Introduction

With the rapid advancement of industries such as new energy vehicles and consumer electronics, the demand for high-performance lithium-ion batteries in industrial applications has increased significantly. Consequently, extensive research efforts have been directed toward improving lithium battery performance through the use of electrolyte additives.1,2 Among these, cyclotriphosphazenes (CTPs) represent one of the most important classes of such electrolyte additives. Their key advantages include highly efficient overcharge protection, excellent electrochemical compatibility, superior thermal stability, and significant flame retardancy. Owing to these beneficial properties, CTPs significantly enhance the safety, longevity, and overall performance of lithium batteries, leading to their widespread inclusion in various battery products. Moreover, hexaphenoxycyclotriphosphazene (HPCTP) is considered a promising alternative to the conventional organophosphorus flame retardant triphenyl phosphate.3,4,5,6,7

In industrial production, CTPs are functionalized by substituting different groups onto the phosphorus atoms within the hexacyclic structure, which is composed of alternating nitrogen and phosphorus atoms, to meet diverse performance requirements as electrolyte additives.8 Commercially prevalent CTP derivatives include fluorinated hexafluorocyclotriphosphazene (HFCTP), chlorinated hexachlorocyclotriphosphazene (HCCTP), phenoxy-substituted HPCTP, alkoxy-substituted hexamethoxycyclotriphosphazene (HMCTP), as well as mixed-substituent derivatives such as pentafluoro(phenoxy) cyclotriphosphazene (PFPCTP) and ethoxy(pentafluoro) cyclotriphosphazene (EPFCTP) (Figure 1). Among these, HCCTP serves as a key precursor for the synthesis of various cyclotriphosphazene derivatives.3,7,9,10,11,12,13,14,15

Figure 1: Three-dimensional structures of the six CTPs(A) HPCTP.(B) PFPCTP.(C) HCCTP.(D) HFCTP.(E) EPFCTP.(F) HMCTP.

Recent environmental investigations have demonstrated the widespread occurrence of CTPs in multiple environmental media. Six common CTPs have been detected in both surface water and sediment samples, with total concentrations (ΣCTPs) in surface water ranging from 4.1 to 556 ng/L and a mean value of 124 ng/L. Among individual compounds, HCCTP and EPFCTP exhibited relatively high detection frequencies of up to 90% and 81%, respectively, whereas other CTPs were detected at lower but still measurable levels. In sediments, detection frequencies of individual CTPs ranged from 19% to 95%. EPFCTP and HPCTP were the dominant compounds, with mean concentrations of 24 and 20 ng/g dry weight (dw).16

In addition to aquatic environments, a recent urban environmental study reported the presence of all six CTPs in dust samples collected from various locations in Guangzhou, China, including homes (11.9–122 ng/g; median 50.5 ng/g), air conditioner filters (75.7–321 ng/g; median 142 ng/g), e-waste recycling plants (24.0–1790 ng/g; median 150 ng/g), major roads (1.95–56.3 ng/g; median 4.94 ng/g), and underground parking garages (3.38–142 ng/g; median 25.0 ng/g). Notably, exposure concentrations at e-waste recycling plants were substantially higher than those observed in other urban settings. Among the analyzed compounds, HPCTP was identified as the most abundant compound, consistent with its large-scale production and widespread application.17

Although detailed production statistics, such as the global output of CTPs used in the lithium-ion battery industry, remain limited,18 these findings collectively provide initial evidence of the widespread occurrence and persistent environmental accumulation of CTPs, suggesting that their production and consumption are likely to continue increasing in response to the growing demand for lithium-ion batteries.

Concerning human exposure, only one study conducted in Hangzhou, China, has reported detection of CTPs in human urine. HFCTP (mean 1.2 ng/mL, range:< LOD −7.7 ng/mL) and EPFCTP (mean 0.96 ng/mL, range:< LOD −11 ng/mL) were identified as the predominant CTPs, with detection frequencies of 79%–84% for HFCTP, EPFCTP, and HMCTP. Currently, reference materials and exposure risk data for CTPs remain highly limited.19 In terms of toxicity and mechanisms, one study demonstrated that HPCTP induced eye malformations, body deformities, and early embryonic mortality in Japanese Medaka by antagonizing retinoic acid X receptors and retinoic acid receptors.18 Additionally, HPCTP caused developmental defects in Danio rerio, including reduced body length and cardiac malformations, and induced dose-dependent depressive-like behavior via suppression of serotonin 1A (5-HT1A) receptor signaling.20 Furthermore, long-term combined exposure to six CTPs (PFPCTP, EPFCTP, HFCTP, HPCTP, HMCTP, and HCCTP) at environmentally relevant concentrations resulted in pathological lung injuries in mice, such as alveolar destruction and pulmonary fibrosis, as well as mitochondrial dysfunction in BEAS-2B cells.21

Although representative CTPs, including PFPCTP, EPFCTP, HFCTP, HPCTP, HMCTP, and HCCTP, are listed in the PubChem database, most remain unregistered as chemicals in China, Japan, the EU, and the US.17 Moreover, while HPCTP is considered an alternative to triphenyl phosphate, its toxicological safety requires comprehensive evaluation. These factors collectively underscore the considerable challenges in environmental regulation of this emerging class of substances.

To summarize, there is a pressing need to establish a comprehensive and systematic evaluation framework to assess the entire life cycle of cyclotriphosphazenes (CTPs). This framework should encompass their environmental behavior, occurrence, biological exposure pathways, bioaccumulation potential, toxic effects, and underlying mechanisms. Such an approach will facilitate a balanced consideration of their industrial benefits against potential environmental risks. Thus, we have employed an integrated methodology combining machine learning, quantitative structure-activity relationship (QSAR) modeling, computational prediction, and network toxicology approaches to perform a preliminary investigation to evaluating the potential of HPCTP, PFPCTP, HCCTP, HFCTP, EPFCTP, and HMCTP to penetrate into the blood-brain barrier (BBB) and central nervous system (CNS) toxicity. The findings are expected to advance our understanding of the toxicological profiles and mechanisms of these compounds, thereby providing a foundation for subsequent in-depth research.