Evaluation of the endocrine disrupting potential of Di-isononyl phthalate

Low molecular weight ortho-phthalate compounds have been implicated in disruption of androgen pathways when exposure occurs during the masculinization programming window. Di-isononyl phthalate (DINP) is a high molecular weight phthalate and a high production volume chemical. To understand the potential for DINP and its metabolites to disrupt endocrine pathways, a weight of evidence assessment was conducted according to the European Chemicals Agency (ECHA)/ European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). Toxicological data related to estrogen (E), androgen (A), thyroid (T), or steroidogenesis (S) pathways was assessed. Literature searches returned 110 articles from which data were extracted and assessed in conjunction with 105 high-throughput assays. An in-silico assessment of the EATS activity for DINP metabolites also was conducted. Based on the available evidence, DINP did not elicit thyroid- or estrogen-related apical outcomes in vivo. There were no studies evaluating thyroid hormone levels in vivo which, according to the ECHA/EFSA guidance, constitutes a data gap and prevents a conclusion being drawn on the T-pathway. The E, A, and S-pathways were sufficiently assessed to conclude on the endocrine disrupting potential of DINP. Based on the lack of apical outcomes, DINP did not disrupt the E-pathway. For the A and S-pathways, there was limited evidence to support adverse apical outcomes, so a mode of action assessment using a structured adverse outcome pathway (AOP) framework was performed. No biologically plausible link could be established between the key events in the hypothesized AOP that lead to adverse outcomes. Further, no dose or temporal concordance for A- and S-mediated findings were identified. Therefore, DINP does not meet the ECHA/EFSA criteria to be considered an endocrine disruptor.