Developmental and Neurobehavioral Toxicity of Hexaphenoxycyclotriphosphazene: Implications for Its Safety as a Flame-Retardant Alternative to Triphenyl Phosphate

Hexaphenoxycyclotriphosphazene (HPCTP) has been introduced
as a
halogen-free replacement for the flame-retardant triphenyl phosphate
(TPhP); however, its environmental behavior and toxicological safety
remain poorly defined. Here, using zebrafish larvae with TPhP as a
benchmark, we systematically evaluated the developmental and neurobehavioral
toxicity of HPCTP at environmentally relevant concentrations (50–5000
ng/L) from 6 to 120 h postfertilization. HPCTP showed greater bioaccumulation
potential than TPhP, suggesting the risk of long-term ecological persistence.
Despite lower acute toxicity, HPCTP induced pronounced developmental
defects, including reduced body length and cardiac malformations.
Strikingly, HPCTP and TPhP produced divergent neurobehavioral outcomes.
HPCTP caused dose-dependent depression-like behaviors (hypoactivity,
light-zone avoidance) through suppression of serotonin 1A (5-HT1A) signaling, supported by decreased htr1aa expression and serotonin levels and partially rescued by the 5-HT1A receptor agonist 8-OH-DPAT. By contrast, TPhP elicited anxiety-like
phenotypes (hyperactivity, thigmotaxis) via CD83-dependent neuroinflammation,
evidenced by decreased cd83 expression and microglial
activation, which were reversed by cd83 overexpression.
Taken together, these findings demonstrate that HPCTP, though marketed
as a safer alternative, poses distinct developmental and neurobehavioral
hazards, underscoring the urgent need for comprehensive risk evaluation
prior to its widespread application.