 68 to now and it is assumed that about half of them are hepatotoxic (Fu et al. 2004; He et al. 2019). 69 Both, composition and concentration of PAs may fluctuate and depend on various factors such as 70 species, age and part of the plant, variety (genotype/chemotype), season, location etc. (Hoogenboom 71 et al. 2011; Bodi et al. 2014). Thus, all known PAs of a PA-containing plant are not necessarily present 72 at the same time. The same species growing in different locations or in different seasons may contain 73 different alkaloids (Mattocks 1986, Flade et al. 2019). The toxins are commonly concentrated in the 74 seeds and the flowering parts of the plant, with decreasing amounts in the leaves, stems and roots. 75 Most plants produce mixtures of PAs in varying concentrations ranging from less than 0.001% to 5% 76 (up to 19% based on dry weight) in certain plant seeds. Reported concentrations vary from trace 77 amounts up to 19% based on dry weight (EFSA 2011, Bodi et al. 2014). 78 1.2. Chemistry and types of PAs 79 Most PAs are esters of hydroxylated 1-methylpyrrolizidines. The basic components, called necines, are 80 derived from bicyclic amino alcohols that, in turn, are derived from the polyamines putrescine and Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with pyrrolizidine alkaloids EMA/HMPC/893108/2011 Page 4/39 81 spermidine via the