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1383838 
Technical Report 
Final report on the safety assessment of Tocopherol, Tocopheryl Acetate, Tocopheryl Linoleate, Tocopheryl Linoleate/Oleate, Tocopheryl Nicotinate, Tocopheryl Succinate, Dioleyl Tocopheryl Methylsilanol, Potassium Ascorbyl Tocopheryl Phosphate .... 
Anonymous 
2002 
RISKLINE/2003040005 
21 
2002 
21 
eng 
Tocopherol, Tocopheryl Acetate, Tocopheryl Linoleate, Tocopheryl Linoleate/Oleate, Tocopheryl Nicotinate, Tocopheryl Succinate, Dioleyl Tocopheryl Methylsilanol, Potassium Ascorbyl Tocopheryl Phosphate, and Tocophersolan all function as antioxidants in cosmetic formulations; they also have other functions, such as skin-conditioning agents. Vitamin E is comprised of alpha-, beta-, gamma-, and delta-Tocopherol and alpha-, beta-, gamma-, and delta tocotrienol. A summary of uses in cosmetic formulations reported to FDA in 1998 is given in Table 14.
Data submitted to CTFA reported that Tocopherol was used at concentrations of <=5%, Tocopheryl Acetate was used at concentrations of <=36% (and at 100% in vitamin E oil), Tocopheryl Linoleate was used at concentrations of <=2%, Tocopheryl Nicotinate was used at concentrations of <=2% (with recommended concentrations of use of 0.1% to 1.0%), Dioleyl Tocopheryl Methylsilanol and oleyl alcohol was recommended for use at 3% to 6%, Potassium Ascorbyl Tocopheryl Phosphate was used at concentrations of 0.02%, and Tocophersolan was used at concentrations of <=0.2%. Tocopherol, Tocopheryl Acetate, Tocopheryl Succinate, and Tocophersolan have functions as dietary supplements.
The following limitations on impurities are indicative of the limitations that can be found on these ingredients as used in foods:
Tocopherol: <20 mg/kg heavy metals, <=10 mg/kg lead, <=25 mg/kg zinc, <=50 mg/kg zinc + copper, and <=0.1% sulfate ash. Tocopherol is not expected. to:, contain pesticides, 1,4-dioxane, free ethylene oxide, monochloroacetic acid, sulfite, organic solvents, nitrosamines residual reactants, or other substances.
Tocopheryl Acetate: <=20 ppm heavy metals, <=10 ppm lead, <=0.1% sulfate ash, and <=3 ppm arsenic. Tocopheryl Acetate is not expected to contain pesticides, 1,4-dioxane, free ethylene oxide, monochloroacetic acid, sulfite, organic solvents, nitrosamines, or other substances.
Tocopheryl Nicotinate: <=20 ppm heavy metals. Tocopheryl Nicotinate is not expected to contain pesticides,1,4-dioxane, free ethylene oxide, monochloroacetic acid, sulfite, organic solvents, nitrosamines, or other substances.
Tocopheryl Succinate: heavy metals (as Pb) must be 10 mg/kg.
In a dermal absorption study using human subjects, Tocopheryl Acetate was substantially absorbed in the skin, but systemic availability was not observed. Also, conversion to Tocopherol was not seen. In a study using rats, approximately 6% of the applied dose penetrated into the epidermis after 5 days. Most studies found that some Tocopheryl Acetate was converted to Tocopherol. Irradiation of animals dosed with Tocopheryl Acetate resulted in a significant increase in the amount of Tocopheryl Acetate found in the skin as compared to nonirradiated animals, and irradiation significantly increased the amount of Tocopherol found in'-the skin of test animals. Tocopherol was "more efficiently" absorbed from w/o than o/w emulsions. The liposomal form increased absorption from o/w emulsions but did not have an effect on w/o emulsions.
