Using read-across to identify isobutylparaben as an endocrine disruptor

Exposure to substances with endocrine disrupting properties is suspected of being associated with a range of negative health effects, including genital malformations, reduced fertility, earlier puberty, hormone-related cancers and earlier menopause (Gore et al., 2015; Parent et al., 2025; WHO/UNEP, 2012). Acknowledging the hazardous effects of endocrine disruptors (EDs), as well as the widespread human exposure (EEA, 2023), EU framed a goal of minimizing exposure to this group of substances in the ‘Chemicals Strategy for Sustainability- Towards a toxic free environment’ in 2020 (EC, 2020). One of the main objectives in this strategy is to introduce a generic approach to risk management, where the most harmful substances, including EDs, are restricted in consumer products. In continuation of this, specific hazard classes for EDs were implemented in the harmonized classification and labelling system in 2022 (EU, 2023). Going forward, it is foreseen that CLP classification will play a central role in ED identification in the EU.

ED identification under REACH has previously consisted of identifying these chemicals as Substances of Very High Concern (SVHCs) (EU 1907/2006, 2006). The WHO/IPCS definition has been used to identify EDs as SVHCs (WHO/IPCS, 2002), as no specific criteria or guidance has been available under the REACH regulation (EU 1907/2006, 2006). Since 2018, the ECHA/EFSA guidance for identification of EDs in the Biocidal Product Regulation (BPR) and the Plant Protection Products Regulation (PPPR) (ECHA/EFSA, 2018) has often been used but is not a prerequisite. However, the substances must fulfill the WHO/IPCS definition. Identification of a substance as an ED requires demonstration of 1) an endocrine activity, 2) an adverse effect and 3) a biologically plausible link between the two (ECHA, 2024; ECHA/EFSA, 2018).

One major challenge for ED identification and classification is, however, lack of relevant information, especially on adversity (Holmer et al., 2024). This is critical for substances registered under REACH, where standard information requirements depend on the registered tonnage level, with no or very little ED-relevant information on adversity available at the lower tonnages (Holmer et al., 2024). ED relevant information on adversity is obtained from animal studies and lack hereof may become even more pertinent in the future, with the EU roadmap to phase out animal testing under development, aiming to reduce and replace in vivo testing with alternative methodologies (EC, 2024, 2023). A way to overcome this challenge is by using read-across in the ED identification process (Holmer et al., 2025). To ensure uniform read-across approaches for data-gap filling under REACH, ECHA has developed a Read-Across Assessment Framework (RAAF), which provides a framework and guidance for evaluating scientific aspects of read-across cases (ECHA, 2017a). Likewise, read-across is acknowledged as an approach to provide information about both endocrine activity and adversity (ECHA, 2024; ECHA/EFSA, 2018).

The antimicrobial agent isobutylparaben was identified as an ED by ECHA in 2022 using read-across from the source substance butylparaben to fill important data gaps on adversity (ECHA, 2022a). In this paper, we show the workflow of this process and exemplify a pragmatic approach to overcome data gaps using grouping and read-across, enabling informed regulatory decisions without further animal testing. 2 Materials and methods