Chemical Composition and Biological Activities of Essential Oils of Curcuma Species

Members of the genus Curcuma L. have been used in traditional medicine for centuries for treating gastrointestinal disorders, pain, inflammatory conditions, wounds, and for cancer prevention and antiaging, among others. Many of the biological activities of Curcuma species can be attributed to nonvolatile curcuminoids, but these plants also produce volatile chemicals. Essential oils, in general, have shown numerous beneficial effects for health maintenance and treatment of diseases. Essential oils from Curcuma spp., particularly C. longa, have demonstrated various health-related biological activities and several essential oil companies have recently marketed Curcuma oils. This review summarizes the volatile components of various Curcuma species, the biological activities of Curcuma essential oils, and potential safety concerns of Curcuma essential oils and their components.


Introduction
The genus Curcuma L. (Zingiberaceae) represents a group of perennial rhizomatous herbs native to tropical and subtropical regions. Curcuma is extensively cultivated in tropical and subtropical regions of Asia, Australia, and South America [1]. There are approximately 93-100 accepted Curcuma species, however the exact number of species is still controversial [2]. The genus is best known for being an essential source of coloring and flavoring agents in the Asian cuisines, traditional medicines, spices, dyes, perfumes, cosmetics, and ornamental plants [3]. Several Curcuma species are used medicinally in Bangladesh, Malaysia, India, Nepal, and Thailand [4] for treating pneumonia, bronchial complaints, leucorrhea, diarrhea, dysentery, infectious wounds or abscesses, and insect bites [2,4,5]. The rhizome is the most commonly used part of the plant. The main active components of the rhizome are the nonvolatile curcuminoids and the volatile oil [6][7][8]. Curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are nontoxic polyphenolic derivatives of curcumin that exert a wide range of biological activities [9]. Several phytochemical studies on Curcuma oils led to the identification of sesquiterpenoids and monoterpenoids as the major components [9]. The essential oil (EO) of Curcuma species possesses a wide variety of pharmacological properties, including anti-inflammatory, anticancerous, antiproliferative, hypocholesterolemic, antidiabetic, antihepatotoxic, antidiarrheal, carminative, diuretic, antirheumatic, hypotensive, antioxidant, antimicrobial, antiviral, insecticidal, larvicidal, antivenomous, antithrombotic, antityrosinase, and cyclooxygenase-1 (COX-1) inhibitory activities, among others [7,[10][11][12][13][14][15][16][17]. Curcuma oils are also known to enhance immune function, promote blood circulation, accelerate toxin elimination, and stimulate digestion [18,19]. C. longa (turmeric) and C. zedoaria (zedoary) are the most extensively studied species of Curcuma due to their high commercial value. Other Curcuma species have been studied to a lesser degree. This review provides an update on recent studies performed on the chemical composition and biological studies on genus Curcuma.
The search engines Google Scholar, PubMed, ScienceDirect, and ResearchGate were used to access the literature.

Volatile Components of Curcuma spp.
Generally, essential oils of Curcuma species are obtained by hydro-or steam distillation of the fresh or dry rhizome [20]. Alternatively, Curcuma volatiles have also been obtained by solvent extraction or supercritical fluid extraction of the powdered rhizome [21]. More recently, solid-phase microextraction (SPME) has been employed as a solvent-free technique to capture and concentrate volatiles from different plant parts. Industrially, Curcuma oil is produced during oleoresin processing as a byproduct of curcumin extraction [22]. After curcumin is isolated from the oleoresin, the mother liquor (about 70-80%) is known as "curcumin-removed turmeric oleoresin" (CRTO) [22]. The oil is then extracted from CRTO by hexane or other organic solvent, a process that could result in the loss of the highly volatile components during solvent evaporation [21]. The use of alcohols as the solvent for oil extraction might cause esterification, etherification, and acetal formation [21]. The volatile components of different Curcuma species, typically identified by gas chromatography mass spectrometry, are summarized in Table 1. In general, Curcuma species produce a wide variety of volatile sesquiterpenes, monoterpenes, and other aromatic compounds [17,23]. The chemical structures of key volatile components are presented in Figure 1. There is a tremendous variation in the composition of Curcuma essential oils (EOs). Differences in the oil chemical profile might be due to genotype, variety, differential geography, climate, season, cultivation practices, fertilizer application, stress during growth or maturity, harvesting time, stage of maturity, storage, extraction, and analysis methods [24][25][26][27]. However, some of the variation could be due to misidentification of the plant species or some of the components. Pahang, Malaysia Rhizome (SD) 8,9-Dehydro-9-formyl-cycloisolongifolene (35.3%), dihydrocostunolide (22.5%), velleral (10.0%), and germacrone (6.5%) [28] C. aeruginosa Roxb. Ratchaburi, Thailand Fresh rhizome (HD) Germacrone (23.5%), curzerenone (11.8%) and 1,8-cineole (10.9%) [29] C. aeruginosa Roxb.

