Compendium of the most significant studies with reference to properties, intake, effects.

Araújo-Filho HG, Dos Santos JF, Carvalho MTB, Picot L, Fruitier-Arnaudin I, Groult H, Quintans-Júnior LJ, Quintans JSS. Anticancer activity of limonene: A systematic review of target signaling pathways. Phytother Res. 2021 Sep;35(9):4957-4970. doi: 10.1002/ptr.7125. 

Abstract. Limonene (LIM) is a monoterpene, which is abundant in essential oils of Citrus fruits peels (Rutaceae). More recently, LIM, as a potential natural anticancer compound, has attracted major attention and exerted a chemopreventive activity, stimulating the detoxification of carcinogenic compounds and limiting tumor growth and angiogenesis in various cancer models. 

Sun C, Theodoropoulos C, Scrutton NS. Techno-economic assessment of microbial limonene production. Bioresour Technol. 2020 Mar;300:122666. doi: 10.1016/j.biortech.2019.122666.

Abstract. A techno-economic analysis is carried out for one such process producing limonene from sugar at an industrial plant scale to assess potential economic viability. A conceptual design of the process is developed, in which a gas stripping-solvent scrubbing method is chosen for recovering limonene from bioreactors based on consideration of payback time and process operability. 

Garre A, Espín JF, Huertas JP, Periago PM, Palop A. Limonene nanoemulsified with soya lecithin reduces the intensity of non-isothermal treatments for inactivation of Listeria monocytogenes. Sci Rep. 2020 Feb 27;10(1):3656. doi: 10.1038/s41598-020-60571-9.

Abstract.  Treatments with a high heating rate (20 °C/min) are more effective than those with a slow heating rate (1 °C/min). This investigation demonstrates that the addition of nanoemulsified D-limonene can greatly reduce the intensity of the thermal treatments currently applied in the food industry. Hence, it can improve the product quality without impacting its safety.

Santana HSR, de Carvalho FO, Silva ER, Santos NGL, Shanmugam S, Santos DN, Wisniewski JO, Junior JSC, Nunes PS, Araujo AAS, de Albuquerque Junior RLC, Dos Santos MRV. Anti-Inflammatory Activity of Limonene in the Prevention and Control of Injuries in the Respiratory System: A Systematic Review. Curr Pharm Des. 2020;26(18):2182-2191. doi: 10.2174/1381612826666200320130443.

Abstract. The purpose of this article is to provide an overview of the anti-inflammatory activity of limonene and its capacity to prevent and control respiratory system injuries.

Gentile D, Berliocchi L, Russo R, Bagetta G, Corasaniti MT. Effects of the autophagy modulators d-limonene and chloroquine on vimentin levels in SH-SY5Y cells. Biochem Biophys Res Commun. 2020 Dec 17;533(4):764-769. doi: 10.1016/j.bbrc.2020.09.073.

Abstract. Here, we report that this monoterpene rapidly enhances Ca2+ levels in SH-SY5Y cells; yet this effect does not lead to calpain- or caspase-mediated proteolysis of α-spectrin, nor calpain activity is required for the established enhancement of LC3-II levels by d-limonene.

 Ciriminna R, Lomeli-Rodriguez M, Demma Carà P, Lopez-Sanchez JA, Pagliaro M. Limonene: a versatile chemical of the bioeconomy. Chem Commun (Camb). 2014 Dec 18;50(97):15288-96. doi: 10.1039/c4cc06147k.

Abstract. We anticipate that the expansion in uses for limonene will translate into increasing production and use of this relevant natural product, especially for advanced applications.

Justino de Araújo AC, Freitas PR, Rodrigues Dos Santos Barbosa C, Muniz DF, Rocha JE, Albuquerque da Silva AC, Datiane de Morais Oliveira-Tintino C, Ribeiro-Filho J, Everson da Silva L, Confortin C, Amaral WD, Deschamps C, Barbosa-Filho JM, Ramos de Lima NT, Tintino SR, Melo Coutinho HD. GC-MS-FID characterization and antibacterial activity of the Mikania cordifolia essential oil and limonene against MDR strains. Food Chem Toxicol. 2020 Feb;136:111023. doi: 10.1016/j.fct.2019.111023. 

