EU-ToxRisk - Prediction of developmental and reproductive toxicity (DART): a read-across case study with short branched carboxylic acids

Keywords

REACH, read-across, DART

Objective

2-Methylhexanoic acid (MHA) is mostly used as a food additive. Developmental and reproductive toxicity (DART) data for MHA were taken to be lacking. The aim was to find structural analogues for which DART data is available and to attempt to show that a NAM-based read-across would rightly predict the DART profile of MHA.

Testing Strategy

MHA and its selected chemical analogues were tested in a battery of in-vitro tests relevant to developmental toxicity, including the zebrafish embryotoxicity test (ZET), the mouse embryonic stem cell test (mEST), an iPSC-based neurodevelopmental model (UKN1), and a series of CALUX reporter assays. Also, toxicokinetic models were developed and applied to calculate effective cellular concentrations and associated in-vivo exposure doses.
The applied NAM-based read-across was used to predict the in-vivo developmental toxicity of MHA from the developmental toxicity data of selected source chemicals. This data would also allow us to further explore the relationship between structure and developmental toxicity within this series of aliphatic carboxylic acids. We also investigated the potential to inhibit histone deacetylase in these test models, as this enzyme is postulated to be the molecular target initiating neural tube defects, an observed developmental toxicity for some of these analogues. NAM results showed that VPA, PHA, EHA, and 4-ene-VPA were correctly predicted as in-vivo developmental toxicants, and EBA and DMPA as non-developmental toxicants. The results indicate that MHA, which is a non-developmental toxicant, cannot be classified as fully negative based on this NAM-based read-across.

Publications

Shinde et al. 2016 [link]; Waldman et al. 2016 [link]; van Vugt-Lussenburg et al. 2018 [link]; Fisher et al. 2017 [link]; Simeon et al. 2020 [link]; Escher et al. 2019 [link]; Brotzmann et al. 2021 [link]; Koch et al. 2021 [link]; Escher et al. 2019 [link]; Rovida et al. 2021 [link]