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Limonene

Limonene is a naturally occurring cyclic monoterpene hydrocarbon with the molecular formula C₁₀H₁₆, existing as a colorless liquid with a characteristic citrus-like odor and serving as the primary component (up to 98%) in the essential oils extracted from citrus fruit peels, such as oranges, lemons, and grapefruits.^[1]^[2] This compound features a cyclohexene ring substituted with a methyl group and an isopropenyl group, rendering it chiral with two main enantiomers: (R)-(+)-limonene, which predominates in citrus sources and contributes an orange scent, and (S)-(-)-limonene, found in coniferous trees, caraway, dill, and bergamot, imparting a pine-like aroma.^[3]^[1] Physical properties include a boiling point of 175.5–178°C, a flash point of 48°C, low water solubility (approximately 13.8–14 mg/L), and a density of 0.84 g/cm³, making it flammable, non-polar, and biodegradable into carbon dioxide and water.^[4]^[3] Limonene is industrially produced at scales of about 50,000 tons annually (as of 2021), primarily as a by-product of citrus processing via steam distillation of peel oils, with a global market value around US$361 million as of 2025; it also occurs in smaller amounts in non-citrus plants like pine and mint species.^[3]^[2]^[5] Its applications span food flavorings (at concentrations up to 1%), fragrances in cosmetics and personal care products (diluted to 0.002–0.2%), and industrial solvents for degreasing, cleaning, and resin dispersion, valued for replacing more toxic chlorinated hydrocarbons.^[1]^[4] Additionally, it functions as an insecticide in products like Orange Guard and is under investigation for potential chemopreventive effects in clinical trials, such as for pulmonary nodules.^[2]^[1] While generally of low acute toxicity (oral LD50 around 5 g/kg in rodents), limonene can act as a skin irritant and sensitizer, particularly when oxidized to form allergens, and its volatile emissions contribute significantly to urban ozone formation as a biogenic volatile organic compound.^[4]^[3]

Physical and Chemical Properties

Structure and Isomers

Limonene is classified as a cyclic monoterpene, a class of naturally occurring hydrocarbons derived from two isoprene units, with the molecular formula C₁₀H₁₆.^[1] Its structure features a six-membered cyclohexene ring with an endocyclic double bond positioned between carbons 1 and 2, a methyl substituent attached to carbon 1, and an isopropenyl group (prop-1-en-2-yl) linked to carbon 4. The isopropenyl moiety introduces an exocyclic double bond between carbons 8 and 9, where carbon 8 is the quaternary carbon directly bonded to carbon 4, carbon 9 represents the terminal =CH₂, and carbon 10 is the methyl group on carbon 8. This arrangement results in two non-conjugated double bonds, contributing to limonene's reactivity and olfactory properties.^[6]^[7] The systematic IUPAC name for the compound is 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene, reflecting the substituted cyclohexene core.^[1] Structural representations typically depict the ring in a half-chair conformation due to the endocyclic double bond, with the isopropenyl group oriented equatorially in the more stable isomer. The molecule's overall architecture underscores its role as a precursor in terpenoid chemistry, though the focus here remains on its foundational skeletal features.^[6] Limonene possesses a single chiral center at carbon 4, the ring carbon bearing the isopropenyl substituent, which gives rise to a pair of enantiomers. The (R)-enantiomer, designated as (R)-(+)-limonene or d-limonene, exhibits a positive optical rotation, while the (S)-enantiomer, known as (S)-(-)-limonene or l-limonene, shows the opposite. These enantiomers are mirror images that differ in their interactions with plane-polarized light and biological receptors. The specific optical rotation values are +123.8° for (R)-(+)-limonene and -123.8° for (S)-(-)-limonene, measured at 19.5 °C using the sodium D-line.^[7] This stereochemical distinction is critical, as natural sources predominantly yield one enantiomer, influencing applications in fragrance and pharmacology.^[7]

Physical Properties

Limonene is a colorless liquid characterized by a strong citrus odor, primarily lemon-like in its natural form.^[7] Its molar mass is 136.23 g/mol.^[7] The compound has a boiling point of 176 °C at 760 mmHg and a melting point of -74 °C.^[7] At 20 °C, limonene exhibits a density of 0.8411 g/cm³ and a refractive index of 1.473.^[7] Limonene is insoluble in water, with a solubility of 0.013 g/L at 25 °C, but it is miscible with organic solvents such as ethanol and ether.^[7] Its vapor pressure is 1.42 mmHg at 25 °C, and the flash point is 50 °C.^[7] The enantiomers of limonene contribute to varied odor perceptions, with the (R)-(+)-form evoking oranges and the (S)-(-)-form a turpentine or piny scent.^[7]^[3]

Property	Value	Conditions
Molar mass	136.23 g/mol	-
Appearance	Colorless liquid, citrus odor	-
Boiling point	176 °C	760 mmHg
Melting point	-74 °C	-
Density	0.8411 g/cm³	20 °C
Refractive index	1.473	20 °C
Water solubility	0.013 g/L	25 °C
Vapor pressure	1.42 mmHg	25 °C
Flash point	50 °C	-

Chemical Reactivity

Limonene demonstrates relative stability under neutral conditions, remaining largely unreactive in the absence of catalysts or oxidants, though prolonged exposure to air can initiate slow autoxidation processes.^[8] This stability stems from its non-polar hydrocarbon nature, but the molecule's exocyclic and endocyclic double bonds render it susceptible to oxidative transformations, particularly allylic oxidation at the 6-position. In the presence of oxygen or catalytic oxidants, limonene undergoes selective oxidation to form carveol as the primary allylic alcohol product, which can further oxidize to the ketone carvone.^[9] The initial oxidation step proceeds via a radical mechanism involving molecular oxygen, as illustrated in the simplified equation:

\text{Limonene} + \mathrm{O_2} \xrightarrow{\text{allylic oxidation}} \text{carveol}

This reaction is well-documented in both atmospheric and catalytic contexts, with carveol and carvone serving as key markers of limonene degradation.^[10] Under acidic conditions, limonene participates in isomerization reactions, where protonation of the double bonds facilitates skeletal rearrangements to yield terpinene isomers such as α-terpinene and γ-terpinene, or further to p-cymene via dehydrogenation or disproportionation steps.^[11] These transformations are catalyzed by solid acids like zeolites or metal oxides, with selectivity depending on acid strength and reaction temperature; for instance, milder conditions favor terpinolene, while stronger acids promote aromatization to p-cymene.^[12] Limonene also undergoes free-radical polymerization when initiated by peroxides such as benzoyl peroxide (BPO) or azobisisobutyronitrile (AIBN), typically at elevated temperatures around 80–90°C, resulting in the formation of poly(limonene) with molecular weights varying based on initiator concentration and monomer conversion rates up to 12–20%.^[13] The polymerization exploits the reactivity of the endocyclic double bond, leading to chain growth while the exocyclic bond often remains intact, yielding a renewable polymer with potential applications in materials science.^[14] Hydrogenation of limonene, employing metal catalysts like ruthenium or palladium on supports such as carbon or alumina, saturates both double bonds to produce p-menthane (1-methyl-4-(1-methylethyl)cyclohexane) under mild conditions of 40–100°C and moderate hydrogen pressure.^[15] This reaction proceeds stepwise, first forming menthene intermediates before full saturation, with high yields achievable in solvent-free systems.^[16] Epoxidation of limonene targets its double bonds using peroxides like hydrogen peroxide or m-chloroperoxybenzoic acid, often in the presence of catalysts such as titanium-based complexes, to form limonene 1,2-oxide or 8,9-oxide as the primary products.^[17] The reaction exhibits regioselectivity, with the endocyclic double bond being more reactive, and can be controlled to achieve mono- or diepoxides depending on oxidant stoichiometry and conditions.^[18]

Occurrence in Nature

In Plants

Limonene is predominantly found in the peels of citrus fruits, where it constitutes a major component of their essential oils. In orange peel oil, (R)-(+)-limonene accounts for 90-97% of the total composition, contributing significantly to the oil's profile.^[19] In lemon peel oil, limonene comprises 50-70%, serving as the primary monoterpene hydrocarbon.^[19] These high concentrations in citrus peels underscore limonene's role as a key volatile compound in fruit rinds. Beyond citrus, limonene occurs in various other plant species, including peppermint (Mentha piperita), juniper (Juniperus spp.), and conifers such as pine (Pinus spp.), where it is present in needles and resins.^[20] In these plants, limonene levels vary widely, typically comprising a minor to moderate portion (e.g., 1-5% in peppermint and juniper, higher in some pine species) of essential oils derived from leaves, berries, and woody tissues.^[21] As a volatile monoterpene in plant essential oils, limonene plays a crucial ecological role in defense mechanisms, repelling herbivores and inhibiting pathogens.^[22] It deters piercing-sucking insects and fungal invaders by disrupting their behavior or growth, thereby protecting plant tissues from damage.^[23] This defensive function is particularly evident in citrus, where limonene emission correlates with reduced susceptibility to pests.^[24] Limonene also imparts characteristic scents to plants, with the (R)-(+)-enantiomer responsible for the fresh, citrusy aroma of oranges. In plants, limonene exists primarily as specific enantiomers, such as (R)-(+)-limonene in citrus species and (S)-(-)-limonene in conifers.^[3]^[25] Concentrations of limonene differ across plant parts, reaching the highest levels in peels and resins, where it can exceed 90% of volatile content in citrus rinds and conifer exudates.^[25] In contrast, lower amounts are found in leaves or fruits, reflecting its targeted accumulation in protective outer layers.^[26]

Other Natural Sources

In animal contexts, limonene appears in trace amounts during metabolism following dietary or environmental exposure, where it is rapidly absorbed and oxidized in organs like the liver and kidneys.^[25] Certain insects also produce limonene as a component of their chemical defenses; for instance, ground beetles such as Ardistomis schaumii and Semiardistomis puncticollis secrete limonene to repel predators, marking the first documented case of terpene production in beetles' defensive secretions.^[27] This compound aids in transporting other noxious secretions through the insect exoskeleton, enhancing their protective efficacy.^[28] Atmospherically, limonene is emitted from natural sources and contributes significantly to secondary organic aerosol (SOA) formation via reactions with oxidants like nitrate radicals and ozone, generating highly oxygenated molecules that nucleate particles in the troposphere.^[29] These processes influence air quality and climate, with limonene's reactivity yielding SOA masses that can exceed those from less unsaturated terpenes. Fossil evidence preserves limonene as part of ancient terpenoid remnants in amber and sedimentary resins, where it occurs alongside other monoterpenes like α-pinene in deposits dating back to the Cretaceous and Eocene periods. These inclusions reflect the diagenetic survival of volatile compounds from prehistoric plant exudates, providing insights into paleoecological terpene distributions.^[30] In soil, limonene persists briefly before undergoing microbial degradation, primarily by actinobacteria such as Rhodococcus erythropolis DCL14, which epoxidizes it to intermediates like limonene-1,2-epoxide, followed by hydrolysis to carveol and carvone.^[31] This pathway follows first-order kinetics, with half-lives ranging from 0.08 to 2.82 days depending on soil type and microbial activity, yielding detectable metabolites like thymol and cymene.^[32] Concentrations from these non-plant sources generally remain lower than those in vegetative tissues.

