title: Biotransformation and toxicokinetics of the insect repellent IR3535® in male and female human subjects after dermal exposure.
abstract: The absorption and excretion of the insect repellent IR3535(®) was studied in human subjects (five males and five females) after dermal application of approx. 3g of a formulation containing 20% IR3535(®), i.e. the amounts of IR3535(®) applied were between 1.94 and 3.4 mmol/person (418-731 mg/person). Blood and urinary concentrations of IR3535(®) and its only metabolite, IR3535(®)-free acid, were determined over time. In plasma, concentrations of the parent compound IR3535(®) were at or below the limit of quantification (0.037 μmol/L). IR3535(®)-free acid peaked in plasma samples 2-6h after dermal application. Cmax mean values were 5.7 μmol/L in males, 3.0 μmol/L in females and 4.2 μmol/L in all volunteers. Mean AUC values were 41.6, 24.5 and 33.9 μmolL(-1)h in males, females and all subjects, respectively. In urine samples from all human subjects, both IR3535(®) and IR3535(®)-free acid were detectable, however, only very small amounts of IR3535(®) were found. Concentrations of IR3535(®)-free acid were several thousand-fold higher than the parent compound and peaked at the first two sampling points (4h and 8h after dermal application). Overall, IR3535(®) and IR3535(®)-free acid excreted with urine over 48 h representing 13.3 ± 3.05% of the dose applied. Since IR3535(®) is rapidly and extensively metabolized, and IR3535(®)-free acid has a low molecular weight and high water solubility, it is expected that urinary excretion of IR3535(®)-free acid and IR3535(®) represents the total extent of absorption of IR3535(®) in humans. Based on the results of this study, the skin penetration rate of IR3535(®) is 13.3% in humans after dermal application.
authors: Non-Clinical Safety, Merck Serono, Merck KGaA, 64271 Darmstadt, Germany.
authors: Thomas H
authors: TH
authors: Broschard
authors: Anja M
authors: AM
authors: Bohlmann
authors: Stefan
authors: S
authors: Konietzny
authors: Ute M D
authors: UM
authors: Schauer
authors: Wolfgang
authors: W
authors: Dekant
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D005260:Female; D006801:Humans; D007302:Insect Repellents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D011422:Propionates / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D012869:Skin Absorption; D055815:Young Adult
chemical_list: D007302:Insect Repellents; D011422:Propionates; C462400:ethyl-3-(N-n-butyl-N-acetyl)aminopropionate