New Study Uncovers Neurotoxic Risks of High-Level Exposure to Rose-Scented Citronellol

A recent groundbreaking study from the Korea Research Institute of Chemical Technology (KRICT) has revealed alarming evidence that citronellol, a fragrant compound widely used in cosmetics and household items, may exert previously unrecognized neurotoxic effects under high exposure conditions. This discovery challenges the long-held perception of citronellol as a benign ingredient and highlights the urgent need for revisiting safety standards and regulatory frameworks surrounding its use in consumer products. Employing a multifaceted, cross-species approach, the research demonstrates how citronellol can influence complex neurobiological pathways, ultimately impairing brain function and behavior.

Citronellol is a naturally occurring monoterpenoid found in a variety of plants such as rose, geranium, and citronella. It has earned its popularity through the cosmetic and fragrance industries because of its pleasant floral scent and purported calming properties. Despite its extensive use and assumed safety profile, this new study elucidates a darker side to this ubiquitous compound. By utilizing a comprehensive battery of experimental models, including zebrafish, rodent systems, human brain organoids, and advanced blood-brain barrier (BBB) organ-on-chip platforms, the researchers offer convincing evidence of citronellol’s neurotoxic potential, which had remained undetected in previous studies.

A central aspect of the investigation was the confirmation that citronellol readily crosses the blood-brain barrier—a critical physiological defense that regulates substance entry into the central nervous system. Traditional safety assessments have often overlooked this property in fragrance compounds. Through quantitative measurements across animal models and human-relevant in vitro systems, the study established that citronellol accumulates within the brain. This accumulation triggers oxidative stress, marked by increased production of reactive oxygen species (ROS), which are chemically reactive molecules known to damage cellular structures and exacerbate neurological dysfunction.

Equally concerning were the findings of neuroinflammatory responses accompanying citronellol exposure. In neural tissues of zebrafish and mice, along with human-derived brain organoids, inflammatory pathways were upregulated. Such neuroinflammation is a hallmark of many neurodegenerative diseases and is associated with disruption of neural network integrity and function. The researchers also documented structural impairment of the BBB itself, evidenced by increased permeability and the infiltration of immune cells into brain tissue, further amplifying neurodegenerative risk.

Beyond these physiological alterations, the study uncovered a crucial metabolic perturbation induced by citronellol involving the kynurenine pathway. Kynurenine metabolism is an essential biochemical route processing tryptophan, an amino acid, into neuroactive metabolites. Importantly, this pathway has two divergent branches: one leading to kynurenic acid, which has neuroprotective properties, and the other producing 3-hydroxykynurenine (3-HK), a compound known for its neurotoxic and oxidative stress-promoting effects. The research team’s metabolomic profiling revealed that citronellol skews this metabolic balance toward the accumulation of 3-HK, thereby exacerbating neuronal damage through oxidative mechanisms.

Behavioral assays in zebrafish further substantiated these biochemical and cellular findings. Zebrafish exposed to varying concentrations of citronellol (2, 4, and 8 mg/L) displayed pronounced anxiety-like behavior and abnormal movement patterns. Notably, exposure diminished phototactic responses—the tendency to move toward or away from light—and increased thigmotaxis, which is a behavior characterized by staying close to the walls of the testing environment, often interpreted as an indicator of stress or anxiety. These behavioral deviations mirror symptoms observed in higher vertebrates under neurotoxic stress, highlighting the translational relevance of the findings.

The novelty and strength of this study lie in its integrative methodology that spans species and model complexities—from whole organisms to micropatterned cell culture devices mimicking human BBB physiology. Human brain organoids derived from induced pluripotent stem cells have increasingly become prominent tools for studying human-specific neurological effects in a dish. Their usage here provides compelling evidence that citronellol’s neurotoxic actions are not confined to animal models but may bear direct implications for human health.

This comprehensive approach is particularly timely considering the widespread use of citronellol in everyday products and the regulatory landscape that currently classifies it primarily as a potential allergen requiring labeling only at certain concentrations. The discovery that under high-exposure conditions citronellol can induce oxidative stress, inflammation, BBB disruption, and metabolic imbalance in neurological pathways invites a re-evaluation of permissible exposure limits and underscores the necessity for stricter safety assessments using advanced biomimetic models.

Dr. Myung Ae Bae, leading the interdisciplinary team at KRICT, emphasized the significance of employing next-generation “human-mimicking platforms” in unveiling subtle yet profound toxicological effects that traditional animal models or chemical assays might miss. This pioneering work exemplifies how integration of physiologically relevant in vitro systems with established animal models can deepen our understanding of chemical safety and human risk assessment.

The implications of this research extend beyond citronellol. They serve as a cautionary narrative regarding the evaluation of commonly used fragrance chemicals and other household compounds. It highlights the vital role of cross-disciplinary and multi-model research frameworks in detecting hidden toxicities that could have widespread public health ramifications. Follow-up studies planned by KRICT aim to further refine these biomimetic platforms to enhance human safety evaluations and guide regulatory policies toward more protective standards.

In conclusion, the KRICT-led study offers a compelling new perspective on citronellol, urging both the scientific community and regulatory agencies to reconsider the safety of this prevalent fragrance chemical. It serves as a wakeup call to investigate the neurological impact of other seemingly innocuous compounds with a nuanced, mechanistic lens enabled by cutting-edge experimental models. As public exposure to a myriad of synthetic and natural compounds continues to grow, enhancing neurotoxicological assessment methodologies remains paramount to safeguarding brain health at the population level.

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Subject of Research: Neurotoxic effects of citronellol and its mechanistic pathways involving kynurenine metabolism
Article Title: Neurotoxic effects of citronellol induced by the conversion of kynurenine to 3-hydroxykynurenine
News Publication Date: 15-Mar-2025
Web References: http://dx.doi.org/10.1016/j.jhazmat.2024.136965
Image Credits: Korea Research Institute of Chemical Technology (KRICT)
Keywords: citronellol, neurotoxicity, blood-brain barrier, oxidative stress, reactive oxygen species, neuroinflammation, kynurenine pathway, 3-hydroxykynurenine, metabolomics, zebrafish, brain organoids, organ-on-chip