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Description of key information

Key value for chemical safety assessment

Absorption rate - oral (%):
Absorption rate - dermal (%):
Absorption rate - inhalation (%):

Additional information

No information from guideline studies for RRR-(alpha-, beta-, gamma-, delta)-tocopherol per se is available.

For the assessment of the toxicokinetic properties, data on the structural analogs alpha-tocopheryl acetate and DL-alpha-tocopherol were taken into account as the Vitamin E ester is rapidly hydrolysed by esterases to alpha-tocopherol under physiological conditions as shown in numerous in vitro and in vivo studies. See read-across hypothesis and justification.

General remarks on absorption and metabolism of Vitamin E (EFSA, 2006 and 2010):

The bioavailability of vitamin E and its esters is related to the efficiency of absorption. Intestinal absorption of lipids and fat-soluble vitamins depends on pancreatic function, biliary secretion to form micelles with the hydrolysed fat, and transfer across intestinal membranes. Nearly all of the vitamin E absorbed across the intestinal mucosa is free tocopherol. In vivo and in vitro studies suggest that the rate of uptake of vitamin E is controlled by passive diffusion. Absorption of tocopherols is incomplete; the extent of absorption is dependent on intake and varies between 20-80%. The proportion absorbed decreases with increasing amount added to experimental diets; the average absorption is about 40-60% while pharmacological doses of 200 mg and more are absorbed to the extent of <10%. Cannulation studies indicate that there is no difference in absorption between alpha-tocopherol and alpha-tocopheryl acetate at physiological doses. At high levels of intake, (> 400 IU/day) a higher degree of absorption was obtained with free tocopherol than tocopheryl esters. About 90% of the free alpha-tocopherol is transported via the lymphatic system into the bloodstream, where it is distributed into lipoproteins on passage into the liver. Tocopherol is excreted as a water-soluble conjugated compound resulting from different oxidation steps.

Oral and intravenous studies:

After oral administration of DL-alpha-tocopheryl acetate (4 ml emulsion with 2 mg DL-alpha-tocopheryl acetate and 50 μC of DL-alpha -tocopheryl-1’,2’-3H2-acetate to rats alpha-tocopheryl acetate is extensively metabolised by rat tissues. The adrenals, ovaries, adipose tissue and heart appeared to extract vitamin E from the blood for up to 48 hours after absorption. The metabolite most abundantly occurring under these conditions was alpha-tocopheryl quinone. In the adrenal glands, however, the most highly labeled compound was unesterified tocopherol. The authors concluded that the adrenal tissue played a definite role in the metabolism of vitamin E. (Gallo-Torres, 1971). From these data on oral uptake, theoral absorption is set at 100% (regardless the vehicle).

Thirty minutes after intravenous administration of DL-alpha-tocopheryl acetate (1 ml emulsion with 136 IU unlabeled DL-alpha-tocopheryl acetate and 25 μC of DL-alpha-tocopheryl-1’,2’-3H2 –acetate) to rats, 96% of the chromatographed radioactivity was due to unchanged alpha-tocopheryl acetate. Forty eight hours after injection, only 8% of the chromotographed radioactivity found in plasma corresponded to alpha-tocopheryl acetate as such. At this period 16% was metabolised to “free” tocopherol and 64% to tocopheryl quinone. Most of the radioactivity accumulated in the liver. In the liver, alpha-tocopheryl acetate, is rapidly and extensively hydrolysed: 48 hours after injection only 2.8% of the chromatographed radioactivity was due to the injected alpha-tocopheryl acetate. Also the spleen and lung tissues metabolized alpha-tocopheryl acetate extensively. The uptake of the brain and pituitary was very slow compared to the skeletal muscle, adipose tissue, small intestine, adrenals and ovaries which showed a gradual increase in radioactivity in time. After i.v. administration only traces of alpha-tocopheryl acetate in the small intestine were observed. The authors conclude that the intestine of the rat is able to hydrolyze alpha-tocopheryl acetate almost completely (Gallo-Torres, 1971).

Dermal studies:

After dermal application an in vitro study has demonstrated the metabolism of alpha-tocopheryl acetate to alpha-tocopherol in viable pig skin. Topically applied alpha-tocopheryl acetate was bioconverted to the active molecule and free radical scavenger alpha-tocopherol within the skin tissue. No metabolism was detectable in the stratum corneum. This study has also elucidated the kinetics of metabolism of alpha-tocopheryl acetate. The extent of metabolism was highest at 6-12 hours after application. Longer time periods failed to produce a higher extent of metabolism, probably due to the saturation of the hydrolytic pathway (Rangarajan and Zatz, 2001).

Dermal absorption:

Skin permeation studies were conducted using modified Franz diffusion cells and human cadaver skin as the membrane. Specifically, 5% (w/w) alpha­-tocopherol acetate was formulated in ethanol, isopropyl myristate, light mineral oil, 1% Klucel® (hydroxypropyl cellulose) gel in ethanol, and 3% Klucel® gel in ethanol (w/w). Samples from the receiver were collected at 2, 4, 6, 8, 12, 24, 30, 36, and 48 hours and analyzed by HPLC for concentrations of alpha-tocopherol acetate and alpha-tocopherol. The permeabilities through human cadaver skin were 1.0 x 10-4 , 1.1 x 10-2 , 1.4 x 10-4 , 2.1 x 10-4 , and 4.7 x 10-4 cm/h for the ethanol solution, isopropyl myristate solution, light mineral oil solution, 1% Klucel® gel, and 3% Klucel® gel, respectively (Mahamongkol et al., 2005).

In an in vitro skin absorption test (similar to OECD 428, non-GLP), it is concluded that DL-alpha-tocopheryl acetate-3H penetrates into and through intact and stripped pig skin (Csato and Klecak, 1995). The total skin penetration rates of DL-alpha tocopheryl acetate 3H from 3 alpha-hydroxy-acid creams were time-, formulation type- and skin condition-dependent, although being not significantly different. The percutaneous absorption observed was in the range of 1.1 – 4.2 %, tested at 1h, 6h and 18h exposure with 3 different formulations (nominal dose 5%).

From this experiment, the dermal absorption rate of RRR-(alpha-, beta-, gamma-, delta)-tocopherol in humans is therefore estimated to be 5%.