Curcuma longa L.
Curcuma longa (syn. C. domestica Valeton and C. brog Valeton) is also known as "turmeric" worldwide, "kurkum" in Arabic, and "haldi" in Hindi and Urdu. Turmeric is cultivated extensively worldwide but is native to Southeast Asia [76]. It is a perennial herb grown on a very large scale in India, Pakistan, Bangladesh, China, Taiwan, Thailand, Sri Lanka, East Indies, Burma, Indonesia, and Northern Australia [66]. In the West, it is produced in Costa Rica, Haiti, Jamaica, Peru, and Brazil [116]. Turmeric is commercially available as a whole rhizome (fresh, dried, and cured by cooking in water, drying in shade, and polishing), turmeric powder, extracts, and oleoresins, with the powder being the most commonly consumed form. India is the largest producer and consumer of turmeric [66,117,118]. The plant is famous for its culinary and medicinal uses. Turmeric is the golden spice that gives many Asian dishes their yellow color and pungent earthy flavor. It is an essential ingredient of curry powders, accounting for about 10-30% of the blend [119]. In traditional medicine, turmeric is extensively used as a carminative, digestive aid, stomachic, appetizer, anthelmintic, tonic and laxative [120]. It is also used for treating fever, gastritis, dysentery, infections, chest congestion, cough, hypercholesterolemia, hypertension, rheumatoid arthritis, jaundice, liver and gall bladder problems, urinary tract infections, skin diseases, diabetic wounds, and menstrual discomfort [66,94,121]. Turmeric is used in many religious rituals, as a dye, and as a cosmetic [122,123]. Turmeric rhizome typically contains carbohydrates (69.4%), protein (6.3%), fat (5.1%), and minerals (3.5%) [124].
Turmeric oleoresin is an orange-red viscous liquid, prepared from the powdered rhizome by solvent extraction with a yield of about 12% [119]. The main active components in the rhizome are essential oil and curcuminoids. The volatile oil is responsible for the turmeric aroma, while the curcuminoids (curcumin and its analogues) are responsible for its bright yellow color [65,119]. It is worth mentioning that curcumin, present in turmeric rhizomes, oleoresin, and CO2 extract, has not been reported in the essential oil [125]. Turmeric chemotypes in the literature vary widely. Hundreds

Curcuma longa L.
Curcuma longa (syn. C. domestica Valeton and C. brog Valeton) is also known as "turmeric" worldwide, "kurkum" in Arabic, and "haldi" in Hindi and Urdu. Turmeric is cultivated extensively worldwide but is native to Southeast Asia [76]. It is a perennial herb grown on a very large scale in India, Pakistan, Bangladesh, China, Taiwan, Thailand, Sri Lanka, East Indies, Burma, Indonesia, and Northern Australia [66]. In the West, it is produced in Costa Rica, Haiti, Jamaica, Peru, and Brazil [116]. Turmeric is commercially available as a whole rhizome (fresh, dried, and cured by cooking in water, drying in shade, and polishing), turmeric powder, extracts, and oleoresins, with the powder being the most commonly consumed form. India is the largest producer and consumer of turmeric [66,117,118]. The plant is famous for its culinary and medicinal uses. Turmeric is the golden spice that gives many Asian dishes their yellow color and pungent earthy flavor. It is an essential ingredient of curry powders, accounting for about 10-30% of the blend [119]. In traditional medicine, turmeric is extensively used as a carminative, digestive aid, stomachic, appetizer, anthelmintic, tonic and laxative [120]. It is also used for treating fever, gastritis, dysentery, infections, chest congestion, cough, hypercholesterolemia, hypertension, rheumatoid arthritis, jaundice, liver and gall bladder problems, urinary tract infections, skin diseases, diabetic wounds, and menstrual discomfort [66,94,121]. Turmeric is used in many religious rituals, as a dye, and as a cosmetic [122,123]. Turmeric rhizome typically contains carbohydrates (69.4%), protein (6.3%), fat (5.1%), and minerals (3.5%) [124].

