Butylated hydroxytoluene (BHT)

Relevant Data

Food Additives Approved in the United States

Food Additives Approved by WHO:

General Information

Chemical nameButylated hydroxytoluene (BHT)
E No.E 321
INS.321
CAS number128-37-0
GroupNo
Component of the group Gallates, TBHQ, BHA and BHT (E 310 - 321)

From webgate.ec.europa.eu

Authorisation of the use of this additive in Food Additives

The additive is authorised to be used in the following category(ies):
category(ies) Individual restriction(s)/exception(s) footnote
  • Fats and oils essentially free from water (excluding anhydrous milkfat) (2.1)(legislation:1129/2011, applicable as from 01/06/2013)
  • ML = 100 mg/kg , only fats and oils for the professional manufacture of heat treated foods; frying oil and frying fat (excluding olive an pomace oil) and lard, fish oil, beef, poultry and sheep fat
  • 41 Expressed on fat basis
  • Other fat and oil emulsions including spreads as defined by Council Regulation (EC) No 1234/2007 and liquid emulsions (2.2.2)(legislation:1129/2011, applicable as from 01/06/2013)
  • ML = 100 mg/kg , only frying fat

From webgate.ec.europa.eu

Computed Descriptors

Download SDF
2D Structure
CID31404
IUPAC Name2,6-ditert-butyl-4-methylphenol
InChIInChI=1S/C15H24O/c1-10-8-11(14(2,3)4)13(16)12(9-10)15(5,6)7/h8-9,16H,1-7H3
InChI KeyNLZUEZXRPGMBCV-UHFFFAOYSA-N
Canonical SMILESCC1=CC(=C(C(=C1)C(C)(C)C)O)C(C)(C)C
Molecular FormulaC15H24O
Wikipediabutylated hydroxytoluene

From Pubchem

Computed Properties

Property Name Property Value
Molecular Weight220.356
Hydrogen Bond Donor Count1
Hydrogen Bond Acceptor Count1
Rotatable Bond Count2
Complexity207.0
CACTVS Substructure Key Fingerprint A A A D c e B w I A A A A A A A A A A A A A A A A A A A A A A A A A A w A A A A A A A A A A A B A A A A G g A A C A A A D g S A m A A y B o A A A g C A A i B C A A A C A A A g I A A A i A A E C I g I J i K C E R K A c A A k w B E I m A e A w O A P o A A C A A A I A A B A A A Q A A B A A A A A A A A A A A A = =
Topological Polar Surface Area20.2
Monoisotopic Mass220.183
Exact Mass220.183
Compound Is CanonicalizedTrue
Formal Charge0
Heavy Atom Count16
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Isotope Atom Count0
Covalently-Bonded Unit Count1

From Pubchem

Food Additives Biosynthesis/Degradation

ADMET Predicted Profile --- Classification

Model Result Probability
Absorption
Blood-Brain BarrierBBB+0.9502
Human Intestinal AbsorptionHIA+0.9941
Caco-2 PermeabilityCaco2+0.8876
P-glycoprotein SubstrateNon-substrate0.6575
P-glycoprotein InhibitorNon-inhibitor0.9160
Non-inhibitor0.9855
Renal Organic Cation TransporterNon-inhibitor0.9076
Distribution
Subcellular localizationMitochondria0.8267
Metabolism
CYP450 2C9 SubstrateNon-substrate0.7402
CYP450 2D6 SubstrateSubstrate0.5915
CYP450 3A4 SubstrateSubstrate0.5169
CYP450 1A2 InhibitorInhibitor0.8681
CYP450 2C9 InhibitorNon-inhibitor0.8477
CYP450 2D6 InhibitorNon-inhibitor0.9368
CYP450 2C19 InhibitorNon-inhibitor0.8752
CYP450 3A4 InhibitorNon-inhibitor0.8309
CYP Inhibitory PromiscuityLow CYP Inhibitory Promiscuity0.7477
Excretion
Toxicity
Human Ether-a-go-go-Related Gene InhibitionWeak inhibitor0.9482
Non-inhibitor0.9156
AMES ToxicityNon AMES toxic0.9494
CarcinogensNon-carcinogens0.7016
Fish ToxicityHigh FHMT0.7983
Tetrahymena Pyriformis ToxicityHigh TPT0.8900
Honey Bee ToxicityHigh HBT0.8332
BiodegradationNot ready biodegradable0.9458
Acute Oral ToxicityIII0.8270
Carcinogenicity (Three-class)Non-required0.7295

