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Description of key information

Short description of key information on bioaccumulation potential result: 
READ Across to structurally similar compound, 2-amino-2-methyl propanol
Oral and Dermal ADME study conducted using radiolabelled AMP.
A second study conducted in choline defficient and non-defficient rats to assess distribution of AMP and the effect of choline defficiency.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

2 -aminobutanol is a structural isomer of 2 -amino-2 -methylpropanol and as such it is considered very likely that they will have similar ADME properties.

A summary of the ADME data on 2 -amino-2 -methylpropanol is given below:

The key study determined the oral and dermal ADME of 2-amino-2-methyl-1-propanol (AMP), Groups of 4 male Fischer 344 rats received either a single bolus oral or dermal dose of 18 mg/kg 14C-AMP in water. The dermal dose was applied to an area of 12 cm2 on the back of the rats for 6 h 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 14C-AMP was rapidly absorbed and eliminated in urine. Elimination of radioactivity from blood was biphasic with a rapid a phase (t1/2a ca.1 h) followed by a slower b phase (t1/2b = 41 ± 4 h 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 168 h post-dosing. The total dermal absorption of 14C-AMP was 42% that included ca. 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 ca. 6% of the dose was found in tissues. Urinary elimination was 43% of the administered dose, most (ca. 17%) within 48 h, and ca. 2% was eliminated in feces. It took much longer to reach plasma Cmax after dermal application (8.5 ± 4.7 h in plasma and 4.0 ± 2.8 h in RBC) than the oral dose (0.3 h) and the AUC0to infintiy for dermal dose was ca. 8-fold lower than with the oral dose. Again, elimination of the radioactivity from blood was biphasic with apparent t1/2a of 9 ± 6 and 2 ± 1 h for plasma and RBC, respectively. However, the a phase was ‘‘flippedflopped’’ due to relatively slow dermal penetration and rapid elimination of the systemically absorbed dose, which was corrected to ca.0.3 h after separating a elimination phase from the absorption. The slope of the b 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.

In vitro data on dermal absorption indicates that AMP is capable of penetrating the epidermis of both rat and human skin samples. However there is a significant difference between the degree of penetration in rats versus human skin. The penetration in rats is, in general, 3 times higher than in human skin. In rats, an aqeuous solution (most likely industrial exposure scenario) led to a penetration of approximately 50% of the applied dose, whereas in humans it was far lower at approxiamtely 14%. This is consistent with what is generally understood about the permeability of rat skin compared to human skin.

There are data published that indicate AMP can become incorporated into phospholipids in the liver. It has been demonstrated that rats placed on a choline deficient diet can incorporate AMP into phospholipids in place of choline and or ethanolamine. However when sufficient choline is present in the diet the degree of incorporation is far less. This incorporation of AMP into phospholipids may be in some part responsible for the apparent sequestering of AMP into some tissues. Similar data exist for 2 -aminobutanol indicating that it also is capable of becoming incorporated into phospholipids (in vitro and in vivo) at the expense of ethanolamine and choline (to some extent). This effect is more potent with 2 -aminobutanol than with AMP.

Discussion:

Considering the available data on AMP, it is concluded that 2 -AB will be absorbed significantly better following oral administration compared to dermal administration. Bioavailability following dermal dosing will not not only be lower following dermal dosing, but also the absorption will take far longer, thus systemic concentrations following dermal dosing are expected to be lower compared to an equivalent oral dose.

The absorbed dose will distributed throughout the body quickly and a major fraction excreted unchanged in the urine within a relatively short period of time. The remaining 2 -AB will probably sequester in some tissues such as the red blood cells in a similar manner to AMP, prolonging the eventual elimination. This may be due to some small incorporation into cellular components such as phospholipids or phospholipid pre-cursors. Since there is no evidence that AMP or 2 -AB are metabolised, any 2 -AB that becomes sequestered into tissues will likely be excreted unchanged. It is likely that 2 -AB will penetrate the skin in a manner similar to AMP and the matrix applied to the skin will likely affect the degree of absorption. 2 -AB is also considered to be corrosive and so at high concentrations it will damage the skin, aiding uptake into systemic circulation. However such circumstances are unlikely to occur during the normal handling and use.

No data ara available on the absorption of AMP following inhalation exposure,however due to the almost complete absorption across the gastrointestinal tract it is assumed that absorption across the respiratory epithelia would be no lower. The same assumption is made for 2 -AB. The subsequent distribution and elimination is not expected to be different to that following oral exposure.