Alpha-Tochopherol PubChem

NIH U.S.
National Library of Medicine National Center for Biotechnology Information
O P E N
CH E M I STRY
Search Compounds 
D A T A B A S E
 Compound Summary for CID 2116
PUBCHEM  COMPOUND  ALPHA-TOCHOPHEROL
alpha-tochopherol  Cite this Record

Vendors

Drug Information

Pharmacology

Literature

Patents

Bioactivities
PubChem CID: 2116
Alpha-tochopherol; DL-ALPHA-TOCOPHEROL; Dl-|A-tocopherol; 10191-
41-0; CHEMBL49563; 2,5,7,8-tetramethyl-2-(4,8,12-

Chemical Names:
trimethyltridecyl)chroman-6-ol; More...
Molecular Formula: C29H50O2
Molecular Weight: 430.7061 g/mol
InChI Key: GVJHHUAWPYXKBD-UHFFFAOYSA-N
Modify Date: 2016-10-01
Create Date: 2005-03-25

 Contents
1 2D Structure
2 3D Conformer
3 Names and Identifiers
4 Chemical and Physical Properties
5 Related Records
6 Chemical Vendors
7 Drug and Medication Information
8 Food Additives and Ingredients
9 Pharmacology and Biochemistry
10 Use and Manufacturing
11 Identification
12 Safety and Hazards
13 Toxicity
14 Literature
15 Patents
16 Biological Test Results
17 Classification
18 Information Sources
1 2D Structure 
 Search  Download  Get Image
 Magnify
 from PubChem
2 3D Conformer 
 Search  Download  Get Image
 Magnify
 Show Hydrogens  Show Atoms  Animate
 from PubChem
3 Names and Identifiers 
3.1 Computed Descriptors 
3.1.1 IUPAC Name 
2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochromen-6-ol
 from PubChem
3.1.2 InChI 
InChI=1S/C29H50O2/c1-20(2)12-9-13-21(3)14-10-15-22(4)16-11-18-29(8)19-17-26-25(7)27(30)23(5)24(6)28(26)31-
29/h20-22,30H,9-19H2,1-8H3
 from PubChem
3.1.3 InChI Key 

GVJHHUAWPYXKBD-UHFFFAOYSA-N
 from PubChem
3.1.4 Canonical SMILES 

CC1=C(C(=C2CCC(OC2=C1C)(C)CCCC(C)CCCC(C)CCCC(C)C)C)O
 from PubChem
3.2 Molecular Formula 

C29H50O2
 from PubChem
3.3 Other Identifiers 

3.3.1 EC Number 
233-466-0
 from European Chemicals Agency - ECHA
215-798-8
606-803-8

3.4 Synonyms 
3.4.1 Depositor-Supplied Synonyms 
1. alpha-tochopherol 11. 2H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12
2. DL-ALPHA-TOCOPHEROL 12. Evitaminum
3. dl-|A-tocopherol 13. Profecundin
4. 10191-41-0 14. Syntopherol
5. CHEMBL49563 15. Waynecomycin
6. 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol 16. Almefrol
7. Vita E 17. Emipherol
8. .alpha.-Tocopherol 18. Ephanyl
9. SBB057399 19. Epsilan
10. d-.alpha.-Tocopherol 20. Etamican
 from PubChem
4 Chemical and Physical Properties 
4.1 Computed Properties 
Molecular Weight 430.7061 g/mol
XLogP3 10.7
Hydrogen Bond Donor Count 1
Hydrogen Bond Acceptor Count 2
Rotatable Bond Count 12
Exact Mass 430.381081 g/mol
Monoisotopic Mass 430.381081 g/mol
Topological Polar Surface Area 29.5 A^2
Heavy Atom Count 31
Formal Charge 0
Complexity 503
Isotope Atom Count 0
Defined Atom Stereocenter Count 0
Undefined Atom Stereocenter Count 3
Defined Bond Stereocenter Count 0
Undefined Bond Stereocenter Count 0
Covalently-Bonded Unit Count 1
 from PubChem
4.2 Experimental Properties 

4.2.1 Color 
Pale yellow oil
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-548
 from HSDB
Transparent needles
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of
Chemistry, 2013., p. 1759
 from HSDB
4.2.2 Odor 
Little or no odor
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co.,
1975., p. 946
 from HSDB
4.2.3 Taste 
Little or no taste
1975., p. 946
 from HSDB
4.2.4 Melting Point 

3 deg C
 from HSDB
4.2.5 Solubility 
In water, 1.9X10-6 mg/L at 25 deg C (est)
US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of July 28, 2015:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
 from HSDB
In water-ethanol solution, 20.82 mg/L at 33 deg C
Yalkowsky, S.H., He, Yan, Jain, P. Handbook of Aqueous Solubility Data Second Edition. CRC Press, Boca Raton, FL 2010, p. 1330
 from HSDB
Soluble in alcohol, ether, acetone, chloroform
 from HSDB
4.2.6 Density 
0.950 g/cu cm at 25 de C
 from HSDB
4.2.7 Vapor Pressure 

1.4X10-8 mm Hg at 25 deg C (est)
 from HSDB
4.2.8 LogP 
log Kow = 12.2 (est)
 from HSDB
4.2.9 Stability 
Unstable to UV light, alkalies, and oxidation. /Tocopherol/
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 1249
 from HSDB
/Tocopherols are/ stable to heat in the absence of oxygen, to strong acids, and to visible light. /Tocopherol/
Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 1249
 from HSDB
Stable under recommended storage conditions.
Sigma-Aldrich; Safety Data Sheet for (+)-alpha-Tocopherol. Product Number: T1539, Version 3.4 (Revision Date 07/01/2014).
Available from, as of June 10, 2015: http://www.sigmaaldrich.com/safety-center.html
 from HSDB
4.2.10 Dissociation Constants 

pKa = 10.8 (est)
ChemSpider; Tocopherol. (59-02-9). London, UK: Royal Chemical Society. Available from, as of July 28, 2015:
http://www.chemspider.com/Search.aspx
 from HSDB
4.2.11 Kovats Retention Index 

Semi-standard non-polar 3149.5, 3149.4, 3138, 3142, 3112, 3130
 from NIST
4.3 Spectral Properties 

MAX ABSORPTION (METHANOL): 292 NM (LOG E= 3.54); DECOMP @ 350 DEG C; SADTLER REF NUMBER: 10277
(IR, PRISM)
Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976., p. C-518
 from HSDB
Specific optical rotation: -3.0 deg at 25 deg C/546.1 deg C (benzene); +0.32 deg at 25 deg C/546.1 deg C (ethanol)
 from HSDB
IR: 18246 (Sadtler Research Laboratories IR Grating Collection)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,
p. V2: 1555
 from HSDB
  1 of 11  
UV: 20771 (Sadtler Research Laboratories Spectral Collection)
p. V2: 1555
 from HSDB
NMR: 366 (Varian Associates NMR Spectra Catalogue)
p. V2: 1555
 from HSDB
MASS: 33141 (NIST/EPA/MSDC Mass Spectral database, 1990 version)
p. V2: 1555
 from HSDB
Specific optical rotation: +0.65 at 25 deg C/D (alc)
p. V2: 1555
 from HSDB
4.3.1 GC-MS 
  1 of 11  
NIST Number 230590
Library Main library
Total Peaks 154
m/z Top Peak 165
m/z 2nd Highest 164
m/z 3rd Highest 430
Thumbnail
 from NIST
5 Related Records 
5.1 Related Compounds with Annotation 
 Download
Literature (7) 3D Structure (1) Bioactivities (20) Patents (87)
didehydroconicol 2,5,7,8-tetramethyl-2-(4,8,… 2,5,7,8-tetramethyl-2-(4,8,… beta-tocopheramine
 from PubChem
5.2 Related Compounds 

Same Tautomer 24 records
Same Connectivity 23 records
Same Isotope 15 records
Same Parent, Tautomer 120 records
Same Parent, Connectivity 119 records
Same Parent, Isotope 111 records
Same Parent, Exact 6 records
Mixtures, Components, and

14 records
Neutralized Forms
Similar Compounds 1214 records
Similar Conformers 28 records
 from PubChem
5.3 Substances 
5.3.1 Related Substances 
All 137 records
Same 104 records
Mixture 33 records
 from PubChem
5.3.2 Substances by Category 
 Download
 Chemical Vendors (33)
 Curation Efforts (10)
 Governmental Organizations (16)
 Journal Publishers (2)
 NIH Initiatives (9)
 Research and Development (42)
 Subscription Services (4)
 Legacy Depositors (5)
 from PubChem
5.4 Entrez Crosslinks 

PubMed 59 records
 from PubChem
6 Chemical Vendors 
 Refine/Analyze  Download
Vendor/Supplier Purchasable Chemical PubChem SID
258024_ALDRICH 24855623
258024_SIGMA 57648149
Sigma-Aldrich
90669_FLUKA 24889393
T3251_SIGMA 24900118
AKos Consulting & Solutions AKOS015960364 152099783
BBL027614 184014485
Vitas-M Laboratory
STL372809 173896193
TCI (Tokyo Chemical Industry) T0251 87576233
Ambinter SBB057399 118306929
3B_SCI_CORP LP068285 254740715
888-004-763 126007344
ChemFrog 888-701-531 125736257
888-915-311 125822898
Mcule MCULE-4241435740 253192869
30100511 126632316
49411325 126672676
ChemMol
49412741 126674092
49416417 126677768
Chembase.cn 102208 162088418
Ark Pharm, Inc. AK-59159 176224458
AAA Chemistry AR-1I6819 103815911
Hangzhou APIChem Technology AC-10544 92709984
100562 85089961
MP Biomedicals
152147 85089958
Assembly Blocks Pvt. Ltd. AB0211519 223389151
TargetMol T1648 312995232
MolPort MolPort-003-665-940 91011051
EMD Millipore 613420 163687221
AN-18278 223653019
AN PharmaTech AN-19826 223663846
AN-23613 223675149
TimTec SBB057399 143431891
Life Chemicals F0001-2420 252091523

 from PubChem
7 Drug and Medication Information 
7.1 Therapeutic Uses 
As a dietary supplement when vitamin E intake may be inadequate.
Drug Facts and Comparisons 2015. Clinical Drug Information, LLC St. Louis, MO 2015, p. 15
 from HSDB
Vitamin E deficiency in premature infants may result in hemolytic anemia, thrombocytosis, and increased platelet
aggregation.
 from HSDB
/Vitamin E/ has also been used in cancer, skin conditions, sexual dysfunction, to reduce the incidence of non-fatal
myocardial infarction, to lower the incidence of coronary artery disease, aging, fibrocystic breast disease (cystic mastitis), to
treat dapsone-associated hemolysis, and arthritis. /not included in the US product label/
 from HSDB
Vitamin E has been used in certain premature infants to reduce the toxic effects of oxygen therapy on the lung
parenchyma... and the retina... /not included in the US product label/
 from HSDB
It has been investigated for the prevention of periventricular hemorrhage in premature infants. /not included in the US
product label/
 from HSDB
Tardive dyskinesia /not in the US product label/
 from HSDB
Postherpetic neuralgia /not included in the US product label/
 from HSDB
Alzheimer disease /not included in the US product label/
 from HSDB
Vitamin E supplement
 from HSDB
EXPTL THER: A single-armphase II study using the nontoxic agent alpha-tocopherol to treat oral premalignant leukoplakia
was performed. Patients with symptomatic leukoplakia or dysplasia were treated orally with alpha-tocopherol (400 IU) twice
daily for 24 wk. Follow-up was performed at 6, 12, and 24 wk after the start of treatment to assess toxicity and response,
and serum alpha-tocopherol levels were determined at baseline and a 6 and 24 wk. Of the 43 patients who have completed
24 wk of treatment, 20 (46%) had clinical responses and nine (21%) had histologic responses. Mean serum alpha-
tocopherol levels were 16.1 ug/mL at baseline and increased to 34.29 ug/ml after 24 wk of treatment. Patient recorded drug
calendars, as well as serum drug levels, indicated excellent patient compliance; an average of 95% of the prescribed pills
were taken. Treatment was extremely well tolerated; no grade 3 or 4 toxic effects were reported. Administration of alpha-
tocopherol resulted in both clinical and histologic responses in premalignant leukoplakia lesions. Abstract: PubMed
Benner SE et al; J Natl Cancer Inst 85 (1): 44-7 (1993)
 from HSDB
Ten control (healthy) subjects and 15 non-insulin dependent diabetics underwent an oral glucose tolerance test and a
euglycemic hyperinsulinemic glucose clamp before and after vitamin E supplementation (900 mg/d for 4 mo). In control
subjects (placebo treated vs vitamin E supplemented subjects, respectively) vitamin E reduced the area under the curve for
glucose (344 + or - 21 vs 287 + or - 13 mmol/l/min; P< 0.05) and increased total body glucose disposal (39.0 + or - 0.3 vs
47.6 + or - 0.4 umol/kg lean body mass/min; P< 0.05) and non-oxidative glucose metabolism (23.4 + or - 0.2 vs 30.8 + or -
0.3 umol/kg lean body mass/min; P< 0.05). In diabetics (placebo treated vs vitamin E-supplemented subjects, respectively)
vitamin E supplementation reduced glucose area under the curve (614 + or - 129 vs 544 + or - 98 mmol/l/min; P< 0.03) and
increased glucose disappearance (19.4 + or - 0.4 vs 26.4 + or - 0.7 umol/kg lean body mass/min; P< 0.03), total glucose
disposal (19.0 + or - 0.7 vs 28.1 + or - 0.4 umol/kg lean body mass/min; P< 0.02), and nonoxidative glucose metabolism (8.5
+ or - 0.3 vs 13.9 + or - 0.3 umol/kg lean body mass/min; P< 0.02). Administration of pharmacologic doses of vitamin E is a
useful tool to reduce oxidative stress and improve insulin action. Abstract: PubMed
Paolisso G et al; Am J Clin Nutr 57 (5): 650-6 (1993)
 from HSDB
Use of vitamin E in combination with vitamin A has been reported in the treatment of keratosis follicularis (Darier's disease),
pityriasis rubra pilaris, ichthyosis, and acne. /not included in the US product label/
 from HSDB
EXPL THER Diabetic pregnancy is still associated with an increased rate of congenital malformations despite extensive
clinical efforts to normalize the risk for the offspring. The etiology of the diabetic embryopathy is not clear; however,
experimental studies have suggested a role for oxidative stress in the teratogenicity of diabetic pregnancy. The antioxidants
alpha-tocopherol and ascorbate have improved fetal outcome in diabetic rodent pregnancy when supplemented in moderate
to high doses. In the present work we investigated if extremely high doses of either alpha-tocopherol or ascorbate may
further improve fetal outcome in offspring of diabetic rats, and, in addition, if such treatment may exert any adverse effects of
fetal development. Non-diabetic and streptozotocin diabetic female rats were fed 2, 5, 10 or 15 % alpha-tocopherol or 4, 10
or 15 % ascorbate in their diet and fetal outcome was assessed on gestational day 20. Maternal diabetes caused increased
malformation (from 0 to 29 %) and resorption (from 5 to 38 %) rates in the offspring. The malformations included
micrognathia (33 %), agnathia (51 %), other facial malformation (6 %), absence of tail (7 %) or omphalocele (3 %). Both
alpha-tocopherol and ascorbate treatment improved fetal morphology (to 9 and 19 % malformations, and to 9 and 26 %
resorptions, respectively) in offspring of diabetic rats. There was a dose-dependent improvement for the alpha-tocopherol
supplementation, where the higher doses diminished fetal dysmorphogenesis more than the 2 % diet. The ascorbate
supplementation was less dose-dependant, however, the higher doses tended to improve fetal outcome more than the lower
doses. No adverse effects of the antioxidants were noted in the offspring with the exception of one case of agnathia in a
fetus of a non-diabetic rat supplemented with 15 % alpha-tocopherol. These results indicate that very high doses of dietary
antioxidants may be needed to normalize the development of the offspring in experimental diabetic pregnancy, but that
treatment with such high doses may also have adverse effects in non-diabetic pregnancy.
Eriksson UJ Cederberg J; Diabetes 54 (Suppl 1): A38 (2005)
 from HSDB
EXPL THER Vitamin E is a dietary compound that functions as an antioxidant scavenging toxic free radicals. Evidence that
free radicals may contribute to the pathological processes of cognitive impairment including Alzheimer's disease has led to
interest in the use of vitamin E in the treatment of mild cognitive impairment (MCI) and Alzheimer's dementia (AD). To
assess the efficacy of vitamin E in the treatment of AD and prevention of progression of MCI to dementia. The Specialized
Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), The Cochrane Library, MEDLINE,
EMBASE, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources were searched on 25
June 2012 using the terms: "Vitamin E", vitamin-E, alpha-tocopherol. All unconfounded, double-blind, randomised trials in
which treatment with vitamin E at any dose was compared with placebo for patients with AD and MCI. Two review authors
independently applied the selection criteria and assessed study quality and extracted and analysed the data. For each
outcome measure data were sought on every patient randomised. Where such data were not available an analysis of
patients who completed treatment was conducted. It was not possible to pool data between studies owing to a lack of
comparable outcome measure. Only three studies met the inclusion criteria: two in an AD population and one in an MCI
population. In the first of the AD studies the authors reported some benefit from vitamin E (2000 IU/day) with fewer
participants reaching an end point of death, institutionalisation, change to a Clinical Dementia Rating (CDR) of three, or loss
of two basic activities of daily living within two years. Of patients completing treatment, 58% (45/77) on vitamin E compared
with 74% (58/78) on placebo reached one of the end points (odds ratio (OR) 0.49; 95% confidence interval (CI) 0.25 to
0.96). The second AD treatment study explored the effects of vitamin E (800 IU/day) on cognitive progression in relation to
oxidative stress levels. Patients whose oxidative stress markers were lowered by vitamin E showed no significant difference
in the percentage change in Mini-Mental State Examination (MMSE) score, between baseline and six months, compared to
the placebo group. The primary aim of the MCI study (Petersen 2005) was to investigate the effect of vitamin E (2000
IU/day) on the time to progression from MCI to possible or probable AD. A total of 214 of the 769 participants progressed to
dementia, with 212 being classified as having possible or probable AD. There was no significant difference in the probability
of progression from MCI to AD between the vitamin E group and the placebo group (hazard ratio 1.02; 95% CI 0.74 to 1.41;
P = 0.91). No convincing evidence that vitamin E is of benefit in the treatment of AD or MCI. Future trials assessing vitamin
E treatment in AD should not be restricted to alpha-tocopherol. Abstract: PubMed
Farina N et al; Cochrane Database Syst Rev. 11: CD002854 (2012)
 from HSDB
EXPL THER Vitamin E (VE) blended ultra-high molecular weight polyethylene (UHMWPE) has been developed in Japan as
a material for use in total knee replacement (TKR). Various results have demonstrated that VE blended UHMWPE reduces
the incidence of delamination failure and lowers the amount of wear produced during knee simulator testing. It was also
found that wear particles from VE blended UHMWPE elicited a reduced biological response compared to conventional
UHMWPE. A great deal of research concerning vitamin E (VE) stabilized ultrahigh molecular weight polyethylene
(UHMWPE) has focused on VE's effects as an antioxidant and its ability to prevent the oxidative degradation of UHMWPE
chains. However, other chemical and mechanical changes have been observed in VE blended UHMWPE that are unrelated
to the oxidative protection that VE provides. This paper provides a general review of VE blended UHMWPE, with a particular
focus on the non-antioxidant effects of VE. The potential application of VE blended UHMWPE in total hip replacement
(THR), along with the differences in loading conditions between the knee and the hip are also discussed. Abstract: PubMed
Turner A et al; J Mech Behav Biomed Mater. 31: 21-30 (2014)
 from HSDB
VET Vitamin E is used as supplement and as treatment of some immune-mediated dermatoses, and hepatobiliary disorders.
Vitamin E has been used as an oral treatment for discoid lupus in dogs; however, efficacy for many skin diseases has been
questioned.
Papich, M.G. Saunders Handbook of Veterinary Drugs Small and Large Animal. 3rd ed. St. Louis, MO: Elsevier Saunders, 2011, p. 807
 from HSDB
VET Supplemental vitamin E appears useful for treating retinal pigment ephitelial dystrophy with neuroaxonal degeneration
in English Cocker Spaniels (and presumably other breeds).
Papich, M.G. Saunders Handbook of Veterinary Drugs Small and Large Animal. 3rd ed. St. Louis, MO: Elsevier Saunders, 2011, p.
1489
 from HSDB
VET Vitamin E may be useful as adjunctive treatment of discoid lupus erythematosus, canine demodicosis, and acantosis
nigricans in dogs ... Vitamin E may also be of benefit in the adjunctive treatment of hepatic fibrosis or adjunctive therapy of
copper-associated hepatopathy in dogs.
Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 1488
 from HSDB
(VET) Retinal Pigment Epithelial Dystrophy (RPED) with neuroaxonal degeneration in English Cocker Spaniels (ECS) is
associated with systemic vitamin E deficiency in the absence of dietary insufficiency. To evaluate the ability of ECS with
RPED to absorb orally administered vitamin E and establish a basis for vitamin E supplementation in affected dogs. 8
RPED-affected ECS and five clinically normal dogs. An oral vitamin E tolerance test (OVETT) was conducted in each dog.
Blood samples were obtained prior to and at 3, 6, 9, 12, 24, 120, and 240 hr following oral administration of 90 iu/kg of RRR-
alpha-tocopherol. Plasma alpha tocopherol(aTOC) content was measured by normal phase, high-performance liquid
chromatography, and indices of vitamin E absorption calculated. There was marked variation in OVETT results between
individuals. In RPED-affected ECS, mean peak plasma aTOC concentration (17.87 +/- 13.21 ug/mL), attained after
administration of a large oral dose of the vitamin, was significantly lower than the mean peak plasma aTOC concentration
attained in normal dogs (47.61 +/- 17.17 ug/mL; P < 0.005). However, the plasma concentrations achieved in 7/8 RPED-
affected dogs remained within the normal reference range for plasma aTOC in vitamin E-replete dogs, for at least 12 hr
postdose. Vitamin E-deficient ECS with RPED are capable of absorbing orally administered vitamin E. Twice daily
administration of 600-900 iu tocopherol is likely to restore plasma vitamin E concentrations to the normal range in most
affected dogs. Abstract: PubMed
McLellan GJ, Bedford PG; Vet Ophthalmol. 15 Suppl 2: 48-56 (2012)

 from HSDB
7.2 Drug Warning 

Vitamin E in high doses (greater than 4000 IU) may increase the hypoprothrombinemic effects of oral anticoagulants.
 from HSDB
Vitamin E may impair the hematologic response to iron therapy in children with iron-defiiency anemia.
 from HSDB
FDA Pregnancy Risk Category: A CONTROLLED STUDIES SHOW NO RISK. Adequate, well controlled studies in pregnant
women have failed to demonstrate a risk to the fetus in any trimester of pregnancy.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 1020
 from HSDB
Vitamin E has not been shown to be teratogenic. There is no evidence that vitamin E requirements in pregnant women differ
from women who are not pregnant.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015
 from HSDB
Reports of toxicity to enterally administered vitamin E are rare in infants. However, increased risks of sepsis and necrotizing
enterocolitis have been reported after both enteral and parenteral vitamin E, primarily when plasma (or serum) vitamin E
levels exceed 3.5 mg/dL. Levels this high are seldom seen with enteral vitamin E when intake is 25 mg d-tocopherol
equivalent/(kg/day) or less. Intakes below this threshold will be provided by infant formulas with vitamin E to energy ratios of
up to 20 mg/100 kcal (30 IU/100 kcal) so long as energy intake does not exceed 125 kcal/(kg/day). Abstract: PubMed
Bell EF; J Nutr 119 (12 Suppl): 1829-31 (1989)
 from HSDB
Evaluations of the Joint FAO/WHO Expert Committee on Food Additives - JECFA: 1 of 1
8 Food Additives and Ingredients 

8.1 JECFA Functional Classes 
Food Additives: ANTIOXIDANT
 from FAO/WHO Food Additive Evaluations - JECFA
8.2 Evaluations of the Joint FAO/WHO Expert Committee on Food Additives -
JECFA 
Evaluations of the Joint FAO/WHO Expert Committee on Food Additives - JECFA: 1 of 1
Chemical Name dl-alpha-TOCOPHEROL
ADI 0.15-2 mg/kg bw
Evaluation Year 1986
Group ADI for dl-alpha-tocopherol and d-alpha-tocopherol concentrate, singly or in
combination. The lower value represents the daily dietary allowance recommended by
Comments
the USA National Academy of Sciences/National Research Council. The upper value
represents the maximum value for the ADI.
Report TRS 751-JECFA 30/18
 from FAO/WHO Food Additive Evaluations - JECFA