From admetSAR

ADMET Predicted Profile --- Regression

Model Value Unit
Absorption
Aqueous solubility-2.3366LogS
Caco-2 Permeability1.7411LogPapp, cm/s
Distribution
Metabolism
Excretion
Toxicity
Rat Acute Toxicity2.2064LD50, mol/kg
Fish Toxicity-0.3153pLC50, mg/L
Tetrahymena Pyriformis Toxicity1.2850pIGC50, ug/L

From admetSAR

Toxicity Profile

Route of ExposureIngestion; Inhalation
Mechanism of ToxicityBHT is metabolized to quinone methides (QMs) which are responsible for promoting tumor formation in many animal models. One example of a QM is 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM). QMs are strongly electrophilic and readily form adducts with proteins. Some of the QM targets include redox proteins such as glutathione S-transferase P1 (GST-P1), peroxiredoxin 6 (Prx6), Cu,Zn-superoxide dismutase (SOD1), carbonyl reductase, and selenium-binding protein 1, which have direct or indirect antioxidant functions. . The modification of these proteins leads to decreased cellular protection from electrophiles and oxidants. Alkylation also may interfere with GSTP1 regulation of stress kinases, thereby influencing phosphorylation and cell growth. BHT also binds to the retinoic acid receptor which can lead to changes in cell development.
MetabolismOxidative metabolism (phase 1 reactions) mediated by the microsomal monooxygenase system is the major route for BHT degradation. Oxidation of the tert-butyl groups is most common in man. Gallates and 2-tert-butylhydroquinone are mainly metabolized by non-oxidative pathways (methylation or conjugation with sulphate and glucuronic acid). . In particular BHT is frequently metabolized to quinone methides (QMs) which are thought to be responsible for promoting tumor formation. One example of a QM is 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM). QMs are strongly electrophilic and readily form adducts with proteins.
Toxicity Values
Lethal DoseIn rats, the oral LD50 was > 2930 mg/kg bw, the LD50 after dermal exposure was > 2000 mg/kg
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans.
Minimum Risk Level25 mg/kg/day for thyroid and liver damage. 100 mg/kg/day for cancer.
Health EffectsBHT is of low acute toxicity. Acute exposure to BHT can cause coughs and sore throat (inhalation), redness on the skin (via contact) and abdominal pain, confusion, dizziness and nausea (via ingestion). Long-term exposure to high doses of BHT is toxic in mice and rats, causing liver, thyroid and kidney problems and affecting lung function and blood coagulation. BHT can act as a tumour promoter in certain situations (A15353) although it is not a genotoxic carcinogen. Limited evidence suggests that high doses of BHT may mimic estrogen (A15354), the primary female sex hormone, and prevent expression of male sex hormones, resulting in adverse reproductive affects. On chronic oral exposure of rats, liver and thyroid are the main targets. Doses above 25 mg/kg bw/day BHT resulted in thyroid hyperactivity and enlargement of the liver.
TreatmentFor acute exposure: EYES: irrigate opened eyes for several minutes under running water. INGESTION: do not induce vomiting. Rinse mouth with water (never give anything by mouth to an unconscious person). Seek immediate medical advice. SKIN: should be treated immediately by rinsing the affected parts in cold running water for at least 15 minutes, followed by thorough washing with soap and water. If necessary, the person should shower and change contaminated clothing and shoes, and then must seek medical attention. INHALATION: supply fresh air. If required provide artificial respiration.
Reference
  1. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. "Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.". Chem Res Toxicol. 2007 Feb;20(2):199-207.[17305404 ]
  2. Conning DM, Phillips JC: Comparative metabolism of BHA, BHT and other phenolic antioxidants and its toxicological relevance. Food Chem Toxicol. 1986 Oct-Nov;24(10-11):1145-8.[3542762 ]
  3. Bauer AK, Dwyer-Nield LD, Hankin JA, Murphy RC, Malkinson AM: The lung tumor promoter, butylated hydroxytoluene (BHT), causes chronic inflammation in promotion-sensitive BALB/cByJ mice but not in promotion-resistant CXB4 mice. Toxicology. 2001 Dec 1;169(1):1-15.[11696405 ]
  4. Wada H, Tarumi H, Imazato S, Narimatsu M, Ebisu S: In vitro estrogenicity of resin composites. J Dent Res. 2004 Mar;83(3):222-6.[14981123 ]
  5. Lemercier JN, Meier BW, Gomez JD, Thompson JA: Inhibition of glutathione S-transferase P1-1 in mouse lung epithelial cells by the tumor promoter 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone (BHT-quinone methide): protein adducts investigated by electrospray mass spectrometry. Chem Res Toxicol. 2004 Dec;17(12):1675-83.[15606144 ]