Abstract. The present study evaluated the effect of the essential oil of Mikania cordifolia (EOMc) and its major constituent limonene alone or associated with antibacterial drugs against Multidrug Resistant Bacteria (MDR). To evaluate the antibacterial activity, the minimum inhibitory concentrations (MIC) of the oil and limonene against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus were determined.

Limonene (4-isopropenyl-1-methylcyclohexene) is a monoterpene hydrocarbon, one of the most frequently found in the plant kingdom, synthesised naturally from plants through a process with geranyl pyrophosphate It has two optical isomers: d-limonene and the more common l-limonene, a slightly yellow transparent liquid with a pleasant lemon scent which is produced industrially by cold pressing of generally dried citrus pulp and peel or by mechanical vaporization processes such as Soxhlet. It dissolves dammar and rosin.  In the presence of inorganic acids, limonene reacts with water to form -terpinol and terpenediol hydrate.

What it is used for and where it is used

Because of its olfactory characteristics and its wide availability in nature, it is a flavouring terpene that is included in beverages, foodstuffs, home cosmetics and personal hygiene products in order to impart a pleasant fragrance to the product.

Medical

Limonene has demonstrated a wide range of health benefits (1): has an anti-stress action (2), and recent studies have also focused on limonene as it could have a preventive anti-tumour action (3) due to its antioxidant activities, which act mainly on apoptosis induced by tumour regression (4). In this study, the antibacterial activity of d-limonene and its potentiating activity of different classes of antibiotics for Gram-positive and Gram-negative bacteria were positively evaluated (5).

Used as a natural solvent in the manufacture of oil and oil-based paints, synthetic resins, synthetic rubbers, metal drying agent and solvent. 

Cosmetics

Limonene is commonly used as a fragrance in cosmetics to pleasantly scent products containing it. It can be obtained from lemon, laurel, bergamot, kumquat, geranium and many other flowers. In cosmetic applications, as limonene is easily oxidised by contact with air, there is a risk of skin allergy (6). Reading many cosmetic texts and reviews, limonene, like linalool, or linalool, are cited as dangerous components, but this is not the case. It is the oxidation of the product that can be potentially dangerous, not the component itself, as limonene, in cosmetics, is processed in a non-sterile way and in contact with components that can accelerate the oxidative process. This is why it is one of the chemicals that can cause allergies and why it is mandatory to write it on the label when its percentage exceeds a certain value. It is a component that is considered safe if it is not oxidised, so remember to close the cap of the package in which it is inserted tightly to prevent air from penetrating inside for a long time and causing oxidation not only of this, but also of any other oxidation-sensitive components.

Safety

Linalool and D-limonene are common fragrances that oxidise easily on exposure to air. The resulting linalool and D-limonene hydroperoxides have been shown to have high frequencies of positive patch test reactions in several European and international studies .... In this study, the frequency of positive patch test reactions to linalool hydroperoxides is 20% (19/96) and the frequency of positive reactions to D-limonene hydroperoxides is 8% (7/90). These high frequencies suggest that patch testing for linalool and limonene hydroperoxides should be performed in all patients with suspected fragrance allergy (7).

