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 assessment