Biosynthesis and Production

Biosynthetic Pathway

Limonene is biosynthesized in plants through the mevalonate or methylerythritol phosphate (MEP) isoprenoid pathways, which generate the C10 precursor geranyl pyrophosphate (GPP) from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via geranyl pyrophosphate synthase.^[33] This linear precursor serves as the substrate for the subsequent cyclization step in monoterpene formation.^[34] The conversion of GPP to limonene is catalyzed by limonene synthase (LS), a class I terpene synthase enzyme localized in plastids such as leucoplasts of secretory cells in oil glands.^[33] The reaction proceeds through a series of carbocation intermediates: GPP first isomerizes to neryl diphosphate (NPP), which upon ionization by Mg²⁺ or Mn²⁺-bound motifs (e.g., DDxxD) forms the neryl carbocation; this cisoid intermediate then undergoes 1,6-cyclization to the α-terpinyl carbocation, followed by deprotonation to yield limonene and release pyrophosphate.^[35]^[34] Aromatic residues in the enzyme active site, such as tryptophan and histidine, stabilize these carbocation intermediates to promote the correct folding and cyclization.^[34] Plant limonene synthases exhibit enantioselectivity, with those from citrus species predominantly producing the (R)-(+)-enantiomer, which constitutes the major form in fruit peels.^[36] Biosynthesis is regulated within the broader terpenoid metabolism network, where expression of synthase genes, such as the limonene synthase (CsLS) in Citrus sinensis, is influenced by developmental and environmental factors to control monoterpene accumulation in glandular tissues.^[36]^[33]

Industrial Production Methods

Limonene is primarily obtained industrially through extraction from citrus byproducts, particularly orange peels, which constitute the main source due to their high content of the compound.^[37] The most common extraction method is steam distillation, where citrus peels are boiled in water to release the essential oil, followed by distillation and separation of the limonene-rich fraction; this process yields approximately 0.5-1% limonene from orange peel waste.^[38] Cold pressing represents another key technique, involving mechanical compression of fresh citrus peels to rupture oil glands and release the crude essential oil, which is then centrifuged to isolate limonene; this method preserves the natural composition better than thermal processes and is widely used in the production of food-grade oils.^[39] Solvent extraction, often employing hexane as the solvent in a Soxhlet apparatus or similar setup, provides higher yields for industrial-scale recovery from dried peels, though it requires subsequent solvent removal to purify the product.^[40]^[19] Chemical synthesis of limonene, such as through isomerization of pinene or dimerization of isoprene units, is possible but rarely employed industrially owing to higher costs compared to extraction from abundant citrus waste.^[41] Biotechnological approaches have emerged as promising alternatives, utilizing engineered microorganisms like Escherichia coli or Saccharomyces cerevisiae expressing limonene synthase enzymes to produce the compound from glucose or glycerol feedstocks; titers up to 15.2 g/L have been achieved in bioreactor fermentations as of 2025, offering potential for sustainable, non-citrus-dependent production.^[37]^[42] Global production of limonene exceeds 70,000 tons annually as of 2023, predominantly derived from citrus processing byproducts.^[43]^[44]

Applications

Industrial Uses

Limonene serves as a versatile solvent in industrial applications, particularly in the formulation of paints, resins, and degreasers, where it effectively dissolves oils, waxes, tars, adhesives, and oil-based inks.^[45] Its nonpolar structure and reactivity enable it to act as a biodegradable, low-toxicity alternative to traditional petroleum-based solvents, reducing environmental persistence in manufacturing processes.^[46]^[47] In polymer chemistry, limonene functions as a biobased monomer for synthesizing renewable plastics and resins, often through epoxidation to form limonene dioxide or acrylate derivatives that copolymerize into durable materials.^[48]^[49] These limonene-derived polymers are particularly valued in adhesives as tackifying agents, enhancing adhesion without relying on petroleum-derived bisphenol A.^[25]^[50] Limonene acts as a key precursor in the industrial production of fragrances and flavors, undergoing oxidation to yield carvone, a compound essential for minty and spearmint-like profiles in perfumes and food additives.^[51] This transformation is achieved through enzymatic or chemical methods, such as biotransformation with glucose oxidase and peroxidase or copper-catalyzed oxidation, enabling scalable synthesis from abundant citrus byproducts.^[52]^[53] Limonene derivatives find application in 3D printing resins, where epoxidized forms like limonene dioxide are photopolymerized with vegetable oils to create crosslinked networks suitable for additive manufacturing.^[54] In the biofuel sector, limonene serves as an additive to diesel-biodiesel blends, functioning as an oxygenate to improve combustion efficiency and reduce emissions in engine fuels.^[55] Hydrogenated limonene variants, such as 1-isopropyl-4-methylcyclohexane, further enhance fuel stability as diesel additives.^[56] As an active ingredient in insecticide formulations, d-limonene is EPA-approved as a low-risk pesticide, with an exemption from the requirement of a tolerance for residues under 40 CFR § 180.1342 when used as an insecticide or herbicide in accordance with good agricultural practices, and as an inert ingredient exempt under 40 CFR §§ 180.910 and 180.930, allowing its use in products like pet shampoos.^[57]^[58]^[59] This status allows its widespread incorporation into low-toxicity pest control solutions targeting insects through surface disruption.^[60]^[61]