9 Pharmacology and Biochemistry 
9.1 Bionecessity 
Increased demand for vitamin E has also been observed in premature infants and patients with malabsorption, but there is
little evidence that the healthy population requires supplementation of vitamin E to a well balanced diet. Abstract: PubMed
Bjorneboe A et al; J Nutr 120 (3): 233-42 (1990)
 from HSDB
In poultry, vitamin E deficiency causes decreased hatchability of eggs because of embryonic death. Young chicks develop
an encephalomalacia and exudative diathesis.
Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press,
1982., p. 631
 from HSDB
Vitamin E is a fat soluble vitamin with actions related to its antioxidant properties. Vitamin E protects cellular constituents
from oxidation and prevents the formation of toxic oxidation products; it preserves red blood cell (RBC) wall integrity and
protects RBCs against hemolysis; it stimulates a cofactor in steroid metabolism; inhibits prostaglandin production; and
supresses platelet aggregation. In combination with selenium, vitamin E protects cell membranes from oxidative damage.
 from HSDB
Clinical deficiency of vitamin E is rare because adequate amounts are supplied in the normal diet. Symptoms of deficiency
include ataxia, muscle weakness, nystagmus, and losses in touch and pain sensations.
 from HSDB
Vitamin E deficiency in premature infants may result in hemolytic anemia, thrombocytosis, and increased platelet
aggregation.
 from HSDB
9.2 Absorption, Distribution and Excretion 

alpha-Tocopherol is absorbed via the lymphatic pathway and transported in association with chylomicrons. In plasma, alpha-
tocopherol is found in all lipoprotein fractions but mostly is associated with apo B containing lipoproteins. alpha-Tocopherol
is associated with very low density lipoprotein when it is secreted from the liver. In the rat, about 90% of total body mass of
alpha-tocopherol is recovered in the liver, skeletal muscle and adipose tissue. Most alpha-tocopherol is located in the
mitochondrial fractions and in the endoplasmic reticulum, whereas little is found in cytosol and peroxisomes. Abstract:
PubMed
Bjorneboe A et al; J Nutr 120 (3): 233-42 (1990)
 from HSDB
The level of retinal alpha-tocopherol of newborn rats could be altered by dietary manipulation of the mothers. The mothers
were fed diets containing either 1 g alpha-tocopherol acetate/kg food or none, starting 21-25 days before the birth of their
litters and lasting throughout the exposure period. This treatment resulted in three to fourfold differences in the retinal alpha-
tocopherol levels of the pups. The combination of dietary and oxygen treatments also resulted in significant differences in
retinal glutathione peroxidase activity, with the vitamin E deprived, oxygen exposed group having highest levels. Newborn
rats both supplemented with and deprived of alpha-tocopherol had less vasoobliteration than did those nursed by mothers
fed rat chow. Abstract: PubMed
Penn JS et al; Invest Ophthalmol Vis Sci 33 (6): 1836-45 (1992)
 from HSDB
Vitamin E is stored unmodified in tissues (principally the liver and adipose tissue) and excreted via the feces. Excess vitamin
E is converted to a lactone, esterified to glucuronic acid, and subsequently excreted in the urine.
 from HSDB
Vitamin E is 20% to 50% absorbed by intestinal epithelial cells in the small intestine. Bile and pancreatic juice are needed for
tocopherol absorption. Absorption is increased when administered with medium-chain triglycerides. Distribution to tissues
via the lymphatic system occurs as a lipoprotein complex. High concentrations of vitamin E are found in the adrenals,
pituitary, testes, and trombocytes.
 from HSDB
We determined the bioavailability of vitamin E from self-assembly structures in patients with diagnosed chronic pancreas
insufficiency. Vitamin E solubilized in dispersed inverted bicontinuous cubic phase and in micellar formulation was delivered
directly to the small intestine by tube-feeding. A cross-over study with randomization of 6 subjects and 2 treatments including
a combined dose of 18 mg (27 IU) of vitamin E (RRR-[5,7-methyl-((2)H6)]-alpha-tocopherol) and 27 mg (27 IU) vitamin E
acetate (RRR-[5-methyl-(2)H3]-alpha-tocopheryl acetate) was applied over a time period of 1 hr. Plasma samples were
collected for 56 hr and analyzed by liquid chromatography-mass spectrometry. Appearance of labeled tocopherols
originating from the treatment started at 25 hr and reached Cmax (0.6-4.6 uM depending on subject) in the 7-9 hr window.
From the Tmax onwards, both forms of tocopherols diminished slowly to 30-50% of their maxima within 56 hr. Strong inter-
individual variation was observed in the plasma appearance curves (relative standard deviation varied between 38-45%). No
significant discrimination was found between the absorption of free or acetylated forms of deuterated alpha-tocopherol
confirming that application of acetylated alpha-tocopherolprovides the same bioavailability as free alpha-tocopherol. This
observation is valid in both dispersed inverted bicontinuous cubic phase and micellar formulations. Furthermore, since the
area-under-the-curve values from cubic phase and from micellar formulations are similar, the cubic phase formulation could
represent an alternative delivery system for lipophilic micronutrients in conditions or studies where polysorbate-based
micelles cannot be generated. Abstract: PubMed
Nagy K et al; Chimia (Aarau). 68 (3): 129-34 (2014)
 from HSDB
The aim of this study was to characterize the pathways of basolateral secretion of common dietary tocopherols from
polarized Caco-2 monolayers, a model of intestinal absorption. Given differences in structure and physical properties, we
hypothesized that secretion may differ between different forms of vitamin E, thus potentially contribute to the selectivity seen
in vivo. Monolayers were incubated apically and simultaneously with 10 umol/L alpha-, gamma-, and delta-tocopherol (1:1:1)
in lipid micelles. Treatment with the microsomal triglyceride transfer protein inhibitor BMS201038 revealed that the
triglyceride-rich particle secretory pathway (apolipoprotein B-dependent pathway) accounted for ~ 80% of total tocopherol
secretion, without selectivity among the three forms of vitamin E. Apolipoprotein B-independent secretion of tocopherols
(and cholesterol) was greatly enhanced by the liver X receptor agonist T0901317. T0901317 induced ATP-binding cassette
transporter A1 (ABCA1) protein expression and basolateral secretion of tocopherols to apolipoprotein A1. ABCA1-dependent
secretion demonstrated vitamer selectivity such that efficiency of secretion of alpha- and gamma-tocopherols exceeded that
of delta-tocopherol. Basal addition of HDL stimulated vitamin E secretion but without selectivity among the three forms,
whereas LDL had no effect. Basal addition of scavenger receptor class B member I (SR-BI) blocking antibody, which inhibits
the interaction between SR-BI and HDL, increased basal accumulation of all tocopherols, demonstrating a role for SR-BI in
cellular re-uptake of secreted vitamin E. These findings demonstrated that vitamin E and cholesterol utilize common
pathways of secretion and that secretion via the ABCA1 pathway favors certain forms of vitamin E.[Nicod N, Parker RS; J
Nutr. 143 (10): 1565-72 (2013)] Full text: PMC3771812 Abstract: PubMed
 from HSDB
Kinetic models enable nutrient needs and kinetic behaviors to be quantified and provide mechanistic insights into
metabolism. Therefore, we modeled and quantified the kinetics, bioavailability, and metabolism of RRR-alpha-tocopherol in
12 healthy adults. Six men and 6 women, aged 27 +/- 6 y, each ingested 1.81 nmol of [5(-14)CH(3)]-(2R, 4'R, 8'R)-alpha-
tocopherol; each dose had 3.70 kBq of (14)C. Complete collections of urine and feces were made over the first 21 d from
dosing. Serial blood samples were drawn over the first 70 d from dosing. All specimens were analyzed for RRR-alpha-
tocopherol. Specimens were also analyzed for (14)C using accelerator MS. From these data, we modeled and quantified the
kinetics of RRR-alpha-tocopherol in vivo in humans. The model had 11 compartments, 3 delay compartments, and
reservoirs for urine and feces. Bioavailability of RRR-alpha-tocopherolwas 81 +/- 1%. The model estimated residence time
and half-life of the slowest turning-over compartment of ?-tocopherol(adipose tissue) at 499 +/- 702 d and 184 +/- 48 d,
respectively. The total body store of RRR-?-tocopherol was 25,900 +/- 6=220 umol (11 +/- 3 g) and we calculated the
adipose tissue level to be 1.53 umol/g (657 ug/g). We found that a daily intake of 9.2 umol (4 mg) of RRR-alpha-tocopherol
maintained plasma RRR-alpha-tocopherol concentrations at 23 umol/L. These findings suggest that the dietary requirement
for vitamin E may be less than that currently recommended and these results will be important for future updates of intake
recommendations.[Novotny JA et al; J Nutr. 142 (12): 2105-11 (2012)] Full text: PMC3497961 Abstract: PubMed
 from HSDB
Vitamin E isoforms are essential nutrients that are widely used as dietary supplements and therapeutic agents for a variety
of diseases. However, their pharmacokinetic (PK) properties remain poorly characterized, and high dosage animal studies
may provide further information on their in vivo functions and pharmacological effects. In this study, alpha-tocopherol (a-toc)
and delta-tocopherol (d-toc) levels were measured in mouse plasma and tissues following their high dosage dietary
supplementation. Average a-toc levels at 5, 10 and 20 g a-toc/kg diet increased over baseline levels 6-fold in plasma, 1.6-
fold in brain, and 4.9-fold in liver. These elevated a-toc concentrations remained constant from 5 to 20 g a-toc/kg diet, rather
than showing further increases across these dosages. No a-toc-related toxicity occurred at these high dosages, and strain-
specific differences in liver and brain a-toc levels between Balb/cJ and C57Bl/6J mice were observed. Relatively high-
dosage administration of dietary d-toc for 1 or 4 weeks resulted in 6-30-fold increases in plasma and liver levels between
dosages of 0.33 and 1.67 g d-toc/kg diet. Co-administration of sesamin with d-toc further increased d-toc levels between
1.3- and 14-fold in plasma, liver, and brain. These results provide valuable PK information on high dosage a-toc and d-toc in
mouse and show that supplementation of sesamin with d-toc further increases d-toc levels over those seen with d-toc
supplementation alone.[Baxter LL et al; Nutrients. 4 (6): 467-90 (2012)] Full text: PMC3397347 Abstract: PubMed
 from HSDB
To investigate the ability of alpha-tocopherol acetate (TA) and alpha-tocopherol (T), widely used ingredients in cosmetics, to
cross the epidermal barrier using the neonatal rat as a model. The content of T and TA in four marketed products (A-D) and
two experimental formulations (F1, F2) was investigated by HPLC. An in vitro permeation study was performed in neonatal
rat epidermis using diffusion cells. In vivo permeation was studied in neonatal rats after repeated application of the products
and analysis of T and TA in the stratum corneum/deeper skin layers. Variable contents of TA were found in the marketed
products (0.12-0.53%). No vitamin permeation was detected through the stratum corneum as in vitro biological barrier after
4 hr. No detectable T and TA were seen in the in vivo permeation study in the epidermis. Variable degrees of drug
penetration (4.3-12.6%) of the applied dose into the deeper skin layers were observed, depending on the formulation. In vivo
application of TA-containing preparations did not result in any transformation of TA into T under the described experimental
conditions. TA and T exhibited variable skin penetration and TA did not transform into T under the experimental conditions.
The data underscored the need for further studies to optimize such formulations to improve vitamin E transdermal
permeation and eventually achieve the expected cosmetic/therapeutic outcome. Abstract: PubMed
Nada A et al; Med Princ Pract 20 (6): 509-13 (2011)
 from HSDB
Relative vitamin E status of pigs fed natural or synthetic vitamin E was evaluated based on serum and tissue alpha-
tocopherol concentrations. Individually fed finishing gilts at a BW of 70.5 kg (n = 24) were allotted to dietary treatments
based on initial BW. The 5 dietary treatments consisted of a positive control diet using synthetic vitamin E acetate (Syn E
Ac) supplemented at 22 mg/kg, and 4 dietary levels of natural vitamin E acetate (Nat E Ac) supplemented at 6.71, 8.33,
11.00, and 16.18 mg/kg of diet. Before initiation of the 32-d experiment, pigs were fed a non-vitamin E-fortified diet for 30 d.
Diets were formulated to contain true ileal digestible lysine of 0.9 and 0.8% for the pretest and test diets. Serum samples
were collected on d 15 and 32, whereas tissue samples were collected on d 32 for alpha-tocopherol analysis. Serum alpha-
tocopherol concentrations on d 15 and 32 were greater (P < 0.05) in pigs fed 8.33, 11.00, or 16.18 mg/kg of Nat E Ac than in
pigs fed 22 mg/kg of Syn E Ac. When compared with pigs fed 22 mg/kg of Syn E Ac, alpha-tocopherol concentrations were
greater (P < 0.05) in 6 tissues (heart, kidney, spleen, liver, lung, and adipose) in pigs fed 16.18 mg/kg of Nat E Ac; greater (P
< 0.05) in heart, kidney, spleen, liver, and adipose tissue in pigs fed 11.00 mg/kg of Nat E Ac; and greater (P < 0.05) in
spleen, loin, and adipose tissue in pigs fed 8.33 mg/kg of Nat E Ac. As dietary Nat E Ac increased from 6.71 to 16.18 mg/kg,
serum alpha-tocopherol increased linearly (P < 0.01) on d 15 and 32 of the experiment. Increasing dietary Nat E Ac linearly
increased (P < 0.05) alpha-tocopherol concentrations for lung, heart, kidney, spleen, and liver. These results indicate that
Nat E Ac was an effective vitamin E source and its relative bioavailability was substantially greater than 1.36 for finishing
swine when compared with Syn E Ac. Abstract: PubMed
Yang H et al; J Anim Sci 87 (12): 4057-63 (2009)
 from HSDB
There are several reports in the literature on the relative bioavailabilities of RRR (natural) vs. all-rac (synthetic) forms of
vitamin E in humans and animal models but none on the bioavailability of alpha-tocopherol in mixed vitamin E formulations.
In the present study we examined the bioavailability of alpha-tocopherol in a typical commercially available product
containing mixed tocopherols. We also tested a formulation containing all-rac-alpha-tocopherol with mixed tocopherols for
purposes of comparison along with straight RRR- and all-rac-alpha-tocopheryl acetate as reference products. Normal male
subjects were given one of the four formulations of vitamin E (800 IU per day in softgel capsule form for 10 days): 1. All-rac-
alpha-tocopheryl acetate, 2. RRR-alpha-tocopheryl acetate, 3. RRR-alpha-tocopherol with mixed tocopherols, and 4. all-rac-
alpha-tocopherol with mixed tocopherols. Both serum alpha- and gamma-tocopherols were determined by HPLC at baseline,
and at days 2, 4, 7 and 10. The values for alpha- at baseline and 10 days were 0.80, 0.80, 0.80 & 0.79 mg/dl and 1.67, 1.72,
1.76 & 1.62 mg/dl. The values for gamma- were 0.28, 0.29, 0.30 & 0.29 mg/dL and 0.11, 0.08, 0.10 & 0.10 mg/dL. Thus the
data show that a) the bioavailability of RRR- and all-rac-alpha-tocopherols is not affected by other tocopherols, and b) both
RRR- and all-rac-alpha-tocopherol (free or esterified) significantly suppress the serum gamma tocopherol to the same
extent. Furthermore, since there was no difference in the serum values of alpha-tocopherol between RRR- and all-rac-
vitamin E given the same dose as IUs, the data also support the currently accepted ratio of 1.36 for the biopotency of RRR-
vs. all-rac-alpha-tocopheryl acetate. Abstract: PubMed
Chopra RK, Bhagavan HN; Int J Vitam Nutr Res. 69 (2): 92-5 (1999)
 from HSDB
9.3 Metabolism/Metabolites 
Vitamin E is stored unmodified in tissues (principally the liver and adipose tissue) and excreted via the feces. Excess vitamin
E is converted to a lactone, esterified to glucuronic acid, and subsequently excreted in the urine.
 from HSDB
Alpha-tocopherol (Vitamin E), formed from homogentisic acid yields, in rabbits 4-hydroxy-4-methyl-6-(2,4,5-trimethyl-3,6-
quinonyl)caproic acid ...
Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. T-15
 from HSDB
Vitamin E is likely the most important antioxidant in the human diet and alpha-tocopherol is the most active isomer. Alpha-
tocopherol exhibits anti-oxidative capacity in vitro, and inhibits oxidation of ldl. Beside this, alpha-tocopherol shows anti-
inflammatory activity and modulates expression of proteins involved in uptake, transport and degradation of tocopherols, as
well as the uptake, storage and export of lipids such as cholesterol. Despite promising anti-atherogenic features in vitro,
vitamin E failed to be atheroprotective in clinical trials in humans. Recent studies highlight the importance of long-chain
metabolites of alpha-tocopherol, which are formed as catabolic intermediate products in the liver and occur in human
plasma. These metabolites modulate inflammatory processes and macrophage foam cell formation via mechanisms
different than that of their metabolic precursor alpha-tocopherol and at lower concentrations. Here we summarize the
controversial role of vitamin E as a preventive agent against atherosclerosis and point the attention to recent findings that
highlight a role of these long-chain metabolites of vitamin E as a proposed new class of regulatory metabolites. We
speculate that the metabolites contribute to physiological as well as pathophysiological processes.[Wallert M et al; Redox
Biol. 2: 495-503 (2014)] Full text: PMC3949092 Abstract: PubMed
 from HSDB
9.4 Biological Half-Life 

Little is known about alpha-tocopherol's bioavailability as a constituent of food or its dependence on a subject's age. To
evaluate the alpha-tocopherol bioavailability from food, we used collard greens grown in deuterated water ((2)H collard
greens) as a source of deuterium-labeled ((2)H) alpha-tocopherol consumed by younger and older adults in a post hoc
analysis of a vitamin K study. Younger (mean +/- SD age: 32 +/- 7 y; n = 12 women and 9 men) and older (aged 67 +/- 8 y; n
= 8 women and 12 men) adults consumed a test breakfast that included 120 g (2)H collard greens (1.2 +/- 0.1 mg (2)H-
alpha-tocopherol). Plasma unlabeled alpha-tocopherol and (2)H-alpha-tocopherol were measured by using liquid
chromatography-mass spectrometry from fasting (>12 hr) blood samples drawn before breakfast (0 hr) and at 24, 48, and 72
hr and from postprandial samples collected at 4, 5, 6, 7, 9, 12, and 16 hr. Times (12.6 +/- 2.5 h) of maximum plasma (2)H-
alpha-tocopherol concentrations (0.82% +/- 0.59% total alpha-tocopherol), fractional disappearance rates (0.63 +/- 0.26
pools/d), half-lives (30 +/- 11 hr), and the minimum estimated (2)H-alpha-tocopherolabsorbed (24% +/- 16%) did not vary
between age groups or sexes (n = 41). Unlabeled alpha-tocopherol concentrations were higher in older adults (26.4 +/- 8.6
umol/L) than in younger adults (19.3 +/- 4.2 umol/L; P = 0.0019) and correlated with serum lipids (r = 0.4938, P = 0.0012). In
addition, (2)H-alpha-tocopherol half-lives were correlated with lipids (r = 0.4361, P = 0.0044). Paradoxically, alpha-
tocopherol remained in circulation longer in participants with higher serum lipids, but the (2)H-alpha-tocopherol absorbed
was not dependent on the plasma lipid status. Neither variable was dependent on age. These data suggest that plasma
alpha-tocopherol concentrations are more dependent on mechanisms that control circulating lipids rather than those related
to its absorption and initial incorporation into plasma.[Traber MG et al; Am J Clin Nutr. 101 (4): 752-9 (2015)] Full text:
PMC4381779 Abstract: PubMed

 from HSDB
9.5 Mechanism of Action 

Cancer development and progression are closely associated with inflammation. NF-kappaB (nuclear factor kappaB)
provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of malignant cells
to resist tumor surveillance mechanisms. NF-kappaB might also regulate tumor angiogenesis and invasiveness and the
signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic
approaches. ROS (reactive oxygen species) initiate inflammation by up-regulation of pro-inflammatory cytokines and
therefore antioxidants provide a major defence against inflammation. alpha-Tocopherol is a lipid-soluble antioxidant. In
addition to decreasing lipid peroxidation, alpha-tocopherol may exert intracellular effects. Hence, the aim of this study was to
test the effect of alpha-tocopherol supplementation in cancer prevention via suppression of NF-kappaB-mediated pro-
inflammatory cytokines. alpha-Tocopherol treatment significantly down-regulates expression, synthesis as well as secretion
of pro-inflammatory cytokine IL-6 (interleukin-6) in cancerous mice. It also suppresses NF-kappaB binding to IL-6 promoter in
liver leading to decreased secretion of IL-6 in serum. The regulation of the signalling pathway by alpha-tocopherol is found
apart from its antioxidant capacity to reduce lipid peroxidation. Thus, the present study provides evidence for the hypothesis
that besides the powerful free radical scavenging effects, alpha-tocopherol has genomic effects in down-regulation of pro-
inflammatory cytokine and cancer prevention via the NF-kappaB-dependent pathway. Abstract: PubMed
Sharma R, Vinayak M; Biosci Rep. 31 (5): 421-8 (2011)
 from HSDB
Mitocans are drugs selectively killing cancer cells by destabilizing mitochondria and many induce apoptosis via generation of
reactive oxygen species (ROS). However, the molecular events by which ROS production leads to apoptosis has not been
clearly defined. In this study with the mitocan alpha-tocopheryl succinate (alpha-TOS) the role of the Bcl-2 family proteins in
the mechanism of malignant cell apoptosis has been determined. Exposure of several different cancer cell lines to alpha-
TOS increased expression of the Noxa protein, but none of the other proteins of the Bcl-2 family, an event that was
independent of the cellular p53 status. alpha-TOS caused a profound conformational change in the pro-apoptotic protein,
Bak, involving oligomerization in all cell types, and this also applied to the Bax protein, but only in non-small cell lung cancer
cells. Immunoprecipitation studies indicated that alpha-TOS activates the two BH1-3 proteins, Bak or Bax, to form high
molecular weight complexes in the mitochondria. RNAi knockdown revealed that Noxa and Bak are required for alpha-TOS-
induced apoptosis, and the role of Bak was confirmed using Bak- and/or Bax-deficient cells. We conclude that the major
events induced by alpha-TOS in cancer cells downstream of ROS production leading to mitochondrial apoptosis involve the
Noxa-Bak axis. It is proposed that this represents a common mechanism for mitochondrial destabilization activated by a
variety of mitocans that induce accumulation of ROS in the early phases of apoptosis. /alpha-Tocopheryl succinate /
Abstract: PubMed
Prochazka L et al; Apoptosis. 15 (7): 782-94 (2010)
 from HSDB
10 Use and Manufacturing 
10.1 Methods of Manufacturing 
... Obtained by vacuum steam distillation of edible vegetable oil products.
21 CFR 184.1890 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available
from, as of June 3, 2015: http://www.ecfr.gov
 from HSDB
Isolation from wheat germ.
 from HSDB
The industrial total synthesis of alpha-tocopherol is based on the condensation of 2,3,6-trimethylhydroquinone with phytol,
phytyl halides, or preferentially isophytol. Lewis and Bronsted acids, especially zinc chloride with a mineral acid, serve as
catalysts for condensation. Boron trifluoride and AlCl3, Fe/HCl, trifluoracetic acid, and boric acid/carboxylic acid are also
good catalysts. A wide range of solvents can be used, e.g., ethyl acetate, acetic acid, (chlorinated) hydrocarbons or
supercritical CO2. When synthetic phytol or isophytol is used, the product consists of equal amounts of all eight alpha-
tocopherol stereoisomers and is thus denominated (all-rac)-alpha-tocopherol. The majority of synthetic alpha-tocopherol is
treated with acetic anhydride to give the acetate, which is stable on storage. In addition, the succinate (monoester of
succinic acid) and the nicotinate are produced commercially. Purification of the crude product is possible at the free
tocopherol or acetate stage by short-path distillation under high vacuum or extraction with supercritical CO2.
Baldenius K-U et al.; Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-
2015). NY, NY: John Wiley & Sons. Online Posting Date: October 15, 2011
 from HSDB
... the commercially significant form of tocopherol is all-rac-alpha-tocopheryl acetate. ... /Commercial/ processes utilize a
Friedel-Crafts-type condensation of 2,3,5-trimethylhydroquinone with either phytol, a phytyl halide, or phytadiene. The
principal synthesis in current commercial use involves condensation of 2,3,5-trimethylhydroquinone with synthetic isophytol
in an inert solvent, such as benzene or hexane, with an acid catalyst, such as zinc chloride, boron trifluoride, or orthoboric
acid/oxalic acid to give the all-rac-a-tocopherol. Free tocopherol is protected as its acetate ester by reaction with acetic
anhydride. Purification of tocopheryl acetate is readily accomplished by high vacuum molecular distillation and rectification
(equation image) to achieve the required USP standard.
Casani R; Vitamin E; Kirk-Othmer Encyclopedia of Chemical Technology (1999-2015). John Wiley & Sons, Inc. Online Posting Date:
December 4, 2000
 from HSDB
The most important natural sources of vitamin E are plant oils and fats. The deodorization of edible oils yields as a
byproduct deodorizer sludges which contain tocopherols in economically interesting concentrations (3-15%). ... Various
processes are available for the purification of tocopherols. The fatty acids can be extracted and separated in the form of
sparingly soluble calcium salts. Alternatively, they can be eliminated by distillation, preferably after esterification. The sterols
can be separated by treatment with hydrogen chloride or CaCl2, by crystallization, or by extraction. Alternatively, the free
sterols can be esterified with the excess fatty acids, and the tocopherols can be separated from the high-boiling sterol fatty
acid esters by distillation. After removal of the free fatty acids, the tocopherols can be concentrated by adsorption on basic
ion exchangers.
Baldenius K-U et al.; Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-
2015). NY, NY: John Wiley & Sons. Online Posting Date: October 15, 2011
 from HSDB
10.2 Formulations/Preparations 
MIXED TOCOPHEROLS
PDR for Nutritional Supplements 2nd ed. Thomson Reuters, Montvale, NJ 2008, p. 699
 from HSDB
D-ALPHA-TOCOPHERYL SUCCINATE ; d-Alpha-tocopheryl succinate is available as a stand-alone supplement and in
combination vitamin preparations. Since the succinate group protects the hydroxyl group of the chromanol ring against
oxidation, it is a more stable form than d-alpha-tocopherol, the free or unesterified form.
 from HSDB
D-ALPHA-TOCOPHERYL ACETATE ; d-Alpha-tocopheryl acetate is available as a stand-alone supplement and in
multivitamin preparations. Since the acetate group protects the hydroxyl group of the chromanol ring against oxidation, it is a
more stable form than d-alpha-tocopherol, the free or unesterified form.
 from HSDB
D-ALPHA-TOCOPHEROL ; d-Alpha-tocopherol is available as a stand-alone supplement and in the form of mixed
tocopherols. d-Alpha-tocopherol is unesterified and thus much more susceptible to oxidation.
 from HSDB
10.3 Consumption 
Almost 100% by itself in prevention & treatment of vitamin E deficiency (1973).
SRI
 from HSDB
10.4 U.S. Production 

