A Health‐Protective Screening Threshold for Personal Care Products: Metabolomic and Endocrine Mechanisms of Adolescent Reproductive Toxicity in Zebrafish

Adolescents are uniquely vulnerable to endocrine-disrupting chemicals (EDCs) due to the critical maturation of the hypothalamic-pituitary-gonadal (HPG) axis, yet current safety assessments overlook whole-formulation risks during this developmental window. Using an adolescent zebrafish model, we established a biologically anchored screening threshold and elucidated the molecular mechanisms of formulation toxicity. Direct exposure to personal care products at unadjusted Scientific Committee on Consumer Safety (SCCS)-derived concentrations caused severe systemic overload (F1 survival ≤ 16.87%). High-dilution screening of a 17α-ethinylestradiol (EE2)-spiked model lotion identified a 160× SCCS dilution as the no-observed-adverse-effect level (NOAEL) for reproductive and neurodevelopmental endpoints. Ovarian metabolomics revealed a dichotomous threshold response: The 160× dilution induced focused, adaptive reprogramming of steroid hormone biosynthesis (modulating methionine, tyrosine, and histidine), whereas the 80× dilution triggered an energetic-inflammatory crisis characterized by acylcarnitine accumulation, tricarboxylic acid cycle suppression, and oxidative stress. This metabolic disruption led to hypothalamic AMP-activated protein kinase (AMPK)-mediated gonadotropin suppression and follicular atresia. Although the formulation matrix partially mitigated EE2-induced ovarian failure, it failed to prevent F1 neurobehavioral hypoactivity, implicating parallel thyroid and monoaminergic disruption. Commercial sunscreen validation confirmed product-specific hazards at a 40× dilution, proving that whole-formulation toxicity cannot be predicted from ingredient lists alone. These findings redefine risk assessment by advocating for whole-formulation, mechanism-informed screening. The 160× dilution threshold offers regulators a pragmatic, health-protective benchmark to safeguard adolescent reproductive and neurodevelopmental health through molecular endocrinology-guided toxicology.