Consumer and Pharmaceutical Applications

Limonene serves as a widely used flavoring agent in foods and beverages, imparting a characteristic citrus taste and aroma due to its fresh, orange-like scent. The U.S. Food and Drug Administration (FDA) recognizes d-limonene as generally recognized as safe (GRAS) for use as a direct food additive in flavorings, with typical concentrations up to 0.01% in finished products to ensure safety and efficacy.^[62]^[63] In the fragrance industry, limonene is a key component in perfumes, soaps, and air fresheners, where it contributes to uplifting, citrus-based scents. The International Fragrance Association (IFRA) establishes standards limiting its use to 1-5% in such products to minimize potential sensitization risks from oxidation products.^[64] Limonene functions as an active ingredient in household cleaning products, particularly those based on orange oil, where it acts as a natural degreaser and solvent for removing oils, adhesives, and residues from surfaces. For example, it is incorporated into eco-friendly detergents and all-purpose cleaners to enhance cleaning performance while providing a pleasant citrus fragrance.^[65]^[66] In pharmaceutical applications, limonene is employed as an excipient to improve drug delivery, notably by enhancing skin penetration in transdermal patches and topical formulations. As a terpene penetration enhancer, it disrupts the lipid structure of the stratum corneum, facilitating the transport of active pharmaceuticals across the skin barrier.^[67]^[68] Limonene is also available as a dietary supplement, often used in aromatherapy contexts for potential stress relief through oral ingestion or inhalation of its citrus aroma. Recommended doses typically range from 100 to 500 mg per day, though higher amounts up to 1,000 mg have been studied for tolerability in adults.^[69]^[70]

Safety, Toxicology, and Environmental Impact

Human Health Effects

Limonene, a naturally occurring monoterpene, exhibits low acute toxicity in humans through various exposure routes, with the oral LD50 in rats reported at 4.4 g/kg body weight, indicating minimal risk at typical environmental or dietary levels.^[71] Human exposure primarily occurs via skin contact in cosmetics and cleaning products, inhalation in fragranced environments, or ingestion in food flavorings, where it is generally recognized as safe in moderate amounts by regulatory bodies.^[72] Regarding dermal exposure, limonene can act as a skin sensitizer, particularly in its oxidized form, leading to contact dermatitis in susceptible individuals. Patch testing studies have shown positive reactions in approximately 5% of patients with suspected fragrance allergy when tested with oxidized limonene at 0.3% concentration, with clinical relevance confirmed in cases of eczema from personal care products.^[73] Prevalence of sensitization varies, but early multicenter evaluations reported 2.8% positive patch tests with 3% oxidized limonene among dermatitis patients, highlighting its role as an emerging allergen in fragrance contact allergy.^[74] Inhalation of limonene vapors may irritate the respiratory tract at high concentrations exceeding 100 ppm, though the sensory irritation threshold in humans is above 80 ppm, with no observed effect levels around 100 ppm in animal models.^[75] Acute inhalation toxicity is low, and occupational exposure limits are set below irritant thresholds to prevent bronchial discomfort or dizziness.^[76] Oral ingestion of limonene is safe in amounts typically found in foods and beverages, such as citrus-derived flavorings, with no adverse effects reported at dietary levels.^[77] However, high doses from supplements or concentrated sources can cause gastrointestinal upset, including nausea, vomiting, and diarrhea, due to rapid absorption in the digestive tract.^[78] Limonene is not classified as a human carcinogen by the International Agency for Research on Cancer (IARC Group 3), based on limited evidence in experimental animals and inadequate data in humans.^[79] Extensive genotoxicity testing, including assays for mutagenicity in bacteria and chromosomal aberrations in mammalian cells, has shown no evidence of DNA damage or clastogenic effects.^[72] Chronic exposure studies in rodents reveal species-specific renal effects in male rats, but these are not relevant to human physiology due to metabolic differences.^[80]

Environmental and Regulatory Aspects

Limonene demonstrates significant acute toxicity to aquatic organisms, posing risks to ecosystems through direct exposure. Reported LC50 values include approximately 0.7 mg/L for fish species such as fathead minnows (Pimephales promelas) over 96 hours, 0.4 mg/L for Daphnia magna over 48 hours, and EC50 values of approximately 0.32 mg/L for green algae species like Pseudokirchneriella subcapitata over 72 hours.^[81]^[82] In terms of persistence, limonene is readily biodegradable under aerobic conditions, meeting OECD 301 criteria with degradation exceeding 60% within 28 days in standard tests such as the closed bottle method (OECD 301D). Its bioaccumulation potential remains low, characterized by a log Kow of 4.5 and an estimated bioconcentration factor (BCF) below 500, indicating limited long-term accumulation in aquatic food chains.^[83]^[84] Atmospherically, limonene serves as a precursor to secondary organic aerosols (SOA) through oxidative processes involving hydroxyl radicals (OH), ozone, and nitrate radicals (NO3). These reactions generate low-volatility products that partition into the particle phase, influencing aerosol formation and contributing to regional air quality dynamics and radiative forcing. Moreover, its oxidation products may exhibit increased toxicity, including respiratory and mutagenic effects.^[85]^[86]^[87] Under regulatory frameworks, limonene is fully registered under the European Union's REACH regulation (EC 1907/2006), requiring notification of its environmental hazards including aquatic toxicity. In the United States, it is listed on the Toxic Substances Control Act (TSCA) inventory, subjecting it to reporting and assessment. As a volatile organic compound (VOC) per the Clean Air Act, limonene contributes to ozone formation potential, yet it qualifies for exemptions or reduced scrutiny in certain eco-labeled green formulations due to its renewable sourcing and rapid degradation.^[88] Sustainability efforts emphasize limonene's derivation from citrus processing byproducts, such as orange peels, which repurposes agricultural waste and mitigates landfill contributions while lowering the overall environmental footprint of production compared to synthetic alternatives.^[89]^[90]