In oral ingestion studies with human subjects, administration of Tocopherol and Tocopheryl Acetate resulted in increased serum Tocopherol concentrations; the mean serum concentration peaked at approximately 7 to 8 hours following dosing. In one study, d-alpha-Tocopherol had a greater bioavailability than dl-alpha-Tocopherol. In a study using rats, Tocopheryl Acetate generally had a greater uptake than Tocopheryl Nicotinate. The liver was the principal storage site, but the adrenal glands had the greatest uptake. Most of the radioactivity was recovered as tocopheryl quinone, but in a few tissues, such as the adrenal glands, it was recovered mostly as Tocopherol. In another study using rats that were fed Tocopheryl Acetate for up to 14 weeks, a linear relationship was found between time and tissue concentration of Tocopherol. In mice that were fed Tocopheryl Acetate and irradiated, a dose-dependent increase was seen for Tocopherol in the ventral skin compared to controls, whereas irradiation decreased dorsal skin Tocopherol concentrations.
Tocopherol is the-major lipid-soluble chain-breaking antioxidant of membranes and an important cellular protectant against oxidative damage. It exerts antioxidant effects by trapping peroxyl radicals. Some researchers found that Tocopheryl was depleted from the skin upon exposure to UV fight; they postulated that other antioxidants that can recycle Tocopherol can also be depleted.
Tocopherol was generally found to inhibit UVB-induced lipid peroxidation. Dermal application of Tocopheryl Acetate also decreased lipid peroxidation, but oral administration was reported not to have an effect. Both single and multiple applications of Tocopherol inhibited 8-MOP photobinding to DNA/RNA and protein. A single application of Tocopheryl Acetate did not affect photobinding, but multiple applications protected.
Application of Tocopherol both prior to and after irradiation increased the MED. Tocopheryl Acetate application after irradiation resulted in decreased skin thickness.
Tocopherol supplementation enhanced indexes of T cell-mediated function in elderly human subjects, and Tocopheryl Acetate improved elderly immune responsiveness. Tocopherol abrogated the capacity of splenocytes from UV irradiated mice o inhibit normal rejection of UVM12 cells, whereas Tocopheryl Acetate and Tocopheryl Succinate enhanced the growth of injected UVM12 tumor cells in mice. Tocopherol and Tocopheryl Acetate had a number of immunologic effects.
alpha-Tocopherol is a good inhibitor of nitrosation because its phenol ring is fully substituted. alpha-Tocopherol might inhibit formation of skin nitrosating agents from NO2, but it did not inhibit nitrosamine production from skin nitrosating agents. Tocopheryl Acetate altered the cellular response of rats to nitrite; it prevented nitrite-related mortality and the decrease in glutathione S-transferase activity.
Tocopheryl Succinate has some cytotoxic activity. Tocopherol and Tocopheryl Succinate protected against UV-induced cytotoxicity.
The dermal LD50 values of Tocopherol and 75% Tocophersolan for rats were3 and2 g/kg, respectively. The oral LD50 values of Tocopherol, Tocopheryl Acetate, Tocopheryl Nicotinate, Tocopheryl Succinate, Tocophersolan, and 75% Tocophersolan for rats were greater than 4, 16, 10, 7, 7, and 5 g/kg, respectively. The oral LD50 values of Tocopherol and Tocopheryl Acetate were25 mg/kg and4 g/kg , respectively, for mice. Tocopherol and Tocopheryl Acetate were not toxic in short-term oral studies. In a subchronic study, 7 of 10 male rats dosed orally with 2000 mg/kg d-alpha-Tocopheryl Acetate died in 9 to 11 weeks because of internal hemorrhage; other signs of toxicity were observed in a dose-dependent manner. Rats fed <=2.0% Tocophersolan did not have any treatment-related effects. In a chronic toxicity study in which rats were fed <=2000 mg/kg/day dl-alpha-Trocopheryl Acetate and supplemented with vitamin K, no significant treatment-related effects were observed. High doses of Tocopherol and Tocopheryl Acetate have hemorrhagic activity.
