Pharmacokinetics of aminomethylpropanol in rats following oral and a novel dermal study design.
This study determined the oral and dermal ADME of 2-amino-2-methyl-1-propanol (AMP), a substituted aliphatic alcohol used in a number of industrial and consumer products. Groups of 4 male Fischer 344 rats received either a single bolus oral or dermal dose of 18 mg/kg (14)C-AMP in water. The dermal dose was applied to an area of 12 cm(2) on the back of the rats for 6h under semi-occluded conditions and fitted with rodent jackets to prevent grooming. Time-course blood and excreta were collected, radioactivity determined and blood and urine analyzed for AMP and metabolites. The orally administered (14)C-AMP was rapidly absorbed and eliminated in urine. Elimination of radioactivity from blood was biphasic with a rapid alpha phase (t(1/2 alpha) approximately 1h) followed by a slower beta phase (t(1/2 beta)=41+/-4h plasma and 69+/-34 h RBC). Total urinary elimination accounted for 87-93% of the dose, most (72-77%) within the first 48 h. Fecal elimination accounted for only 3-10%. Only 3-4% of the dose was found in tissues 168h post-dosing. The total dermal absorption of (14)C-AMP was 42% that included approximately 8% of the dose remaining at the application site 162 h after washing. Less than 1% of the applied dose remained in the stratum corneum and approximately 6% of the dose was found in tissues. Urinary elimination was 43% of the administered dose, most ( approximately 17%) within 48 h, and approximately 2% was eliminated in feces. It took much longer to reach plasma C(max) after dermal application (8.5+/-4.7 h in plasma and 4.0+/-2.8h in RBC) than the oral dose (0.3h) and the AUC(0-->alpha) for dermal dose was approximately 8-fold lower than with the oral dose. Again, elimination of the radioactivity from blood was biphasic with apparent t(1/2 alpha) of 9+/-6 and 2+/-1h for plasma and RBC, respectively. However, the alpha phase was "flipped-flopped" due to relatively slow dermal penetration and rapid elimination of the systemically absorbed dose, which was corrected to approximately 0.3 h after separating alpha elimination phase from the absorption. The slope of the beta phase became parallel to the oral route upon cessation of the absorption from the dose site skin, between 18 and 42 h post-washing. No metabolite of AMP was detected either in blood or excreta of any rat. Results of this study suggests that toxicologically significant concentrations of AMP are unlikely to be achieved in the systemic circulation and/or target tissues in humans as a result of dermal application of products containing AMP. Additionally, systemically absorbed dose will be rapidly eliminated from the body with little remaining at the application site.
Saghir
Shakil A
SA
Toxicology and Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, United States. ssaghir@dow.com
Clark
Amy J
AJ
McClymont
E Lynn
EL
Staley
Jennifer L
JL
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D019540:Area Under Curve; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D007408:Intestinal Absorption; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D012869:Skin Absorption
D011412:Propanolamines; C006551:2-amino-2-methyl-1-propanol