Kenneth R. Schrankel

Subchronic inhalation studies of complex fragrance mixtures in rats and hamsters

Users of consumer products are invariably and intentionally exposed to complex mixtures in such products. With finished fragrance products, these mixtures may represent 100 or more fragrance raw materials (FRMs). The objective of the described studies was to evaluate the safety of finished fragrance products via the inhalation route. In total, the finished products contained approximately 100 FRMs at concentrations of 1% or greater. Major FRMs evaluated included benzyl acetate, coumarin, hydroxycitronellal, musk ketone, 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta-gamma-2-be nzopyran (HHCB) and phenyl ethyl alcohol. Groups of rats or hamsters were exposed by inhalation (whole body) to the mixtures at 5, 9 or 50 mg/m3 for 4 h per day, 5 days per week for 6 or 13 weeks. For each of the fragrance products, the doses used generally represented a ten- to 100-fold exaggeration of levels expected to be achieved during typical use by consumers. With one exception, the fragrances were aerosolized prior to introduction into the inhalation chamber. The exception product was formulated with a propellant, packaged in a pressurized container and expelled with an automated actuator. In all studies, chamber concentrations of fragrance were monitored. Particle sizes ranged from 0.5 to 7.5 microm, depending on the study. Subchronic exposure to all fragrance mixtures resulted in no toxicologically significant effects on animal survival, behavior, body weights or weight gains, organ weights, or in hematology, clinical chemistry, or urinalysis parameters. No gross pathological or histopathological findings related to test material exposures were observed. These studies support the conclusions that the fragrance mixtures would not pose a hazard to product users based on repeated and exaggerated inhalation exposures of animals.