Curcuma caesia Roxb.
Curcuma caesia is commonly known as "black turmeric" in India due to the dark bluish color of its rhizome. It grows wild in some parts of India, Malaysia, Thailand, and Indonesia. Leaves and rhizomes of black turmeric are used in traditional medicine. C. caesia rhizome is aromatic, carminative, and a stimulant. A paste of the rhizome is used for treating dysentery and as poultice in rheumatic pain, sprains, and bruises. When applied externally, black turmeric is used in India to alleviate toothaches, treat skin and wound infections, and cure rheumatism. Chewing small amounts of the rhizomes is used to relieve digestive problems and kidney disorders; however, excessive intake of black turmeric may lead to vomiting [155]. The rhizome EO of C. caesia from south India was composed mainly of 1,8-cineole (30.1%) followed by camphor, ar-curcumene, and camphene [17], while the oil from central India has camphor (28.3%), followed by ar-turmerone, (Z)-β-ocimene, ar-curcumene, and 1,8-cineole [57]. The leaf EO is made of 1,8-cineole (27.0%) and camphor (16.8%) [58].

Turmeric (C. longa) Essential Oil
Turmeric EO has the potential to provide protection against cardiovascular diseases. The oil was reported to have antihyperlipidemic effects on high-fat diet (HFD)-induced hyperlipidemia in rats [75]. It markedly decreased the levels of triglycerides, free fatty acids, total cholesterol in serum, and low-density lipoprotein (LDL) cholesterol, while increasing the level of high-density lipoprotein (HDL) cholesterol. Turmeric EO also showed antihyperlipidemic effects in hyperlipidemic golden Syrian hamsters via reducing lipid-induced oxidative stress, platelet activation, and vascular dysfunction [163]. Chronic dietary supplementation of turmeric EO (≥620 mg/kg/day) showed antidiabetic and hypoglycemic effects in diabetic mice by normalizing serum glucose [164]. Ingestion of turmeric oleoresin and essential oil inhibited both the increase in blood glucose and the development of abdominal fat mass in obese diabetic rats [165]. Turmeric EO also inhibited α-glucosidase and α-amylase activities in a dose-dependent manner due to the presence of ar-turmerone [96,166,167].
In addition, the oil showed remarkable antioxidant activity as judged by 1,1-diphenyl-2 -picrylhydrazyl (DPPH) radical scavenging activity assay, ferric reducing/antioxidant power (FRAP) assay, superoxide anion radical scavenging activity assay, and metal-chelating activity assay [50,74,168,169]. Turmeric EO prevented oxidative stress in Brycon amazonicus via reducing the synthesis or release of cortisol and increasing the activity of antioxidant enzymes, and thereby protecting from the formation of reactive oxygen species excess [23,67,96]. The potent antioxidant activity of turmeric EO is thought to be responsible for inhibiting brain-edema formation, one of the most dangerous consequences of ischemic brain injury [170]. Treatment with turmeric EO reduced nitric oxide production derived by inducible nitric oxide synthase (iNOS) during ischemic injury [231]. Turmeric EO inhibited copper-mediated oxidation of LDL in the thiobarbituric acid reactive substances assay (IC 50 = 7.8 ± 0.2 µg/mL) [71]. Turmeric EO (250-500 mg/kg p.o. or i.p.) showed neuroprotective effects in rat embolic-stroke model [170,171]. In filament model of middle cerebral-artery occlusion, pretreatment with turmeric EO showed a neuroprotective effect by inhibiting the generation of free radicals [170,171]. Its neuroprotective efficacy was mediated by reducing endothelial cell-mediated inflammation in postmyocardial ischemia/reperfusion in rats [166,172]. It was also suggested that the ability of the oil to access the brain after stroke was via the transcellular lipophilic pathway [170]. Turmeric EO (500 mg/kg, p.o.) was an efficacious and safe antiplatelet agent [174] and was protective against intravascular thrombosis in myocardial ischemia-reperfusion and thrombosis rat models [172,173]. Turmeric oil was effective in treating some respiratory disorders by preventing asthma, removing sputum, and relieving cough [232]. The oil was reported to have anticancer and anti-inflammatory effects [176,178]. It was active against human mouth epidermal carcinoma (KB) cells and mouse leukemia (P388) cells, with respective IC 50 values of 1.088 and 0.084 mg/mL [177]. It was also cytotoxic to the pancreatic cancer (PANC-1), melanoma (B16), prostate cancer (LNCaP), and human cervical adenocarcinoma (HeLa) cell lines due to the presence of ar-turmerone, α-turmerone, β-turmerone, curlone, ar-curcumene, zingiberene, and β-sesquiphellandrene [23,74,175,176]. Crude organic extracts of turmeric-inhibited lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α (IC 50 = 15.2 µg/mL) and prostaglandin E2 (PGE2; IC 50 = 0.92µg/mL) in human leukemia (HL-60) cells [181]. In combination with curcumin, turmerones from turmeric EO abolished inflammation-associated mouse-colon carcinogenesis [233]. Turmeric EO demonstrated strong protective effect against benzo[a]pyrene-induced increase in micronuclei in circulating lymphocytes and protected against cytogenetic damage in patients suffering from oral submucous fibrosis, a precancerous condition for oral cancer [179,180].
Moreover, turmeric EO showed potent antiarthritic and joint protective effects on an animal model of rheumatoid arthritis [23,182]. As a result of treatment with crude or refined turmeric oil (i.p.), joint swelling was dramatically inhibited (90-100% inhibition) in female rats with streptococcal cell wall-induced arthritis [182]. Turmeric EO was reported to have antihepatotoxic [23,183], antiatherosclerotic [96], hypothermic, anxiolytic, sedative, anticonvulsant [81], and spasmolytic [185] activities. Turmeric EO protected against accelerated atherosclerosis, inflammation, and macrophage foam-cell formation induced by arterial injury through modulating the genes involved in plaque stability, lipid homeostasis, and inflammation [184]. Turmeric EO (200 mg/kg) exhibited antifatty liver and hepatoprotective activities in acute ethanol-induced fatty liver in rats through decreasing the activities of serum enzymes and levels of serum triglyceride, serum total cholesterol, and hepatic malondialdehyde, while restoring the level of reduced glutathione as well as the activities of glutathione-S-transferase and superoxide dismutase [186]. The oil was markedly antimutagenic against sodium azide in the Ames test [178,187]. Turmeric oil showed remarkable sedative and anesthetic effects in mice [81] and fish [96] in different experimental protocols. Interestingly, ar-turmerone isolated from turmeric EO is a potent antivenom against snakebites. It neutralized both the hemorrhagic activity present in Bothrops jararaca venom, and the lethal effect of Crotalus durissus venom in mice [188].