Research and Therapeutic Potential

Anticancer Studies

Preclinical studies have demonstrated that limonene inhibits the growth of mammary tumors in rat models. In experiments conducted in the 1990s under the auspices of the National Cancer Institute, dietary administration of d-limonene led to significant regression of chemically induced mammary carcinomas in responsive models when initiated early in tumor development. These findings established limonene's chemopreventive potential in rodent mammary carcinogenesis, though species-specific metabolism limits direct extrapolation to humans.^[91]^[92] Limonene exerts anticancer effects through multiple mechanisms, including the inhibition of Ras protein prenylation, which disrupts oncogenic signaling and cell proliferation in tumor cells. Its metabolites further impair farnesyl protein transferase activity, preventing the membrane association of Ras and thereby suppressing tumor growth. These actions collectively contribute to limonene's ability to suppress tumor initiation, angiogenesis, and metastasis in preclinical settings.^[93]^[94] Clinical trials evaluating limonene's anticancer potential have primarily focused on safety and pharmacokinetics, with limited efficacy data. A phase I trial in patients with advanced solid tumors, including breast cancer, established doses up to 8 g/m² per day as tolerable, with no dose-limiting toxicities observed, though objective responses were rare. In early-stage breast cancer patients, daily oral doses of 2 g for 2-6 weeks achieved detectable levels in breast tissue without significant adverse effects, but showed only modest modulation of biomarkers like isoprenylation inhibition. Overall, while well-tolerated, these studies indicate insufficient evidence to support limonene as an effective human cancer treatment, with no endorsement for curative use.^[95]^[96]^[97] The metabolite perillyl alcohol, derived from limonene oxidation, exhibits greater potency in preclinical anticancer models and is under investigation in ongoing clinical studies for various cancers, including glioblastoma and breast cancer, due to enhanced inhibition of similar pathways. Phase I/II trials of perillyl alcohol have explored intranasal and oral formulations, showing preliminary antitumor activity in some patients, though larger efficacy trials are needed. This analog builds on limonene's profile but addresses its limitations in bioavailability and potency.^[98]^[99]

Other Biological and Medical Research

Limonene exhibits antimicrobial activity against a range of bacteria and fungi. Against Gram-positive bacteria such as Staphylococcus aureus, limonene inhibits growth at a minimum inhibitory concentration (MIC) of 20 mL/L, disrupting cell membrane integrity and leading to leakage of cellular contents.^[100] For fungi, including dermatophytes like Trichophyton rubrum, the MIC is reported at 0.5% v/v, where limonene acts fungicidally by altering membrane permeability and inhibiting ergosterol biosynthesis.^[101] Additionally, limonene disrupts biofilms formed by pathogens such as Staphylococcus epidermidis and Pseudomonas aeruginosa, reducing biofilm biomass by over 50% at sub-MIC concentrations through interference with quorum sensing and extracellular matrix production.^[102] In anti-inflammatory research, limonene has shown promise in rodent models of arthritis. Oral administration of d-limonene (25-100 mg/kg) in complete Freund's adjuvant-induced arthritic rats reduced paw edema and joint inflammation by modulating pro-inflammatory cytokines like TNF-α and IL-6, while elevating anti-inflammatory IL-4 levels; this effect was observed in studies from the early 2020s.^[103] These findings suggest limonene inhibits NF-κB signaling pathways, providing a basis for its potential in managing inflammatory joint disorders. Neuroprotective investigations highlight limonene's role in Alzheimer's disease models. In vitro studies using primary rat cortical neurons exposed to Aβ1-42 oligomers demonstrate that limonene (10 µg/mL) mitigates neurotoxicity by scavenging reactive oxygen species (ROS), preserving mitochondrial function, and inhibiting acetylcholinesterase with an IC50 of 7.7 µg/mL.^[104] This amyloid-beta inhibition prevents neuronal apoptosis and maintains cell viability, indicating limonene's potential to counteract oxidative stress and protein aggregation in neurodegenerative contexts. Regarding metabolic effects, limonene aids in obesity management through lipid modulation in preclinical models. In high-fat diet-induced obese rats, daily d-limonene supplementation (154-1000 mg/kg) reduced body weight gain by approximately 10-14% via activation of the AMPK signaling pathway.^[105] A protocol for a 2022 human exploratory randomized trial has been published to investigate d-limonene-enriched supplements for metabolism-associated fatty liver disease in overweight individuals, but results are not yet available as of 2025.^[106] Recent preclinical research has explored limonene's role in wound healing. Topical application of d-limonene (50-100 mg/kg in a mouse excisional wound model) accelerated re-epithelialization, promoting collagen deposition and reducing inflammation through antioxidant mechanisms that lower ROS levels at the wound site.^[107]

