Subscribe to RSS
DOI: 10.1055/a-1505-8524
Support for Regulatory Assessment of Percutaneous Absorption of Retronecine-type Pyrrolizidine Alkaloids through Human Skin
Supported by: Procter & Gamble![](https://www.thieme-connect.de/media/plantamedica/202202/lookinside/thumbnails/10-1055-a-1505-8524_pmf0244-1.jpg)
Abstract
1,2-unsaturated pyrrolizidine alkaloids are found naturally in Symphytum officinale, well known as comfrey, which has a longstanding use for the topical treatment of painful muscle and joint complaints. Pyrrolizidine alkaloids (PA) are a relevant concern for the safety assessment due to their liver genotoxicity profile, and close attention is paid during manufacturing to minimizing their levels. Current regulatory risk assessment approaches include setting limits that derive from toxicity data coming from the oral route of exposure. This study investigated to what extent pyrrolizidine alkaloids are bioavailable following topical exposure, assessing penetration of retronecine-type PAs in an in vitro human skin model. A single comfrey root formulation was spiked with 3 different congeners (a 7R-monoester, an open-chained 7R-diester, and a cyclic diester) and percutaneous absorption measured per OECD guidelines and good laboratory practices. The measured penetration for all 3 PAs was low and compared favourably with existing in vitro data. Although consideration of different regulatory guidance influences the determination of dermally absorbed dose, these data facilitate the understanding of absorption differences following topical exposure, which in turn can be taken into account in the risk assessment.
Key words
Boraginaceae - Symphytum officinale - comfrey root - pyrrolizidine alkaloids - skin penetration - risk assessmentPublication History
Received: 02 March 2021
Accepted after revision: 10 May 2021
Article published online:
11 June 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Mattocks AR, Driver HE, Barbour RH, Robins DJ. Metabolism and toxicity of synthetic analogues of macrocyclic diester pyrrolizidine alkaloids. Chem Biol Interact 1986; 58: 95-108
- 2 Ruan J, Yang M, Fu P, Ye Y, Lin G. Metabolic activation of pyrrolizidine alkaloids: insights into the structural and enzymatic basis. Chem Res Toxicol 2014; 27: 1030-1039
- 3 Hadi NSA, Bankoglu EE, Schott L, Leopoldsberger E, Ramge V, Kelber O, Sievers H, Stopper H. Genotoxicity of selected pyrrolizidine alkaloids in human hepatoma cell lines HepG2 and Huh6. Mutat Res 2021; 861 – 862: 503305
- 4 Schrenk D, Gao L, Lin G, Mahony C, Mulder PPJ, Peijnenburg A, Pfuhler S, Rietjens I, Rutz L, Steinhoff B, These A. Pyrrolizidine alkaloids in food and phytomedicine: occurrence, exposure, toxicity, mechanisms, and risk assessment–a review. Food Chem Toxicol 2020; 136: 111107
- 5 European Food Safety Authority (EFSA). Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements. EFSA J 2017; 15: 4908
- 6 European Medicines Agency (EMA). 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 Rev. 1. Accessed June 1, 2021 at: https://www.ema.europa.eu/en/documents/public-statement/draft-public-statement-use-herbal-medicinal-products-containing-toxic-unsaturated-pyrrolizidine_en-0.pdf
- 7 Seigner J, Junker-Samek M, Plaza A, DʼUrso G, Masullo M, Piacente S, Holper-Schichl YM, de Martin R. A Symphytum officinale root extract exerts anti-inflammatory properties by affecting two distinct steps of NF-kappaB signaling. Front Pharmacol 2019; 10: 289
- 8 Jedlinszki N, Balazs B, Csanyi E, Csupor D. Penetration of lycopsamine from a comfrey ointment through human epidermis. Regul Toxicol Pharmacol 2017; 83: 1-4
- 9 Kuchta K, Schmidt M. Safety of medicinal comfrey cream preparations (Symphytum officinale s.l.): the pyrrolizidine alkaloid lycopsamine is poorly absorbed through human skin. Regul Toxicol Pharmacol 2020; 118: 104784
- 10 European Food Safety Authority (EFSA). Guidance on dermal absorption. EFSA J 2017; 15: 4873
- 11 Steinert C, Broschard T. Lycopsamine in Placebo Cream: In vitro dermal Penetration through human Skin. GLP Complaint Study No. 1630102. Rossdorf: Harlan Cytotest Cell Research GmbH; 2015
- 12 Organisation for Economic Co-operation and Development (OECD). Guidance Document for the Conduct of Skin Absorption Studies, OECD Series on Testing and Assessment Number 28. Paris: OECD Publishing; 2004
- 13 European Commission Scientific Committee on Consumer Safety (SCCS). Basic criteria for the in vitro assessment of dermal absorption of cosmetic ingredients. SCCS/1358/10. Accessed June 1, 2021 at: https://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_s_002.pdf
- 14 Roper C, Craig S, Toner F. Evaluation of the Effect of Occlusion on the Absorption of the Reference Test Item, [14C]-Testosterone, applied to human Skin in vitro . Edinburgh, United Kingdom: Charles River Laboratories; 2017
- 15 Zhai H, Maibach HI. Occlusion vs. skin barrier function. Skin Res Technol 2002; 8: 1-6
- 16 U. S. Food and Drug Administration (FDA). Bioanalytical Method Validation Guidance for Industry. FDA-2013-D-1020. Accessed June 1, 2021 at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioanalytical-method-validation-guidance-industry
- 17 European Medicines Agency (EMA). Guideline on Bioanalytical Method Validation; 2011. EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2. Accessed June 1, 2021 at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf
- 18 Organisation for Economic Co-operation and Development (OECD). OECD Guideline for the Testing of Chemical: Skin Absorption: In vitro Method. No. 428. Paris: OECD Publishing; 2004