From T3DB

Taxonomic Classification

KingdomOrganic compounds
SuperclassBenzenoids
ClassBenzene and substituted derivatives
SubclassPhenylpropanes
Intermediate Tree NodesNot available
Direct ParentPhenylpropanes
Alternative Parents
Molecular FrameworkAromatic homomonocyclic compounds
SubstituentsPhenylpropane - P-cresol - Toluene - Phenol - Organic oxygen compound - Hydrocarbon derivative - Organooxygen compound - Aromatic homomonocyclic compound
DescriptionThis compound belongs to the class of organic compounds known as phenylpropanes. These are organic compounds containing a phenylpropane moiety.

From ClassyFire

Targets

Target Details

Carbonyl reductase [NADPH] 1

General Function:
Prostaglandin-e2 9-reductase activity
Specific Function:
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione.
Gene Name:
CBR1
Uniprot ID:
P16152
Molecular Weight:
30374.73 Da
References
  1. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. "Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.". Chem Res Toxicol. 2007 Feb;20(2):199-207. [17305404 ]
Target Details

Peroxiredoxin-1

General Function:
Thioredoxin peroxidase activity
Specific Function:
Involved in redox regulation of the cell. Reduces peroxides with reducing equivalents provided through the thioredoxin system but not from glutaredoxin. May play an important role in eliminating peroxides generated during metabolism. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2). Reduces an intramolecular disulfide bond in GDPD5 that gates the ability to GDPD5 to drive postmitotic motor neuron differentiation (By similarity).
Gene Name:
PRDX1
Uniprot ID:
Q06830
Molecular Weight:
22110.19 Da
References
  1. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. "Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.". Chem Res Toxicol. 2007 Feb;20(2):199-207. [17305404 ]
Target Details

Selenium-binding protein 1

General Function:
Selenium binding
Specific Function:
Selenium-binding protein which may be involved in the sensing of reactive xenobiotics in the cytoplasm. May be involved in intra-Golgi protein transport (By similarity).
Gene Name:
SELENBP1
Uniprot ID:
Q13228
Molecular Weight:
52390.575 Da
References
  1. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. "Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.". Chem Res Toxicol. 2007 Feb;20(2):199-207. [17305404 ]
Target Details

Superoxide dismutase [Cu-Zn]

General Function:
Zinc ion binding
Specific Function:
Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Gene Name:
SOD1
Uniprot ID:
P00441
Molecular Weight:
15935.685 Da
References
  1. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. "Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.". Chem Res Toxicol. 2007 Feb;20(2):199-207. [17305404 ]
Target Details

Retinoic acid receptor beta

General Function:
Zinc ion binding
Specific Function:
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of hormone ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function.
Gene Name:
RARB
Uniprot ID:
P10826
Molecular Weight:
50488.63 Da
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details

Nuclear receptor subfamily 1 group I member 3

General Function:
Zinc ion binding
Specific Function:
Binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes. Transactivates both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element.
Gene Name:
NR1I3
Uniprot ID:
Q14994
Molecular Weight:
39942.145 Da
References
  1. Dring AM, Anderson LE, Qamar S, Stoner MA: Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands. Chem Biol Interact. 2010 Dec 5;188(3):512-25. doi: 10.1016/j.cbi.2010.09.018. Epub 2010 Oct 20. [20869355 ]
Target Details

Glutathione S-transferase P

General Function:
S-nitrosoglutathione binding
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name:
GSTP1
Uniprot ID:
P09211
Molecular Weight:
23355.625 Da
References
  1. Meier BW, Gomez JD, Kirichenko OV, Thompson JA. "Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: electrophilic metabolites alkylate and inactivate antioxidant enzymes.". Chem Res Toxicol. 2007 Feb;20(2):199-207. [17305404 ]
Target Details

Retinoic acid receptor RXR-beta

General Function:
Zinc ion binding
Specific Function:
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (By similarity). Specifically binds 9-cis retinoic acid (9C-RA).
Gene Name:
RXRB
Uniprot ID:
P28702
Molecular Weight:
56921.38 Da
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

From T3DB