Mechanistic pathways of cosmetic ingredient toxicity: a critical review of in vitro and in vivo evidence.

Every day, billions of people apply cosmetic products containing dozens of bioactive compounds whose combined toxicological profile has never been formally evaluated. Human biomonitoring confirms systemic deposition of these compounds in blood, adipose tissue, placenta, and breast milk worldwide. This scoping review, following PRISMA-ScR, synthesizes in vitro and in vivo mechanistic toxicology evidence for six major cosmetic ingredient categories-preservatives, UV filters, engineered nanoparticles, fragrances, surfactants, and colorants-and maps findings onto established adverse outcome pathways (AOPs). Searches of PubMed/MEDLINE, Embase, and Web of Science identified 1231 records, of which 48 studies met eligibility criteria. Critical appraisal exposes three structural failures: most studies test at concentrations orders of magnitude above realistic dermal exposures; nearly all assess single ingredients in isolation; and the field over-relies on targeted assays over untargeted omics. The evidence nonetheless reveals mechanistic convergence: parabens, benzophenones, UV filters, and surfactants activate overlapping estrogen receptor, oxidative stress, and innate immune pathways, with biological plausibility supported by cohort data linking benzophenone-3 to lower testosterone and altered pubertal timing, and the preservatives chloromethylisothiazolinone/methylisothiazolinone to Th2-skewed atopic responses. AOP mapping shows uneven regulatory readiness: skin sensitization (AOP40) is the most mature pathway; estrogen and androgen receptor activity (AOP29, AOP19) and thyroid disruption (AOP54) are existing anchors needing refinement; and three candidate AOPs are proposed. We propose a four-tier, largely non-animal integrated testing strategy compatible with EU Regulation 1223/2009 and the US Modernization of Cosmetics Regulation Act of 2022, alongside six priority research gaps to guide future regulatory risk assessment of cosmetic ingredients.