(1972) 1.32X10+9 G (1972) 1.32X10+9 G
SRI
 from HSDB
(1975) 9.87X10+8 G
SRI
 from HSDB
(1984) 5.28X10+9 g
USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.98
 from HSDB
(1986) >1 million-10 million pounds
US EPA; Non-confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986-2002 Inventory
Update Rule (IUR). Vitamin E (59-02-9). Available from, as of May 17, 2006: http://www.epa.gov/oppt/iur/tools/data/2002-vol.html
 from HSDB
 from HSDB

 from HSDB
2H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-, (2R)- is listed as a High
Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1
million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710
subpart B; 51FR21438).[EPA/Office of Pollution Prevention and Toxics; High Production Volume (HPV) Challenge Program.
2H-1-Benzopyran-6-ol, 3,4-dihydro-2,5,7,8-tetramethyl-2-
(4R,8R)-4,8,12-trimethyltridecyl]-, (2R)- (59-02-9). Available from, as of June 9, 2015:
http://www.epa.gov/hpv/pubs/general/opptsrch.htm
 from HSDB
10.5 U.S. Imports 

(1975) 2.35X10+8 G (PRINCPL CUSTMS DISTS)
SRI
 from HSDB
(1984) 1.02X10+9 g /Vitamin E (DL-Alpha-Tocopherol and its Esters/
BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-343
 from HSDB
10.6 U.S. Exports 

(1984) 5.68X10+8 g /bulk/
BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-100
 from HSDB
11 Identification 
11.1 Analytic Laboratory Methods 
Method: AOAC 975.43; Procedure: polarimetric method; Analyte: alpha-tocopherol; Matrix: pharmaceutical preparations and
food or feed supplements; Detection Limit: not provided.
Horwitz W, ed.; Official Methods of Analysis of AOAC International 17th ed. (2003). CD-ROM, AOAC International, Gaithersburg, MD
 from HSDB
... Methods of quant assay of vit e depend either directly or indirectly upon ease with which free alpha tocopherol is oxidized
... (1) formation of red orthoquinone by treatment ... with concn nitric acid & (2) reduction of ferric chloride in presence of
alpha-alpha'-dipyridyl ... forms red-colored complex with ferrous ions.
1975., p. 942
 from HSDB
Method: AOAC 971.30; Procedure: colorimetric method; Analyte: alpha-tocopherol and alpha-tocopherol acetate; Matrix:
food and feeds; Detection Limit: not provided.
 from HSDB
HPLC of vitamin e. Other methods in current use for assay of vit E are reversed phase for routine anal & straight phase on
silica gel if intention is to separate all forms of vit E. Abstract: PubMed
ERIKSSON T, SORENSEN B; ACTA PHARM SUEC 14 (5-6): 475-84 (1977)
 from HSDB
Method: AOAC 969.40; Procedure: gas chromatography; Analyte: vitamin e; Matrix: drugs; Detection Limit: not provided.
 from HSDB
Determination of vitamin E using a GC equipped with a FID.
USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial
Convention, Inc., 1990., p. 1452
 from HSDB
Two dimensional spectral analysis (COSY, HETCOR) was utilized to make the complete (13)C and H-Nuclear magnetic
resonance assignments for alpha, beta, tau, and delta-tocopherol as well as for the acetate and succinate esters of alpha-
tocopherol. (13)C nuclear magnetic resonance was especially useful in distinguishing between the various tocopherols and
distinguishing between the d-isomer and the dl-racemic mixture. HETCOR spectra were also found to be useful for the
qualitative identification of mixtures of the tocopherols and sesame oil. Using a procedure designed to minimize errors
arising from spin relaxation and nuclear Overhauser effects, (13)C nuclear magnetic resonance peak integrals were used to
quantitate alpha-tocopherol and delta-tocopherol in the presence of sesame oil using benzoic acid as the standard of
calibration of the quantitation. The nuclear magnetic resonance results were compared to a capillary column GC analysis of
the individual alpha-tocopherol and delta-tocopherol reference materials. Abstract: PubMed
Baker JK, Myers CW; Pharm Res 8 (6): 763-70 (1991)
 from HSDB
The results of the analysis of several derivatives of (all-racemic)-alpha-tocopherol by HPLC on a chiral stationary phase and
by capillary GC on a chiral stationary phase are reported. Consecutive application of both methods to the ethyl ether
derivatives allows the separation and quantification of all 8 possible stereoisomers of (all-racemic)-alpha-tocopherol.
Vecchi M et al; Helv Chim Acta 73 (4): 782-9 (1990)
 from HSDB
A description is given for the analysis of vitamin A and E acetates in cosmetics by 2nd-derivative UV/visible
spectrophotometry. The determinations are carried out on an emulsified cosmetic form previously solubilized in
tetrahydrofluoride. The procedure is highly sensitive and allows the cmpd to be determined singly or together.
Galiano F et al; Cosmet Toiletries Ed Ital 11 (1): 27-32, 34 (1990)
 from HSDB
Analyte: vitamin E; matrix: chemical identification; procedure: preparation in dehydrated alcohol; addition of nitric acid and
heat; formation of a bright red or orange color
U.S. Pharmacopeia. The United States Pharmacopeia, USP 29/The National Formulary, NF 24; Rockville, MD: U.S. Pharmacopeial
Convention, Inc., p2258 (2006)
 from HSDB
Analyte: vitamin E; matrix: chemical identification; procedure: determination of the optical rotation
 from HSDB
Analyte: vitamin E; matrix: chemical identification; procedure: retention time of gas chromatogram with comparison to
standards
 from HSDB
Analyte: vitamin E; matrix: chemical purity; procedure: gas chromatography with flame-ionization detection and comparison
to standards
 from HSDB
Analyte: vitamin E; matrix: pharmaceutical preparation (solid or liquid preparation; capsule); procedure: preparation in
dehydrated alcohol; addition of nitric acid and heat; formation of a bright red or orange color (chemical identification)
 from HSDB
Analyte: vitamin E; matrix: pharmaceutical preparation (solid or liquid preparation; capsule); procedure: determination of the
optical rotation (chemical identification)
 from HSDB
Analyte: vitamin E; matrix: pharmaceutical preparation (solid or liquid preparation; capsule); procedure: retention time of gas
chromatogram with comparison to standards (chemical identification)
 from HSDB
Analyte: vitamin E; matrix: pharmaceutical preparation (solid or liquid preparation; capsule); procedure: gas chromatography
with flame-ionization detection and comparison to standards (chemical purity)
 from HSDB
Analyte: vitamin E; matrix: solution; procedure: reversed-phase high-performance liquid chromatography with ultraviolet
detection at 330 nm
Jedrzejewski RT, Taylor, LT; J Chromatogr Sci 33: 438-445 (1995). As cited in: Lunn G, Schmuff N; HPLC Methods for Pharmaceutical
Analysis. New York, NY: John Wiley & Sons, 1997., p.230
 from HSDB
Analyte: vitamin E; matrix: food (cheese); procedure: high-performance liquid chromatography with fluorescence detection;
limit of detection: 0.90 ng
Panfili G et al; Analyst 119: 1161-1165 (1994). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New
York, NY: John Wiley & Sons, 2000., p.1730
 from HSDB
Analyte: vitamin E; matrix: food (broccoli, infant formula, margarine); procedure: high-performance liquid chromatography
with fluorescence detection; limit of detection: 100 ng/mL
Konings EJM et al; J AOAC Int 79: 902-906 (1996). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
New York, NY: John Wiley & Sons, 2000., p.1731
 from HSDB
Analyte: vitamin E; matrix: food (cheese); procedure: high-performance liquid chromatography with fluorescence detection;
limit of detection: 500-900 pg
Manzi R et al; Chromatographia 43: 89-91 (1996). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New
 from HSDB
Analyte: vitamin E; matrix: food (infant formula); procedure: high-performance liquid chromatography with fluorescence
detection; limit of detection: 3.14 ng/mL
Chase GW Jr et al; J Liq Chromatogr Rel Technol 20: 3317-3327 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical
Analysis. Volumes 2-4. New York, NY: John Wiley & Sons, 2000., p.1732
 from HSDB
Analyte: vitamin E; matrix: food (soy-based infant formula); procedure: high-performance liquid chromatography with
fluorescence detection
Chase GW Jr et al; J AOAC Int 81: 577-581 (1998). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: pharmaceutical preparation (cream, lotion); procedure: high-performance liquid chromatography
with ultraviolet detection at 280 nm
Scalia S et al; J Pharm Biomed Anal 13: 273-277 (1995). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-
4. New York, NY: John Wiley & Sons, 2000., p.1733
 from HSDB
Analyte: vitamin E; matrix: pharmaceutical preparation (tablet); procedure: high-performance liquid chromatography with
ultraviolet detection at 280 nm
Scalia S et al; J Pharm Sci 84: 433-436 (1995). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New
 from HSDB
Analyte: vitamin E; matrix: food (margarine, spread); procedure: high-performance liquid chromatography with fluorescence
detection; limit of detection: 232 ng/g
Ye L et al; J Liq Chromatogr Rel Technol 21: 1227-1238 (1998). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis.
Volumes 2-4. New York, NY: John Wiley & Sons, 2000., p.1736
 from HSDB
Analyte: vitamin E; matrix: milk; procedure: high-performance liquid chromatography with ultraviolet detection at 250 nm
Gong BY, Ho JW; J Liq Chromatogr Rel Technol 20: 2389-2397 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical
 from HSDB
Analyte: vitamin E; matrix: milk; procedure: high-performance liquid chromatography with ultraviolet detection at 323 and
292 nm; limit of detection: 300 ng/mL
Albala-Hurtado S et al; J Chromatogr A 778: 243-246 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis.
 from HSDB
Analyte: vitamin E; matrix: milk; procedure: high-performance liquid chromatography with electrochemical detection; limit of
detection: 0.19 ng
Delgado-Zamarreno MM et al; Analyst 120: 2489-2492 (1995). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis.
 from HSDB
Analyte: vitamin E; matrix: milk; procedure: high-performance liquid chromatography with electrochemical detection; limit of
detection: 311 nM
Delgado-Zamarrefio MM et al; J Chromatogr A 694: 399-406 (1995). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis.
 from HSDB
Analyte: vitamin E; matrix: ophthalmic silicone oil; procedure: high-performance liquid chromatography with ultraviolet
detection at 210 nm; limit of detection: 604.9 ng/mL
Del Nozal MJ et al; J Liq Chromatogr Rel Technol 19: 1151-1167 (1996). As cited in: Lunn G; HPLC Methods for Pharmaceutical
 from HSDB
11.2 Clinical Laboratory Methods 

Measurement of vitamin E in serum and plasma by HPLC with electrochemical detection. Abstract: PubMed
Castle MC, Cooke WJ; Ther Drug Monit 7: 364-8 (1985)
 from HSDB
Analyte: vitamin E; matrix: blood (serum); procedure: high-performance liquid chromatography with fluorescence detection;
limit of detection: 50 ng/mL
Moriyama H et al; J Chromatogr A 798: 125-130 (1998). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-
 from HSDB
Analyte: vitamin E; matrix: blood (erythrocyte); procedure: high-performance liquid chromatography with ultraviolet detection
at 282 nm
Bonina R et al; Pharm Res 13: 1343-1347 (1996). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New
 from HSDB
Analyte: vitamin E; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at
292 nm
Lane JR et al; J Chromatogr A 787: 111-118 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: blood (serum); procedure: high-performance liquid chromatography with ultraviolet detection at
292 nm; limit of detection: 50 ng/mL
Steghens JR et al; J Chromatogr B 694: 71-81 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: blood (plasma, serum); procedure: high-performance liquid chromatography with ultraviolet
detection at 292 nm
Kaplan LA et al; Methods Enzymol 189: 155-167 (1990). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-
 from HSDB
325, 295, and 450 nm or electrochemical detection; limit of detection: 96 ug/mL (UV), 650 ng/mL (E)
MacCrehan WA; Methods Enzymol 189: 172-181 (1990). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-
 from HSDB
325, 291, and 450 nm; limit of detection: 180 nM
Arnaud J et al; J Chromatogr 572: 103-116 (1991). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at
290 nm
Khachik R et al; Anal Chem 64: 2111-2122 (1992). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: blood (plasma, serum); procedure: high-performance liquid chromatography with ultraviolet
detection at 340, 290, 280, and 450 nm; limit of detection: 500 ng/mL
Lee BL et al; J Chromatogr 581: 41-47 (1992). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4. New
 from HSDB
Analyte: vitamin E; matrix: blood (plasma); procedure: high-performance liquid chromatography with electrochemical
detection; limit of detection: 50 pg
Takeda H et al; J Chromatogr 722: 287-294 (1996). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: blood (plasma), tissue (liver, lung); procedure: high-performance liquid chromatography with
ultraviolet detection at 292 nm; limit of detection: 60 ng/mL
Van Vliet T et al; J Chromatogr 553: 179-186 (1991). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
Analyte: vitamin E; matrix: blood (plasma), urine; procedure: high-performance liquid chromatography with ultraviolet
detection at 290 nm; limit of detection: 5 ng
Papadoyannis IN et al; J Liq Chromatogr Rel Technol 20: 3203-3231 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical
 from HSDB
Analyte: vitamin E; matrix: tissue (liver); procedure: high-performance liquid chromatography with fluorescence detection;
limit of detection: 3 pmoles
Analyte: vitamin E; matrix: tissue (liver); procedure: high-performance liquid chromatography with fluorescence detection; limit of
detection: 3 pmoles
 from HSDB
Analyte: vitamin E; matrix: tissue (brain, liver, placenta); procedure: high-performance liquid chromatography with
fluorescence detection
Barbas C et al; J Chromatogn A 778: 415-420 (1997). As cited in: Lunn G; HPLC Methods for Pharmaceutical Analysis. Volumes 2-4.
 from HSDB
12 Safety and Hazards 
12.1 Fire Fighting Measures 
Wear self contained breathing apparatus for fire fighting if necessary.
 from HSDB
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide
 from HSDB
12.2 Accidental Release Measures 

12.2.1 Cleanup Methods 
ACCIDENTAL RELEASE MEASURES Personal precautions, protective equipment and emergency procedures: Avoid
breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Keep in suitable, closed
containers for disposal.
 from HSDB
12.2.2 Disposal Methods 

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to
implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for
guidance on acceptable disposal practices.
 from HSDB
Product Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging Dispose of as
unused product.
 from HSDB
12.2.3 Other Preventative Measures 

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid
skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good
laboratory practices. Wash and dry hands.
 from HSDB
12.3 Handling and Storage 

12.3.1 Storage Conditions 
Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 deg C.
 from HSDB
12.4 Exposure Control and Personal Protection 

12.4.1 Protective Equipment and Clothing 
Skin protection: Handle with gloves.
 from HSDB
Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such
as NIOSH (US) or EN 166(EU).
 from HSDB
Respiratory protection: Respiratory protection not required. For nuisance exposures use type OV/AG (US) or type ABEK (EU
EN 14387) respirator cartridges. Use respirators and components tested and approved under appropriate government
standards such as NIOSH (US) or CEN (EU).
 from HSDB
Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and
amount of the dangerous substance at the specific workplace.
 from HSDB
12.5 Stability and Reactivity 

12.5.1 Reactivities and Incompatibilities 
Strong oxidizing agents
 from HSDB
12.6 Regulatory Information 

12.6.1 FDA Requirements 
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug
products, including vitamin E, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal
Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 22,
2015: http://www.fda.gov/cder/ob/
 from HSDB
Tocopherols used as chemical preservatives are generally recognized as safe when used in accordance with good
manufacturing practice. /Tocopherols/
 from HSDB
Tocopherols used as nutrients are generally recognized as safe when used in accordance with good manufacturing practice.
/Tocopherols/
 from HSDB
alpha-Tocopherol acetate used as a nutrient is generally recognized as safe when used in accordance with good
manufacturing practice. /alpha-Tocopherol acetate /
 from HSDB
Substance added directly to human food affirmed as generally recognized as safe (GRAS).
 from HSDB
Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active
ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence
currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these
ingredients for the specified uses: Vitamin E is included in topical acne drug products.
21 CFR 310.545(a)(1) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations.
Available from, as of June 3, 2015: http://www.ecfr.gov
 from HSDB
Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active
ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence
currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these
ingredients for the specified uses: Vitamin E is included in weight control drug products.
21 CFR 310.545(a)(20) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations.
Available from, as of June 3, 2015: http://www.ecfr.gov
 from HSDB
Tocopherols used as chemical preservatives in animal drugs, feeds, and related products are generally recognized as safe
when used in accordance with good manufacturing or feeding practice. /Tocopherols/
 from HSDB
Tocopherols used as a nutrient and/or dietary supplements in animal drugs, feeds, and related products are generally
recognized as safe when used in accordance with good manufacturing or feeding practice. /Tocopherols/

 from HSDB
alpha-Tocopherol acetate used as a nutrient and/or dietary supplement in animal drugs, feeds, and related products is
generally recognized as safe when used in accordance with good manufacturing or feeding practice. /alpha-Tocopherol
acetate/
 from HSDB
12.7 Other Safety Information 