Zedoary (C. zedoaria) Essential Oil
Curcuma zedoaria EO showed potent radical-scavenging effects evaluated by DPPH assay [7,23,111,196,197]. The strong antioxidant activity of C. zedoaria EO is utilized in the food industry to minimize or prevent lipid oxidation. Zedoary EO also showed potent, selective cytotoxic activity and inhibited the proliferation of human cervical cancer (SiHa), colorectal cancer (SNU-1), human hepatoma (HepG2) [198], human gastric adenocarcinoma (AGS) [114], hepatic stellate cells [110], mouse melanoma (B16BL6) cells, human hepatoma (SMMC-7721) cells, and HL-60 cells [7,110]. It is worth noting that normal endothelial cells were less sensitive to zedoary EO than cancer cells in the in vitro assays [200]. The cytotoxic activity of zedoary EO is mediated by efficiently inhibiting monocytic differentiation, inhibiting cell proliferation, arresting cell cycle and inducing apoptosis [109,110,234]. The oil exhibited efficient cytotoxic effects against nonsmall cell lung carcinoma (NSCLC) cells via inducing apoptosis [199]. Zedoary EO showed antiproliferative activity against human colon-cancer cells (HCT116) by causing senescence and apoptosis in a dose-and time-dependent manner [235]. Zedoary EO in a combination with paclitaxel synergistically enhanced their antitumor activity and increased the apoptosis of human ovarian cancer (SKOV3) cells [202]. Zedoary EO (i.p.) significantly inhibited the growth of human lung-cancer cells (H1299) in vivo via inhibiting protein kinase B (Akt)/nuclear factor-kappa B (NF-κB) signaling pathways [199]. Zedoary EO was reported to inhibit angiogenesis in vitro and in vivo, which results in tumor inhibition [200]. Zedoary EO strongly inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and tumor angiogenesis in vivo via downregulating matrix metalloproteinases [200]. In rodent experiments, zedoary oil showed antitumor action in hepatoma-transplanted rats [203]. In addition, it has been used clinically in China for treating hepatic carcinoma [201]. In China, zedoary oil is used for treating gynecologic inflammation, monilial vaginitis, and tumors [236]. Zedoary EO is also known for its hypoglycemic effects [204]. In a study performed on streptozotocin-induced hyperglycemic Wistar rats, oral administration of the oil for seven days was able to significantly decrease blood-glucose levels and prevent gingivitis [204]. Zedoary EO has been used for oral-health maintenance because of its antimicrobial, hypoglycemic, and anti-inflammatory properties [14], which can help in reducing gingival inflammation. Zedoary EO exhibited antimicrobial activity against Vibrio parahaemolyticus, Staphylococcus aureus, Bacillus cereus, Salmonella typhimurium, and Pseudomonas aeruginosa [110]. It also demonstrated antifungal activity against Colletotrichum falcatum [37] and good insecticidal activity against the sugarcane pest, Odontotermes obesus Rhamb [37]. Zedoary oil displayed larvicidal effects against the malaria vector, Anopheles dirus (LC 50 = 29.69 ppm), and the hemorrhagic fever vector, Aedes aegypti (LC 50 = 31.87 ppm) [129].

