Bisphenol A (BPA, CAS 80-05-7) is used as a starting substance for the manufacture of polycarbonate plastics and epoxy resins. BPA is a well-known endocrine-disrupting chemical (EDC), and its exposure has been linked to impacts across multiple organs, including the brain, heart, prostate, mammary gland, and ovaries, even at low doses (FPF reported). The European Union banned the use of BPA in food contact materials (FCMs) in December 2024 (FPF reported), followed by Switzerland in July 2025 (FPF reported).
With the growing awareness of the health concerns of BPA, it has been replaced with other structurally similar bisphenols such as bisphenol S (BPS, CAS 80-09-1), bisphenol F (BPF, CAS 620-92-8), which have a similar functionality and prevent a complex redesign of products or manufacturing process. However, since the (adverse) effect of a chemical is dependent on its structure, bisphenol alternatives structurally similar to BPA are not less concerning (FPF reported and here). Yet, they have received less scientific and regulatory attention than BPA.
In an article published August 16, 2025, in the peer-reviewed journal Environmental Science & Technology, Vanessa Srebny and co-authors from the Helmholtz Centre for Environmental Research − UFZ, Leipzig, Germany, investigated the safety of BPA and 26 alternatives using in vitro bioassays, such as single-cell-based test systems, and found that many BPA replacements are regrettable substitutions.
The scientists observed that the effects of the compounds varied depending on their structure. Structurally very similar BPA alternatives, such as bisphenol AF (BPAF, CAS 1478-61-1) and bisphenol Z (BPZ, CAS 843-55-0) were comparably potent in activating the estrogen receptor α (ERα) – one of the pathways that is known to be connected to BPA’s adverse outcomes. In contrast, bulky substitutions at the para- and ortho-positions of the phenols eliminated the chemicals’ estrogenic activity, likely because the molecules are too large to fit into the ER α’s binding site. However, many of these modified compounds were found to activate another receptor, namely the peroxisome proliferator-activated receptor γ (PPARγ), which is not activated by BPA. Additionally, the researchers detected mitochondrial dysfunction and neurotoxicity in response to some BPA alternatives.
Srebny and co-authors identified 2,2,4,4-tetramethyl-1,3-cyclobutanediols (TMCD) as the most promising BPA alternative, as it showed no specific activity in any of the tested assays. But, due to TMCD’s distinct physicochemical properties and dissimilar chemical structure compared to BPA, it is not suitable as a 1:1 functional replacement.
The authors concluded that they “cannot find any reason why compounds with a similar toxicological profile […] should be regulated differently merely because of missing in vivo data. In contrast, until proven otherwise, they should be treated as toxicological analogues and assessed as groups.” They also emphasize that the concepts and tools developed in their study could be applied to other chemical groups for prioritization and substitution. Notably, the group of bisphenols has also been highlighted as a group of concern in the recent PlastChem report (FPF reported).
The researchers tested the chemicals in six in vitro biological assays, which are used to measure if and how a substance affects biological functions. This study targeted cytotoxicity, endocrine disruption, xenobiotic metabolism, adaptive stress responses, mitochondrial toxicity, and neurotoxicity. To compare the alternatives to BPA, a Cumulative Specificity Ratio score was calculated based on the degree of specific activation and overall toxicological activity across the test battery.
Reference
Srebny, V. (2025). “Beyond Estrogenicity: A Comparative Assessment of Bisphenol A and Its Alternatives in In Vitro Assays Questions Safety of Replacements.” Environmental Science & Technology. DOI: 10.1021/acs.est.5c07018