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The monoterpene limonene in orange peels attracts pests and ...
Plant volatiles include terpenoids, which are generally involved in plant defense, repelling pests and pathogens and attracting insects for herbivore ...
[24]
d-LIMONENE - Some Naturally Occurring Substances - NCBI - NIH
Limonene is widely distributed among citrus and other plant species. It has been reported in more than 300 essential oils, at concentrations up to 90–95%, and ...
[25]
Limonene - an overview | ScienceDirect Topics
Limonene is defined as a common essential oil constituent of aromatic plants, belonging to the terpene group, known for its strong aroma that helps deter ...
[26]
A Gram-Scale Limonene Production Process with Engineered ...
Apr 18, 2020 · In this study, a limonene production process was developed with metabolically engineered Escherichia coli at the bioreactor scale.Missing: bacteria | Show results with:bacteria
[27]
Limonene Production: Insights, Techniques, and Future Directions
Feb 16, 2025 · Escherichia coli engineering has so far resulted in high yields received from the production of limonene, i.e., 1.35 g limonene per liter ...
[28]
Ground beetles produce lemon/orange-scented aromas as predator ...
Aug 13, 2009 · Some ground beetles produce the natural repellent limonene as their major defensive chemical. The paper is the result of a collaborative research project.
[29]
Non-polar Compounds Facilitate Movement of Chemicals - AskNature
Aug 23, 2016 · Limonene, a non-polar solvent, is somehow able to facilitate the transport of polar defensive chemicals through the non-polar exoskeleton of predatory ...
[30]
Non-linear effects of secondary organic aerosol formation ... - Nature
Dec 22, 2022 · Here, we investigate the formation and properties of SOA from nitrate radical oxidation of two common monoterpenes, α-pinene and limonene.
[31]
Terpenoids in extracts of Lower Cretaceous ambers from the ...
Our results suggest that the amber from Cantabria could be fossilized resin from Frenelopsis and other undetermined botanical sources. The biological terpenoid ...
[32]
Rhodococcus erythropolis DCL14 Contains a Novel Degradation ...
These results show thatR. erythropolis DCL14 metabolizes both enantiomers of limonene via a novel degradation pathway that starts with epoxidation at the 1,2 ...
[33]
Degradation Study of Limonene and trans-Cinnamaldehyde in ...
Apr 8, 2025 · The degradation of both compounds followed first-order kinetics with 50% degradation values (DT50) ranging from 0.08 and 2.82 days for limonene, ...
[34]
https://doi.org/10.1073/pnas.1501203112
[35]
https://doi.org/10.1186/s13068-021-01998-8
[36]
https://pubs.acs.org/doi/10.1021/acssynbio.5c00078
[37]
Limonene through Targeted Engineering of Citrus sinensis ...
May 28, 2025 · (18) Sustainable and biobased production of limonene using microbes becomes a promising alternative, which is pesticide-free, resilient to ...
[38]
Biotechnological production of limonene in microorganisms - PMC
In this review, we discuss the ins and outs of microbial limonene production in comparison with plant-based and chemical production.
[39]
Extracting limonene from oranges | Class experiment - RSC Education
This experiment demonstrates the extraction of plant oils. The peel of oranges is boiled in water and the oil produced (limonene) distilled in steam.
[40]
The effects of different extraction methods on essential oils from ...
Oct 25, 2023 · Among several extraction methods for citrus fruits, cold pressing (CP) and hydrodistillation (HD) are considered conventional. During HD, citrus ...
[41]
Orange peel waste valorisation through limonene extraction using ...
Nov 15, 2019 · Conventional solvent extraction for limonene recovery has been carried out using hexane as extractant due to its low boiling point and ...
[42]
How will we synthesize Limonene and what type of subsituation ...
Feb 27, 2019 · It's usually not synthesized, but extracted from citrus peels. You might be able to get it from Diels-Alder reaction of isoprene with itself.
[43]
Techno-economic assessment of microbial limonene production
Nowadays, most limonene is produced from citrus rind, a major by-product generated during fruit processing in citrus juice industries (Crawshaw, 2001). Limonene ...
[44]
[PDF] Chemical Synthesis of Various Limonene Derivatives
... limonene and (b) l-limonene. Being most abundant naturally occurring monoterpene, the enantiomers of limonene are found in a number of plant's essential oil ...
[45]
[PDF] Vendor List - Precision Cleaning Solvent Substitutes - US EPA
Applications include degreasing, removal of oils, wax, tar, adhesives, fresh paint and oil- based inks.
[46]
Terpenes as Green Solvents for Extraction of Oil from Microalgae - NIH
They represent an optimal alternative to petroleum solvents in many industrial applications. d-Limonene is a low cost, low toxicity biodegradable terpene ...
[47]
cleaning solvent d-limonene: Topics by Science.gov
Limonene has the capability to be a "green" alternative to petroleum-based solvents in CCC applications. Nonhazardous solvent composition and method for ...
[48]
Use of Limonene Epoxides and Derivatives as Promising Monomers ...
Jul 28, 2022 · The epoxidation of limonene leads to oxygen-rich epoxides that could replace common monomers based on bisphenol A, used in the polymer industry.
[49]
Limonene as biobased building block for functional monoterpene ...
Jan 22, 2025 · Limonene, a natural raw material, is used as a biobased building block for acrylate monomers due to its double bonds, high availability, and ...
[50]
[PDF] d-Limonene, a Renewable Component for Polymer Synthesis
Nowadays, the commercial application of poly(terpene) is more common as resins and as tackifiers in adhesive applications. The homo- or copolymers of terpenes ...
[51]
Biotransformation of d-limonene to carvone by means of glucose ...
Aug 6, 2025 · A novel method for enzymatic biotransformation of limonene to carvone has been developed. It involves addition glucose oxidase and ...
[52]
Water accelerated transformation of d-limonene induced by ...