12.7.1 Toxic Combustion Products 
Carbon oxides
 from HSDB
12.7.2 Other Hazardous Reactions 

Air Light.
 from HSDB
13 Toxicity 
13.1 Toxicological Information 
13.1.1 Interactions 
Free radicals vary widely in their thermodynamic properties, ranging from very oxidizing to very reducing. These
thermodynamic properties can be used to predict a pecking order, or hierarchy, for free radical reactions. Using one-electron
reduction potentials, the predicted pecking order is in agreement with experimentally observed free radical electron
(hydrogen atom) transfer reactions. These potentials are also in agreement with experimental data that suggest that vitamin
E, the primary lipid soluble small molecule antioxidant, and vitamin C, the terminal water soluble small molecule antioxidant,
cooperate to protect lipids and lipid structures against peroxidation. Although vitamin E is located in membranes and vitamin
C is located in aqueous phases, vitamin C is able to recycle vitamin E; i.e., vitamin C repairs the tocopheroxyl (chromanoxyl)
radical of vitamin E, thereby permitting vitamin E to function again as a free radical chain-breaking antioxidant. This review
discusses: (i) the thermodynamics of free radical reactions that are of interest to the health sciences; (ii) the fundamental
thermodynamic and kinetic properties that are associated with chain-breaking antioxidants; (iii) the unique interfacial nature
of the apparent reaction of the tocopherol free radical (vitamin E radical) and vitamin C; and (iv) presents a hierarchy, or
pecking order, for free radical electron (hydrogen atom) transfer reactions. Abstract: PubMed
Buettner GR; Arch Biochem Biophys. 300 (2): 535-43 (1993)
 from HSDB
Ascorbic acid appears to have two opposite roles in animal tissues: to act as an antioxidant or to act as a prooxidant. The
effects of ascorbic acid supplementation on the tissue antioxidant status seem to be dependent on the dose of ascorbic acid
and the vitamin E status. Adequate doses of ascorbic acid supplementation to vitamin E-deficient subjects or animals help to
partially maintain vitamin E levels, probably through sparing the degradative metabolism of vitamin E, and thus increase the
antioxidant effectiveness. The sparing effect of ascorbic acid on vitamin E metabolism is also shown in the partial reversal of
the manifestation of vitamin E deficiency. On the other hand, when the animals are marginally adequate in vitamin E status,
ascorbic acid supplementation in large doses appears to promote lipid peroxidation and significantly decreases the
antioxidant potential of animals. An increase of the level of vitamin E supplementation overcomes the prooxidant effect of
large doses of ascorbic acid. This observation suggests that vitamin E requirement may be increased with a large dose of
ascorbic acid supplementation. Abstract: PubMed
Chen LH; In Vivo 3 (3): 199-209 (1989)
 from HSDB
Numerous lipid- and aqueous-phase inhibitors of nitrosation, as well as a number of other general antioxidants and free-
radical trapping agents, were examined for their effectiveness in blocking the mutagenic effects of nitric oxide. The
mutagenic activity of nitric oxide was most effectively inhibited by beta-carotene and tocopherols. BHT, dimethyl sulfoxide
and mannitol also blocked the mutagenic effects of nitrogen oxides but appeared less effective than beta-carotene or
vitamin E, while ascorbate was ineffective as an inhibitor of mutation resulting from nitric oxide exposure. Abstract: PubMed
Arroyo PL et al; Mutat Res 281 (3): 193-202 (1992)
 from HSDB
The effects of zidovudine on the fetus were investigated in pregnant mice by using parameters such as the number of
fetuses, fetal size, and the fetal hepatic cell clonogenic assay. Zidovudine caused dose-dependent toxicity to the fetus upon
administration via drinking water to pregnant mice from days 1 to 13 of gestation. At the 0.5 mg/ml dose level, zidovudine
caused a decrease in the number of fetuses to 12 from an average of 16.5 in control animals, and the fetal size (crown-rump
length) was reduced from 10.5 to 8.5 mm. The CFU of the erythroid progenitor cell colonies derived from the fetal hepatic
cells were decreased to 38% of that of the control, and the hematocrit dropped to 33.5 + or - 1.7 from a control value of 42.6
+ or - 2.5. Concomitant administration of erythropoietin, vitamin E, or interleukin-3 to the zidovudine treated pregnant mice
caused a significant reversal in the zidovudine induced toxicity to the fetu and to the mother's bone marrow. The success of
therapeutic intervention was demonstrated by restoration of the number of fetuses to the level of untreated controls, an
increase in the size of fetuses to normal values, and an increase i hematocrit to > 40.[Gogu SR et al; Antimicrob Agents
Chemother 36 (11): 2370-4 (1992)] Full text: PMC284337 Abstract: PubMed
 from HSDB
The effect of chronic treatment with vitamin E on acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced neurotoxicity,
as assessed by striatal dopamine depletion, was studied. Male C57B1/6J mice were fed vitamin E (48 mg/kg/day,
intragastric) for 4, 8, or 12 wk prior to administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (20 mg/kg, ip x 3, 2 hr
intervals) or its diluent. Brain vitamin E concn was increased by exogenous supplements for 12 wk. Striatal dopamine
content was reduced by 85% to 90% after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in control and vitamin E treated
mice. Mice with elevated cerebral vitamin E were not protected from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity,
with dopamine content as an indicator. These findings indicate that moderate elevation of brain vitamin E is not adequate for
protecting dopamine containing neurons against the toxic actions of a high dose of 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine. Abstract: PubMed
Gong L et al; Neuroreport 2 (9): 544-6 (1991)
 from HSDB
The effect of increased vitamin E liver content by dietary supplementation on chronic liver damage and cirrhosis induced by
carbon tetrachloride was investigated in rat. Data indicate that vitamin E supplementation did not interfere with the growth
rate of the animals and increased about threefold the liver's content of the vitamin. Vitamin E supplementation significantly
reduced oxidative liver damage, but it was not effective in protecting against development of fatty liver and did not interfere
with metabolic activation of carbon tetrachloride. Moreover, vitamin E-fed animals showed incomplete but significant
prevention of liver necrosis and cirrhosis induced by carbon tetrachloride. This has been shown by means of histological
examination, analysis of serum parameters and biochemical evaluation of collagen content. These results show that an
increased liver content of vitamin E can afford a significant degree of protection against carbon tetrachloride induced chronic
liver damage and cirrhosis. Abstract: PubMed
Parola M et al; Hepatology 16 (4): 1014-21 (1992)
 from HSDB
The effect of pretreatment with vitamin E on cytotoxicity, DNA single strand breaks, and chromosomal aberrations as well as
on mutation induced by UV-B light was investigated in Chinese hamster V-79 cells. Cellular pretreatment with non-toxic
levels of 25 uM alpha-tocopherol succinate (vitamin E) for 24 hr prior to exposure resulted in a 10 fold increase in cellular
levels of alpha-tocopherol. Using a colony-forming assay, this pretreatment decreased the cytotoxicity of UV-B light.
However, alkaline elution assays demonstrated that pretreatment with vitamin E did not affect the number of DNA single
strand breaks caused by UV-B light. In addition, UV-B exposure produced a dose-dependent induction of chromosomal
aberrations and mutations at the HGPRT locus, and neither of these actions of UV-B was influenced by pretreatment with
the vitamin. These results suggest that vitamin E protects cells from UV-B induced cytotoxicity, possibly through its ability to
scavenge free radicals. The results also suggest that the extent of genotoxicity induced by UV-B light may not correlate
directly with the cytotoxic action of this wavelength region in sunlight. Abstract: PubMed
Sugiyama M et al; Photochem Photobiol 56 (1): 31-4 (1992)
 from HSDB
The present study was undertaken to investigate whether alpha-tocopherol, entrapped in liposomes and delivered directly to
the lung, could protect against paraquat induced lung damage in the rat. Plain liposomes (composed of
dipalmitoylphosphatidylcholine) or dipalmitoylphosphatidylcholine/alpha-tocopherol liposomes were administered
intratracheally to animals 24 hr prior to an ip injection of paraquat (20 mg/kg); rats were killed 24 or 48 hr after paraquat
treatment. Results of this study showed that lungs of animals treated with paraquat were damaged extensively as evidenced
by an increase in lung weight and a significant reduction in lung angiotensin converting enzyme activity and cytochrome
p450 concn. Furthermore, paraquat treatment resulted in a significant decrease in reduced glutathione concn and a marked
elevation in microsomal lipid peroxidation levels as measured by the formation of diene conjugates. Pretreatment of rats with
dipalmitoylphosphatidylcholine liposomes alone did not alter significantly the paraquat induced changes of all parameters
examined. Pretreatment of rats with dipalmitoylphosphatidylcholine/alpha-tocopherol liposomes 24 hr prior to paraquat
challenge resulted in a significant increase in pulmonary alpha-tocopherol concn and antagonized paraquat induced
changes in lipid peroxidation, glutathione/GSSG ratio, lung angiotensin converting enzyme activity and cytochrome p450
concn. Results of this study suggested that alpha-tocopherol, delivered directly to the lung in a liposomal formulation 24 hr
prior to paraquat administration, confers protection against paraquat-induced lung damage. Abstract: PubMed
Suntres ZE et al; Biochem Pharmacol 44 (9): 1811-8 (1992)
 from HSDB
The effects of combined dietary vitamin E supplementation and a relatively low increase in selenium levels on 7,12-
dimethylbenz(a)anthracene induction of lipid peroxidation in the short term and development of mammary tumors in the long
term were investigated in female Sprague Dawley rats. Control animals were fed the basal diet (20 mg/kg vitamin E and 0.6
mg/kg selenium) throughout the experiment. Three other groups received a high vitamin E diet (235 mg/kg vitamin E and 0.6
mg/kg selenium) at different times, the first two from three weeks after 7,12-dimethylbenz(a)anthracene treatment and the
other throughout the experiment. When the vitamin E diet with selenium supplementation was applied until three weeks after
7,12-dimethylbenz(a)anthracene or until the termination of the experiment, tumor yields (tumors per rat) were significantly
inhibited compared with the control group. On the other hand, delaying the supplementation of vitamin E until three weeks
postcarcinogen produced no prophylactic effect. The elevation of lipid peroxidation levels observed immediately after 7,12-
dimethylbenz(a)anthracene administration was also significantly inhibited in both mammary fat pads and livers of animals in
the high vitamin E group. Abstract: PubMed
Takada H et al; Nutr Cancer 17 (2): 115-22 (1992)
 from HSDB
The influence of vitamin E on cadmium intoxication was investigated in rats. The exposure to cadmium (1 mg/kg, cadmium
as cadmium chloride dihydrate, ip for 7 days) decreased the activity of hepatic and renal glutamic oxalacetic and glutamic
pyruvic transaminases and alkaline phosphatase accompanied by increase in the levels of SGOT and SGPT and urinary
protein. Simultaneous administration of vitamin E (5 mg/kg, im for 7 days) reduced these cadmium induced biochemical
alterations. The accumulation of cadmium in blood, liver and kidney also decreased significantly upon co-exposure to
vitamin E. The antioxidant property of vitamin E seems to be responsible for the observed protection of cadmium
intoxication. Abstract: PubMed
Tandon SK et al; Biomed Environ Sci 5 (1): 39-45 (1992)
 from HSDB
Exposure of the skin of the back of skh-1 hairless mice to UVB (310 nm peak) irradiation at doses of 0.115-0.23 J/sq cm
results after 24-48 hr in an erythema which can be quantified using an erythema meter. Application of pure d-alpha-
tocopherol acetate, a thick oil, to the skin immediately following the exposure to UVB significantly reduces the increase in
erythema index, by 40-55%. At the lower dose (0.115 J/sq cm), skin thickness (associated with edematous swelling of the
sunburned skin) was measured by magnetic resonance imaging. In two experiments the UVB induced increase in skin
thickness was significantly reduced at 24 hr by 29 and 54%, and at 48 hr by 26 and 61%. After 8 days the untreated
irradiated mouse skin still showed a significant increase in thickness (24%) compared to the untreated unirradiated control,
while the treated irradiated control was not significantly thicker than the unexposed control. Skin sensitivity was tested using
a modification of the technique of esthesiometry, by observing rapid avoidance responses of the mouse to a pressure of
0.96 g/sq cm exerted by applying to the skin the tip of a nylon esthesiometer fiber extended to 60 mm in length. The
untreated irradiated mice were more sensitive (p< 0.07, Wilcoxon test) than the treated irradiated mice, and also significantly
different from the untreated unirradiated control mice (p< 0.04, Wilcoxon test), but the treated irradiated mice were not
significantly differently sensitive when compared to the unirradiated controls (p< 0.32). Taken together these data indicate
that the erythema, edema, and skin sensitivity commonly associated with UVB induced sunburn are significantly reduced by
topical application of tocopherol acetate even after the exposure has occurred. Abstract: PubMed
Trevithick JR et al; Arch Biochem Biophys 296 (2): 575-82 (1992)
 from HSDB
Isolated rat hepatocytes exposed to carbon tetrachloride showed a stimulated formation of malonaldehyde after only 30-60
min incubation. Conversely, the onset of hepatocyte death was a relatively late event, being significant only after 2-3 hr of
treatment. A cause-effect relationship between the two phenomena has been demonstrated by using hepatocytes isolated
from rats pretreated with alpha-tocopherol. Comparable results were obtained in vivo where supplementation with alpha-
tocopherol 15 hr before carbon tetrachloride dosing induced a partial or complete protection against the drug's necrogenic
effect, depending on the concn of the haloalkane used. Moreover, the vitamin supplementation prevented the carbon
tetrachloride induced increase of liver total calcium content, probably by blocking alterations in the liver cell plasma
membranes due to lipid peroxidation. Abstract: PubMed
Biasi F et al; Cell Biochem Funct 9 (2): 111-8 (1991)
 from HSDB
alpha-Tocopherol inhibited aminopyrene-nitrite induced hepatotoxicity in rats and reduced amount of nitrosodimethylamine
formed in cigarette smoke. Also significant reduction of nitrosopyrolidine formation in fried bacon.
MERGENS WJ ET AL; IARC SCI PUBL, VOL 19, ENVIRON ASPECTS N-NITROSO COMPD, PP 199-212 (1978)
 from HSDB
The aim of this study was to elucidate how vitamin E (alpha tocopherol) may ameliorate the toxicity of the pesticide
chlorpyrifos in Atlantic salmon. Freshly isolated hepatocytes were exposed to vitamin E, chlorpyrifos or a combination of
vitamin E and chlorpyrifos (all 100 uM). Transcriptomics (RNA-seq) and metabolomics were used to screen for effects of
vitamin E and chlorpyrifos. By introducing vitamin E, the number of upregulated transcripts induced by chlorpyrifos exposure
was reduced from 941 to 626, while the number of downregulated transcripts was reduced from 901 to 742 compared to the
control. Adding only vitamin E had no effect on the transcriptome. Jak-STAT signaling was the most significantly affected
pathway by chlorpyrifos treatment according to the transcriptomics data. The metabolomics data showed that accumulation
of multiple long chain fatty acids and dipeptides and amino acids in chlorpyrifos treated cells was partially alleviated by
vitamin E treatment. Significant interaction effects between chlorpyrifos and vitamin E were seen for 15 metabolites,
including 12 dipeptides. The antioxidant had relatively modest effects on chlorpyrifos-induced oxidative stress. By combining
the two data sets, the study suggests that vitamin E supplementation prevents uptake and accumulation of fatty acids, and
counteracts inhibited carbohydrate metabolism. Overall, this study shows that vitamin E only to a moderate degree modifies
chlorpyrifos toxicity in Atlantic salmon liver cells.[Olsvik PA et al; PLoS One. 10 (3): e0119250 (2015)] Full text:
 from HSDB
Bisphenol A (BPA) is a commonly used material in daily life, and it is argued to cause oxidative stress in liver and ovarian
tissue. alpha-Lipoic acid (ALA) and alpha-tocopherol (ATF), two of the most effective antioxidants, may play a role in
preventing the toxic effect. Therefore, the purpose of this study was to examine the beneficial effects of ALA, ATF, and that
of ALA + ATF combination on oxidative damage induced by BPA. Female Wistar rats were divided into five groups (control,
BPA, BPA + ALA, BPA + ATF, and BPA + ALA + ATF). BPA (25 mg/kg/day), ALA (100 mg/kg/day), and ATF (20 mg/kg/day)
were administered for 30 days. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT),
liver malondialdehyde (L-MDA) and glutathione peroxidase (L-GPx), and ovarian malondialdehyde (Ov-MDA) and nitric oxide
(Ov-NO) were significantly higher in the BPA-treated groups compared with the control group. The levels of AST and ALT
decreased in the BPA + ALA, BPA + ATF, and BPA + ALA + ATF groups compared with the BPA group. Similarly, BPA +
ALA or BPA + ATF led to decreases in L-MDA and Ov-MDA levels compared with the BPA group. However, the BPA + ALA +
ATF group showed a significant decrease in L-MDA levels compared with the BPA + ALA group and the BPA + ATF group.
The levels of L-GPx decreased in the BPA + ATF and the BPA + ALA + ATF groups compared with the BPA group. The
administration of ATF and ALA + ATF significantly decreased the Ov-NO levels. This study demonstrates that BPA causes
oxidative damage in liver and ovarian tissues. ALA, ATF, or their combination were found to be beneficial in preventing BPA-
induced oxidative stress.[Avci B et al; Toxicol Ind Health. 2014 Dec 29. pii: 0748233714563433. Abstract: PubMed
Epub ahead of print]
 from HSDB
HIV/AIDS patients are probably more predisposed to vitamin E deficiency, considering that they are more exposed to
oxidative stress. Additionally, there are an extensive number of drugs in the highly active antiretroviral therapy (HAART)
regimens that may interfere with vitamin E concentrations. The objective of this study was to compare serum concentrations
of alpha-tocopherol in 182 HIV/AIDS patients receiving different HAART regimens. The patients were divided into three
groups according to regimen: nucleoside analog reverse-transcriptase inhibitors (NRTIs) + non-nucleoside analog reverse-
transcriptase inhibitors (NNRTIs); NRTIs + protease inhibitors + ritonavir; NRTIs + other classes. Alpha-tocopherol was
assessed by high-performance liquid chromatography. Multiple linear regression analysis was used to evaluate the effects of
HAART regimen, time of use, and compliance with the regimen on alpha-tocopherol concentrations. Alpha-tocopherol
concentrations were on average 4.12 umol/L lower for the NRTIs + other classes regimen when compared to the NRTIs +
NNRTIs regimen (p = 0.037). A positive association (p < 0.001) was observed between alpha-tocopherol and cholesterol
concentrations, a finding due, in part, to the relationship between liposoluble vitamins and lipid profile. This study
demonstrated differences in alpha-tocopherol concentrations between patients using different HAART regimens, especially
regimens involving the use of new drugs.[Itinoseki Kaio DJ et al; Nutrients. 6 (9): 3641-52 (2014)] Full text: PMC4179180
Abstract: PubMed
 from HSDB
The aim of this study was to evaluate the protective effects of different concentrations of vitamin E alpha-tocopherol (a-T)
isomer against the toxicity of hydrogen peroxide (H2O2) on dental pulp cells. The cells (MDPC-23) were seeded in 96-well
plates for 72 hours, followed by treatment with 1, 3, 5, or 10mM a-T for 60 minutes. They were then exposed or not to H2O2
for 30 minutes. In positive and negative control groups, the cells were exposed to culture medium with or without H2O2
(0.018%), respectively. Cell viability was evaluated by MTT assay (Kruskal-Wallis and Mann-Whitney tests; a = 5%).
Significant reduction of cell viability (58.5%) was observed in positive control compared with the negative control. Cells
pretreated with a-T at 1, 3, 5, and 10mM concentrations and exposed to H2O2 had their viability decreased by 43%, 32%,
25%, and 27.5%, respectively. These values were significantly lower than those observed in the positive control, thereby
showing a protective effect of ?-T against the H2O2 toxicity. Overall, the vitamin E a-T isomer protected the immortalized
MDPC-23 pulp cells against the toxic effects of H2O2. The most effective cell protection was provided by 5 and 10mM
concentrations of a-T.[da Silveira Vargas F et al; Biomed Res Int. 2014:895049 (2014)] Full text: PMC3918697 Abstract:
PubMed
 from HSDB
To evaluate the correlation between reactive oxygen species (ROS) production and micronucleus formation induced by a
vitamin complex in peripheral blood mononuclear cells from healthy people aged between 40 and 85 years old. Peripheral
blood mononuclear cells (PBMNCs) were purified utilizing ficoll-hypaque gradient. ROS production by PBMNCs was
quantified by luminol-dependent chemiluminescence in the presence or in the absence of the vitamin complex. DNA
damage in PBMNC by the vitamin complex was detected by the micronucleus technique. Statistical analyses were made
with the Student's 't' test and the Pearson correlation. P < 0.05 was considered significant. The vitamin complex induced MN
formation in PBMNC but did not augment ROS production. There was no correlation between ROS production and MN
formation either in the presence or in the absence of the vitamin complex. There was no increase in the ROS production in
the presence of the vitamin complex. The vitamin complex induced an augmentation in the MN formation. There was no
correlation between ROS production and the induction of MN formation. Since no association could be detected between
ROS production and MN formation, additional studies are required in order to investigate the possible mechanism of vitamin-
induced MN formation. Abstract: PubMed
Veloso CA et al; Redox Rep. 18 (6): 219-23 (2013)
 from HSDB
The effects of tocotrienol-rich fraction (TRF), alpha-tocopherol (T) and alpha-tocopheryl acetate (TA) on lipopolysaccharide
(LPS)-induced inflammatory responses in mouse peritoneal macrophages were examined. Results showed that at 5-30
ug/mL, all test compounds plus 1 ug/ml LPS exhibited no cytotoxic effects on macrophage cells. Compared with T and TA,
TRF showed the strongest anti-inflammatory activity as demonstrated by its potency in inhibiting the LPS-induced nitric
oxide (NO), prostaglandin E(2) (PGE(2)), and proinflammatory cytokine (TNF-alpha, IFN-gamma, IL-1beta and IL-6)
production. At 10 ug/mL, it significantly blocked the LPS induction of inducible nitric oxide synthase (iNOS) and
cyclooxygenase-2 (COX-2) expression, but has no effect on cyclooxygenase-1 (COX-1). Furthermore, TRF also showed a
greater inhibition on the nuclear factor kappa B (NF-kappaB) expression than T and TA. These results suggest that TRF
could be a better agent than T and TA for use in the prevention of chronic inflammatory diseases. Abstract: PubMed
Ng LT, Ko HJ; Food Chem 134 (2): 920-5 (2012)
 from HSDB
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species (ROS) and
a biological system's ability to readily detoxify the reactive intermediates or repair the resulting damage. Our objective was to
verify the existence of an in vitro dual effect of alpha-tocopherol, beta-carotene and ascorbic acid in peripheral blood
mononuclear cells (PBMNC) of healthy donors and the inflammatory capacity by IL-6 production. PBMNC were incubated
with two concentrations of vitamin complex: [A] = Ascorbic Acid = 0.08uM, alpha- tocopherol= 0.04uM, beta-carotene =
0.0008 uM and [20A] = Ascorbic Acid = 1.6uM, alpha-tocopherol = 0.82uM, beta-carotene = 0.016uM. Oxidizing and
reducing response were measured by chemiluminescence and MTT assays, respectively. IL-6 production was measured by
sandwich ELISA. /The/ results demonstrated that PBMNC (from 20-39-year-old donors) incubated with vitamins activated
free radical production only in [20A] concentration. However, in the age groups of 40-59 and 60-80 years old, there was a
significant reduction and activation of the oxidizing response with both concentrations, respectively. The inflammatory profile
showed an elevation of IL-6 production in pro-oxidant and a decrease in antioxidant conditions. Correlation between ROS
production and IL-6 releasing was observed. With this experiment we concluded that vitamins can exert an antioxidant effect
and a pro-oxidant effect according to their concentration, and could be an inductor of an inflammatory process in vitro
generating severe complications to the body in cellular levels. Abstract: PubMed
de Oliveira BF et al; Curr Aging Sci. 5 (2): 148-56 (2012)
 from HSDB
Epidemiological evidence indicates that supplementation with some dietary factors is associated with a lower incidence of
cancer. An effective cancer prevention strategy for the millions of people worldwide who have been exposed to asbestos
could have enormous benefit. We tested whether dietary supplementation of the antioxidants vitamin A, E, and selenium
could alter the pattern of disease in the MexTAg transgenic mouse model, in which mice uniformly develop mesothelioma
after asbestos exposure. We focused on antioxidants because one of the most widely accepted hypotheses for the
mechanism by which asbestos fibers cause cancer proposes the involvement of reactive oxygen and nitrogen species. We
compared the survival of MexTAg mice that had been inoculated with asbestos fed on diets supplemented with 250,000
IU/kg vitamin A (retinoic acid), or 1,000 mg/kg vitamin E (alpha-tocopherol acetate) or 3 mg/kg selenium, or both vitamin E
and selenium concurrently and, additionally, diets deficient in each antioxidant. We found that neither the time to develop
symptoms of disease nor overall survival times were altered by any of the diets. We conclude that the data do not support
the notion that dietary antioxidants will moderate the rate of mesothelioma in asbestos-exposed populations. Abstract:
PubMed
Robinson C et al; Nutr Cancer64 (2): 315-22 (2012)
 from HSDB
The aim of this study was to evaluate tissue distribution of vitamin E isoforms such as a- and g-tocotrienol and g-tocopherol
and interference with their tissue accumulation by a-tocopherol. Rats were fed a diet containing a tocotrienol mixture or g-
tocopherol with or without a-tocopherol, or were administered by gavage an emulsion containing tocotrienol mixture or g-
tocopherol with or without a-tocopherol. There were high levels of a-tocotrienol in the adipose tissue and adrenal gland, g-
tocotrienol in the adipose tissue, and g-tocopherol in the adrenal gland of rats fed tocotrienol mixture or g-tocopherol for 7
weeks. Dietary a-tocopherol decreased the a-tocotrienol and g-tocopherol but not g-tocotrienol concentrations in tissues. In
the oral administration study, both tocopherol and tocotrienol quickly accumulated in the adrenal gland; however, their
accumulation in adipose tissue was slow. In contrast to the dietary intake, a-tocopherol, which has the highest affinity for a-
tocopherol transfer protein (aTTP), inhibited uptake of g-tocotrienol to tissues including adipose tissue after oral
administration, suggesting that the affinities of tocopherol and tocotrienol for aTTP in the liver were the critical determinants
of their uptake to peripheral tissues. Vitamin E deficiency for 4 weeks depleted tocopherol and tocotrienol stores in the liver
but not in adipose tissue. These results indicate that dietary vitamin E slowly accumulates in adipose tissue but the levels
are kept without degradation. The property of adipose tissue as vitamin E store causes adipose tissue-specific accumulation
of dietary tocotrienol. Abstract: PubMed
Uchida T et al; Lipids 47 (2): 129-39 (2012)
 from HSDB
The red blood cell system and the activity of free radical processes were studied in pregnant rats during chronic nitrite
intoxication (oral 0.2% sodium nitrite solution) and during alpha-tocopherol administration (in an intramuscular dose of 150
mg/kg). In intact pregnant rats, alpha-tocopherol decreased the activity of free radical processes and increased the
antioxidant potential. Its administration to pregnant rats with nitrite intoxication prevents the elevated concentration of
hemoglobin, considerably decreases the activity of free radical processes, and increases the antioxidant activity of serum.
Abstract: PubMed
Ivanova AS et al; Gig Sanit (3): 78-80 (2011)
 from HSDB
We have reported that supplemental doses of the a- and g-tocopherol isoforms of vitamin E decrease and increase,
respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For
these studies, mice were treated with Ag and supplemental tocopherols in a first phase of treatment followed by a 4-wk
clearance phase, and then the mice received a second phase of Ag and tocopherol treatments. The proinflammatory effects
of supplemental levels of g-tocopherol in phase 1 were only partially reversed by supplemental a-tocopherol in phase 2, but
were completely reversed by raising a-tocopherol levels 10-fold in phase 2. When g-tocopherol levels were increased 10-fold
(highly elevated tocopherol) so that the lung tissue g-tocopherol levels were equal to the lung tissue levels of supplemental
a-tocopherol, g-tocopherol reduced leukocyte numbers in the lung lavage fluid. In contrast to the lung lavage fluid, highly
elevated levels of g-tocopherol increased inflammation in the lung tissue. These regulatory effects of highly elevated
tocopherols on tissue inflammation and lung lavage fluid were reversible in a second phase of Ag challenge without
tocopherols. In summary, the proinflammatory effects of supplemental g-tocopherol on lung inflammation were partially
reversed by supplemental levels of a-tocopherol but were completely reversed by highly elevated levels of a-tocopherol.
Also, highly elevated levels of g-tocopherol were inhibitory and reversible in lung lavage but, importantly, were
proinflammatory in lung tissue sections. These results have implications for future studies with tocopherols and provide a
new context in which to review vitamin E studies in the literature.[McCary CA et al; J Immunol186 (6): 3674-85 (2011)] Full
text: PMC3271805 Abstract: PubMed
 from HSDB
/In a 1949 study/ mice treated with carcinogenic doses of dibenzanthrene had a higher incidence of lung tumors when given
2 mg alpha-tocopherol every 2 days than when fed a vitamin E-deficient diet; subcutaneous tumors were also more
common...
WHO; Tocopherol, alpha: Toxicological Evaluation of Certain Food Additives and Contaminants (WHO Food Additive Series 21), 1987;
Available from as of June 10, 2015: http://www.inchem.org/documents/jecfa/jecmono/v21je01.htm
 from HSDB
13.1.2 Toxicity Summary 

IDENTIFICATION AND USE: Vitamin E is pale yellow viscous oil. Previously, the term vitamin E was used as the generic
term for four tocopherols (alpha, beta, gamma, delta) and four tocotrienols (alpha, beta, gamma, delta), that are organic
compounds which possess antioxidant activity to a different degree. Factors have been used to convert food contents of
tocopherols and tocotrienols to alpha-tocopherol equivalents. Recent literature considers vitamin E as being d-alpha-
tocopherol only. Vitamin E is used as antioxidant for fats; animal feed additive. It is also used as human and animal
medication and dietary supplement. HUMAN EXPOSURE AND TOXICITY: Clinical studies indicate that, generally, intakes of
below about 720 mg/day are without adverse effects in man, but one investigation in elderly patients showed an increase in
serum cholesterol at doses of 300 mg alpha-tocopherol daily. Clinical deficiency of vitamin E is rare because adequate
amounts are supplied in the normal diet. Symptoms of deficiency include ataxia, muscle weakness, nystagmus, and losses
in touch and pain sensations. Vitamin E deficiency in premature infants may result in hemolytic anemia, thrombocytosis, and
increased platelet aggregation. Incidences of allergic reactions seem to be very rare. Vitamin E appears to have no effect on
all-cause mortality at doses up to 5,500 IU/d. Epidemiological studies have associated higher vitamin E status with reduced
cancer risk. However, a recent cancer prevention trial found that dietary supplementation with vitamin E significantly
increased the risk of prostate cancer among healthy men. Epidemiological studies found significant inverse associations
between serum concentrations of vitamin E and adiposity among children. alpha-Tocopherol could improve
teratozoospermia motility and viability. ANIMAL STUDIES: Rats were reported to tolerate doses of 4 g/kg daily for two
months, and mice tolerated oral doses of 50 g/kg daily for two months. However, recent study indicates that pharmacological
dose of alpha-tocopherol supplementation can induce cardiotoxicity in healthy rats. In rats vitamin E depressed body-weight
gain at concentrations of 10,000 and 25,000 IU/kg diet, and increased relative heart and spleen weights were seen at 8
months and 16 months, respectively. In developmental studies vitamin E was administered in amounts of 150 or 300
mg/kg/day to pregnant mice sc on days 6, 8 and 10 of gestation. Growth retardation and fetal survival were increased in the
treated group. The incidence of cleft palate was increased. Developmental studies with rat (75 mg/day) were negative.
Developmental neurotoxicity has been described in several studies in rats following maternal supplementation with vitamin
E. alpha-Tocopherol was non-carcinogenic. Mice treated with carcinogenic doses of dibenzanthrene had a higher incidence
of lung tumors when given 2 mg alpha-tocopherol every 2 days than when fed a vitamin E-deficient diet; subcutaneous
tumors were also more common. Conversely, in more recent studies, vitamin E has been found to reduce skin tumor
incidence induced by 7,12-dimethylbenzanthrene. In rats when the vitamin E diet with selenium supplementation was
applied until three weeks after 7,12-dimethylbenz(a)anthracene or until the termination of the experiment, tumor yields
(tumors per rat) were significantly inhibited compared with the control group. The mutagenic activity of nitric oxide was
effectively inhibited by tocopherols.
 from HSDB
13.1.3 Antidote and Emergency Treatment 

