A Review of the Potential Endocrine Bioactivity of 2‐Ethylhexyl 4‐Hydroxybenzoate (2‐EHHB)

Available data, including results from six in vivo studies conducted by the United States (US) Environmental Protection Agency (EPA) were reviewed to assess the potential of 2-ethylhexyl 4-hydroxybenzoate (2-EHHB) to affect endocrine pathways. 2-EHHB is a paraben, and parabens are used in the cosmetics, food, and pharmaceutical industries. It was selected for testing based on in vitro bioactivity scores from androgen receptor (AR) and estrogen receptor (ER) pathway models provided in the US EPA Computational Toxicology Chemicals Dashboard. The following assays were performed using US EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 and Tier 2 test guidelines: Hershberger, male pubertal, amphibian metamorphosis assay (AMA), fish short-term reproduction assay (FSTRA; medaka, fathead minnow, and zebrafish), larval amphibian growth and development assay (LAGDA), and medaka extended one-generation reproduction test (MEOGRT). Published data from uterotrophic assays performed in Japan were also reviewed. Based on this evaluation, estrogen agonism was the best supported mechanism of action and there was no clear support for thyroid hormone perturbation. Among the in vivo assays reviewed, the Japanese medaka and African clawed frog were the most sensitive test species. Results from the MEOGRT indicated decreased fecundity (all generations) at concentrations ≥ 5.32 μg/L. Decreased fecundity and fertilization at ≥ 10.6 μg/L in the medaka FSTRA support those results. LAGDA results indicated delayed development at ≥ 5.33 μg/L, but the mechanism was unclear based on the available data.