CDP and RDP as Alternatives to TPhP: Comparative Effects on Glucose Homeostasis and Hepatic and Whole-Pancreas Molecular Endpoints in Mice

Organophosphate flame retardants (OPFRs) are widely used as replacements for brominated flame retardants, yet the metabolic effects of cresyl diphenyl phosphate (CDP) and resorcinol bis(diphenyl phosphate) (RDP), two structurally related alternatives to the major aryl OPFR triphenyl phosphate (TPhP), remain poorly characterized. Male C57BL/6J mice received TPhP, CDP, or RDP by oral gavage every 3 days for 70 days at time-weighted average doses of 20 ng/kg body weight/day or 20 μg/kg body weight/day. The lower level was exposure-informed; the higher level served as a toxicological contrast. Glucose tolerance, systemic insulin responsiveness, and hepatic and whole-pancreas biochemical, histological, transcriptomic, and protein endpoints were evaluated. All three compounds altered glucose homeostasis, with overlapping but compound-dependent effects. Hepatic measurements showed lower insulin-signaling and glycogen-storage markers, including lower post-insulin AKT phosphorylation. Whole-pancreas measurements showed lower ESRRG and higher LDHA abundance, generating hypotheses about metabolic and secretion-associated pathways. Across the measured endpoints, CDP and RDP did not show a consistently smaller metabolic response than TPhP. Thus, their substitution cannot be presumed to improve metabolic safety. This comparison is restricted to the tested nominal doses and intermittent oral-gavage regimen; it does not establish overall toxicity or internal-dose-normalized relative potency. Internal dosimetry and comparisons with continuous exposure are needed to assess the relevance to human exposure.