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start
artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained.
Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If
vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway
and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and
B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier
Mosby, St. Louis, MO 2007, p. 160
 from HSDB
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if
necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather
mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... .
Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye
continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5
mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover
skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Mosby, St. Louis, MO 2007, p. 160
 from HSDB
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is
unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with
a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta
agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start
IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if
signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of
fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... .
/Poisons A and B/
Mosby, St. Louis, MO 2007, p. 160-1
 from HSDB
13.1.4 Human Toxicity Excerpts 

/HUMAN EXPOSURE STUDIES/High blood pressure (BP) variability, which may be an important determinant of
hypertensive end-organ damage, is emerging as an important predictor of cardiovascular health. Dietary antioxidants can
influence BP, but their effects on variability are yet to be investigated. The aim of the present study was to assess the effects
of vitamin E, vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation. To assess these
effects, two randomised, double-blind, placebo-controlled trials were performed. In the first trial (vitamin E), fifty-eight
individuals with type 2 diabetes were given 500 mg/d of RRR-alpha-tocopherol, 500 mg/d of mixed tocopherols or placebo
for 6 weeks. In the second trial (vitamin C-polyphenols), sixty-nine treated hypertensive individuals were given 500 mg/d of
vitamin C, 1000 mg/d of grape-seed polyphenols, both vitamin C and polyphenols, or neither (placebo) for 6 weeks. At
baseline and at the end of the 6-week intervention, 24 hr ambulatory BP and rate of measurement-to-measurement BP
variation were assessed. Compared with placebo, treatment with alpha-tocopherol, mixed tocopherols, vitamin C and
polyphenols did not significantly alter the rate of daytime or night-time systolic BP, diastolic BP or pulse pressure variation
(P>0.05). Treatment with the vitamin C and polyphenol combination resulted in higher BP variation: the rate of night-time
systolic BP variation (P= 0.022) and pulse pressure variation (P= 0.0036) were higher and the rate of daytime systolic BP
variation was higher (P= 0.056). Vitamin E, vitamin C or grape-seed polyphenols did not significantly alter the rate of BP
variation. However, the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and
polyphenols could be detrimental to treated hypertensive individuals. Abstract: PubMed
Hodgson JM et al; Br J Nutr. 112 (9): 1551-61 (2014)
 from HSDB
/HUMAN EXPOSURE STUDIES/ Vitamin E is a natural antioxidant and its most common biologically active form is alpha-
tocopherol. The antiproliferative effects of alpha-tocopherol have been previously demonstrated. In this study the
antimutagenic effects of vitamin E on oncology and non oncology hospital nurses was investigated. A total of 138 female
nurses from oncology and non oncology hospitals participated in the study. They received 200 mg/day vitamin E for 2
weeks. The urine samples before and after intake of vitamin E were collected and the nucleus of urothelial cells were
evaluated with comet assay. The length of epithelial cells nuclei correlated with increased fracture rate of DNA. Nucleolus
length of urine epithelial cells of all nursing staff before and after vitamin E treatment were measured and the data were
evaluated by student t-test and SPSS. Our study showed that 20% of nursing staff have apoptosis and DNA fracture in the
nucleolus of their urine epithelial cells and DNA damage in the urothelial cells of exposed nurses was significantly higher
than the control group (P<0.05). The antimutagenic activity of vitamin E had significant effects on oncology hospital nurses
effectively in repairing DNA damage and decreasing their nucleus length in urine epithelial cells. We propose that the higher
therapeutic doses of vitamin E and increasing the length of treatment period will be effective against DNA strand breakage
and may have more effect on oncology nurses. Abstract: PubMed
Rezaei-Basiri M et al; Drug Res (Stuttg). 64 (7): 337-42 (2014)
 from HSDB
/HUMAN EXPOSURE STUDIES/ Vitamin E inhibits lipid peroxidation in cell membranes, prevents oxidative damage to DNA
by scavenging free radicals, and reduces carcinogen production. No study to our knowledge, however, has examined the
association between genetic variants and response to long-term vitamin E supplementation. We conducted a genome-wide
association study (GWAS) of common variants associated with circulating alpha-tocopherol concentrations following 3 y of
controlled supplementation. The study population included 2112 middle-aged, male smokers in the Alpha-Tocopherol , Beta-
Carotene Cancer Prevention Study cohort who received a trial supplementation of alpha-tocopherol (50 mg/d) and had
fasting serum alpha-tocopherol concentrations measured after 3 years. Serum concentrations were log-transformed for
statistical analysis and general linear models adjusted for age, BMI, serum total cholesterol, and cancer case status.
Associations with serum response to alpha-tocopherol supplementation achieved genome-wide significance for 2 single
nucleotide polymorphisms (SNP): rs964184 on 11q23.3 (P = 2.6 x 10(-12)) and rs2108622 on 19pter-p13.11 (P = 2.2 x
10(-7)), and approached genome-wide significance for one SNP, rs7834588 on 8q12.3 (P = 6.2 x 10(-7)). Combined, these
SNP explain 3.4% of the residual variance in serum alpha-tocopherol concentrations during controlled vitamin E
supplementation. A GWAS has identified 3 genetic variants at different loci that appear associated with serum
concentrations after vitamin E supplementation in men. Identifying genetic variants that influence serum nutrient biochemical
status (e.g., alpha-tocopherol) under supplementation conditions improves our understanding of the biological determinants
of these nutritional exposures and their associations with cancer etiology.[Major JM et al; J Nutr 142 (5): 866-71 (2012)] Full
 from HSDB
/HUMAN EXPOSURE STUDIES/ The current analysis reexamines the relationship between supplemental vitamin E and all-
cause mortality. All randomized, controlled trials testing the treatment effect of vitamin E supplementation in adults for at
least one year were sought. MEDLINE, the Cochrane Library, and Biological Abstracts databases were searched using the
terms "vitamin E," "alpha-tocopherol," "antioxidants," "clinical trial," and "controlled trial" for studies published through April
2010; results were limited to English, German, or Spanish language articles. Studies were also obtained through reference
mining. All randomized controlled trials using vitamin E, with a supplementation period of at least one year, to prevent or
treat disease in adults were identified and abstracted independently by two raters. Mortality data from trials with a
supplementation period of at least one year were pooled. The selected trials (n = 57) were published between 1988 and
2009. Sample sizes range from 28 to 39,876 (median = 423), yielding 246,371 subjects and 29,295 all-cause deaths.
Duration of supplementation for the 57 trials range from one to 10.1 years (median = 2.6 years). A random effects meta-
analysis produce an overall risk ratio of 1.00 (95% confidence interval: 0.98, 1.02); additional analyses suggest no
relationship between dose and risk of mortality. Based on the present meta-analysis, supplementation with vitamin E
appears to have no effect on all-cause mortality at doses up to 5,500 IU/d.[Abner EL et al; Curr Aging Sci. 4 (2): 158-70
(2011)] Full text: PMC4030744 Abstract: PubMed
 from HSDB
/HUMAN EXPOSURE STUDIES/ Vitamin E, of which the most biologically active form is alpha-tocopherol, has become
widely known for its antioxidant effects. It has been ingested or applied topically for purported anti-aging effects and for
cosmetic enhancement. To determine whether the incidence of allergic contact dermatitis from vitamin E has increased in
recent years. With the approval of the Mayo Clinic institutional review board, we retrospectively analyzed patch-test data
from patients tested from June 1987 through December 2007. A total of 2,950 patients were patch-tested during this period,
and 18 patients (0.61%) had positive reactions toalpha-tocopherol; 6 (0.53%) of 1,136 patients tested from June 1987
through December 1997 had positive results, and 12 (0.66%) of 1,814 patients tested from January 1998 through December
2007 had positive results (p = .69). Vitamin E appears to be a relatively rare contact allergen... Abstract: PubMed
Adams AKConnolly SM; Dermatitis. 21 (4): 199-202 (2010)
 from HSDB
/HUMAN EXPOSURE STUDIES/ The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found
no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant
increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into
the relationship of vitamin E and prostate cancer. To determine the long-term effect of vitamin E and selenium on risk of
prostate cancer in relatively healthy men. A total of 35,533 men from 427 study sites in the United States, Canada, and
Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific
antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older
for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned
to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis
reflect the final data collected by the study sites on their participants through July 5, 2011. Oral selenium (200 ug/d from L-
selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) with matched
selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12
years. Prostate cancer incidence /was/ used as main outcome measure/. This report includes 54,464 additional person-
years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo
(referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer
(hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P =
.18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the
absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the
combination. Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.
[Klein EA et al; JAMA 306 (14): 1549-56 (2011)] Full text: PMC4169010 Abstract: PubMed
 from HSDB
/HUMAN EXPOSURE STUDIES/ When patients with porphyria cutanea tarda were given daily doses of 1000 mg alpha-
tocopherol for 3 months, there were marked increases in 24-hour urinary excretion of androsterone and etiocholanone +
dehydroepiandrosterone and a large decrease in 24-hour excretion of pregnanediol.
 from HSDB
/HUMAN EXPOSURE STUDIES/ Effects of alpha-tocopherol on some biochemical parameters have been reported in man.
A group of 52 patients (average age 72 years) showed a mean increase in serum cholesterol of 74 mg/dL while receiving
300 mg alpha-tocopherol daily, but no such increase was seen in a small group of healthy young men taking 800 mg daily.
 from HSDB
/HUMAN EXPOSURE STUDIES/ Adult humans have tolerated 1 g per day alpha-tocopherol for months or larger doses for
shorter periods with no undesirable effects. Therapeutically, daily doses of 20 to 600 mg of alpha-tocopherol or its acetate
salt are often taken with no toxic effects.
 from HSDB
/HUMAN EXPOSURE STUDIES/ A strong positive correlation exists between teratozoospermia /a condition characterized
by the presence of sperm with abnormal morphology that affects fertility in males/ and reactive oxygen species production,
which in turn has negative effects on their in vitro fertilization outcome. Our aim of this study was to determine potential
protective effects of alpha-tocopherol on teratozoospermia motility, viability, acrosome reaction and DNA integrity after 1-hr
in vitro incubation. Teratozoospermic semen samples were obtained from 15 volunteers aged between 20 and 30 years after
3-5 days of sexual abstinence. Samples were washed, centrifuged and incubated in 37 deg C and 5% CO(2) until sperm
swam-up. Spermatozoa were counted in the supernatant and divided into four groups, each contained 2 x 10(6) sperm/mL.
Groups one to four were incubated for 1 hr with Ham's F-10 solution as control group, 10 um A23187, 40 um alpha-
tocopherol and 10 um A23187 + 40 um alpha-tocopherol respectively. The results indicated that alpha-tocopherol has ability
to enhance teratozoospermia viability and motility, while there were no ameliorative effects on acrosome reaction and DNA
fragmentation. A23187 induced acrosome reaction in teratozoospermia and alpha-tocopherol significantly diminished this
effect. In conclusion, although alpha-tocopherol could improve teratozoospermia motility and viability, its effects on DNA
integrity and acrosome reaction ability as supplementation IVF culture media are not obvious. Abstract: PubMed
Keshtgar S et al; Andrologia 44 (Suppl 1): 721-7 (2012)
 from HSDB
/SIGNS AND SYMPTOMS/ Clinical deficiency of vitamin E is rare because adequate amounts are supplied in the normal
diet. Symptoms of deficiency include ataxia, muscle weakness, nystagmus, and losses in touch and pain sensations.
 from HSDB
/SIGNS AND SYMPTOMS/ Vitamin E deficiency in premature infants may result in hemolytic anemia, thrombocytosis, and
increased platelet aggregation.
 from HSDB
/SIGNS AND SYMPTOMS/ Some adults given repeated doses of 2 to 3 g/day, in an attempt to reduce angina pectoris,
developed skin rashes and mild GI irritation with diarrhea, but 1 g daily was consumed for months without untoward effects.
Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p.
II-266
 from HSDB
/SIGNS AND SYMPTOMS/ Reports of toxicity to enterally administered vitamin E are rare in infants. However, increased
risks of sepsis and necrotizing enterocolitis have been reported after both enteral and parenteral vitamin E, primarily when
plasma (or serum) vitamin E levels exceed 3.5 mg/dL. Levels this high are seldom seen with enteral vitamin E when intake is
25 mg d-tocopherol equivalent/(kg/day) or less. Intakes below this threshold will be provided by infant formulas with vitamin
E to energy ratios of up to 20 mg/100 kcal (30 IU/100 kcal) so long as energy intake does not exceed 125 kcal/(kg/day).
Abstract: PubMed
Bell EF; J Nutr 119 (12 Suppl): 1829-31 (1989)
 from HSDB
/SIGNS AND SYMPTOMS/ Side effects reported in clinical use of vitamin E supplements include severe weakness and
fatigue induced in healthy adults by daily doses of around 720 mg alpha-tocopherol. These side effects were observed in a
double-blind study on two healthy young males receiving 720 mg alpha-tocopherol daily. In the latter study, the symptoms
were associated with an increase in serum creatine kinase activity and greatly increased 24-hour urinary creatine excretion;
asymptomatic creatinuria was reported in a young male taking high doses of vitamin E.
 from HSDB
/EPIDEMIOLOGY STUDIES/ Mexican-American children have a high prevalence of overweight/obesity. Micronutrient
deficiencies may be contributing to the development of greater adiposity in these children. This study investigated the
relations between adiposity and serum concentrations of carotenoids, retinol, and vitamin E among Mexican-American
children 8-15 years of age included in the 2001-2004 U.S. NHANES. Associations of the outcomes of children's body mass
index (BMI), truncal fat mass (TrFM), and total body fat mass (TBFM) with serum concentrations of beta-carotene, cis-beta-
carotene, trans-beta-carotene, retinol, and alpha-tocopherol were determined by using linear, quantile, and multinomial
regression models. BMI was inversely associated with serum concentrations of beta-carotene (b = -0.88, P < 0.05), trans-
beta-carotene (b = -2.21, P < 0.01), cis-beta-carotene (beta = -2.10, P < 0.01), and alpha-tocopherol adjusted for total
cholesterol ratio (b = -3.66, P < 0.01), respectively. Similar inverse associations were found with TrFM and TBFM. Higher
cis-beta-carotene and alpha-tocopherol serum concentrations were associated with reduced probability of overweight (OR:
0.57; 95% CI: 0.37, 0.89; P < 0.05; and OR: 0.56; 95% CI: 0.37, 0.86; P < 0.05; respectively) and obesity (OR: 0.39; 95%
CI: 0.26, 0.58; P < 0.01; and OR: 0.38; 95% CI: 0.24, 0.60; P < 0.01; respectively). Higher retinol serum concentrations were
associated with increased probability of overweight and obesity (OR: 2.01; 95% CI: 1.26, 3.22; P < 0.01; and OR: 2.90; 95%
CI: 1.65, 5.09; P < 0.01; respectively). Significant inverse associations were found between serum concentrations of
carotenoids and vitamin E and adiposity among Mexican-American children, but serum retinol concentrations were positively
associated with adiposity. Abstract: PubMed
Gunanti IR et al; J Nutr 144 (4): 489-95 (2014)
 from HSDB
/EPIDEMIOLOGY STUDIES/ Carotenoids, vitamin A, and vitamin E are important for the normal growth, immunity, and
development of infants and are mainly obtained through breast milk in breastfeeding infants. We hypothesized that plasma
carotenoids, retinol and alpha-tocopherol would be highly associated among mothers and their infants. 174 HIV-
seronegative women and their infants were followed in Malawi, and all infants were known to be breastfeeding from birth
until 12 months of age. Plasma carotenoids, retinol, and alpha-tocopherol were measured in women at 2 weeks post-partum
and in infants at 12 months. The mean concentrations of plasma carotenoids in umol/L among mothers and infants were,
respectively, for alpha-carotene (0.042 and 0.015), beta-carotene (0.300 and 0.081), beta-cryptoxanthin (0.073 and 0.056),
lutein (0.357 and 0.252), zeaxanthin (0.077 and 0.044), lycopene (0.192 and 0.096), total carotenoids (1.042 and 0.545),
retinol (1.01 and 0.786), and alpha-tocopherol (18.5 and 16.1). Spearman correlations between maternal and infant plasma
were 0.255, 0.284, 0.338, 0.274, 0.275, 0.497, 0.242, 0.230, 0.252 (all P <0.005) respectively. These findings suggest that
maternal plasma carotenoid, retinol, and alpha-tocopherol concentrations in the early post-partum period are strongly
associated with respective plasma concentrations in their breastfeeding infants at 12 months.
Dancheck B et al; FASEB J 18(4 Pt 1): A509-A510 (2004)
 from HSDB
/EPIDEMIOLOGY STUDIES/ Alpha -tocopherol is the most plentiful circulating form of vitamin E and an important
antioxidant, but effects on fetal growth have rarely been examined. We investigated this relationship in a prospective study of
1,190 young (22.4+/-0.1 yr) healthy pregnant women from Camden, NJ. Plasma -tocopherol was assayed at entry to care
(week 16) and at week 28; concentrations increased between entry and the 3rd trimester (p<0.01). Higher alpha-tocopherol
(highest quintile vs other quintiles) at both entry and during the 3rd trimester was significantly associated with increased birth
weight (beta+/-SE, 80+/-29 g, p<0.01 for entry and 108+/-31 g, p<0.001 for the 3rd trimester) by multiple regression
analysis. Similar results were found after adjustment for plasma cholesterol (95+/-30 g, p<0.01 at entry and 88+/-29 g,
p<0.01 at the 3rd trimester). In addition, during the 3rd trimester, women in the highest alpha-tocopherol quintile had a
greater than two-fold reduction in the risk of bearing a small for gestational age infant (AOR 0.44, 95% CI 0.21, 0.92, p
<0.03). These data thus suggest that increased circulating levels of alpha-tocopherol are associated with increased fetal
growth; and that positive effects are evidenced from early pregnancy.
Scholl TO et al; FASEB J 20 (4): A622 (2006)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Calcium (Ca(2+)) and reactive oxygen species (ROS) constitute the most influential
intracellular signaling molecules participating in the regulation of different sperm functions. Elevating intracellular Ca(2+) and
ROS in physiologic range regulate capacitation, motility, acrosome reaction, and sperm-oocyte fusion; whereas cytosolic
Ca(2+) overload and ROS overproduction have pathologic effects. Our aim of this study was determination of antioxidant
effects of alpha-tocopherol on sperm motility, viability, and DNA integrity in a condition where cytosolic calcium overload was
induced by A23187 (a calcium ionophore). Our results indicated that, alpha-tocopherol has ability to prevent sperm mortality
and save sperm rapid motility after 1 hour incubation. At the same time, A23187 reduced significantly percentage of rapid
sperm motility and increased sperm mortality and DNA damage. Results of sperms incubation in the medium contain a
combination of A23187 and alpha-tocopherol showed that alpha-tocopherol can reduce many of the deleterious effects of
A23187. In conclusion, it seems that the harmful effects of A23187 are due to excessive ROS production, and alpha-
tocopherol neutralizes these effects. Abstract: PubMed
Fanaei H et al; Reprod Sci. 18 (10): 978-82 (2011)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Vitamin E succinate (RRR-alpha-tocopheryl succinate, VES), an efficient inducer of
apoptosis, acts as a potent agent for cancer therapy. However, the mechanism by which VES mediates the effects are not
yet fully understood. Here we studied the effect of endoplasmic reticulum (ER) stress and unfolded protein response (UPR)
on VES-induced apoptosis of SGC-7901 human gastric cancer cells. VES caused cytological changes typical of apoptosis,
increased ER dilation and cytosolic Ca(2+) concentration. And endogenous ER stress markers, GRP78 and GRP94 were
transcriptionally and translationally altered. In response to VES, induction of CHOP, activation of caspase-4 and JNK were
observed. Furthermore, VES also triggered activation of UPR components, including RNA-dependent protein kinase (PKR)-
like ER kinase (PERK), activating transcription factor 6 (ATF6), X-box-binding protein 1 (XBP1), and ATF4 in a concentration-
and time-dependent manner. Consequently, our results suggest that VES-induced apoptosis is coupled to ER stress and
UPR activation in SGC-7901 human gastric cancer cells. /Vitamin E succinate/ Abstract: PubMed
Huang X et al; Cancer Lett 296 (1): 123-31 (2010)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Vitamin E, a micronutrient (comprising alpha-, beta-, gamma- and delta-tocopherols,
alpha-, beta-, gamma- and delta-tocotrienols), has documented antioxidant and non-antioxidant effects, some of which
inhibit inflammation and angiogenesis. We compared the abilities of alpha-, gamma- and delta-tocopherols to regulate
human blood cytotoxicity (BEC) and lymphatic endothelial cytotoxicity (LEC), proliferation, invasiveness, permeability,
capillary formation and suppression of TNF-alpha-induced VCAM-1 as in vitro models of inflammatory angiogenesis. alpha-,
gamma- and delta-tocopherols were not toxic to either cell type up to 40 microM. In BEC, confluent cell density was
decreased by all concentrations of delta- and gamma-tocopherol (10-40 microM) but not by alpha-tocopherol. LEC showed
no change in cell density in response to tocopherols. delta-Tocopherol (40 microM), but not other isomers, decreased BEC
invasiveness. In LEC, all doses of gamma-tocopherol, as well as the highest dose of alpha-tocopherol (40 microM),
decreased cell invasiveness. delta-Tocopherol had no effect on LEC invasiveness at any molarity. delta-Tocopherol dose
dependently increased cell permeability at 48 hr in BEC and LEC; alpha- and gamma-tocopherols showed slight effects.
Capillary tube formation was decreased by high dose (40 microM) concentrations of alpha-, gamma- and delta-tocopherol,
but showed no effects with smaller doses (10-20 microM) in BEC. gamma-Tocopherol (10-20 microM) and alpha-tocopherol
(10 microM), but not delta-tocopherol, increased LEC capillary tube formation. Lastly, in BEC, alpha-, gamma- and delta-
tocopherol each dose-dependently reduced TNF-alpha-induced expression of VCAM-1. In LEC, there was no significant
change to TNF-alpha-induced VCAM-1 expression with any concentration of alpha-, gamma- or delta-tocopherol. These
data demonstrate that physiological levels (0-40 microM) of alpha-, gamma- and delta-tocopherols are nontoxic and dietary
tocopherols, especially delta-tocopherol, can limit several BEC and LEC endothelial behaviors associated with angiogenesis.
Tocopherols may therefore represent important nutrient-signals that limit cell behaviors related to
inflammation/angiogenesis, which when deficient, may predispose individuals to risks associated with elevated angiogenesis
such as inflammation and cancer; further differences seen from the tocopherols may be due to their blood or lymphatic cell
origin. Abstract: PubMed
Wells SR et al; J Nutr Biochem. 21 (7): 589-97 (2010)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Vitamin E (alpha-tocopherol) is the major lipid-soluble antioxidant in most animal
species. By controlling the secretion of vitamin E from the liver, the alpha-tocopherol transfer protein regulates whole-body
distribution and levels of this vital nutrient. However, the mechanism(s) that regulates the expression of this protein is poorly
understood. Here we report that transcription of the TTPA gene in immortalized human hepatocytes is induced by oxidative
stress and by hypoxia, by agonists of the nuclear receptors PPARalpha and RXR, and by increased cAMP levels. The data
show further that induction of TTPA transcription by oxidative stress is mediated by an already-present transcription factor
and does not require de novo protein synthesis. Silencing of the cAMP response element-binding (CREB) transcription
factor attenuated transcriptional responses of the TTPA gene to added peroxide, suggesting that CREB mediates responses
of this gene to oxidative stress. Using a 1.9-kb proximal segment of the human TTPA promoter together with a site-directed
mutagenesis approach, we found that single-nucleotide polymorphisms that are commonly found in healthy humans
dramatically affect promoter activity. These observations suggest that oxidative stress and individual genetic makeup
contribute to vitamin E homeostasis in humans. These findings may explain the variable responses to vitamin E
supplementation observed in human clinical trials.[Ulatowski L et al; Free Radic Biol Med. 53 (12): 2318-26 (2012)] Full
 from HSDB
/OTHER TOXICITY INFORMATION/ Numerous epidemiological studies have associated higher vitamin E status with
reduced cancer, including lung, colorectal, prostate, colon, stomach, reproductive organs, upper gastrointestinal tract,
bladder, breast, cervix, mouth, pharynx and thyroid cancer. Reduced serum vitamin E levels are also associated with a
higher incidence of lymphoma and leukemia in some populations. Not all epidemiological studies have shown an inverse
relationship between vitamin E status and cancer risk, but the majority have.
 from HSDB
13.1.5 Non-Human Toxicity Excerpts 