For instance, it has been reported that d-limonene could transform to limonene oxides, l-carvone and carveols by copper-catalyzed oxidation (Nguyen et al., ...
[53]
Photopolymerization of Limonene Dioxide and Vegetable Oils as ...
Epoxidized vegetable oils and limonene dioxide, a bis-epoxide derived from the terpene limonene, are photo-copolymerized to yield highly crosslinked networks.
[54]
[PDF] effects of the use of d-limonene as an additive to diesel-biodiesel ...
This paper presents the preliminary results obtained from the tests in a stationary diesel engine fuelled with mixtures of diesel-biodiesel and d-limonene, in ...Missing: 3D printing resins
[55]
Hydrogenated monoterpenes as diesel fuel additives - NASA ADS
Myrcene and limonene were hydrogenated to their fully saturated forms, 2,6-dimethyloctane and 1-isopropyl-4-methylcyclohexane, respectively.<|separator|>
[56]
Fact Sheet Reregistration Eligibility Decision (RED) Limonene
EPA has granted limonene an exemption from the requirement of a tolerance when it is used as an inert ingredient in pesticide formulations, and when used as an ...
[57]
[PDF] d-Limonene Summary Document Registration Review: Initial Docket ...
Limonene is listed in 40 CFR §180.539 without numeric tolerances and is identified as being safe for use, as an insecticide, in tablecloths and repellant ...
[58]
D-Limonene; Reregistration Eligibility Decision for Low Risk Pesticide
Jan 19, 2005 · EPA has reviewed the low risk pesticide D-Limonene through a modified, streamlined version of the public participation process that the Agency ...Missing: formulations minimum
[59]
Less Toxic Insecticides - HGIC@clemson.edu
Feb 21, 2025 · Limonene has low oral and dermal toxicity to ... minimum risk to users no longer require EPA approval to be marketed as insecticides.
[60]
Substances Added to Food (formerly EAFUS)
... GRAS status of flavoring substances. The FEMA number is provided here as a reference to FEMA's GRAS assessments. The GRAS Pub. No. is the FEMA GRAS ...
[61]
Case Studies of the Implementation of the Direct Food and Color ...
FDA recognized d-limonene to be GRAS as a synthetic flavoring substance. 1965, FEMA expert panel determined d-limonene to be GRAS. 1976, FEMA expert panel ...<|separator|>
[62]
IFRA Standards library - International Fragrance Association
Access the IFRA Standards—scientifically developed guidelines to ensure safe use of fragrance ingredients worldwide.
[63]
What Is d-Limonene? The Natural Citrus Solvent Powering Multiple ...
One of the most common uses of d-limonene oil is in degreasers, adhesive removers, and general-purpose cleaners. It can easily remove heavy residues from ...Missing: detergents | Show results with:detergents
[64]
Interviews With An Expert #10: Orange Oil & Cleaning – A Powerful ...
With its fresh citrus scent and powerful solvent qualities, orange oil makes an ideal addition to cleaning solutions, cosmetic items, soaps and detergents. It's ...
[65]
Transdermal Drug Delivery Enhancement by Compounds of Natural ...
The aim of this article is to give a comprehensive summary of the results from scientific research conducted on skin penetration enhancers of natural origin.
[66]
Natural Terpenes as Penetration Enhancers for Transdermal Drug ...
In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of their action, the factors affecting their penetration enhancement effect, as ...
[67]
Limonene: Uses, Benefits, Side Effects, and Dosage - Healthline
May 22, 2019 · Limonene is a compound extracted from the peels of citrus fruits. Studies suggest that limonene may have anti-inflammatory, antioxidant, and anticancer effects.
[68]
Anti-stress effects of d-limonene and its metabolite perillyl alcohol
These studies show that d-limonene exerts, through its metabolite POH, a significant anti-stress action measurable by behavioral and physiologic parameters.Missing: aromatherapy | Show results with:aromatherapy
[69]
Hazardous substance assessment – D-Limonene - Canada.ca
Sep 28, 2023 · In an acute rat oral toxicity study, mortality was observed close to the oral LD50 value (4,400 mg/kg in males). No clinical signs were reported ...
[70]
Limonene (CICADS) - INCHEM
Biotic degradation of limonene has been shown with some species of microorganisms, such as Penicillium digitatum, Corynespora cassiicola, Diplodia gossypina ( ...
[71]
Contact allergy to oxidized linalool and oxidized limonene: Patch ...
Sep 25, 2021 · The prevalence rates of contact allergy to ox. linalool and ox. limonene were 7.0% and 5.1%, respectively. Significantly increasing trends of ...
[72]
[PDF] Limonene and linalool hydroperoxides review: pros and cons ... - HAL
Feb 8, 2022 · An early multicenter study with 2273 dermatitis patients using 3% oxidized limonene showed 2.8% positive patch test reactions13.
[73]
Effects of R-(+)- and S-(-)-limonene on the respiratory tract in mice
The reported sensory irritation threshold is above 80 ppm in humans while the no-observed-effect level was estimated to be 100 ppm in mice.
[74]
[PDF] Limonene Method number: PV2036 Target concentration - OSHA
Local effects include irritation to the eyes, skin, and respiratory tract ... The sampling tubes were spiked with 12.612 mg (226.4 ppm or 1261 mg/m3) limonene, ...
[75]
Limonene - Uses, Side Effects, and More - WebMD
When taken by mouth: Limonene is LIKELY SAFE when taken in food amounts. It is POSSIBLY SAFE for most people when taken by mouth in medicinal amounts for up to ...Missing: gastrointestinal | Show results with:gastrointestinal
[76]
d-limonene | SpringerLink
Jun 5, 2024 · Acute oral exposure to high doses of d-limonene can cause mild gastrointestinal symptoms like diarrhea, vomiting, and nausea. It may also ...Missing: ingestion | Show results with:ingestion
[77]
[PDF] d-Limonene - IARC Publications
There is limifed evidence in experimental animais for the carcinogenicity of d-limonene. Overall evaluation d-Limonene is not classifiable as to ifs ...
[78]
d-limonene mechanistic data and risk assessment - PubMed
Genotoxicity tests for d-limonene are negative, and the mechanism of tumorigenesis involves tumor promotion and enhanced cell proliferation.Missing: evidence | Show results with:evidence