In one study, Tocopherol was a weak primary skin irritant n rabbits and in another, it was a weak cumulative skin irritant in guinea pigs. Cosmetic formulations containing 2% dl-Tocopherol, 12% vitamin E in wheat germ, and 32% mixed Tocopherols in a wheat germ and vegetable oil base had mean cumulative irritation scores of 31, 7, and 12 (maximum possible of 64) in rabbits, respectively. Tocopheryl Acetate and Tocopheryl Nicotinate were generally not irritating .to rabbit skin. A single dose of a mixture of Dioleyl Tocopheryl Methylsilanol and oleic acid was not irritating to rabbits, but slight erythema was observed following multiple applications. The same was observed with 75% Tocophersolan in guinea pigs. A mixture containing <0.1% Tocopherol was not a sensitizer in an open epicutaneous test, whereas "higher concentrations (30%<=)" of Tocopheryl Acetate can cause sensitization in this test. However, Tocopheryl Acetate was not sensitizing in a guinea pig maximization test. Tocophersolan was not a sensitizer in a Buehler test. In ocular irritation studies, Tocopherol was nonirritating in some tests and a minimal or very slight ocular irritant in others. Tocopheryl Acetate, Tocopheryl Nicotinate, and a mixture of Dioleyl Tocopheryl Methylsilanol and oleic alcohol were not irritating to rabbit eyes. Tocophersolan was a slight ocular irritant.
Oral administration of Tocopherol, Tocopheryl Succinate, and Tocophersolan did not have reproductive or developmental effects in rats, and Tocopheryl Acetate generally did not have any reproductive or developmental effects in rabbits, hamsters, rats, or mice. Tocopherol and Tocopheryl Acetate had some effect on reducing the number of malformations observed in neonates from diabetic dams. Tocopherol did not have an effect on zinc deficiency-induced teratogenicity. In some studies, Tocopheryl Acetate potentiated the embryolethal effect of cortisone acetate. Tocopheryl Succinate reduced some reproductive effects, but not all, induced by TCDD.
Tocopherol, Tocopheryl Acetate, Tocopheryl Succinate, and a mixture of Dioleyl Tocopheryl Methylsilanol and oleic acid were generally not mutagenic. The only effects observed were a dose-dependent increased elution rate of DNA in alkali in a DNA strand breakage assay and 50% inhibition in the incorporation of [3 H]-thymidine in a thymidine incorporation assay using Tocopherol. Tocopherol has some antimutagenic activity and was able to modulate some mutagenic effects. Tocopheryl Succinate also had some mutagenicity modulatory activity. Tocopherol and Tocopheryl Succinate generally did not affect UV-induced mutagenicity.
In an oral study, Tocopheryl Acetate was not carcinogenic. Neoplasms developed in animals injected subcutaneously with Tocopherol or Tocopheryl Acetate and soya oil; however, neoplasms were not seen in animals dosed with Tocopherol or Tocopheryl Acetate only.
The modulation of the carcinogenic effect of other agents was studied with Tocopherol, Tocopheryl Acetate, and Tocopheryl Succinate was mixed. In most cases, there was inhibition of the effect of the other agent; in some cases, no effect was seen. However, in one study, Tocopherol acted as a complete tumor promoter, with an efficiency approaching a standard promoter, the same promoter, whose activity was inhibited by Tocopherol in other studies. In a modulation study, Tocopherol reduced spontaneous pulmonary tumorigenesis in A/J mice. In a dermal study using mice, Tocopherol reduced photocarcinogenesis. However, dermally applied Tocopheryl Acetate and Tocopheryl Succinate were reported to enhance photocarcinogenesis. After oral administration, Tocopherol appeared to reduce UV induced lesions. Orally administered Tocopheryl Acetate reduced the incidence of skin cancer, but toxicity was observed. Tocopherol had some other protective effects on UV-induced skin damage. Slight protection from wrinkling was observed in hairless mice with Tocopheryl Acetate and Tocopheryl Linoleate; Tocopheryl Nicotinate and Tocopheryl Succinate did not have any protective effects.
