Lyral

The core biological function of Lyral (CAS No. 31906-04-4) is as a fragrance ingredient (with a floral odor, used in perfumes, cosmetics, etc.); it is also a common contact allergen and a cytotoxic substance, with no therapy-related function. Its targets and modes of action include: (1) activation of the human olfactory receptor OR10J5 and the mouse olfactory receptor Olfr16 (via physical adsorption binding, mediating olfactory perception; adsorption is a spontaneous exothermic process), and (2) inhibition of mitochondrial electron transport chain complexes I and II (interfering with energy metabolism). The EC50 is 100 nM (50% death in HaCat cells); the IC50 values for inhibition of rat liver mitochondrial complexes I and II are 125 μM and 400 μM, respectively. Animal studies have no disease-model induction or therapeutic applications, and are only used for the local lymph node assay (LLNA) to assess skin sensitization (EC3 value 171%, classified as a weak sensitizer). Common concentrations used in cell culture: HaCat cells 0.006-10 μM (for EC50 determination), 10 μM (complete inhibition of cell viability); HEK293T/N×G108CC15 cells 10⁻⁶-3×10⁻⁴ mol/L (for olfactory receptor functional studies). Clinically relevant concentrations: actual use concentration in cosmetics 0.02%-3.8%, recommended safe concentration ≤0.3%, elicitation threshold for contact allergy 1-10 μg/cm², patch testing commonly uses a 5% petrolatum preparation (2.0 mg/cm²). There is no effective therapeutic concentration; only safe exposure limits exist (SCCS recommends ≤200 ppm in cosmetics, i.e., 0.02%). High concentrations can trigger allergic contact dermatitis and cytotoxicity (decreased ATP, increased ROS, disruption of mitochondrial membrane potential).

References:

[1] Bruze M, Andersen KE, Goossens A; ESCD; EECDRG. Recommendation to include fragrance mix 2 and hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) in the European baseline patch test series. Contact Dermatitis. 2008 Mar;58(3):129-33. doi: 10.1111/j.1600-0536.2007.01292.x. PMID: 18279149.

[2] Braendstrup P, Johansen JD; Danish Contact Dermatitis Group. Hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) is still a frequent allergen. Contact Dermatitis. 2008 Sep;59(3):187-8. doi: 10.1111/j.1600-0536.2008.01397.x. PMID: 18759910.

[3] Johansen JD, Frosch PJ, Svedman C, Andersen KE, Bruze M, Pirker C, Menné T. Hydroxyisohexyl 3-cyclohexene carboxaldehyde- known as Lyral: quantitative aspects and risk assessment of an important fragrance allergen. Contact Dermatitis. 2003 Jun;48(6):310-6. doi: 10.1034/j.1600-0536.2003.00126.x. PMID: 14531869.

[4] Usta J, Hachem Y, El-Rifai O, Bou-Moughlabey Y, Echtay K, Griffiths D, Nakkash-Chmaisse H, Makki RF. Fragrance chemicals lyral and lilial decrease viability of HaCat cells' by increasing free radical production and lowering intracellular ATP level: protection by antioxidants. Toxicol In Vitro. 2013 Feb;27(1):339-48. doi: 10.1016/j.tiv.2012.08.020. Epub 2012 Aug 24. PMID: 22940465.

[5] Kumar M, Devi A, Sharma M, Kaur P, Mandal UK. Review on perfume and present status of its associated allergens. J Cosmet Dermatol. 2021 Feb;20(2):391-399. doi: 10.1111/jocd.13507. Epub 2020 Jun 16. PMID: 32445606.

[6] Ben Khemis I, Aouaini F, Ben Hadj Hassine S, Ben Lamine A. Theoretical study of the olfactory perception of floral odorant on OR10J5 and Olfr16 using the grand canonical ensemble in statistical physics approach. Int J Biol Macromol. 2022 Dec 31;223(Pt B):1667-1673. doi: 10.1016/j.ijbiomac.2022.10.201. Epub 2022 Oct 26. PMID: 36306901.