A dermal 90-day subchronic toxicity study conducted in rats determined the NOAEL to be 250 mg/kg/day, based on reduced body weights

A series of in vitro human skin penetration studieswere conducted with 4% linalool under in-use (unoccluded) and occluded conditions in diethyl phthalate (DEP), dipropylene glycol (DPG), ethanol/water, petrolatum, ethanol/DEP or ethanol/DPG vehicles.Twelve active dosed diffusion cells were prepared from seven donors for each application condition (unoccluded, occluded, and an unoccluded control cell). Epidermalmembranes were used, and their integrity was assessed by measuring the permeation rate of tritiated water over a period of 1 h. Permeation of linalool froma 5 μl/cm2 dosewas then measured at 12 time-points over 24 h. Occluded conditions reduced the loss of volatile application vehicles and test compounds but may have also increased skin hydration, factors which caused a significant increase in the permeation of linalool. Under unoccluded experimental conditions, there was a gradual but comprehensive evaporative loss. Total absorbed dose values from an unoccluded application ranged from 1.8% to 3.57% (DPG < ethanol/ DPG < ethanol/DEP < DEP < petrolatum < ethanol/water). Total absorbed dose values from an occluded application ranged from 5.73% to 14.4% (DEP < ethanol/DEP < DPG < petrolatum < ethanol/DPG < ethanol/ water). Conservatively, 14.4% dermal absorption was selected for this safety assessment.