In clinical studies, Tocopherol and Tocopheryl Acetate were not irritants or sensitizers. A very small percentage of patients patch-tested by the NACDG reacted to Tocopherol. A cosmetic line containing Tocopheryl Linoleate introduced in Switzerland in 1992 resulted in a large number of outbreaks; positive patch tests with Tocopheryl Linoleate were seen. However, the outbreaks were thought to be due to a metabolite or contamination of the product. Tocopheryl Nicotinate was not an irritant or a sensitizer. Case reports exist for Tocopherol- and Tocopheryl Acetate-containing products. Tocopheryl Acetate was not phototoxic. In a study in which subjects were given a supplement containing Tocopherol and ascorbic acid, a significant increase in MED was observed as compared to the controls.
Clinically, Tocopherol is relatively nontoxic. Excess Tocopherol can, however, prolong clotting time, depress vitamin K-dependent clotting factors, and affect platelet aggregation via prostaglandin metabolism. Large doses can produce a number of other effects.
Discussion.
The Expert Panel found the data included in this review adequate to determine that Tocopherol, Tocopheryl Acetate, Tocopheryl Linoleate, Tocopheryl Linoleate/Oleate, Tocopheryl Nicotinate, Tocopheryl Succinate, Dioleyl Tocopheryl Methylsilanol, Potassium Ascorbyl Tocopheryl Phosphate, and Tocophersolan are safe as used in cosmetic formulations. It is understood that the Tocopherol in cosmetic products is of similar grade to that used in foods.
The Expert Panel was initially concerned with possible irritation and sensitization because of a large number of outbreaks reported in Switzerland with the release of a new line of cosmetics that contained Tocopheryl Linoleate. However, the researchers thought that the outbreaks were due either to a contaminant or a metabolite. Safety data summarized in this report indicated that Tocopherol was not an irritant or sensitizer. Also, the limited number of case studies available on the ingredients of the Tocopherol family, which have widespread use, was an indication that dermal irritation and sensitization was not a concern.
Tocopherol and Tocopheryl Acetate were reported to be used in hair sprays. Initially, the Expert Panel was concerned with the lack of inhalation toxicity data. However, this concern was allayed because of the low reported concentrations used in hair sprays, 0.0001% to 0.2%.
The Panel did carefully consider that the tumor promoting ability of Tocopherol, Tocopheryl Acetate, and Tocopheryl Succinate has been extensively studied. In most studies, Tocopherol is reported to inhibit tumor promotion: Of concern to the Panel, however, was one study .m mice in which Tocopherol acted as a complete tumor promoter. The procedures used in this study were different from most tumor promotion studies and the results have not been repeated. The general experience of the Cosmetic Ingredient Review (CIR) Expert Panel is that Tocopherol is not a tumor promoter.
Finally, the Expert Panel was concerned that hydroquinone is used in the manufacture of Tocopherol and could be an impurity. The Expert Panel stated that residual levels of hydroquinone were to be limited to those achieved by good manufacturing processes.
Conclusion.
On the basis of the animal and clinical data included in this report; the CIR Expert Panel concludes that Tocopherol, Tocopheryl Acetate, Tocopheryl Linoleate, Tocopheryl Linoleate/ Oleate, Tocopheryl Nicotinate, Tocopheryl Succinate, Dioley Tocopheryl Methylsilanol, Potassium Ascorbyl Tocopheryl Phosphate, and Tocophersolan are safe as used in cosmetic formulations. 
ANIMAL; acute toxicity; subacute toxicity; subchronic toxicity; chronic toxicity; irritancy; hypersensitivity; immunotoxicity; carcinogenicity; genetic toxicity; reproductive and developmental tests; toxicokinetics; eye; skin; promotion; HUMAN; case report; human exposure; irritancy; hypersensitivity; toxicokinetics; skin; cosmetics 
• Arsenic (Inorganic)
     1. Literature
          Toxline, TSCATS, & DART
     2. Initial Filter
          Non peer-reviewed