Unregistered Hexaphenoxycyclotriphosphazene and Its Metabolite Antagonize Retinoic Acid and Retinoic X Receptors and Cause Early Developmental Damage

Hexaphenoxycyclotriphosphazene (HPCTP), an unregistered chemical, has been used as a substitute for triphenyl phosphate in flame retardants and plasticizers. Here, we identified its metabolite, pentaphenoxycyclotriphosphazene (PPCTP) in the liver of Japanese medaka exposed to HPCTP. When sexually mature female medaka were exposed to HPCTP at 37.0, 90.4, and 465.4 ng/L for 35 days, the HPCTP concentration (642.1–2531.9 ng/g lipid weight [lw]) in the embryos considerably exceeded that (34.7–298.1 ng/g lw) in the maternal muscle, indicating remarkable maternal transfer. During 0–9 days postfertilization, the HPCTP concentration in the embryos decreased continuously, while the PPCTP concentration increased. HPCTP and PPCTP antagonized the retinoic X receptor with 50% inhibitory concentrations (IC50) of 34.8 and 21.2 μM, respectively, and PPCTP also antagonized the retinoic acid receptor with IC50 of 2.79 μM. Such antagonistic activities may contribute to eye deformity (4.7% at 465.4 ng/L), body malformation (2.1% at 90.4 ng/L and 6.8% at 465.4 ng/L), and early developmental mortality (11.6–21.7% in all exposure groups) of the embryos. HPCTP was detected in a main tributary of the Yangtze River Basin. Thus, HPCTP poses a risk to wild fish populations, given the developmental toxicities associated with this chemical and its metabolite.