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Record Information
Version2.0
Creation Date2014-09-11 05:21:57 UTC
Update Date2014-12-24 20:26:59 UTC
Accession NumberT3D4911
Identification
Common Name2,6-Di-tert-butyl-4-methylphenol
ClassSmall Molecule
Description2,6-Di-tert-butyl-4-methylphenol is also known as butylated hydroxytoluene (BHT) or butylhydroxytoluene, is a lipophilic (fat-soluble) organic compound that is primarily used as an antioxidant food additive (E number E321) as well as an antioxidant additive in cosmetics, pharmaceuticals, jet fuels, rubber, petroleum products, electrical transformer oil, and embalming fluid. It is also found in certain plants, including soft-necked garlic. A recent study has found that phytoplankton, including the green algae, Botryococcus braunii, as well as three different cyanobacteria (Cylindrospermopsis raciborskii, Microcystis aeruginosa and Oscillatoria sp.) are capable of producing this compound.
Compound Type
  • Cosmetic Toxin
  • Food Additive
  • Food Toxin
  • Fuel
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
2,6-Bis(1,1-dimethylethyl)-4-methylphenol, 9CI
2,6-Di-t-butyl-4-methylphenol
2,6-Di-tert-butyl-p-cresol, 8CI
BHT
Butyl hydroxy toluene
Butylated hydroxytoluene
Butylhydroxytoluene
E321
FEMA 2184
Ionol
Popol
Chemical FormulaC15H24O
Average Molecular Mass220.351 g/mol
Monoisotopic Mass220.183 g/mol
CAS Registry Number128-37-0
IUPAC Name2,6-di-tert-butyl-4-methylphenol
Traditional Nameional
SMILESCC1=CC(=C(O)C(=C1)C(C)(C)C)C(C)(C)C
InChI IdentifierInChI=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 KeyInChIKey=NLZUEZXRPGMBCV-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenylpropanes. These are organic compounds containing a phenylpropane moiety.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylpropanes
Direct ParentPhenylpropanes
Alternative Parents
Substituents
  • Phenylpropane
  • P-cresol
  • Toluene
  • Phenol
  • Organic oxygen compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder
Experimental Properties
PropertyValue
Melting Point72 °C
Boiling Point265 °C
Solubility1.1 mg/mL
LogP5.10
Predicted Properties
PropertyValueSource
Water Solubility0.015 g/LALOGPS
logP5.25ALOGPS
logP5.27ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)11.6ChemAxon
pKa (Strongest Basic)-4.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area20.23 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity70.41 m³·mol⁻¹ChemAxon
Polarizability27.35 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-2190000000-9fbadde6214d71846540JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-7490000000-b8f13a22c093b1883667JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-8590000000-bb65eb9156b08a98eb13JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-4490000000-a19c5b42b06567024d6fJSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-3490000000-ddeff8b438c2941c327eJSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-2190000000-9fbadde6214d71846540JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-7490000000-b8f13a22c093b1883667JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-8590000000-bb65eb9156b08a98eb13JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-4490000000-a19c5b42b06567024d6fJSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-0a4i-3490000000-ddeff8b438c2941c327eJSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a4i-4890000000-937a0d7c9f6bc6884917JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-00fr-3190000000-b316f5f5da9b2ca1a836JSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - DI-ESI-qTof , Negativesplash10-0gb9-0090000000-beb559334e11b52a6a6bJSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0090000000-f5adfac3bff91424bb5aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-1490000000-16fb4ab4552b3f6dc2d2JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0ab9-3920000000-413f3c2e53c1dfbc97f2JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-0090000000-361c47d317a34fbbf403JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-0090000000-27b24d01f4d65ae3d8ffJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-014i-0970000000-c5d8c2d3517a4486f6c2JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-0a4i-7790000000-b645e922d4fa7b593cbcJSpectraViewer | MoNA
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
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. (4, 5). 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). (1). 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 ValuesNot Available
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. (7)
Uses/SourcesBHT is primarily used as an antioxidant food additive (E number E321) as well as an antioxidant additive in cosmetics, pharmaceuticals, jet fuels, rubber, petroleum products, electrical transformer oil, and embalming fluid.
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 (2) although it is not a genotoxic carcinogen. Limited evidence suggests that high doses of BHT may mimic estrogen (3), 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.
SymptomsNot Available
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.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDHMDB33826
PubChem Compound ID31404
ChEMBL IDNot Available
ChemSpider ID13835296
KEGG IDC14693
UniProt IDNot Available
OMIM ID
ChEBI ID34247
BioCyc IDNot Available
CTD IDD002084
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkButylated_hydroxytoluene
References
Synthesis ReferenceNot Available
MSDST3D4911.pdf
General References
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  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 ]
  6. Yannai, Shmuel. (2004) Dictionary of food compounds with CD-ROM: Additives, flavors, and ingredients. Boca Raton: Chapman & Hall/CRC.
  7. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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 ]
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 ]
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 ]
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 ]
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 ]
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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.87 uMATG_RXRb_TRANSAttagene
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 ]
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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC507.65 uMATG_RARb_TRANSAttagene
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 ]
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 ]