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The effect of pharmacological dose of alpha-tocopherol on
heart health was determined in Wistar rats. Animals were randomly assigned to either C (control, n = 11) or E (alpha-
tocopherol, n = 11) group. Animals received corn oil (C) or alpha-tocopherol dissolved in corn oil (250 mg alpha-
tocopherol/[kg body wt/day]) (E) by gavage for a 7-week period. Rats underwent echocardiogram and were analyzed for
cardiomyocyte histology and cardiac alpha-tocopherol absorption at the end of the study period. As compared to the C
group, alpha-tocopherol-supplemented group showed significantly (p < 0.05) lower body weight (E, 412.8 g vs C, 480.3 g)
and total cardiac weight (E, 0.94 g vs C, 1.08 g); cardiomyocyte histological impairment; smaller left ventricle (LV) (LV end-
diastolic diameter (E, 7.22 mm vs C, 7.37 mm), lower LV systolic [left ventricle fractional shortening (E, 47.6% vs C, 53.6%)
and ejection fraction ratio (E, 85.4 vs C, 89.9)] and diastolic [early peak velocities of diastolic transmitral flow (E, 64.6 cm/sec
vs C, 75.1 cm/sec)] function. The alpha-tocopherol uptake in target tissue was confirmed by determination of alpha-
tocopherol concentration medians in cardiac tissue (E, 109.91 nmol/kg vs C, 52.09 nmol/kg). The current study indicates
that pharmacological dose of alpha-tocopherol supplementation can induce cardiotoxicity in healthy rats. Abstract: PubMed
Nascimento MC et al; Hum Exp Toxicol. 30 (10): 1540-8 (2011)
 from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Five groups of weanling rats were fed a control diet
containing the normal level of 35 mg d-alpha-tocopheryl acetate/kg diet or 25, 50, 100, or 1000 times this amount. After 8
weeks, rats in the highest-dose group had significantly lower feed and protein efficiencies. Serum and liver vitamin E levels
increased progressively with dose. After 13 weeks, hemoglobin, serum cholesterol, and urinary creatine and creatinine were
unaffected by treatment, but SGPT was elevated in the highest-dose group.
 from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Rats receiving alpha-tocopherol at a dosage of 100
mg/rat/day for 19 weeks showed an increase in phosphorus metabolism, but no effect was found when the dose was 10
mg/rat/day.
 from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Rats were reported to tolerate doses of 4 g/kg daily for two
months.
 from HSDB
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ It has been found that mice will tolerate oral doses of 50
g/kg daily for two months.
 from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ We hypothesized that zebrafish (Danio rerio) undergoing
long-term vitamin E deficiency with marginal vitamin C status would develop myopathy resulting in impaired swimming.
Zebrafish were fed for 1 yr a defined diet without (E-) and with (E+) vitamin E (500 mg alpha-tocopherol/kg diet). For the last
150 days, dietary ascorbic acid concentrations were decreased from 3500 to 50 mg/kg diet and the fish sampled periodically
to assess ascorbic acid concentrations. The ascorbic acid depletion curves were faster in the E- compared with E+ fish (P <
0.0001); the estimated half-life of depletion in the E- fish was 34 days, while in it was 55 days in the E+ fish. To assess
swimming behavior, zebrafish were monitored individually following a "startle-response" stimulus, using computer and video
technology. Muscle histopathology was assessed using hematoxylin and eosin staining on paramedian sections of fixed
zebrafish. At study end, E- fish contained 300-fold less alpha-tocopherol (p < 0.0001), half the ascorbic acid (p = 0.0001)
and 3-fold more malondialdehyde (p = 0.0005) than did E+ fish. During the first minute following a tap stimulus (p < 0.05),
E+ fish swam twice as far as did E- fish. In the E- fish, the sluggish behavior was associated with a multifocal, polyphasic,
degenerative myopathy of the skeletal muscle. The myopathy severity ranged from scattered acute necrosis to widespread
fibrosis and was accompanied by increased anti-hydroxynonenal staining. Thus, vitamin E deficiency in zebrafish causes
increased oxidative stress and a secondary depletion of ascorbic acid, resulting in severe damage to muscle tissue and
impaired muscle function.[Lebold KM et al; Comp Biochem Physiol C Toxicol Pharmacol. 157 (4): 382-9 (2013)] Full text:
 from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ alpha-Tocopherol is a required, lipid-soluble antioxidant
that protects PUFA. We hypothesized that alpha-tocopherol deficiency in zebrafish compromises PUFA status. Zebrafish
were fed for 1 y either an alpha-tocopherol-sufficient (E+; 500 mg alpha-tocopherol/kg) or -deficient (E-; 1.1 mg alpha-
tocopherol/kg) diet containing alpha-linolenic (ALA) and linoleic (LA) acids but without arachidonic acid (ARA), EPA, or DHA.
Vitamin E deficiency in zebrafish decreased by ~20% (n-6) (P < 0.05) and (n-3) (P < 0.05) PUFA and increased the (n-6):(n-
3) PUFA ratio (P < 0.05). In E- compared to E+ females, long chain-PUFA status was impaired, as assessed by a ~60%
lower DHA:ALA ratio (P < 0.05) and a ~50% lower ARA:LA ratio (P < 0.05). fads2 (P < 0.05) and elovl2 (P < 0.05) mRNA
expression was doubled in E- compared to E+ fish. Thus, inadequate vitamin E status led to a depletion of PUFA that may
be a result of either or both increased lipid peroxidation and an impaired ability to synthesize sufficient PUFA, especially (n-
3) PUFA.[Lebold KM et al; J Nutr 141 (12): 2113-8 (2011)] Full text: PMC3223870 Abstract: PubMed
 from HSDB
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of weanling female Wistar rats were fed diets
containing 0, 25, 250, 2500, 10,000, or 25,000 IU vitamin E/kg diet for 8 and 16 months. Vitamin E depressed body-weight
gain at concentrations of 10,000 and 25,000 IU/kg diet, and increased relative heart and spleen weights were seen at 8
months and 16 months, respectively. There was an increase in plasma alkaline phosphatase and a decrease in the ash
content of bone after 16 months at these two dose levels. Prothrombin time was reduced at 12 months, but not at 9 or 16
months. Urinary excretion of creatine and creatinine was normal at 11 months. No histological examinations were reported.
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Vitamin E /was administered/ in amounts of 150 or 300
mg/kg/day to pregnant mice sc on days 6, 8 and 10 of gestation. Growth retardation and fetal survival were increased in the
treated group. The incidence of cleft palate was increased. Studies with the rat (75 mg/day) were negative.
Shepard, T.H. Catalog of Teratogenic Agents. 13th ed. Baltimore, MD: The Johns Hopkins University Press, 2010., p. 478
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ To test the hypothesis that embryogenesis depends
upon alpha-tocopherol (E) to protect embryo polyunsaturated fatty acids (PUFAs) from lipid peroxidation, new
methodologies were applied to measure alpha-tocopherol and fatty acids in extracts from saponified zebrafish embryos. A
solid phase extraction method was developed to separate the analyte classes, using a mixed mode cartridge (reverse
phase, pi-pi bonding, strong anion exchange), then alpha-tocopherol and cholesterol were measured using standard
techniques, while the fatty acids were quantitated using a novel, reverse phase liquid chromatography-mass spectrometry
(LC-MS) approach. We also determined if alpha-tocopherol status alters embryonic lipid peroxidation products by analyzing
24 different oxidized products of arachidonic or docosahexaenoic (DHA) acids in embryos using LC with hybrid quadrupole-
time of flight MS. Adult zebrafish were fed E- or E+ diets for 4 months, and then were spawned to obtain E- and E+
embryos. Between 24 and 72 hours post-fertilization (hpf), arachidonic acid decreased 3-times faster in E- (21 pg/hr)
compared with E+ embryos (7 pg/hr, P<0.0001), while both alpha-tocopherol and DHA concentrations decreased only in E-
embryos. At 36 hpf, E- embryos contained double the 5-hydroxy-eicosatetraenoic acids and 7-hydroxy-DHA concentrations,
while other hydroxy-lipids remained unchanged. Vitamin E deficiency during embryogenesis depleted DHA and arachidonic
acid, and increased hydroxy-fatty acids derived from these PUFA, suggesting that alpha-tocopherol is necessary to protect
these critical fatty acids.[Lebold KM et al; Redox Biol. 2: 105-13 (2013)] Full text: PMC3887274 Abstract: PubMed
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Interleukins (IL) play an important role in angiogenesis.
Tocopherol possesses immunomodulating effect in addition to antioxidant property. The objective of this study was to
determine whether gamma tocopherol's (gT) angiogenic activity in placental network is enhanced via promoting interleukins.
Pregnant ewes (N=18) were supplemented, orally, with 500 mg of alpha tocopherol (aT; N=6) or 1,000 mg of gT (N=7) or
placebo (CON; N=5) once daily from 107 to 137 days post breeding. Uterine and placental tissue samples were obtained at
the end of supplementation to evaluate relative mRNA expressions of IL-1b, IL-6, IL-8, Tumor Necrosis Factor (TNF)alpha,
Vascular Endothelial Growth Factor (VEGF), kinase insert domain receptor (KDR; VGFR2; a type III receptor tyrosine
kinase), and soluble fms-like tyrosine kniase-1 (sFlt1 or sVEGFR1) in uterus, caruncle and cotyledon. Oral supplementation
of gT increased IL-6, IL-8, KDR and VEGF mRNA abundances whereas sFlt1 mRNA abundance was suppressed in uterus,
caruncle and cotyledon, compared to aT and placebo treated ewes (P<0.05). The TNFalpha and IL-1b mRNA abundances
were suppressed in uterus, caruncle and cotyledon but TNF alpha is higher in gT group compared to aT group (P<0.05),
whereas IL-1b was similar between treatment groups (P>0.1). Gamma tocopherol supplementation increased IL-6, IL-8, and
KDR mRNA abundances and suppressed sFlt1 and TNFalpha mRNA abundances thereby increased VEGF mRNA
expression and angiogenesis in placental vascular network during late gestation. It is plausible that the angiogenic effect of
gamma tocopherol in placental vascular network is exerted via an alternate path by enhancing IL-6 and IL-8.[Kasimanickam
RK et al; Reprod Biol Endocrinol 10: 4 (2012)] Full text: PMC3398327 Abstract: PubMed
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Tocopherols have biphasic, proangiogenic and
antiangiogenic therapeutic effects. The objective of this clinical trial was to clarify tocopherol's placental angiogenic potential
in late pregnant ewes following oral supplementation. Eighteen pregnant ewes during late gestation were selected for this
study. Ewes were given oral supplementation of 500 mg of alpha-tocopherol (aT; N=6) or 1000 mg of gamma-tocopherol
(gT; N=7) or placebo (CON; N=5) once daily from 107 to 137 days post breeding. Serum was obtained at weekly intervals
and tissue samples were obtained at the end of supplementation to: 1) evaluate tocopherol concentrations in serum, uterus
and placentome; 2) evaluate relative mRNA expressions of Vascular Endothelial Growth Factor (VEGF), Placental Growth
Factor (PlGF), endothelial Nitric Oxide Synthase (eNOS) and Hypoxia Inducible Factors (HIF) in uterus, caruncle and
cotyledon; 3) analyze the morphometry of the placental vascular network. Supplementation of aT or gT resulted in increased
concentrations in serum, placentome and uterus compared to control (P<0.05). In aT group, mRNA expressions of PlGF,
eNOS and HIF-1alpha in cotyledon were greater than the CON group. In gT group, mRNA expressions of VEGF, eNOS,
HIF-1 alpha and HIF-2 alpha in caruncle and uterus, and HIF-1alpha in cotyledon, were greater than the CON group.
Morphometry analysis revealed increased angiogenesis in the supplemented groups. Daily oral supplementation of aT or gT
increased angiogenesis in the placental vascular network in pregnant ewes during late gestation. Increase in placental
angiogenesis may provide nutrients required for the development and growth of fetus during late pregnancy.[Kasimanickam
RK et al; Reprod Biol Endocrinol. 8: 86 (2010)] Full text: PMC2913989 Abstract: PubMed
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The objective of this study was to determine the effects
of maternally supplemented natural- or synthetic-source vitamin E on suckling calf performance and immune response. In a
2-yr study, one hundred fifty-two 2- and 3-yr-old, spring-calving, Angus-cross beef cows were blocked by age, BW, and BCS
into 1 of 3 isocaloric, corn-based dietary supplements containing 1) no additional vitamin E (CON), 2) 1,000 IU/d of
synthetic-source vitamin E (SYN), or 3) 1,000 IU/d of natural-source vitamin E (NAT). Maternal supplementation began
approximately 6 wk prepartum and continued until the breeding season. Colostrum from cows and blood from calves was
collected 24 hr postpartum for analysis of IgG concentration as an indicator of passive transfer and circulating alpha-
tocopherol concentration. At 19 d of age, blood was collected from calves to determine the expression of CD14 and CD18
molecules on leukocytes. At 21 and 35 d of age, humoral immune response was measured by a subcutaneous injection, in
the neck, with ovalbumin (20 mg; OVA) and blood samples collected weekly until d 63 of age to determine antibodies
produced against OVA. At d 63 of age, calves were administered an intradermal injection of OVA (1 mg) in the neck to
assess cell-mediated immunity, which was determined on d 65 of age by measuring nodule size with calipers. Circulating
alpha-tocopherol concentrations were increased at both 24 hr (P = 0.001) and at the day of initial OVA challenge (P < 0.001)
in SYN and NAT compared with CON calves. No differences were detected (P > 0.05) for calf birth BW, ADG, or weaning
BW. There were no differences (P > 0.05) in calf serum total IgG or cow colostrum total IgG at 24 hr or presence of CD14
and CD18 receptors at d 19 of age. The NAT calves had a greater antigen response to OVA at d 63 than SYN calves (P =
0.01; treatment x day interaction). As an indicator of cell-mediated immunity to OVA, nodule size at 65 d of age was not
affected (P = 0.92) by maternal dietary supplementation. In conclusion, calves suckling cows supplemented with natural-
and synthetic-source vitamin E had increased circulating concentrations of alpha-tocopherol at 24 hr, which appeared to
continue throughout maternal supplementation; however, calf immune function and performance were not affected.
Abstract: PubMed
Horn MJ et al; J Anim Sci 88 (9): 3128-35 (2010)
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The objective was to determine the effects of natural- or
synthetic-source vitamin E on reproductive efficiency in Angus-cross beef cows. In Exp. 1, one hundred fifty-two cows were
fed hay and corn silage based diet and assigned to 1 of 3 dietary supplements (3 pens/treatment): 1) containing no
additional vitamin E (CON), 2) formulated to provide 1,000 IU x d(-1) of synthetic-source vitamin E (SYN; all-rac or dl-alpha-
tocopherol acetate), or 3) formulated to provide 1,000 IU x d(-1) of natural-source vitamin E (NAT; RRR or D-alpha-
tocopherol acetate). In Exp. 2, seventy-five cows (2 reps/treatment) were assigned to similar treatments as Exp. 1; however,
a vitamin-mineral supplement was offered for ad libitum intake and vitamin intake was calculated from predicted mineral
intakes. Cows grazed pastures rather than being fed hay and corn silage as in Exp. 1. In Exp. 1 and 2, supplementation
began 6 wk prepartum and continued until initiation of the breeding season. Blood samples were collected at calving (Exp.
1) or breeding (Exp. 2) to determine alpha-tocopherol concentration and weekly beginning 4 wk postpartum (Exp. 1) or 7
and 14 d before estrus synchronization (Exp. 2) to determine return to estrus via progesterone concentration. Cows were
synchronized and bred by AI based on heat detection; nonresponding cows were time bred (AI) 66 h after PGF(2 alpha)
injection, and cows returning to estrus after AI were bred by natural service. In Exp. 1, cows supplemented with NAT and
SYN had greater (P < 0.001) serum concentrations of alpha-tocopherol at calving compared with CON cows. Dietary
supplement did not affect (P >or= 0.55) the percentage of cows cycling before synchronization or the number of days to
return to estrus by cows that resumed estrus before synchronization. Cows supplemented with SYN tended to have greater
first service conception rates compared with CON and NAT (P = 0.09); however, first plus second services combined and
overall conception rates were not affected (P >or= 0.23). In Exp. 2, NAT cows had greater (P = 0.002) concentrations of
alpha-tocopherol at breeding, whereas there was no difference (P > 0.05) between SYN and CON. Supplementation of SYN
or NAT did not affect (P >or= 0.17) days to resumption of estrus before breeding, first service, first plus second services
combined, or overall conception rates. These data suggest that supplementation of SYN or NAT source vitamin E increased
alpha-tocopherolconcentration in cows; however, effects on reproductive efficiency are minima Abstract: PubMed
Horn M et al; J Anim Sci 88 (9): 3121-7 (2010)
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ To investigate the effects of 0.1% and 2% vitamin E
(alpha-tocopherol) supplementation on the expression of nitric oxide (NO) in penile tissue of rats with experimentally
induced diabetes mellitus (DM). In all, 30 male rats were divided into six groups: normoglycaemic (NG), NG treated with
0.1% vitamin E (NGE1), NG treated with 2% vitamin E (NGE2), DM, DM treated with 0.1% vitamin E (DME1), and DM
treated with 2% vitamin E (DME2). After 120 days the rats were killed, and penile tissue was collected and processed for
neuronal NO synthase (nNOS) immunohistochemistry to determine areas of nNOS-immunoreactive varicosities. nNOS-
immunoreactive varicosities in DME2 rats were similar to those of controls (NG) and controls supplemented with vitamin E
(NGE1 and NGE2). Varicosity sizes in the NGE1 group were similar to the DM rats with no vitamin E supplementation.
Supplementation with 2% vitamin E had a positive effect on areas of nNOS-immunoreactive varicosities of penile tissue in
DM rats. Abstract: PubMed
Tronchini EA et al; BJU Int 106 (11): 1788-93 (2010)
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Diabetic pregnancy is still associated with an increased
rate of congenital malformations despite extensive clinical efforts to normalize the risk for the offspring. The etiology of the
diabetic embryopathy is not clear; however, experimental studies have suggested a role for oxidative stress in the
teratogenicity of diabetic pregnancy. The antioxidants alpha-tocopherol and ascorbate have improved fetal outcome in
diabetic rodent pregnancy when supplemented in moderate to high doses. In the present work we investigated if extremely
high doses of either alpha-tocopherol or ascorbate may further improve fetal outcome in offspring of diabetic rats, and, in
addition, if such treatment may exert any adverse effects of fetal development. Non-diabetic and streptozotocin diabetic
female rats were fed 2, 5, 10 or 15 % alpha-tocopherol or 4, 10 or 15 % ascorbate in their diet and fetal outcome was
assessed on gestational day 20. Maternal diabetes caused increased malformation (from 0 to 29 %) and resorption (from 5
to 38 %) rates in the offspring. The malformations included micrognathia (33 %), agnathia (51 %), other facial malformation
(6 %), absence of tail (7 %) or omphalocele (3 %). Both alpha-tocopherol and ascorbate treatment improved fetal
morphology (to 9 and 19 % malformations, and to 9 and 26 % resorptions, respectively) in offspring of diabetic rats. There
was a dose-dependent improvement for the alpha-tocopherol supplementation, where the higher doses diminished fetal
dysmorphogenesis more than the 2 % diet. The ascorbate supplementation was less dose-dependant, however, the higher
doses tended to improve fetal outcome more than the lower doses. No adverse effects of the antioxidants were noted in the
offspring with the exception of one case of agnathia in a fetus of a non-diabetic rat supplemented with 15 % alpha-
tocopherol. These results indicate that very high doses of dietary antioxidants may be needed to normalize the development
of the offspring in experimental diabetic pregnancy, but that treatment with such high doses may also have adverse effects in
non-diabetic pregnancy.
Eriksson UJ Cederberg J; Diabetes 54 (Suppl 1): A38 (2005)
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ At the end of a 90-day study on d-alpha-tocopherol
(polyethylene glycol) 1000 succinate (TPGS), a water-soluble form of vitamin E (see rat study under Short-term studies), half
the rats from each dose group were maintained on their respective diets and used for a reproduction study. The dietary
concentrations of TPGS were 0, 0.002, 0.2, & 2%. The animals were mated on day 112 of treatment to produce the F1a
generation and on day 175 to produce the F1b generation. The F0 animals were maintained on their respective diets to 265-
265 days of treatment, then sacrificed and examined histopathologically. Reproductive indices (mean gestation period, litter
size, sex ratio, and mortality of pups or parents) were unaffected by treatment. Clinical chemical and haematological
parameters were normal in the F0 generation 10 days before terminal sacrifice. /Water-soluble form of vitamin E/
 from HSDB
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant ICR mice were given daily doses of 591 mg
d-alpha- tocopherol by gavage on days 7 to 11 of pregnancy; control animals were untreated or received the same volume of
saline by gavage. In a total of 91 offspring from 7 litters, one malformation (exencephaly, open eye, and micrognathia) was
observed in the offspring from treated animals; no malformations were seen in 177 offspring (13 litters) from untreated dams
or 117 offspring (8 litters) from dams given saline by gavage. This type of malformation has never been seen in control
animals of this strain in this testing laboratory, but it can be induced by known teratogens.
 from HSDB
/LABORATORY ANIMALS: Neurotoxicity/ We hypothesized that brains from vitamin E-deficient (E-) zebrafish (Danio rerio)
would undergo increased lipid peroxidation because they contain highly polyunsaturated fatty acids, thus susceptible lipids
could be identified. Brains from zebrafish fed for 9 months defined diets without (E-) or with (E+) added vitamin E (500 mg
RRR-alpha-tocopheryl acetate per kilogram diet) were studied. Using an untargeted approach, 1-hexadecanoyl-2-
docosahexaenoyl-sn-glycero-3-phosphocholine [DHA-PC 38:6, PC 16:0/22:6]was the lipid that showed the most significant
and greatest fold-differences between groups. DHA-PC concentrations were approximately 1/3 lower in E- (4.3 +/- 0.6 mg/g)
compared with E+ brains (6.5 +/- 0.9 mg/g, mean +/- SEM, n = 10 per group, P = 0.04). Using lipidomics, 155 lipids in brain
extracts were identified. Only four phospholipids (PLs) were different (P < 0.05) between groups; they were lower in E-
brains and contained DHA with DHA-PC 38:6 at the highest abundances. Moreover, hydroxy-DHA-PC 38:6 was increased in
E- brains (P = 0.0341) supporting the hypothesis of DHA peroxidation. More striking was the depletion in E- brains of nearly
60% of 19 different lysophospholipids (lysoPLs) (combined P = 0.0003), which are critical for membrane PL remodeling.
Thus, E- brains contained fewer DHA-PLs, more hydroxy-DHA-PCs, and fewer lysoPLs, suggesting that lipid peroxidation
depletes membrane DHA-PC and homeostatic mechanisms to repair the damage resulting in lysoPL depletion.
Choi J et al; J Lipid Res. 56 (6): 1182-90 (2015)
 from HSDB
/DEVELOPMENTAL NEUROTOXICITY/ An increased intake of the antioxidant alpha-Tocopherol (vitamin E) is
recommended in complicated pregnancies, to prevent free radical damage to mother and fetus. However, the anti-PKC and
antimitotic activity of alpha-Tocopherol raises concerns about its potential effects on brain development. Recently, we found
that maternal dietary loads of alpha-Tocopherol through pregnancy and lactation cause developmental deficit in
hippocampal synaptic plasticity in rat offspring. The defect persisted into adulthood, with behavioral alterations in
hippocampus-dependent learning. Here, using the same rat model of maternal supplementation, ultrastructural
morphometric studies were carried out to provide mechanistic interpretation to such a functional impairment in adult
offspring by the occurrence of long-term changes in density and morphological features of hippocampal synapses. Higher
density of axo-spinous synapses was found in CA1 stratum radiatum of alpha-Tocopherol -exposed rats compared to
controls, pointing to a reduced synapse pruning. No morphometric changes were found in synaptic ultrastructural features,
i.e., perimeter of axon terminals, length of synaptic specializations, extension of bouton-spine contact. Glia-synapse
anatomical relationship was also affected. Heavier astrocytic coverage of synapses was observed in Tocopherol-treated
offspring, notably surrounding axon terminals; moreover, the percentage of synapses contacted by astrocytic endfeet at
bouton-spine interface (tripartite synapses) was increased. These findings indicate that gestational and neonatal exposure to
supranutritional tocopherol intake can result in anatomical changes of offspring hippocampus that last through adulthood.
These include a surplus of axo-spinous synapses and an aberrant glia-synapse relationship, which may represent the
morphological signature of previously described alterations in synaptic plasticity and hippocampus-dependent learning.
[Salucci S et al; Eur J Histochem. 58 (2): 2355 (2014)] Full text: PMC4083323 Abstract: PubMed
 from HSDB
/DEVELOPMENTAL NEUROTOXICITY/ Vitamin E (alpha-tocopherol) supplementation has been tested as prophylaxis
against gestational disorders associated with oxidative damage. However, recent evidence showing that high maternal
alpha-tocopherol intake can adversely affect offspring development raises concerns on the safety of vitamin E extradosages
during pregnancy. Besides acting as an antioxidant, alpha-tocopherol depresses cell proliferation and modulates cell
signaling through inhibiting protein kinase C (PKC), a kinase that is deeply involved in neural maturation and plasticity.
Possible effects of alpha-tocopherol loads in the maturing brain, where PKC dysregulation is associated to developmental
dysfunctions, are poorly known. Here, supranutritional doses of alpha-tocopherol were fed to pregnant and lactating dams to
evaluate the effects on PKC signaling and morphofunctional maturation in offspring hippocampus. Results showed that
maternal supplementation potentiates hippocampal alpha-tocopherol incorporation in offspring and leads to marked
decrease of PKC phosphorylation throughout postnatal maturation, accompanied by reduced phosphorylation of growth-
associated protein-43 and myristoylated alanine-rich C kinase substrate, two PKC substrates involved in neural development
and plasticity. Although processes of neuronal maturation, synapse formation and targeting appeared unaffected, offspring
of supplemented mothers displayed a marked reduction of long-term synaptic plasticity in juvenile hippocampus.
Interestingly, this impairment persisted in adulthood, when a deficit in hippocampus-dependent, long-lasting spatial memory
was also revealed. In conclusion, maternal supplementation with elevated doses of alpha-tocopherol can influence cell
signaling and synaptic plasticity in developing hippocampus and promotes permanent adverse effects in adult offspring. The
present results emphasize the need to evaluate the safety of supranutritional maternal intake of alpha-tocopherol in humans.
Abstract: PubMed
Betti M et al; J Nutr Biochem. 22 (1): 60 (2011)

