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Record Information
Version1.0
Created at2006-08-12 19:51:01 UTC
Updated at2021-10-07 20:38:50 UTC
NP-MRD IDNP0000635
Secondary Accession NumbersNone
Natural Product Identification
Common Named-Limonene
Description(+)-Limonene, also known as d-limonene, is a naturally occurring monoterpene which is the major component in orange oil. Currently, (+)-limonene is widely used as a flavour and fragrance and is listed to be generally recognized as safe in food by the Food and Drug Administration (21 CFR 182.60 In the Code of Federal Regulations, U.S.A.). Recently, however, (+)-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to (+)-limonene causes a significant incidence of renal tubular tumours exclusively in male rats. Although (+)-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of (+)-limonene may raise some concern regarding the safety of (+)-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of (+)-limonene results from the accumulation of a protein, alpha 2u-globulin, in male rat kidney proximal tubule lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with alpha 2u-globulin. However, none of these proteins, including the mouse equivalent of alpha 2u-globulin, can produce this toxicity, indicating a unique specificity for alpha 2u-globulin. With chronic exposure to (+)-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensatory cell proliferation. Both (+)-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in vitro mutagenicity screens. Therefore, the toxicity-related renal cell proliferation is believed to be integrally involved in the carcinogenicity of (+)-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The scientific data demonstrates that the tumorigenic activity of (+)-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of (+)-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that alpha 2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both (+)-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation (PMID: 2024047 ).
Structure
Thumb
Synonyms
ValueSource
(+)-(4R)-LimoneneChEBI
(+)-(R)-LimoneneChEBI
(+)-4-Isopropenyl-1-methylcyclohexeneChEBI
(4R)-1-Methyl-4-isopropenylcyclohex-1-eneChEBI
(4R)-4-Isopropenyl-1-methylcyclohexeneChEBI
(R)-(+)-LimoneneChEBI
(R)-(+)-p-Mentha-1,8-dieneChEBI
(R)-1-Methyl-4-(1-methylethenyl)cyclohexeneChEBI
(R)-4-Isopropenyl-1-methyl-1-cyclohexeneChEBI
(R)-p-Mentha-1,8-dieneChEBI
4BetaH-p-mentha-1,8-dieneChEBI
D-(+)-LimoneneChEBI
D-LimonenChEBI
D-LimoneneChEBI
(4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohexeneKegg
AISA 5203-L (+)limoneneHMDB
DipenteneHMDB
(-)-LimoneneHMDB
1-Methyl-4-(1-methylethenyl)cyclohexeneHMDB
LimoneneHMDB
Limonene, (+-)-isomerHMDB
(D)-LimoneneHMDB
4-Mentha-1,8-dieneHMDB
Limonene, (R)-isomerHMDB
(+)-DipenteneHMDB
(+)-alpha-LimoneneHMDB
(+)-p-Mentha-1,8-dieneHMDB
(+)-Α-limoneneHMDB
(4R)-(+)-LimoneneHMDB
(4R)-1-Methyl-4-(1-methylethenyl)cyclohexeneHMDB
(4R)-LimoneneHMDB
(R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-eneHMDB
(R)-LimoneneHMDB
1-Methyl-4-prop-1-en-2-yl-cyclohexeneHMDB
(+)-(R)-4-Isopropenyl-1-methylcyclohexeneHMDB
D LimoneneHMDB
4 Mentha 1,8 dieneHMDB
(R)-4-Isopropenyl-1-methylcyclohexeneHMDB
(4R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-eneHMDB
R-LimoneneHMDB
p-Mentha-1,8-dieneHMDB
(±)-dipenteneHMDB
(±)-limoneneHMDB
(±)-alpha-limoneneHMDB
(±)-α-limoneneHMDB
1,8-p-MenthadieneHMDB
1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-eneHMDB
1-Methyl-4-isopropenyl-1-cyclohexeneHMDB
1-Methyl-4-isopropenylcyclohexeneHMDB
1-Methyl-p-isopropenyl-1-cyclohexeneHMDB
4-Isopropenyl-1-methyl-1-cyclohexeneHMDB
4-Isopropenyl-1-methylcyclohexeneHMDB
DL-LimoneneHMDB
DipentenHMDB
LimonenHMDB
alpha-LimoneneHMDB
Α-limoneneHMDB
(+)-LimoneneHMDB, ChEBI
Chemical FormulaC10H16
Average Mass136.2340 Da
