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Description of key information

Short description of key information on absorption rate: 
The potential penetration of 2-amino-2-propanol (AMP) across a skin barrier has been characterized at several different concentrations utilizing both rat and human in vitro models and in vivo in rats.

Key value for chemical safety assessment

Additional information

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 AUC 0 to infinity 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.

Discussion:

AMP is absorbed significantly better following oral administration compared to dermal administration. Bioavailability following dermal dosing is not only lower following dermal dosing, but also the absorption takes far longer, thus systemic concentrations following dermal dosing are lower compared to an equivalent oral dose.

The absorbed dose is distributed throughout the body quickly and a major fraction is excreted unchanged in the urine within a relatively short period of time. The remaining AMP appears to sequester in some tissues such as the red blood cells, 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 of metabolites in the urine, the AMP that becomes sequestered must eventually be released unchanged. The data also indicate that whilst AMP can also cross the human epidermis, it does so to a lesser extent than in rats and is somewhat dependant on the matrix (specifically, the pH) in which the AMP is applied to the skin.

A very important aspect to the bioavailability of AMP is the significant difference in kinetics following oral application versus dermal application. As indicated above, the kinetics following dermal application of AMP are 'flipflopped', i.e. the rate of absorption is slower than the rate of excretion, leading to a significant difference in the AUC and Cmax reached when applying the same dose either orally or dermally. Therefore, when using oral toxicity studies to determine a Dermal DNEL it is important to take this into consideration rather than using the innapropriately simplistic comparison of '% bioavailability'. In the attached document is a summary of the toxicokinetic differences between the oral and dermal route of exposure. The document uses a PBPK model (compiled using the TK data from the Key study) to compare the oral and dermal exposure paradigm. Specifically, it compares the dermal and oral doses required to produce the same AUC of AMP. The document demonstrates that at least 4 times the dose would be needed dermally in order to deliver the same AUC (for a given CMax). Threrefore, when extrapolating from oral to dermal routes at least a factor of 4 must be used to. In addition to this, although there were some issues with the recovery of material in the dermal penetration study (in vivo), it did demonstrate that the AMP penetrated rat skin far better than it penetrated human skin (at least a factor of 2 difference). Therefore, when extrapolating from the oral toxicity data on AMP to a human, dermal equivalent dose, a factor of 8 should be used.

When deriving the DNELS for professional and consumer uses, an additional factor of 10 should be taken into consideration to address the significant difference between the penetration of AMP salt vs base. (refer to Dermal Absorption summary).

No data are 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 subsequent distribution and elimination is not expected to be different to that following oral exposure.

Discussion on absorption rate:

The skin penetration of AMP has been evaluated in an in vitro model employing both rat and human donor skin. Test materials consisted of samples of a 95% concentrated AMP solution with a pH of approximately 12.6, a 40% aqueous solution with a pH of 9.5, and a 4% solution in a generic skin lotion formulation, all spiked with14C-AMP. Penetration was evaluated in up to six samples of rat and human skin per assay using a flow-through method for 24 hours. The rate at which penetration occurred or “Rate of Flux”, and the “Percent Absorption” (amount present in skin excludingstratum corneumand receptor fluid) were calculated. In all instances, human skin was less permeable to AMP than was rat skin. In rat skin, rates of penetration for all three AMP test materials increased or reached a plateau during the 24 hour exposure period with average maximal flux values of approximately 197 to 411 µg/cm2/hr. The slowest penetration occurred with the 4% AMP-lotion preparation. In human skin, maximal rates of penetration were lower than with rat skin for all test materials, averaging approximately 107 to 155 µg/cm2/hr. Again, the slowest penetration occurred with the 4% AMP-lotion preparation. Penetration of human skin by test materials followed a similar pattern as in rat skin with the notable exception that uptake of the 4% AMP-lotion test material reached maximal rates within 2 hours of application, decreasing thereafter. The calculated “Percent Absorption” averaged approximately 30 to 51% in the rat and 7 to 17% in the human skin models with the lowest values found with the 4% AMP-lotion formulation for both species. The observed absorption of AMP in a lotion formulation by rat skin was consistent with that observed for a similar concentration of AMP in vivo.

It should be noted however that in this study there were a number of issues with recovery of the material that may have led to innacuracy when determining the total percent absorbed. As such, although this study provides information on the potential for AMP to penetrate the skin, it cannot be used to determine the percent absorbed for the subsequent determination of Dermal DNELs.

 

Further evidence for the slow penetration of skin by low concentrations of AMP have come from the evaluation of dermal absorption of AMP as part of a pharmacokinetics study in rats reported by Saghiret al. (2008). This study determined the oral dermal adsorption, distribution, metabolism and elimination of AMP in male Fischer 344 administered either an oral or dermal dose of 18 mg/kg14C-AMP in aqueous vehicle. The dermal dose consisted of a 120 µL/kg application of a 3.5% aqueous solution of AMP spread over an occluded area of 12 cm2in the interscapular region for 6 hours.Time-course blood and excreta were collected, radioactivity determined and blood and urine analyzed for AMP and metabolites. Table 1 presents the balance data for oral versus dermal administration obtained in this study. The total dermal absorption of14C-AMP was approximately 34-42%. The lower value does not include an approximately 8%14C-AMP which was observed to remain immobile within the skin column for up to 162 hours and thus was considered by the authors to not be available for systemic circulation. This level of absorption is similar to that observed in vitro using rat skin, approximately 30%, lending support to the accuracy of the findings for both rat and human skin in the latter skin penetration study (ANGUS, 2007).

 

The slow dermal penetration of AMP in rats was further evidenced by the long latency period to reach plasma Cmaxfollowing dermal application (8.5±4.7 hours in plasma and 4.0±2.8 h in RBC) than following oral dosing (0.3 h) (Figure 3). The plasma Cmaxfor dermally applied AMP was 49-fold lower than that following an oral dose (0.09mg/g versus 4.42mg/g, respectively). The plasma AUC0®µfor dermally applied AMP was also approximately 8-fold lower than with orally administered AMP. As noted, approximately 8% of the penetrated radioactivity remained at the application site, as skin bound residue, 162 h after washing the site with soapy water and was assumed to not be systemically available. Subtraction of this immobile test material from the estimated total percent absorbed value (42%) reduced the dermal bioavailability of AMP to 34%, which is similar to that (approximately 30%) calculated by modeling the amount recovered in the excreta of rats dosed dermally and orally using the methods outlined by Thongsinthusaket al. (1999). 

When considering the amount of AMP that would be absorbed following dermal exposure, it is important to recognise that the dermal penetration potential of AMP will vary according to the pH of the matrix in which it is applied. AMP is used primarily as a neutralizer in formulations intended for professional and consumer uses. These products typically have a pH of approximately 7 to 8. Due to the pKa of AMP, at this pH almost all of the AMP would be in the salt form, rather than the base form. This substantially affects absorption, with the salt predicted (using DERMWIN) to penetrate at a far lower rate than the base. The difference in rate could account for at least a 10x lower percentage absorption of AMP at pH 7 compared to the base at pH 10 and higher. In the attached document there is a summary of the dermal penetration of AMP as it varies with pH.

 

Thongsinthusak, T., Ross, J. H., Saiz, S. G. and Krieger, R. I. (1999). Estimation of dermal absorption using the exponential saturation model.Regul. Toxicol. Pharmacol.29, 37-43.