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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Absorption rate - oral (%):
50
Absorption rate - dermal (%):
5
Absorption rate - inhalation (%):
100

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%.