Monoisotopic Mass136.12520 Da
IUPAC Name(4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene
Traditional Nameα-limonene
CAS Registry Number5989-54-8
SMILES
CC(=C)[C@@H]1CCC(C)=CC1
InChI Identifier
InChI=1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,10H,1,5-7H2,2-3H3/t10-/m0/s1
InChI KeyXMGQYMWWDOXHJM-JTQLQIEISA-N
Experimental Spectra
Spectrum TypeDescriptionDepositor EmailDepositor OrganizationDepositorDeposition DateView
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, CDCl3, experimental)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
Predicted Spectra
Spectrum TypeDescriptionDepositor IDDepositor OrganizationDepositorDeposition DateView
1D NMR13C NMR Spectrum (1D, 25 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 252 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 50 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 75 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 101 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 126 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 151 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 176 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 201 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
1D NMR13C NMR Spectrum (1D, 226 MHz, D2O, predicted)Wishart LabWishart LabDavid Wishart2021-06-20View Spectrum
Chemical Shift Submissions
Not Available
Species
Species of Origin
Species NameSourceReference
Abies albaKNApSAcK Database
Abies balsameaLOTUS Database
Abies grandisLOTUS Database
Achillea abrotanoidesLOTUS Database
Acorus calamusLOTUS Database
Acorus gramineusLOTUS Database
Aframomum malaLOTUS Database
African marigoldLOTUS Database
Agastache rugosaLOTUS Database
Agastache rugosusKNApSAcK Database
Agathosma betulinaLOTUS Database
Alpinia galangaLOTUS Database
Ammodaucus leucotrichusLOTUS Database
Anethum graveolensKNApSAcK Database
Anethum spp.KNApSAcK Database
Angelica archangelicaLOTUS Database
Apium graveolensFooDB
Apium graveolens var. dulceFooDB
    • Harvey J. Gold, Charles W. Wilson III The Volatile Flavor Substances of Celery. Journal of Food S...
Araucaria cunninghamiiLOTUS Database
Artemisia annuaKNApSAcK Database
Artemisia capillarisKNApSAcK Database
Artemisia vulgarisLOTUS Database
Artemisia xerophyticaLOTUS Database
Asarum heterotropoides var.mandshuricumKNApSAcK Database
Asarum sieboldiiKNApSAcK Database
Atalantia guillauminiiKNApSAcK Database
Azadirachta indicaLOTUS Database
Blumea mollisLOTUS Database
Boswellia carteriiKNApSAcK Database
Brassica oleracea var. botrytisFooDB
Bupleurum chinenseKNApSAcK Database
Bupleurum gibraltaricumLOTUS Database
Canarium zeylanicumLOTUS Database
Cannabis sativaCannabisDB
      Not Available
Carum carviFooDB
Carum carvi L.KNApSAcK Database
Castanopsis cuspidataLOTUS Database
Cecropia pachystachyaLOTUS Database
Cedrus libaniLOTUS Database
Chamaecyparis formosensisLOTUS Database
Cinnamomum camphoraLOTUS Database
Cinnamomum verumLOTUS Database
Cistus clusiiLOTUS Database
Cistus incanusLOTUS Database
Citrus aurantiifoliaLOTUS Database
Citrus aurantiumLOTUS Database
Citrus junosLOTUS Database
Citrus limonFooDB
Citrus maximaLOTUS Database
Citrus medicaKNApSAcK Database
Citrus natsudaidaiLOTUS Database
Citrus reticulataKNApSAcK Database
Citrus sinensisLOTUS Database
Citrus unshiuLOTUS Database
Citrus wilsoniiLOTUS Database
Citrus X sinensis (L.) Osbeck (pro. sp.)FooDB
Clausena anisataLOTUS Database
Conocephalum supradecompositumLOTUS Database
Coriandrum sativumKNApSAcK Database
Cryptotaenia japonicaKNApSAcK Database
Cymbopogon citratusLOTUS Database
Cymbopogon martiniiLOTUS Database
Cyperus rotundusLOTUS Database
Daucus carotaKNApSAcK Database
Daucus carota ssp. sativusFooDB
Echinops grijsiiKNApSAcK Database
Elettaria cardamomumFooDB
Eucalyptus staigerianaKNApSAcK Database
