Comparative Acute Intravenous and Percutaneous Pharmacokinetic Studies with Bis [2-(Dimethylamino)Ethyl] Ether in the Fischer 344 Rat and New Zealand White Rabbit

Abstract

Bis[2-(dimethylamino)ethyl]ether (DMAEE: CAS number 3033-62-3) is a liquid industrial chemical used principally as an amine catalyst, and having a potential for skin contact. Using [¹⁴C]DMAEE the absorption, plasma pharmacokinetics, and elimination were studied following intravenous (IV) and occluded (48 h) epicutaneous dosing, and differential tissue distribution was determined by the percutaneous route. By the IV route (2 and 200 mg/kg rat; 1 and 100 mg/kg rabbit) there was rapid distribution, with half-life (t1/2) of distribution in the rat of 0.67 min (200 mg/kg) and 0.82 min (2 mg/kg), and in the rabbit 1.95 min (100 mg/kg) and 1.42 min (1 mg/kg). Elimination was comparatively slow, with t1/2 in the rat of 1053 min (200 mg/kg) and 841 min (2 mg/kg), and in the rabbit 2429 min (100 mg/kg) and 1588 min (1 mg/kg). Excretion was mainly in the urine with the proportions of recovered dose in the rat being 64% (200 mg/kg) and 61% (2 mg/kg), and in the rabbit 33.8% (100 mg/kg) and 43.6% (1 mg/kg). By occluded cutaneous application, ¹⁴C absorption was rapid with t1/2 ranging from 16.45 to 81.51 min in the rat and 21.8 to 76.2 min in the rabbit. Absolute bioavailability ranged from 50.8 to 93.6% in the rat, and from 54.1 to 63.0% in the rabbit. Elimination rates were moderately slow with t1/2 in the rat ranging from 18.2 to 31.5 h and in the rabbit from 40.7 to 61.0 h. Excretion of ¹⁴C was mainly in the urine, accounting for 24-52% with the rat and 22-25% with the rabbit of the total recovered dose. Urine analyses by high-performance liquid chromatography (HPLC) showed the majority of the recovered ¹⁴C was as unaltered DMAEE, with only a small (up to 1%) second peak possibly due to a metabolite. Also, plasma analysis showed that unchanged DMAEE accounted for the majority of ¹⁴C. Tissue analyses showed that only the rabbit kidney appeared to have significant accumulation of radioactivity. The pharmacokinetic profile of IV and percutaneously absorbed DMAEE is consistent with a two-compartment open model in which elimination is primarily by excretion of unmetabolized DMAEE. The findings accord with the known percutaneous toxicity of DMAEE.