 from HSDB
/BEHAVIORAL STUDIES/ alpha-Tocopherol , the main component of vitamin E, is well known to be a radical scavenger, so
an increased intake of vitamin E is recommended in complicated pregnancy, to prevent possible fetus damage by free
radical. In a previous work, we found that maternal alpha-tocopherol supplementation affects PKC-mediated cellular
signaling and hippocampal synaptic plasticity in developing brain; the latter effect persists in adulthood. Here, adult rats
maternally exposed to supranutritional doses of alpha-tocopherol were evaluated for Contextual Fear Conditioning and
spatial learning in Morris Water Maze, two different hippocampus-dependent learning tasks. Moreover, anxiety, spontaneous
activity, and explorative drive were also evaluated as factors potentially affecting learning performance. Treated rats showed
a different behavior with respect to controls: performance in Contextual Fear Conditioning was improved, while spatial
learning tested in Morris Water Maze, was impaired. The improvement of fear response was not ascribable to differences in
anxiety level and/or spontaneous activity; thus it appears to be a specific effect of alpha-tocopherol overloading during brain
development. On the contrary, the impaired performance in Morris Water Maze exhibited by treated rats can be in part
explained by their enhanced explorative drive. Although extrapolation from rats to humans is difficult, a caveat in assuming
supranutritional doses of vitamin E in pregnancy arises from this study. Abstract: PubMed
Ambrogini P et al; Physiol Behav. 104 (5): 809-15 (2011)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ The controversial role of extracellular Ca2+ in toxicity to in vitro hepatocyte systems
is reviewed. Recent reports demonstrate that extracellular Ca2+ related cytotoxicity is dependent on Ca2+ influenced
vitamin E (alpha-tocopherol) content of isolated hepatocytes. Based on a Ca2+ omission model of in vitro oxidative stress,
the role of vitamin E in cytotoxicity is further explored. This model demonstrates the interdependence of the GSH redox
system and vitamin E as protective agents during oxidative stress. Following chemical oxidant induced depletion of
intracellular GSH, cell morphology and viability are maintained by the continuous presence of cellular alpha-tocopherol
above a threshold level of 0.6-1.0 nmol/10+6 cells. alpha-Tocopherol threshold dependent cell viability is directly correlated
with the prevention of the loss of cellular protein thiols in the absence of intracellular GSH. Potential mechanisms for this
phenomenon are explored and include a direct reductive action of alpha-tocopherol on protein thiyl radicals, and the
prevention of oxidation of protein thiols by scavenging of lipid peroxyl radicals by alpha-tocopherol. It is suggested that in
light of the threshold phenomenon of vitamin E prevention of potentially severe oxidative stress induced cytotoxicity, its use
as a protective agent against an oxidative challenge in vivo should be reassessed. Abstract: PubMed
Pascoe GA, Reed DJ; Free Radic Biol Med 6 (2): 209-24 (1989)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ The effects of vitamin E supplementation on cellular alpha-tocopherol concentrations
of neutrophils from Holstein calves and the mechanism of scavenger receptor class B type I (SR-BI)-mediated uptake of
alpha-tocopherol were examined. Cellular alpha-tocopherol concentrations in vitamin E-treated calves increased from 3.5 +/-
0.38 to 7.2 +/- 0.84 ug/10+7 cells, respectively, within 14 d after vitamin E supplementation; these concentrations were
significantly higher than those of control calves (P < 0.01). The expression indices of SR-BI [a major receptor that
recognizes high-density lipoprotein (HDL)] mRNA in neutrophils were two to five times higher (P < 0.01) in neutrophils
obtained from vitamin E-supplemented calves compared with those from control calves, and anti-SR-B1 antibody, ranging
from 0.1 to 1.0 ug/mL, significantly (P < 0.01) decreased cellular alpha-tocopherolconcentrations of neutrophils.
Cytochalasin D and latrunculin B, major inhibitors of actin polymerization of neutrophils, significantly decreased cellular
alpha-tocopherol concentrations of neutrophils (P < 0.01). Our results demonstrated that in vitamin E-supplemented calves:
1) alpha-tocopherol is mainly distributed with HDL, 2) alpha-tocopherol within HDL is recognized by SR-BI on the surface of
neutrophils, and 3) rearrangement of the actin cytoskeleton is a crucial step for the uptake of alpha-tocopherol by
neutrophils.[Higuchi H et al; Can J Vet Res 77 (2): 120-5 (2013)] Full text: PMC3605927 Abstract: PubMed
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ To determine the effects of alpha-tocopherol supplementation to oocyte maturation
media and embryo culture media on the yield of ovine embryos. alpha-Tocopherol , at concentrations of 0, 50, 100, 200, 400
and 500 uM was supplemented to ovine oocyte or embryo culture media and cultured at 5% or 20% O(2) levels.
Percentages of cleavage, morula and blastocyst, total cell count and comet assay were taken as indicators of developmental
competence of embryos. 200 uM alpha-Tocopherol in embryo culture medium at 20% O(2) level significantly increased the
rates of cleavage (P<0.05), morulae (P<0.05) and blastocyst (P<0.01) formation and blastocyst total cell number (P<0.01)
when compared with control. The rates of blastocyst formation were also significantly higher in 100 uM (P<0.01) and 400 uM
(P<0.05) supplemented groups than control. alpha-Tocopherol supplementation may enhance the in vitro developmental
competence of ovine embryos by protecting them from oxidative damage.[Natarajan R et al; J Assist Reprod Genet. 27 (8):
483-90 (2010)] Full text: PMC2941590 Abstract: PubMed
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ Reactive oxygen species contribute to cellular ageing and an increased level of
oxidative stress is often associated with ageing in many organisms. Supplementation of antioxidants has been advocated to
decrease cellular oxidative stress and potentially extend lifespan. A genetically modified K6001 strain of Saccharomyces
cerevisiae was employed to determine the effect of several antioxidants, including D-erythroascorbic acid, alpha-tocopherol
and coenzyme Q(10) on yeast cell replicative ageing. The replicative lifespan of the K6001 strain was assessed by
absorbance change as cells exhibited a linear growth in glucose medium. In this study, water-soluble D-erythroascorbic acid
had little effect on cell replicative lifespan. However, supplementation of the growth medium with the lipophilic antioxidants
alpha-tocopherol increased oxidative stress and decreased cell lifespan. The use of alpha-tocopherol analogues revealed
that the antioxidant activity and the membrane retention ability of alpha-tocopherol were involved in the lifespan reduction
effect. Supplementation with either coenzyme Q(10) alone, or in combination with alpha-tocopherol also led to a reduction in
yeast replicative lifespan. This study highlights a potential pro-oxidant action of antioxidants. Abstract: PubMed
Lam YT et al; Free Radic Biol Med 49 (2): 237-44 (2010)
 from HSDB
/ALTERNATIVE and IN VITRO TESTS/ The pregnane X receptor (PXR) has been postulated to play a role in the metabolism
of alpha-tocopherol owing to the up-regulation of hepatic cytochrome P450 (P450) 3A in human cell lines and murine
models after alpha-tocopherol treatment. However, in vivo studies confirming the role of PXR in alpha-tocopherol
metabolism in humans presents significant difficulties and has not been performed. PXR-humanized (hPXR), wild-type, and
Pxr-null mouse models were used to determine whether alpha-tocopherolmetabolism is influenced by species-specific
differences in PXR function in vivo. No significant difference in the concentration of the major alpha-tocopherol metabolites
was observed among the hPXR, wild-type, and Pxr-null mice through mass spectrometry-based metabolomics. Gene
expression analysis revealed significantly increased expression of Cyp3a11 as well as several other P450s only in wild-type
mice, suggesting species-specificity for alpha-tocopherol activation of PXR. Luciferase reporter assay confirmed activation
of mouse PXR by alpha-tocopherol. Analysis of the Cyp2c family of genes revealed increased expression of Cyp2c29,
Cyp2c37, and Cyp2c55 in wild-type, hPXR, and Pxr-null mice, which suggests PXR-independent induction of Cyp2c gene
expression. This study revealed that alpha-tocopherol is a partial agonist of PXR and that PXR is necessary for Cyp3a
induction by alpha-tocopherol. The implications of a novel role for alpha-tocopherol in Cyp2c gene regulation are also
discussed.[Johnson CH et al; Drug Metab Dispos. 41 (2): 406-13 (2013)] Full text: PMC3558860 Abstract: PubMed
 from HSDB
/IMMUNOTOXICITY/ Of the 8 different analogues (alpha-, beta-, gamma-, delta-tocopherols and tocotrienols) designated as
vitamin E, alpha-tocopherol (a-T) has been mostly studied, together with gamma-tocopherol (g-T) which is abundant in the
US diet. We compared the effect of dietary supplementation with adequate or high doses of a-T or g-T on the number and
type of genes expressed following T cell activation. C57BL/6 mice were fed diets containing adequate (30 ppm) or high (500
ppm) amounts of a-T or g-T for 4 weeks. Spleen T cells were stimulated ex vivo with plate-bound anti-CD3 and soluble anti-
CD28, and gene expression changes were assessed by gene array analysis. The data obtained indicated significant
qualitative and quantitative differences between the two analogs in regulating gene expression induced by T cell stimulation.
Genes were found uniquely responding to either high a-T (e.g. induced: CD40 ligand, lymphotoxin A) or g-T (e.g. repressed:
poliovirus receptor-related-2). Interestingly, in stimulated T-cells from mice supplemented with high amounts of a-T a bigger
number of genes were activated than in mice supplemented with the same amounts of g-T; under the same conditions g-T
repressed the expression of a number of genes larger than a-T. It is possible that the observed diminution in gene
expression in T cells after high g-T in vivo supplementation modulates inflammation or other T cell mediated functions.
Abstract: PubMed
Zingg JM et al; Arch Biochem Biophys. 538 (2): 111-9 (2013)
 from HSDB
/OTHER TOXICITY INFORMATION/ beta-Carotene, canthaxanthin, lutein, lycopene and alpha-carotene increased gap
junctional intercellular communication in a dose-dependent manner in the above order of potency. alpha-Tocopherol , a
potent chain-breaking antioxidant, caused a marginal enhancement of junctional communication. The enhancement of
junctional communication by diverse carotenoids showed a strong statistical correlation with their previously determined
ability to inhibit methylcholanthrene induced neoplastic transformation (r = -0.75). All carotenoids tested inhibited lipid
peroxidation, but with differing potencies. alpha-Tocopherol was the most active inhibitor followed by m-bixin. The capacity
of carotenoids or alpha-tocopherol to inhibit lipid peroxidation was neither consistent with their ability to inhibit neoplastic
transformation (r = 0.30) nor to increase junctional communication (r = 0.12). Since junctional communication appears to
play an important role in cell growth control and carcinogenesis, it is proposed that in this system carotenoid-enhanced
intercellular communication provides a mechanistic basis for the cancer chemopreventive action of carotenoids. These data
also imply that carotenoids function in a manner analogous to retinoids in the 10T1/2 assay system. Interestingly this activity
appears independent of their provitamin A status. Abstract: PubMed
Zhang LX et al; Carcinogenesis 12 (11): 2109-14 (1991)
 from HSDB
/OTHER TOXICITY INFORMATION/ Free radicals vary widely in their thermodynamic properties, ranging from very oxidizing
to very reducing. These thermodynamic properties can be used to predict a pecking order, or hierarchy, for free radical
reactions. Using one-electron reduction potentials, the predicted pecking order is in agreement with experimentally observed
free radical electron (hydrogen atom) transfer reactions. These potentials are also in agreement with experimental data that
suggest that vitamin E, the primary lipid soluble small molecule antioxidant, and vitamin C, the terminal water soluble small
molecule antioxidant, cooperate to protect lipids and lipid structures against peroxidation. Although vitamin E is located in
membranes and vitamin C is located in aqueous phases, vitamin C is able to recycle vitamin E; i.e., vitamin C repairs the
tocopheroxyl (chromanoxyl) radical of vitamin E, thereby permitting vitamin E to function again as a free radical chain-
breaking antioxidant. This review discusses: (i) the thermodynamics of free radical reactions that are of interest to the health
sciences; (ii) the fundamental thermodynamic and kinetic properties that are associated with chain-breaking antioxidants;
(iii) the unique interfacial nature of the apparent reaction of the tocopherol free radical (vitamin E radical) and vitamin C; and
(iv) presents a hierarchy, or pecking order, for free radical electron (hydrogen atom) transfer reactions. Abstract: PubMed
Buettner GR; Arch Biochem Biophys. 300 (2): 535-43 (1993)
 from HSDB
/OTHER TOXICITY INFORMATION/ The antioxidant properties of alpha-tocopherol have been proposed to play a beneficial
chemopreventive role against cancer. However, emerging data also indicate that it may exert contrasting effects on the
efficacy of chemotherapeutic treatments when given as dietary supplement, being in that case harmful for patients. This dual
role of alpha-tocopherol and, in particular, its effects on the efficacy of anticancer drugs remains poorly documented. For this
purpose, we studied here, using high throughput flow cytometry, the direct impact of alpha-tocopherol on apoptosis and cell
cycle arrest induced by different cytotoxic agents on various models of cancer cell lines in vitro. Our results indicate that
physiologically relevant concentrations of alpha-tocopherol strongly compromise the cytotoxic and cytostatic action of
various protein kinase inhibitors (KI), while other classes of chemotherapeutic agents or apoptosis inducers are unaffected
by this vitamin. Interestingly, these anti-chemotherapeutic effects of alpha-tocopherol appear to be unrelated to its
antioxidant properties since a variety of other antioxidants were completely neutral toward KI-induced cell cycle arrest and
cell death. In conclusion, our data suggest that dietary alpha-tocopherol could limit KI effects on tumour cells, and, by extent,
that this could result in a reduction of the clinical efficacy of anti-cancer treatments based on KI molecules.[Pedeboscq S et
al; PLoS One 7 (5): e36811 (2012)] Full text: PMC3348137 Abstract: PubMed
 from HSDB
/OTHER TOXICITY INFORMATION/ Bone homeostasis is maintained by the balance between osteoblastic bone formation
and osteoclastic bone resorption. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion.
Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone
remodeling is unknown. Here, we show that mice deficient in alpha-tocopherol transfer protein (Ttpa(-/-) mice), a mouse
model of genetic vitamin E deficiency, have high bone mass as a result of a decrease in bone resorption. Cell-based assays
indicated that alpha-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the
expression of dendritic-cell-specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of
mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct
recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter. Indeed, the bone abnormality seen in Ttpa(-/-) mice was
rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an alpha-tocopherol-supplemented diet, which
contains a comparable amount of alpha-tocopherol to supplements consumed by many people, lost bone mass. These
results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion. Abstract:
PubMed
Fujita K et al; Nat Med. 18 (4): 589-94 (2012)
 from HSDB
/OTHER TOXICITY INFORMATION/ Vitamin E has long been identified as a major lipid-soluble chain-breaking antioxidant in
mammals. alpha-Tocopherol is a vitamin E component and the major form in the human body. We propose that, besides its
direct chain-breaking antioxidant activity, alpha-tocopherol may exert an indirect antioxidant activity by enhancing the cell's
antioxidant system as a Phase II enzyme inducer. We investigated alpha-tocopherol's inducing effect on Phase II enzymes
and its protective effect on acrolein-induced toxicity in a human retinal pigment epithelial (RPE) cell line, ARPE-19. Acrolein,
a major component of cigarette smoke and also a product of lipid peroxidation, at 75 umol/L over 24 hr, caused significant
loss of ARPE-19 cell viability, increased oxidative damage, decreased antioxidant defense, inactivation of the Keap1/Nrf2
pathway, and mitochondrial dysfunction. ARPE-19 cells have been used as a model of smoking- and age-related macular
degeneration. Pretreatment with ?-tocopherol activated the Keap1/Nrf2 pathway by increasing Nrf2 expression and inducing
its translocation to the nucleus. Consequently, the expression and/or activity of the following Phase II enzymes increased:
glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase 1, heme-oxygenase 1, glutathione S-transferase and
superoxide dismutase; total antioxidant capacity and glutathione also increased. This antioxidant defense enhancement
protected ARPE-19 cells from an acrolein-induced decrease in cell viability, lowered reactive oxygen species and protein
oxidation levels, and improved mitochondrial function. These results suggest that alpha-tocopherol protects ARPE-19 cells
from acrolein-induced cellular toxicity, not only as a chain-breaking antioxidant, but also as a Phase II enzyme inducer.
Abstract: PubMed
Feng Z et al; J Nutr Biochem. 21 (12): 1222-31 (2010)
 from HSDB
/OTHER TOXICITY INFORMATION/ Certain microsomal hydroxylations appear to be regulated by alpha-tocopherol, and d-
alpha-tocopherol acetate given as a single oral dose or in 3 consecutive daily doses of 450 mg/kg to rats caused a
significant increase in aminopyrine demethylase activity in the liver.
 from HSDB
/OTHER TOXICITY INFORMATION/ Rats given high doses of alpha-tocopherol had elevated liver cholesterol levels and
altered tissue fatty acids.
 from HSDB
/OTHER TOXICITY INFORMATION/ Rats treated with weekly oral doses of about 50 mg of a vitamin E concentrate were
found to have fatty changes in the liver. In addition, intimal sclerosis of the aorta was seen, with the over-development of
collagenous tissue at the base of the aortic valve and in the medial coat of the aorta.
 from HSDB
/OTHER TOXICITY INFORMATION/ Vitamin E has shown significant activity against various cancers in vitro and in
experimental animal models of carcinogenesis.
 from HSDB
13.1.6 Non-Human Toxicity Values 

LD50 Rats oral >7000 mg/kg b.w. /d-alpha-tocopheryl succinate/
 from HSDB
13.2 Ecological Information 

13.2.1 Environmental Fate/Exposure Summary 
Vitamin E's production and use as an antioxidant in vegetable oils and shortening, as an antioxidant in cosmetics and as a
dietary supplement may result in its release to the environment through various waste streams. Vitamin E occurs in wide
variety of plants including green vegetables, grains and plant oils. If released to air, an estimated vapor pressure of 1.4X10-8
mm Hg at 25 deg C indicates vitamin E will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase
vitamin E will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for
this reaction in air is estimated to be 1.7 hours. Particulate-phase vitamin E will be removed from the atmosphere by wet and
dry deposition. Vitamin E absorbs at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by
sunlight. If released to soil, vitamin E is expected to have no mobility based upon an estimated Koc of 2.5X10+7.
Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law
constant of 7.9X10-5 atm-cu m/mole. However, adsorption to soil is expected to attenuate volatilization. Vitamin E is not
expected to volatilize from dry soil surfaces based upon its vapor pressure. Vitamin was biodegraded by aerobic bacterial
communities isolated from marine sediment. However, biodegradation data relevant to environmental importance in soil and
water were not available. If released into water, vitamin E is expected to adsorb to suspended solids and sediment based
upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this
compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 29
hours and 15 days, respectively. However, volatilization from water surfaces is expected to be attenuated by adsorption to
suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is >10 years if
adsorption is considered. An estimated BCF of 39 suggests the potential for bioconcentration in aquatic organisms is
moderate. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional
groups that hydrolyze under environmental conditions. Occupational exposure to vitamin E may occur through dermal
contact with this compound at workplaces where vitamin E is produced or used. Monitoring and use data indicate that the
general population may be exposed to vitamin E via ingestion of food and food supplements, and dermal contact with
consumer products containing vitamin E. (SRC)
 from HSDB
13.2.2 Natural Occurring Sources 

The richest sources of vitamin E are green vegetables, grains, and oils; particularly palm, safflower, and sunflower oils(1).
Vitamin E occurs in wheat germ, soybean, sunflower, rape, corn, and peanut oil(2). Vitamin E has been quantified in a wide
variety of plants(3).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1759 (2013) (2) Baldenius KU et al;
Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2015). New York, NY:
John Wiley & Sons. Online Posting Date: Oct 15, 2011. (3) USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants
with a chosen chemical. alpha-Tocopherol. Washington, DC: US Dept Agric, Agric Res Service. Available from, as of July 28, 2015:
http://www.ars-grin.gov/duke/
 from HSDB
Vitamin E is a fat-soluble vitamin which is present in many foods including vegetable oils, cereal grains, animal fats, meat,
poultry, eggs, fruits, and vegetables. Wheat germ oil is a particularly rich source of vitamin E.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital
Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 2313
 from HSDB
13.2.3 Artificial Sources 

Vitamin E's production and use as an antioxidant in vegetable oils and shortening(1), as an antioxidant in cosmetics(2) and
as a dietary supplement(3) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 1759 (2013) (2) Rieger MM; Cosmetics.
Kirk-Othmer Encyclopedia of Chemical Technology. (1999-2015). New York, NY: John Wiley & Sons. Online Posting Date: Apr 17,
2009. (3) Nat Institute Health; Vitamin E. Office of Dietary Supplements. Available from, as of July 28, 2015:
https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/
 from HSDB
13.2.4 Environmental Fate 

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2.5X10+7(SRC), determined from a
structure estimation method(2), indicates that vitamin E is expected to be immobile in soil(SRC). Volatilization of vitamin E
from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of
7.9X10-5 atm-cu m/mole(SRC), using a fragment constant estimation method(2). However, adsorption to soil is expected to
attenuate volatilization(SRC). Vitamin E is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated
vapor pressure of 1.4X10-8 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2). Vitamin was
biodegraded by aerobic bacterial communities isolated from marine sediment(3). However, biodegradation data relevant to
environmental importance in soil were not available(SRC, 2015). Vitamin E has a UV absorption maxima at 292 nm(4), and
therefore, may be susceptible to direct photolysis on soil surfaces exposed to sunlight(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available
from, as of July 28, 2015: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Rontani JF et al; Organic Geochem 39: 676-88
(2008) (4) Baldenius KU et al; Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols). Ullmann's Encyclopedia of Industrial Chemistry. 7th
ed. (1999-2015). New York, NY: John Wiley & Sons. Online Posting Date: Oct 15, 2011.
 from HSDB
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2.5X10+7(SRC), determined from a
structure estimation method(2), indicates that vitamin E is expected to adsorb to suspended solids and sediment(SRC).
Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 7.9X10-5 atm-cu
m/mole(SRC), developed using a fragment constant estimation method(2). Using this Henry's Law constant and an
estimation method(3), volatilization half-lives for a model river and model lake are 29 hours and 15 days, respectively(SRC).
However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in
the water column(SRC). The estimated volatilization half-life from a model pond is >10 years if adsorption is considered(4).
According to a classification scheme(5), an estimated BCF of 39(SRC), from an estimated log Kow of 12.2(2) and a
regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Vitamin
was biodegraded by aerobic bacterial communities isolated from marine sediment(5). However, biodegradation data relevant
to environmental importance in water were not available(SRC, 2015). Vitamin E is not expected to undergo hydrolysis in the
environment due to the lack of functional groups that hydrolyze under environmental conditions(3).
(1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available
from, as of July 28, 2015: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Lyman WJ et al; Handbook of Chemical Property
Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 15-1 to 15-29 (1990) (4) US EPA; EXAMS II Computer Simulation
(1987) (5) Rontani JF et al; Organic Geochem 39: 676-88 (2008)
 from HSDB
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the
atmosphere(1), vitamin E, which has an estimated vapor pressure of 1.4X10-8 mm Hg at 25 deg C(SRC), determined from a
fragment constant method(2), will exist in both the vapor and particulate phases (in the ambient atmosphere. Vapor-phase
vitamin E is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for
this reaction in air is estimated to be 1.7 hours(SRC), calculated from its rate constant of 1.7X10-10 cu cm/molecule-sec at
25 deg C(SRC) that was derived using a structure estimation method(2). Particulate-phase vitamin E may be removed from
the air by wet and dry deposition(SRC). Vitamin E has a UV absorption maxima at 292 nm(3) and, therefore, may be
susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012.
Available from, as of July 28, 2015: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Baldenius KU et al; Vitamins, 4. Vitamin
E (Tocopherols, Tocotrienols). Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2015). New York, NY: John Wiley & Sons.
Online Posting Date: Oct 15, 2011.
 from HSDB
13.2.5 Biodegredation 
PURE CULTURE: Vitamin E was biodegraded by aerobic bacterial communities (genera Idiomarina and Bacillus), isolated
from marine sediment and microbial mat sample(1); biodegradation appeared to involve an initial omega-oxidation of the
isoprenoid side chain and subsequent beta-oxidation, affording 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman(1).
(1) Rontani JF et al; Organic Geochem 39(6): 676-688 (2008)
 from HSDB
13.2.6 Abiotic Degredation 