Euthamia graminifoliaLOTUS Database
Evodia rutaecarpaKNApSAcK Database
Foeniculum vulgareKNApSAcK Database
Forsythia suspensaKNApSAcK Database
Frullania fragilifoliaLOTUS Database
Halocarpus kirkiiLOTUS Database
Houttuynia cordataKNApSAcK Database
Houttuynia emeiensisKNApSAcK Database
Hyssopus officinalis L.FooDB
Illicium verumFooDB
Isocoma wrightiiLOTUS Database
Isodon melissoidesLOTUS Database
Juniperus communisLOTUS Database
Juniperus excelsaLOTUS Database
Keteleeria davidianaLOTUS Database
Lantana camaraLOTUS Database
Larix sukaczewiiLOTUS Database
Laurus nobilisLOTUS Database
Laurus nobilis L.FooDB
Lavandula angustifoliaLOTUS Database
Lavandula stoechasLOTUS Database
Lindera aggregataLOTUS Database
Liquidambar formosanaKNApSAcK Database
Litsea cubebaLOTUS Database
Machilus thunbergiiLOTUS Database
Magnolia obovataLOTUS Database
Magnolia officinalisKNApSAcK Database
Mangifera indicaKNApSAcK Database
Marsupella emarginataLOTUS Database
Matricaria matricarioidesLOTUS Database
Medicago sativaKNApSAcK Database
Melaleuca alternifoliaLOTUS Database
Mentha aquaticaLOTUS Database
Mentha haplocalyxKNApSAcK Database
Mentha piperitaKNApSAcK Database
Mentha rotundifoliaLOTUS Database
Mentha x piperitaFooDB
Methylosinus trichosporiumLOTUS Database
Molopospermum peloponnesiacumLOTUS Database
Mosla chinensisLOTUS Database
Mosla diantheraKNApSAcK Database
Murraya paniculataKNApSAcK Database
Myrica galeLOTUS Database
Myristica fragransFooDB
Nicotiana tabacumKNApSAcK Database
Notopterygium forbesiiKNApSAcK Database
Notopterygium incisumKNApSAcK Database
Ocimum americanumKNApSAcK Database
Ocimum basilicumKNApSAcK Database
Ocimum gratissimumKNApSAcK Database
Ocimum kilimandscharicimKNApSAcK Database
Ocimum sanctumKNApSAcK Database
Ocimum tenuiflorumKNApSAcK Database
Oenanthe aquaticaLOTUS Database
Pandanus tectoriusKNApSAcK Database
Parthenium argentatumLOTUS Database
Pelargonium graveolensKNApSAcK Database
Perilla frutescensLOTUS Database
Perilla frutescens var.acutaKNApSAcK Database
Perilla frutescens var.crispaKNApSAcK Database
Persea americanaLOTUS Database
Persicaria minorLOTUS Database
Petroselinum crispumFooDB
Phyllocladus trichomanoidesLOTUS Database
Picea abiesLOTUS Database
Pieris napiLOTUS Database
Pimpinella anisumLOTUS Database
Pinus banksianaKNApSAcK Database
Pinus bungeanaKNApSAcK Database
Pinus cembraLOTUS Database
Pinus contorta var. latifoliaKNApSAcK Database
Pinus jeffreyiLOTUS Database
Pinus koraiensisKNApSAcK Database
Pinus serotinaLOTUS Database
Pinus taedaKNApSAcK Database
Piper aduncumLOTUS Database
Piper arboreumLOTUS Database
Piper betleLOTUS Database
Piper nigrum L.FooDB
Pistacia atlanticaLOTUS Database
Pittosporum eugenioidesLOTUS Database
Pittosporum tenuifoliumLOTUS Database
Pittosporum undulatumLOTUS Database
Plagiochila rutilansLOTUS Database
Porophyllum ruderaleLOTUS Database
Pseudotsuga menziesiiLOTUS Database
Psidium guajavaFooDB
Rabdosia rubescensKNApSAcK Database
Rhaponticum carthamoidesLOTUS Database
Rhodiola roseaLOTUS Database
Rhododendron anthopogonoidesKNApSAcK Database
Rosmarinus officinalisKNApSAcK Database
Salvia rosmarinusFooDB
Santiria trimeraLOTUS Database
Schisandra chinensisKNApSAcK Database
Schizonepeta multifidaLOTUS Database
Schizonepeta tenuifoliaKNApSAcK Database
Sideritis leucanthaLOTUS Database
Siphonochilus aethiopicusLOTUS Database
Sium latifoliumLOTUS Database
Solidago canadensisLOTUS Database
Tanacetum vulgareLOTUS Database
Thuja occidentalisLOTUS Database
Thujopsis dolabrataLOTUS Database
Thymus fedtschenkoiLOTUS Database
Thymus revolutusLOTUS Database
Thymus vulgarisKNApSAcK Database
Toddalia asiaticaLOTUS Database
Vaccinium vitis-idaeaLOTUS Database
Valeriana jatamansiiKNApSAcK Database
Valeriana officinalisLOTUS Database
Valeriana officinalis var.latifoliaKNApSAcK Database
Vitis rotundifoliaLOTUS Database