The most relevant studies on the subject have been selected with a summary of their contents:

Limonene studies

Typical optimal characteristics of the commercial product d-limonene

• Molecular Formula : C₁₀H₁₆
• Molecular Weight : 136.238 g/mol
• Exact Mass    136.125198
• CAS : 138-86-3  9003-73-0  65996-98-7  7705-14-8  5989-27-5  8008-56-8  8008-57-9  8028-38-4  0008008-57-9
• UNII GFD7C86Q1W
• EC Number: 227-815-6     205-341-0     266-034-5     231-732-0
• DSSTox Substance ID:    DTXSID6028288    DTXSID2029612
• MDL number  MFCD00062992
• PubChem Substance ID 
• InChI=1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,10H,1,5-7H2,2-3H3 
• InChl Key   XMGQYMWWDOXHJM-UHFFFAOYSA-N   
• SMILES    CC1=CCC(CC1)C(=C)C
• IUPAC   1-methyl-4-prop-1-en-2-ylcyclohexene
• ChEBI   15384
• NSC    757069    21466    844
• RTECS    GW6360000
• UN Number    2052

Synonyms :

• Dipentene
• Polylimonene
• Nesol
• Cyclohexene, 1-methyl-4-(1-methylethenyl)-, homopolymer
• 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene
• p-Mentha-1,8-diene, polymers
• +)-p-Mentha-1,8-diene
• (+)-Carvene
• 4-Isopropenyl-1-methyl-1-cyclohexene
• EINECS 205-341-0
• EINECS 231-732-0
• MDL number: MFCD00062991
• PubChem Substance ID 329759707

References______________________________________________________________________

(1) Vieira AJ, Beserra FP, Souza MC, Totti BM, Rozza AL. Limonene: Aroma of innovation in health and disease. Chem Biol Interact. 2018 Mar 1;283:97-106. doi: 10.1016/j.cbi.2018.02.007.

(2) d'Alessio PA, Bisson JF, Béné MC. Anti-stress effects of d-limonene and its metabolite perillyl alcohol. Rejuvenation Res. 2014 Apr;17(2):145-9. doi: 10.1089/rej.2013.1515. 

(3) Miller JA, Pappan K, Thompson PA, Want EJ, Siskos AP, Keun HC, Wulff J, Hu C, Lang JE, Chow HH. Plasma metabolomic profiles of breast cancer patients after short-term limonene intervention. Cancer Prev Res (Phila). 2015 Jan;8(1):86-93. doi: 10.1158/1940-6207.CAPR-14-0100. 

da Silva CEH, Gosmann G, de Andrade SF. Limonene and Perillyl Alcohol Derivatives: Synthesis and Anticancer Activity. Mini Rev Med Chem. 2021;21(14):1813-1829. doi: 10.2174/1389557521666210212150504.

(4) de Vasconcelos C Braz J, de Carvalho FO, de Vasconcelos C Meneses D, Calixto FAF, Santana HSR, Almeida IB, de Aquino LAG, de Souza Araújo AA, Serafini MR. Mechanism of Action of Limonene in Tumor Cells: A Systematic Review and Meta-Analysis. Curr Pharm Des. 2021;27(26):2956-2965. doi: 10.2174/1381612826666201026152902.

(5) Costa MDS, Rocha JE, Campina FF, Silva ARP, Da Cruz RP, Pereira RLS, Quintans-Júnior LJ, De Menezes IRA, De S Araújo AA, De Freitas TS, Teixeira AMR, Coutinho HDM. Comparative analysis of the antibacterial and drug-modulatory effect of d-limonene alone and complexed with β-cyclodextrin. Eur J Pharm Sci. 2019 Feb 1;128:158-161. doi: 10.1016/j.ejps.2018.11.036.

(6) Deza G, García-Bravo B, Silvestre JF, Pastor-Nieto MA, González-Pérez R, Heras-Mendaza F, Mercader P, Fernández-Redondo V, Niklasson B, Giménez-Arnau AM; GEIDAC. Contact sensitization to limonene and linalool hydroperoxides in Spain: a GEIDAC* prospective study. Contact Dermatitis. 2017 Feb;76(2):74-80. doi: 10.1111/cod.12714.

(7) Nath NS, Liu B, Green C, Atwater AR. Contact Allergy to Hydroperoxides of Linalool and D-Limonene in a US Population. Dermatitis. 2017 Sep/Oct;28(5):313-316. doi: 10.1097/DER.0000000000000318.