Curcuma aeruginosa Essential Oil
Curcuma aeruginosa EO showed antiandrogenic [30], antinociceptive, antipyretic, and anti-inflammatory activities [15]. Topical application of C. aeruginosa extract (5% w/w) stimulated hair regrowth on patients with androgenic alopecia [205]. In a randomized controlled trial, C. aeruginosa rhizome extract promoted hair regrowth in bald males [205]. The bioactive compounds were identified as sesquiterpenes, with germacrone being the most potent [137]. Coapplication of C. aeruginosa EO, hexane extract, and germacrone improved the skin penetration of minoxidil, a hair-growth promoter approved as topical treatment of androgenic alopecia [30]. Skin penetration of minoxidil with EO, hexane extract, and germacrone was enhanced 20-fold, 4-fold, and 10-fold, respectively [30]. In a randomized, double-blinded trial, C. aeruginosa rhizome EO formulated as a lotion (1% and 5% w/w EO) was reported to safely and effectively slow the growth of axillary hair and to rapidly and robustly increase axillary skin brightness (within three weeks) [206]. Interestingly, these effects persisted for two weeks after ending the treatment. The rhizome EO of C. aeruginosa showed potent antibacterial activity against Enterococcus faecalis (MIC = 6.25 µg/mL) [29] and Streptococcus mutans (MIC = 15.63 µg/mL) and as a teeth-biofilm degradation [207], which makes it a good candidate as a natural antibacterial agent in a mouthwash or a toothpaste. It exhibited moderate antibacterial activity against Staphylococcus aureus (MIC = 125 µg/mL) and Bacillus cereus (MIC = 125 µg/mL) [2]. The oil showed antifungal activity against Candida albicans (MIC = 250 µg/mL) [2]. The oil showed weak inhibitory effect against Mycobacterium tuberculosis strain H37Ra (MIC = 2500 µg/mL) when tested by green fluorescent protein microplate assay [29]. The oil also showed strong radical-scavenging power evaluated by DPPH scavenging assay (EC 50 = 24.32 µg/mL) due to the presence of germacrone and curzerenone [29].

Wild Turmeric (Curcuma aromatica) Essential Oil
Wild turmeric EO is reported to promote blood circulation, remove blood stasis, and treat cancers [148]. C. aromatica EO showed a remarkable anti-inflammatory activity via suppressing the production of proinflammatory cytokines including protein kinase C (PKC), Akt, tumor-necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), NF-κB, and IκB kinase (IKK) in vivo in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema model [47,49]. It is thought that turmerone, ar-turmerone, 8,9-dehydro-9-formyl-cycloisolongifolene, ar-curcumene, α-zingiberene, and germacrone are responsible for the anti-inflammatory activity of C. aromatica EO [15]. The oil showed good cytotoxic activities against LNCaP HepG2, and B16 cell lines [47,49]. The oil can also suppress the growth of hepatoma cells in vivo and in vitro [214]. The oil was reported to induce apoptosis in NSCLC cells [208]. ar-Tumerone, turmerone, and curdione from C. aromatica EO have in vitro and in vivo antiproliferative effect on laryngeal cancer (Hep-2) cells [210]. Wild turmeric oil infused via hepatic artery inhibited hepatic tumors in patients with primary liver cancer [213], rats with transplanted hepatoma [211], and mice [212]. C. aromatica EO showed antiproliferative effects on hepatoma by inhibiting its growth in mice (51-52%) via decreasing the DNA synthesis of hepatocellular carcinoma and shrinking the nucleus area [212]. The antitumor activity of wild turmeric EO was attributed to the presence of β-elemene, curcumol, and curdione [237]. C. aromatica EO showed hepatic chemopreventive activity against hepatocellular carcinoma both in vivo and in vitro [214]. Pretreatment with C. aromatica oil (100 mg/kg for 3 days) protected mice from hepatic injury from inflammation and oxidative damage induced by concanavalin A, which can decrease the incidence of hepatocellular carcinoma.