Zingiber officinaleKNApSAcK Database
Chemical Taxonomy
Description Belongs to the class of organic compounds known as menthane monoterpenoids. These are monoterpenoids with a structure based on the o-, m-, or p-menthane backbone. P-menthane consists of the cyclohexane ring with a methyl group and a (2-methyl)-propyl group at the 1 and 4 ring position, respectively. The o- and m- menthanes are much rarer, and presumably arise by alkyl migration of p-menthanes.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassMonoterpenoids
Direct ParentMenthane monoterpenoids
Alternative Parents
Substituents
  • P-menthane monoterpenoid
  • Monocyclic monoterpenoid
  • Branched unsaturated hydrocarbon
  • Cycloalkene
  • Cyclic olefin
  • Unsaturated aliphatic hydrocarbon
  • Unsaturated hydrocarbon
  • Olefin
  • Hydrocarbon
  • Aliphatic homomonocyclic compound
Molecular FrameworkAliphatic homomonocyclic compounds
External Descriptors
Physical Properties
StateLiquid
Experimental Properties
PropertyValueReference
Melting Point-90 °CNot Available
Boiling Point175.00 to 177.00 °C. @ 760.00 mm HgThe Good Scents Company Information System
Water Solubility13.8 mg/L @ 25 °C (exp)The Good Scents Company Information System
LogP4.38Griffin, S., Wyllie, S. G., & Markham, J. (1999). Determination of octanol-water partition coefficient for terpenoids using reversed-phase high-performance liquid chromatography. Journal of Chromatography A, 864(2), 221-228.
Predicted Properties
PropertyValueSource
Water Solubility0.46 g/LALOGPS
logP4.5ALOGPS
logP3.22ChemAxon
logS-2.5ALOGPS
Physiological Charge0ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity46.48 m³·mol⁻¹ChemAxon
Polarizability17.55 ųChemAxon
Number of Rings1ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
HMDB IDHMDB0003375
DrugBank IDDB08921
Phenol Explorer Compound IDNot Available
FoodDB IDFDB013861
KNApSAcK IDC00010868
Chemspider ID389747
KEGG Compound IDC06099
BioCyc IDCPD-4886
BiGG IDNot Available
Wikipedia LinkLimonene
METLIN IDNot Available
PubChem Compound440917
PDB IDNot Available
ChEBI ID15382
Good Scents IDrw1013771
References
General References
  1. Bhatia KS, Singh J: Effect of linolenic acid/ethanol or limonene/ethanol and iontophoresis on the in vitro percutaneous absorption of LHRH and ultrastructure of human epidermis. Int J Pharm. 1999 Apr 15;180(2):235-50. [PubMed:10370194 ]
  2. Cal K, Janicki S, Sznitowska M: In vitro studies on penetration of terpenes from matrix-type transdermal systems through human skin. Int J Pharm. 2001 Aug 14;224(1-2):81-8. [PubMed:11472817 ]
  3. Matura M, Goossens A, Bordalo O, Garcia-Bravo B, Magnusson K, Wrangsjo K, Karlberg AT: Oxidized citrus oil (R-limonene): a frequent skin sensitizer in Europe. J Am Acad Dermatol. 2002 Nov;47(5):709-14. [PubMed:12399762 ]
  4. Falk A, Gullstrand E, Lof A, Wigaeus-Hjelm E: Liquid/air partition coefficients of four terpenes. Br J Ind Med. 1990 Jan;47(1):62-4. [PubMed:2310709 ]
  5. Lim PF, Liu XY, Kang L, Ho PC, Chan YW, Chan SY: Limonene GP1/PG organogel as a vehicle in transdermal delivery of haloperidol. Int J Pharm. 2006 Mar 27;311(1-2):157-64. Epub 2006 Jan 31. [PubMed:16451823 ]
  6. Yamane MA, Williams AC, Barry BW: Terpene penetration enhancers in propylene glycol/water co-solvent systems: effectiveness and mechanism of action. J Pharm Pharmacol. 1995 Dec;47(12A):978-89. [PubMed:8932680 ]
  7. Cornwell PA, Barry BW, Stoddart CP, Bouwstra JA: Wide-angle X-ray diffraction of human stratum corneum: effects of hydration and terpene enhancer treatment. J Pharm Pharmacol. 1994 Dec;46(12):938-50. [PubMed:7536240 ]
  8. Flamm WG, Lehman-McKeeman LD: The human relevance of the renal tumor-inducing potential of d-limonene in male rats: implications for risk assessment. Regul Toxicol Pharmacol. 1991 Feb;13(1):70-86. [PubMed:2024047 ]