[79]
[PDF] RIFM fragrance ingredient safety assessment, dl -limonene (racemic ...
Dec 9, 2021 · Based on available data, dl-limonene (racemic) does not present a concern for genotoxic potential, and existing information supports its use.
[80]
Registration Dossier - ECHA
... 96h-EC50 of 0.904 mg/L and a chronic toxicity value of 0.514 mg/L. The ECOSAR model has been validated to estimate the toxicity of l-limonene on algae.
[81]
Partition coefficient - Registration Dossier - ECHA
log Kow of d-limonene was determined using HPLC method: 4.38 at 37°C. Supporting results were obtained at 25°C using shake-fllask method. Key value for chemical ...Missing: BCF | Show results with:BCF
[82]
Secondary Organic Aerosol from OH-Initiated Oxidation of Mixtures ...
Jul 17, 2024 · Multiphase Composition Changes and Reactive Oxygen Species Formation during Limonene Oxidation in the New Cambridge Atmospheric Simulation ...
[83]
(I) Secondary organic aerosol formation from the oxidation of a ...
This work merges kinetic models for α-pinene and d-limonene which were individually developed to predict secondary organic aerosol (SOA) formation from these ...
[84]
Technical Overview of Volatile Organic Compounds | US EPA
Sep 8, 2025 · Volatile organic compounds (VOC) means any compound of carbon, excluding carbon monoxide, carbon dioxide, carbonic acid, metallic carbides or carbonates and ...Missing: REACH TSCA
[85]
Valorization of Residual Orange Peels: Limonene Recovery, Volatile ...
Apr 13, 2020 · Considering the OEOY and the limonene concentration, n-hexane was selected as the best solvent for limonene recovery from OPs. Thus, the solid/ ...
[86]
Review Citrus waste as feedstock for bio-based products recovery
Citrus peel and fruit juices waste streams are rich in limonene molecule. · Limonene can be used in the nutritional, pharmaceutical and cosmetic fields.
[87]
Limonene chemoprevention of mammary carcinoma ... - PubMed - NIH
Jul 1, 1994 · Dietary limonene has been shown to be capable of preventing the development and causing the regression of chemically induced mammary carcinomas.Missing: enzyme | Show results with:enzyme
[88]
Regression of rat primary mammary tumors following dietary d ...
There was a highly significant increase in the regression of the first tumors in the rats fed d-limonene. In addition, d-limonene given at this time inhibited ...Missing: 1990s | Show results with:1990s
[89]
The inhibition of protein prenyltransferases by oxygenated ... - PubMed
Limonene is currently undergoing clinical testing in cancer patients. These monoterpenes and their oxygenated metabolites have been previously shown to inhibit ...
[90]
Inhibition of protein prenylation by metabolites of limonene - PubMed
The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, ...Missing: ras | Show results with:ras
[91]
Anticancer activity of limonene: A systematic review of target ...
Apr 17, 2021 · Anticancer activity of LIM was related to the inhibition of tumor initiation, growth, and angiogenesis and the induction of cancer cells apoptosis.
[92]
Phase I and pharmacokinetic study of D-limonene in patients with ...
Methods: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles.
[93]
Human breast tissue disposition and bioactivity of limonene in ... - NIH
Discussion. In this single arm, open label trial of limonene in early stage breast cancer patients, we found that taking 2 g of limonene daily for 2-6 weeks ...
[94]
Can lemons cure cancer? - National Academies
Feb 22, 2019 · Lemons cannot cure cancer. Currently, there is no evidence that lemons or other citrus fruits help treat cancer.
[95]
Preclinical development and clinical use of perillyl alcohol for ...
POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models.
[96]
Perillyl alcohol as a treatment for cancer: A systematic review
Studies on the metabolism of limonene in humans demonstrated that perillyl alcohol (POH) is one of the most important metabolites of limonene (Crowell et al ...
[97]
Antimicrobial activity and mechanism of limonene against ...
Aug 15, 2021 · The results showed that limonene effectively inhibited bacterial growth at a minimum inhibitory concentration (MIC) of 20 ml/L.
[98]
In vitro Antifungal Activity of Limonene against Trichophyton rubrum
The MIC value was 0.5% v/v in the broth microdilution assay. The antifungal activity of limonene against T. rubrum was characterized as a fungicidal effect.
[99]
Terpenes Combinations Inhibit Biofilm Formation in Staphyloccocus ...
All combinations of terpenes can inhibit biofilm formation in more than 50% without affecting bacterial growth.
[100]
(PDF) Therapeutic potential of d‐limonene in rheumatoid arthritis
It has reported anti‐inflammatory and anti‐nociceptive properties and was selected for the current study as a potential anti‐arthritic candidate. It was ...
[101]
The Antioxidant Activity of Limonene Counteracts Neurotoxicity ...
We tested the neuroprotective effect of limonene, one of the main components of the genus Citrus, against the neurotoxicity elicited by Aβ 1-42 oligomers.
[102]
D-Limonene Promotes Anti-Obesity in 3T3-L1 Adipocytes and High ...
This study showed that LIM reduced the lipid anabolism of high-calorie diet-induced obese rats by decreasing the mRNA expression of PPARγ, SREBP-1c, and ACC.Missing: appetite pilot
[103]
(PDF) D‐Limonene for regulating metabolism‐associated fatty liver ...
Oct 18, 2025 · The protocol describes the first study evaluating the treatment of metabolism‐associated fatty liver disease (MAFLD).Missing: appetite | Show results with:appetite
[104]
Enhanced wound healing by topical administration of d-limonene in ...
These characteristics suggest a beneficial role for d-limonene in rebalancing the wound environment in diabetes and therefore promote healing.Missing: 2024 | Show results with:2024
[105]
Therapeutic potential of limonene-based syringic acid nanoemulsion
Jul 20, 2024 · A preclinical study demonstrated that limonene-based SA-NE is effective in alleviating psoriasis-like skin lesions against imiquimod-induced psoriasis in rats.