Toxicity studies

26.04.2022 | Toxicity studies

Bisphenol A and its substitutes

Bisphenols form a group of organic compounds that contain two phenolic groups in their structure. The best known of these is bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl) propane; CAS 80-05-7) because it is the most widely used as a monomer in the manufacture of polycarbonate plastics (used in plastic food packaging) and epoxy resins (used in the inner lining of food cans), as a dental sealant or in thermal paper.

Due to its multiple uses, it is widely distributed in different environmental compartments, including the food we humans eat. On the other hand, toxic effects related to its oestrogenic properties by mimicking the effects of endogenous hormones (alteration of reproductive function, cardiovascular diseases or type 2 diabetes mellitus) have been observed, which has led to its production and use being regulated in many countries. In this regard, the United States Environmental Protection Agency (USEPA) established an intake limit of 50 µg/kg body weight/day in 1993. In 2015, the European Food Safety Authority (EFSA) published a global re-evaluation of the exposure and toxicity of BPA and reduced this limit to 4 µg/kg bw/day. In addition, its use in the manufacture of infant feeding bottles has been banned in Canada (2008), France (2010) or the European Union (2011). The EU has also regulated, in 2011, specific migration limits (SMLs) for many compounds, including BPA and BPS, with values of 0.6 and 0.05 mg/kg, respectively. Similarly, in 2016, the EU added BPA to the list of restricted substances with a consequent ban on its use in thermal papers in concentrations above 0.02% from January 2020, which has spurred the use of BPA substitutes.

The most recent toxicity data is from 15 December 2021, when EFSA published the conclusions of the expert panel on the re-evaluation of the risk from the intake of BPA. Although it is a draft, the reduction of the Tolerable Daily Intake from 4 µg/kg to 0.04 ng/kg bw/day is advanced. From now until 8 February 2022, the public consultation period is open for comments from interested parties.

Due to the toxicity associated with BPA and the restrictions on its use, other molecules with a similar structure have been synthesised in order to progressively replace it in many of its applications. These new compounds are generically known as BPA substitutes or analogues. These include BPS (CAS 80-09-1), BPF (CAS 1333-16-0), BPAF (CAS 1478-61-1), BPAP (CAS 1571-75-1), BPB (CAS 77-40-7), BPP (CAS 2167-51-3), BPZ (CAS 843-55-0), BPE (CAS 2081-08-5), BPC (CAS 79-97-0), or BPAP (CAS 1571-75-1). However, although they were initially considered less toxic alternatives, over time, some have been shown to exhibit greater genotoxicity than BPA in human liver carcinoma cells (BPF and BPAF), have been linked to obesity in children and adolescents (BPA, BPF and BPS), or reduce testosterone secretion in adult testicular explants (BPB).

For all these reasons, there is a growing interest in the analysis of BPA and its substitutes, as well as in the need to study exposure to these compounds through their determination in different matrices suspected of containing significant levels of these bisphenols. So far, both BPA and its substitutes have been found in a wide variety of matrices, including fresh, frozen and canned foods (vegetables, fruits, fruit juices, meat, fish, cereals, dairy products, etc.), which has made the presence of this contaminant and its possible substitutes a topic of great interest for consumers and the scientific community.

Useful links:

Integrated Risk Information System (IRIS) (1993). URL:

EFSA – Bisphenol A (BPA)

Scientific Opinion on Public Health Risks Related to the Presence of Bisphenol A (BPA) in Foodstuffs: Executive Summary. EFSA Journal, 13(1), 3978.

Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact with food: Vol. 10/2011 (p. L12/1-L12/89). (English)

EFSA – Bisphenol A (BPA)

Bisphenol A: EFSA’s draft opinion proposes to reduce the tolerable daily intake (Published: 15 December 2021)

Laura Herrero, Belén Gómara, Mario Fernández

Institute of General Organic Chemistry (IQOG-CSIC)