The rate constant for the vapor-phase reaction of vitamin E with photochemically-produced hydroxyl radicals has been
estimated as 2.3X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to
an atmospheric half-life of about 1.7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1).
Vitamin E has a UV absorption maxima at 292 nm(2) and, therefore, may be susceptible to direct photolysis by
sunlight(SRC). Vitamin E is reported to be unstable in the presence of light(3). It is gradually oxidized by atmospheric
oxygen producing a reddish color(2). Vitamin E is not expected to undergo hydrolysis in the environment due to the lack of
functional groups that hydrolyze under environmental conditions(4).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of July 28, 2015:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (2) Baldenius KU et al; Vitamins, 4. Vitamin E (Tocopherols, Tocotrienols).
Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2015). New York, NY: John Wiley & Sons. Online Posting Date: Oct 15,
2011. (3) Block JH; Vitamins, Survey. Kirk-Othmer Encyclopedia of Chemical Technology. (1999-2015). New York, NY: John Wiley &
Sons. Online Posting Date: Jun 16, 2006. (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC:
Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)
 from HSDB
13.2.7 Bioconcentration 
An estimated BCF of 39 was calculated in fish for vitamin E(SRC), using an estimated log Kow of 12.2(1) and a regression-
derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic
organisms is moderate(SRC), provided the compound is not metabolized by the organism(SRC).
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (2) Franke C et al; Chemosphere 29: 1501-14 (1994)
 from HSDB
13.2.8 Soil Adsorption/Mobility 

Using a structure estimation method based on molecular connectivity indices(1), the Koc of vitamin E can be estimated to be
2.5X10+7(SRC). According to a classification scheme(2), this estimated Koc value suggests that vitamin E is expected to be
immobile in soil.
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (2) Swann RL et al; Res Rev 85: 17-28 (1983)
 from HSDB
13.2.9 Volatilization from Water/Soil 

The Henry's Law constant for vitamin E is estimated as 7.9X10-5 atm-cu m/mole(SRC) using a fragment constant estimation
method(1). This Henry's Law constant indicates that vitamin E is expected to volatilize from water surfaces(2). Based on this
Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is
estimated as 29 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5
m/sec)(2) is estimated as 15 days(SRC). However, volatilization from water surfaces is expected to be attenuated by
adsorption to suspended solids and sediment in the water column(SRC). The estimated volatilization half-life from a model
pond is >10 years if adsorption is considered(3). Vitamin E's Henry's Law constant indicates that volatilization from moist soil
surfaces may occur(SRC), but volatilization from soil is expected to be attenuated by adsorption(SRC). Vitamin E is not
expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.4X10-8 mm Hg(SRC),
determined from a fragment constant method(1).
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods.
Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) US EPA; EXAMS II Computer Simulation (1987)
 from HSDB
13.2.10 Effluents Concentrations 

Vitamin E was detected at 0.4 mg/g organic carbon emitted following the combustion of red oak(1). It was not detected
following the combustion of red maple, paper birch, white pine, and balsam fir(1).
(1) Fine PM et al; Environ Sci Technol 35: 2655-2675 (2001)
 from HSDB
13.2.11 Sediment/Soil Concentrations 

SEDIMENT: Vitamin E was identified, not quantified, in sediment from 7 locations within the German Bight of the North
Sea(1).
(1) Schwarzbauer J et al; Org Geochem 31: 1713-1731 (2000)
 from HSDB
13.2.12 Food Survey Values 

Selected Food Sources of Vitamin E (Alpha-Tocopherol )(1).
Food Item, Serving size Milligrams/serving
Wheat germ oil, 1 tablespoon 20.3
Sunflower seeds, dry roasted, 1 ounce 7.4
Almonds, dry roasted, 1 ounce 6.8
Sunflower oil, 1 tablespoon 5.6
Safflower oil, 1 tablespoon 4.6
Hazelnuts, dry roasted, 1 ounce 4.3
Peanut butter, 2 tablespoons 2.9
Peanuts, dry roasted, 1 ounce 2.2
Corn oil, 1 tablespoon 1.9
Spinach, boiled, 1/2 cup 1.9
Broccoli, chopped, boiled, 1/2 cup 1.2
Soybean oil, 1 tablespoon 1.1
Kiwifruit, 1 medium 1.1
Mango, sliced, 1/2 cup 0.7
Tomato, raw, 1 medium 0.7
Spinach, raw, 1 cup 0.6
(1) NIH; Vitamin E. Fact Sheet for Health Professionals. Nat Institute Health, Office of Dietary Supplements. Available from, as of July
28, 2015: https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/
 from HSDB
13.2.13 Plant Concentrations 

Vitamin E (as alpha-tocopherol) concentrations in plant oils (mg/100 g product): Canola, 21.0; Castor, 2.8; Coconut, 0.5;
Corn, 11.2; Cottonseed, 38.9; Olive, 11.9; Palm, 25.6; Palm kernel, 6.2; Peanut, 13.0; Rice bran, 32.4; Safflower, 34.2;
Sesame, 13.6; Soybean, 7.5; Sunflower, 48.7; Walnut, 56.3(1).
(1) EFSA; Opinion on mixed tocopherols, tocotrienol tocopherol and tocotrienols as sources for vitamin E added as a nutritional
substance in food supplements. The EFSA Journal 640: 1-34 (2008). Available from, as of July 28, 2015:
http://www.efsa.europa.eu/de/scdocs/doc/640.pdf
 from HSDB
Vitamin E detections in plants(1).
Concn
Genus species Family Common name Part
(ppm)
Triticum aestivum L. Poaceae Wheat Oil 2,170
Lepidium sativum L. Brassicaceae Garden Cress Oil 1,830
Triticum aestivum L. Poaceae Wheat Seed 1,271
Rheum rhabarbarum L. Polygonaceae Rhubarb Leaf 1,238
Daucus carota L. Apiaceae Carrot Leaf 788
Brassica oleracea var. sabellica Curly Kale, Kale, Kitchen Kale, Scotch
Brassicaceae Leaf 785
l. var. acephala DC Kale
Phaseolus vulgaris subsp. var. Black Bean, Field Bean, Green Bean,
Fabaceae Leaf 719
vulgaris Kidney Bean
Helianthus annuus L. Asteraceae Girasol, Sunflower Oil 622
Carthamus tinctorius L. Asteraceae Safflower Oil 449
Beta vulgaris subsp. subsp.

Chenopodiaceae Beet, Beetroot, Garden Beet, Sugar Beet Leaf 439
vulgaris
Brassica oleracea var. botrytis l.

Brassicaceae Cauliflower Leaf 439
var. botrytis L.
Spinacia oleracea L. Chenopodiaceae Spinach Leaf 419
Cowgrass, Peavine Clover, Purple Clover,

Trifolium pratense L. Fabaceae Inflorescence 400
Red Clover
Abelmoschus esculentus (L.)

Malvaceae Okra Oil 310
MOENCH
Bell Pepper, Cherry Pepper, Cone
Capsicum annuum L. Solanaceae Pepper, Green Pepper, Paprika, Sweet Fruit 284
Pepper
Glycine max (L.) MERR. Fabaceae Soybean Leaf 280
Prunus dulcis (MILLER) D. A.

Rosaceae Almond Seed 275
WEBB
Medicago sativa subsp. sativa Fabaceae Alfalfa, Lucerne Plant 257
Zea mays L. Poaceae Corn Oil 257
Petroselinum crispum (MILLER)

Apiaceae Parsley Leaf 252
NYMAN EX A. W. HILLL
Rosa canina L. Rosaceae Dog Rose, Dogbrier, Rose Fruit 204
Brassica rapa L. Brassicaceae Sarson Oil 189
Anethum graveolens L. Apiaceae Dill, Garden Dill Leaf 147
Lycopersicon esculentum
Solanaceae Tomato Fruit 143
MILLER
Lactuca sativa L. Asteraceae Lettuce Fruit 139
Ribes nigrum L. Grossulariaceae Black Currant; Fruit 120
Cucurbita pepo L. Cucurbitaceae Pumpkin Fruit 119
Olea europaea subsp. europaea Oleaceae Olive Oil 119
Arachis hypogaea L. Fabaceae Groundnut, Peanut Seed 116
Vaccinium corymbosum L. Ericaceae Blueberry Fruit 116
Glycine max (L.) MERR. Fabaceae Soybean Oil 95
Urtica dioica L. Urticaceae European Nettle, Stinging Nettle Leaf 94
Arachis hypogaea L. Fabaceae Groundnut, Peanut Oil 89
Prunus persica (L.) BATSCH Rosaceae Peach Fruit 86
American Cranberry, Cranberry, Large

Vaccinium macrocarpon AITON Ericaceae Fruit 81
Cranberry
Apium graveolens L. Apiaceae Celery Pt 67
Lepidium sativum L. Brassicaceae Garden Cress Leaf 66
Apium graveolens L. Apiaceae Celery Plant 64
Brassica oleracea var.

Brassicaceae Brussel-Sprout, Brussels-Sprouts Leaf 63
gemmifera var. gemmifera DC
Elaeis guineensis JACQ. Arecaceae African Oil Palm Fruit 75-125
Prunus domestica L. Rosaceae Plum Fruit 62
(1) USDA; Dr. Duke's Phytochemical and Ethnobotanical Databases. Plants with a chosen chemical. alpha-Tocopherol. Washington,
DC: US Dept Agric, Agric Res Service. Available from, as of July 28, 2015: http://www.ars-grin.gov/duke/
 from HSDB
13.2.14 Fish/Seafood Concentrations 

Vitamin E occurs in fish as part of the total tocopherol content(1).
(1) Casani R; Vitamin E. Kirk-Othmer Encyclopedia of Chemical Technology. (1999-2015). New York, NY: John Wiley & Sons. Online
Posting Date: Dec 4, 2000.
 from HSDB
13.2.15 Milk Concentrations 

ENVIRONMENTAL: Milk of nursing mothers on a normal diet contains 2-5 units of vitamin E per liter.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists,
Bethesda, MD. 2006., p. 3585
 from HSDB
ENVIRONMENTAL: Vitamin E is distributed into breast milk; however, problems in humans have not been documented with
intake of normal daily recommended amounts.
Thomson.Micromedex. Drug Information for the Health Care Professional. 25th ed. Volume 1. Plus Updates. Content Reviewed by the
United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2005., p. 2968
 from HSDB
ENVIRONMENTAL: The adequate supply of vitamins A and E to newborns is essential. However, factors such as maternal
nutritional status and nutrient interaction may limit its bioavailability. The aim of this study was to establish nutritional status
for vitamins A and E and evaluate the correlation of retinol on colostrum alpha-tocopherol in lactating women. A total of 103
lactating women were recruited at a Brazilian public maternity hospital. Fasting serum and colostrum samples were collected
in the immediate post-partum. Retinol and alpha-tocopherol levels were determined by high-performance liquid
chromatography and nutritional status for these vitamins was defined from specific cut-off points for serum and colostrum.
Mean serum and colostrum retinol (1.49 umol L(-1) , 2.18 umol L(-1)) and alpha-tocopherol (26.4 umol L(-1) , 26.1 umol
L(-1)) indicated satisfactory biochemical status. However, we found a prevalence of subclinical deficiency of vitamin A and
vitamin E in serum (15.5% and 16%) and colostrum (50% and 60%). Lactating women with serum retinol <1.05 umol L(-1)
showed an inverse correlation between serum retinol andalpha-tocopherol concentration in the colostrum (P = 0.008, r =
-0.28). This association was not observed in serum level < 1.05 umol L(-1) . The nutritional status of lactating women for
vitamins A and E was adequate, although there is a risk of subclinical deficiency. The negative correlation of serum retinol
on alpha-tocopherol concentration in the colostrum must be carefully evaluated in situations of vitamin A supplementation,
because alpha-tocopherol bioavailability in maternal milk may be compromised. Abstract: PubMed
de Lira LQ et al; Matern Child Nutr 9 (1): 31-40 (2013)
 from HSDB
EXPERIMENTAL: Vitamins A and E are recognisably important in the initial stages of life, and the newborn depends on
nutritional adequacy of breast milk to meet their needs. These vitamins share routes of transport to the tissues and
antagonistic effects have been observed in animals after supplementation with vitamin A. The present study aimed to
determine the effect of maternal supplementation with a megadose of retinyl palmitate in the immediate post-partum on
alpha-tocopherol concentration in the colostrum. Healthy parturient women at a Brazilian public maternity were recruited for
the study and divided into two groups: control (n = 37) and supplemented (n = 36). Blood and colostrum samples were
collected up to 16 hr post-partum. The supplemented group was administered with a retinyl palmitate capsule and, 24 hr
after the first collection, the second colostrum sample was obtained in the two groups for analysis of alpha-tocopherol. The
cut-off points for deficiency are <1.05 umol L(-1) for retinol and <11.6 umol L(-1) for alpha-tocopherol. The mean (SD) serum
concentration of 1.77 (0.50) umol L(-1) for retinol and 30.81 (6.46) umol L(-1) for alpha-tocopherolindicates an adequate
biochemical status. The supplemented group showed an increase of alpha-tocopherol in the colostrum 24hr after
supplementation (P = 0.04), and this finding was not observed in the control group. Supplementation with a 200,000 IU
megadose of vitamin A did not negatively affect alpha-tocopherol levels in colostrum Abstract: PubMed
Garcia L et al; J Hum Nutr Diet 23 (5): 529-34 (2010)
 from HSDB
EXPERIMENTAL: Vitamin E is distributed into breast milk.
 from HSDB
13.2.16 Probable Routes of Human Exposure 

NIOSH (NOES Survey 1981-1983) has statistically estimated that 6,957 workers (3,599 of these were female) were
potentially exposed to vitamin E in the US(1). Occupational exposure to vitamin E may occur through dermal contact with
this compound at workplaces where vitamin E is produced or used. Monitoring and use data indicate that the general
population may be exposed to vitamin E via ingestion of food and food supplements, and dermal contact with consumer
products containing vitamin E(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially
exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of July 28, 2015:
http://www.cdc.gov/noes/
 from HSDB
13.2.17 Body Burdens 

/Stored in/ ... all body tissues, especially fatty tissues. ... Vitamin E is distributed into breast milk.
 from HSDB
Milk of nursing mothers on a normal diet contains 2-5 units of vitamin E per liter.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists,
Bethesda, MD. 2006., p. 3585
 from HSDB
PMID Date Title Journal
14 Literature 
14.1 Depositor Provided PubMed Citations 
1 to 10 of 61 1 2 3 ... 7

 Date

PMID Date Title Journal
Bioorganic &
Synthesis and SAR studies of 1, 4-benzoxazine MenB inhibitors: novel
20850304 2010-11-01 medicinal chemistry
antibacterial agents against Mycobacterium tuberculosis.
letters
Antioxidants can inhibit basal autophagy and enhance Human molecular

20566712 2010-09-01
neurodegeneration in models of polyglutamine disease. genetics
22254062 2010-08-01 The role of phytonutrients in skin health. Nutrients
Superparamagnetic iron oxide--loaded poly(lactic acid)-D-alpha-
20434210 2010-07-01 tocopherol polyethylene glycol 1000 succinate copolymer Biomaterials
nanoparticles as MRI contrast agent.
Langmuir : the ACS

Solubilization of vitamin E into H(II) LLC mesophase in the presence
20175578 2010-03-02 journal of surfaces
and in the absence of vitamin C.
and colloids
European journal of
19823814 2010-02-01 Dosage and formulation issues: oral vitamin E therapy in children.
clinical pharmacology
International journal
20559505 2010-01-01 Lutein protects RGC-5 cells against hypoxia and oxidative stress.
of molecular sciences
Hepatitis C virus infection: molecular pathways to steatosis, insulin

21994542 2009-09-01 Viruses
resistance and oxidative stress.
Journal of
Isoforms of vitamin E have opposing immunoregulatory functions immunology

19299740 2009-04-01
during inflammation by regulating leukocyte recruitment. (Baltimore, Md. :
1950)
Modulation of inflammation by vitamin E and C supplementation prior Free radical biology &
19111610 2009-03-01
to anterior cruciate ligament surgery. medicine
 from PubChem
Patent ID Date Patent Title
15 Patents 
15.1 Depositor-Supplied Patent Identifiers 
 Download
1 to 10 of 930 1 2 3 ... 93

 Date

Patent ID Date Patent Title
US2016074451 2016-03-17 PHARMACEUTICAL COMPOSITION AND METHOD OF MANUFACTURING
US2016075823 2016-03-17 POLYCARBONATE MOLDED ARTICLE
US2016075860 2016-03-17 AN ETHYLENE-BASED COMPOSITION
US2016032078 2016-02-04 STABILIZED POLYMER COMPOSITIONS AND METHODS OF MAKING SAME
US2015374603 2015-12-31 HAIR GROWTH COMPOSITION AND METHOD
US9206314 2015-12-08 Resin composition and molded article thereof
US2015335737 2015-11-26 ADJUVANT COMPOSITIONS AND METHODS OF USE
US9186386 2015-11-17 Pharmaceutical composition and method of manufacturing
US2015309021 2015-10-29 Advanced Drug Development and Manufacturing
US2015297550 2015-10-22 SUSTAINED RELEASE OF TOPICAL ANESTHETICS
 from PubChem
Substance BioAssay
Activity BioAssay Name
SID AID
16 Biological Test Results 
16.1 BioAssay Results 
1 to 10 of 239 1 2 3 ... 24

 Activity

Substance BioAssay
Activity BioAssay Name
SID AID
Counterscreen qHTS for Inhibitors of Tau Fibril Formation, Fluorescence

Inconclusive 26749212 1463
Polarization
Inconclusive 26749212 1519 qHTS Assay for Lipid Storage Modulators
Screen for compounds that inhibit mitochondrial permeability transition

(MitoPT)
Screen of Compounds to Block PAR4 - aPKC Interaction for Treatment of

Neurodegeneration (Par4_PKC)
Yeast cell-based screen for Novel HDAC inhibitors using a PHO84-LacZ

reporter gene (PHO84)
Inconclusive 8149176 1584 Screen for compounds that inhibit in vitro mutant huntingtin aggregation (QA1)
Screen for compounds that inhibit the ability of solid phase synthetic
Inconclusive 8149176 1585 polyglutamine aggregates to elongate by incorporating solution-phase biotin-
tagged, monomeric polyglutamine (QA3)
A 2-Hybrid Test for Interactions Between Polyglutamine-Containing Proteins in

the Yeast Nucleus (Qn2Hy)
Screen for compounds that increase the expression of EAAT-2 in rat spinal
cord organotypic slice cultures (X4_EAAT2)
Screen for compounds that reduce polyglutamine aggregation as measured by

turbidity (QTHIO)
 from PubChem
17 Classification 
17.1 Ontologies 
17.1.1 KEGG: ATC 
1 to 1 of 1  List View  Tree View
Tocopherol (JP17)
 from KEGG
17.1.2 KEGG: JP15 

Tocopherol
 from KEGG
17.1.3 KEGG: Risk Category of Japanese OTC Drugs 

Tocopherol (JP17)
 from KEGG
17.1.4 KEGG: OTC drugs 

Tocopherol (JP17)
 from KEGG
17.1.5 WIPO IPC 
1 to 10 of 1,309 1 2 3 ... 131  List View  Tree View
A61P11/06 - Antiasthmatics
A61P13/08 - of the prostate
A61P13/10 - of the bladder
A61P13/12 - of the kidneys
A61P15/00 - Drugs for genital or sexual disorders; Contraceptives
A61P15/10 - for impotence
A61P15/12 - for climacteric disorders
A61P17/00 - Drugs for dermatological disorders
A61P17/02 - for treating wounds, ulcers, burns, scars, keloids, or the like
A61P17/04 - Antipruritics
 from WIPO
18 Information Sources
1. HSDB /source/HSDB
VITAMIN E
http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+59-02-9 http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?
dbs+hsdb:@term+@rn+@rel+59-02-9
2. NIST /source/NIST
dl-.alpha.-Tocopherol
http://www.nist.gov/srd/nist1a.cfm http://www.nist.gov/srd/nist1a.cfm
3. FAO/WHO Food Additive Evaluations - JECFA /source/FAO/WHO Food Additive Evaluations -
JECFA
dl-alpha-TOCOPHEROL
http://apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=3025 http://apps.who.int/food-additives-
contaminants-jecfa-database/chemical.aspx?chemID=3025
4. European Chemicals Agency - ECHA /source/European Chemicals Agency - ECHA
Vitamin E
https://echa.europa.eu/ https://echa.europa.eu/
5. PubChem
Data deposited in or computed by PubChem
https://pubchem.ncbi.nlm.nih.gov https://pubchem.ncbi.nlm.nih.gov
6. KEGG /source/KEGG
ATC
http://www.genome.jp/dbget-bin/www_bget?brite:br08303 http://www.genome.jp/dbget-bin/www_bget?brite:br08303
JP17
Risk category of Japanese OTC drugs
OTC drugs
7. WIPO /source/WIPO
International Patent Classification
http://www.wipo.int/classifications/ipc/ http://www.wipo.int/classifications/ipc/

Alpha-Tochopherol PubChem

Uploaded by

Copyright:

Available Formats

You might also like

Alpha-Tochopherol PubChem

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Alpha-Tochopherol PubChem

Uploaded by

Copyright:

Available Formats

NIH U.S.

National Library of Medicine National Center for Biotechnology Information

 Compound Summary for CID 2116

PUBCHEM  COMPOUND  ALPHA-TOCHOPHEROL

alpha-tochopherol  Cite this Record

PubChem CID: 2116

Alpha-tochopherol; DL-ALPHA-TOCOPHEROL; Dl-|A-tocopherol; 10191-

41-0; CHEMBL49563; 2,5,7,8-tetramethyl-2-(4,8,12-

Molecular Formula: C29H50O2

Molecular Weight: 430.7061 g/mol

InChI Key: GVJHHUAWPYXKBD-UHFFFAOYSA-N

Modify Date: 2016-10-01

Create Date: 2005-03-25

3 Names and Identiﬁers

4 Chemical and Physical Properties

7 Drug and Medication Information

8 Food Additives and Ingredients

9 Pharmacology and Biochemistry

10 Use and Manufacturing

12 Safety and Hazards

16 Biological Test Results

 Show Hydrogens  Show Atoms  Animate

3.1.3 InChI Key 

3.1.4 Canonical SMILES 

3.2 Molecular Formula 

3.3 Other Identiﬁers 

 from European Chemicals Agency - ECHA

 from European Chemicals Agency - ECHA

 from European Chemicals Agency - ECHA

2. DL-ALPHA-TOCOPHEROL 12. Evitaminum

3. dl-|A-tocopherol 13. Profecundin

4. 10191-41-0 14. Syntopherol

5. CHEMBL49563 15. Waynecomycin

6. 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol 16. Almefrol

7. Vita E 17. Emipherol

8. .alpha.-Tocopherol 18. Ephanyl

9. SBB057399 19. Epsilan

10. d-.alpha.-Tocopherol 20. Etamican

Hydrogen Bond Donor Count 1

Hydrogen Bond Acceptor Count 2

Rotatable Bond Count 12

Exact Mass 430.381081 g/mol

Monoisotopic Mass 430.381081 g/mol

Topological Polar Surface Area 29.5 A^2

Heavy Atom Count 31

Isotope Atom Count 0

Deﬁned Atom Stereocenter Count 0

Undeﬁned Atom Stereocenter Count 3

Deﬁned Bond Stereocenter Count 0

Undeﬁned Bond Stereocenter Count 0

Covalently-Bonded Unit Count 1

4.2 Experimental Properties 

Chemistry, 2013., p. 1759

4.2.4 Melting Point 

In water-ethanol solution, 20.82 mg/L at 33 deg C

Soluble in alcohol, ether, acetone, chloroform

4.2.7 Vapor Pressure 