EU-ToxRisk - Parabens

Keywords

Cosmetics regulation, industry-sponsored case study, read-across, ab-initio

Objective

This case study aims at establishing a proof-of-concept approach for the use of NAM-enhanced read-across in a next-generation risk assessment context. Parabens are esters of para-hydroxybenzoic acid (pHBA) that are widely used as preservatives in diverse product sectors including agrochemical, pharmaceutical, food, and cosmetics. In this case study, the use of in silico information, in vitro toxicodynamic (toxicogenomics, endocrine activity) and toxicokinetic data were combined to support biological similarity among analogues and establish potency trends to inform the selection of the best source chemical from within a category. This approach, along with consideration of aggregate exposure, was here used in an example safety assessment of low-toxicity chemicals. The chemical category under consideration is short linear chain parabens.

Testing Strategy

The external dermal cosmetic exposure to four parabens of primary interest (methyl, ethyl, propyl, and butyl) was analysed. Deterministic external exposure values were used to predict human plasma systemic exposure to the compounds.
A comprehensive human in vitro dataset was obtained, which enabled PBPK modelling of systemic plasma concentrations of the parent compounds following dermal exposure in humans. This data comprised human skin penetration data; biotransformation data in skin, liver, enterocytes (Caco-2 cells), and plasma, which characterized major metabolites and intrinsic clearance rates; plus plasma protein binding. The parabens are readily hydrolysed to p-hydroxy benzoic acid in presence of metabolic activation. The human ADME parameters were used to develop PBPK-based multi-compartment models of human systemic plasma parabens concentrations following dermal external exposure to compounds.
Parabens were shown to lack specific target organ toxicity at very high doses in repeated dose toxicity studies. However, they are active in some uterotrophic assays and were assigned a conservative point of departure (PoD) by the Scientific Committee for Consumer Safety. Also, data have emerged in the literature that show parabens exhibit low activity in in vitro assays relevant for endocrine activity. These in vitro assays suggest that parabens (the parent compounds but not the main metabolite) possess very weak activity on some nuclear receptors involved in endocrine homeostasis, many orders of magnitude lower than natural estrogens/androgens. In this case study, NAMs have been applied to explore this oestrogenic activity as an approach to inform on biological similarity and relative potency of the category members. This relative potency is then used to adjust the conservative PoD derived from butylparaben to carry out a theoretical risk assessment for propylparaben based on read-across.
For the read-across risk assessment, a margin of safety was derived using internal concentrations: margin of internal exposure –MoiE- which is protective of human health.
In conclusion this case study demonstrated the value added by NAMs in identifying, characterizing analogues, in informing similarities/differences on toxicokinetic and toxicodynamic properties and in the calculation of the internal margin of safety.