Metabolism of 2-ethylhexanoic acid administered orally or dermally to the female Fischer 344 rat1

Abstract

1. Excretion balance studies were conducted with 2-ethylhexanoic acid (EHA) in the female Fischer 344 rat following single high (1 g kg) or low (0.1 g kg) oral doses of \[2- Chexyl]EHA,following repeated oraldosing with unlabelled EHA and a final\ [C]EHAoral dose at the low dose level, following dermal exposure with a high (1 g kg) and low (0.1 g kg) applied dose of \ [C]EHA, and following a 1 mg kg i.v. dose of \ [C]EHA. 2. Oral, i.v. and dermal doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing. 3. After oral dosing of 0.1 g kg, the mean peak blood level was 85.1 mu g equivalents EHA g. Maximum blood concentrations were detected at either 15 or 30 min in individual animals. After dermal application of 0.1 g kg, the mean peak blood level of 7.9 mu g equivalents EHA g was attained at 8 h. 4. Occlusive dermal exposure caused damage to the epidermis in the first 24 h after application and resulted in dermal absorption of 70% relative to i.v. dosing, based on the ratio of percent dose in excreta. 5. Dermal application followed by prompt washing of the skin resulted in recovery of 101.9% from the skin surface and 0.2% in the excreta. 6. The major urinary metabolites were the glucuronide of EHA, 2-ethyl-1,6- hexanedioic acid (namely 2-ethyladipic acid), 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-6- hydroxyhexanoicacidandethylketohexanoicacid.Evidencefor metabolismvia beta -oxidation was alsofound,consistent with the incorporationofEHAinto normalcellular intermediary metabolism.