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.

中文翻译：

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支持通过人体皮肤对 Retronecine 型吡咯里西啶生物碱的经皮吸收进行监管评估

1,2-不饱和吡咯里西啶生物碱天然存在于 Symphytum officinale（众所周知的紫草）中，长期用于局部治疗疼痛的肌肉和关节疾病。吡咯里西啶生物碱 (PA) 因其肝脏遗传毒性而成为安全性评估的一个相关问题，并且在制造过程中密切关注以尽量减少其水平。当前的监管风险评估方法包括设定来自口服接触途径的毒性数据的限值。本研究调查了局部暴露后吡咯里西啶生物碱的生物利用度，评估了体外人体皮肤模型中逆转录型 PA 的渗透。一种紫草根配方中添加了 3 种不同的同系物（一种 7R-单酯、一种开链 7R-二酯、和循环二酯）和经皮吸收根据经合组织指南和良好实验室规范测量。所有 3 种 PA 的测量渗透率都很低，与现有的体外数据相比是有利的。尽管考虑不同的监管指导会影响皮肤吸收剂量的确定，但这些数据有助于理解局部暴露后的吸收差异，进而可以在风险评估中考虑这些差异。