Curcuma amada Essential Oil
Mango ginger possess central nervous system depressant, analgesic, antioxidant, anti-inflammatory, antiplatelet, cytotoxic, hypotriglyceridemic, antibacterial, and antifungal activities [157]. C. amada rhizome EO and ethanolic extracts showed hepatoprotective effects against carbon tetrachloride-induced hepatotoxicity in male Wister rats mainly due to their strong antioxidant activities [156]. The supercritical CO 2 extract of mango ginger was selectively cytotoxic to human glioblastoma cell line (U-87MG; IC 50 = 4.92 µg/mL). The extract was able to induce apoptosis in brain-tumor cells in a dose-dependent manner [226]. The supercritical CO 2 extract also exhibited antitumor effects in human glioblastoma multiforme cells both in vitro and in nude mice xenografts. It was synergistic with irinotecan, a chemotherapy drug. In fact, treatment with a combination of irinotecan and C. amada extract showed almost a complete inhibition of tumor growth [227]. The extract was highly cytotoxic to human alveolar (SJRH30) and embryonal (RD) rhabdomyosarcoma cell lines, with IC 50 values of 7.13 µg/mL and 7.50 µg/mL, respectively. It also showed synergistic cytotoxic effects with vinblastine and cyclophosphamide via inducing a higher percentage of apoptosis than individual agents [225]. C. amada EO showed strong antioxidant activity as evaluated by DPPH radical scavenging assay, total antioxidant assay, ferric-reducing antioxidant power and nitric oxide scavenging assay [229]. Moreover, C. amada EO showed 100% insect repellency and direct insecticidal effects against laboratory bred houseflies, Musca domestica L. [230]. The oil was antibacterial against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella paratyphi, Vibrio cholera, Enterobacter aerogenes, Streptococcus pneumoniae, Bacillus subtilis, Bacillus cereus, Proteus mirabilis, Proteus vulgaris, and Serratia marcescens [229]. Organic extracts of mango ginger also demonstrated antibacterial effects against E. coli, Bacillus subtilis, B. cereus, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes, Enterococcus fecalis, and Salmonella typhi [156]. C. amada EO showed antifungal activity against sugarcane pathogenic fungi such as Physalospora tucumanensis, Sclerotium rolfsii, Helminthosporium sacchari, and Cephalosporium sacchari [228].

Toxicity and Safety
In general, Curcuma EOs are nontoxic, nonmutagenic, noncarcinogenic and nonphototoxic [125,239]. Turmeric EO has been classified as generally recognized as safe (GRAS) [125]. Undiluted turmeric rhizome oil was slightly irritating to rabbits, but was not irritating to mice. When tested at 4% on 25 volunteers, it was neither irritating nor sensitizing [239]. There is a possible drug interaction when used orally, especially with antidiabetic medications [125]. The acute dermal LD 50 of turmeric rhizome oil was >5 g/kg in rabbits, and the acute oral LD 50 was >5 g/kg in rats [239]. When administered intraperitoneally (i.p.) at doses higher than 28 mg/kg/day, 20-36% of normal and streptococcal cell wall-injected animals died after two weeks of treatment, while lower vehicle or oil doses (≤2.8 mg/kg/day) caused no deaths [182]. Oral administration of a dose of turmeric oil that is 20-fold higher than the lowest effective i.p. doses was nontoxic [182]. No hazards or adverse skin reactions were reported for turmeric-leaf EO; however, the α-phellandrene chemotype might cause skin sensitization on oxidation.
Zedoary EO has GRAS status [125]. No acute toxicity or adverse reactions were reported for the zedoary oil; however, its consumption may interfere with gestation and may induce abortion [125]. For this reason, the oil and extracts are strictly prohibited during pregnancy and should be avoided during breastfeeding. Zedoary EO showed obvious embryotoxicity ex vivo and reproductive toxicity in animal and developmental experiments [109,200]. In addition, treatment with aqueous extracts of C. zedoaria rhizome (10 g/kg/day for 20 days) exhibited reproductive toxicity in pregnant mice [240]. Chinese zedoary EO prevented implantation in dose-dependent manner. When given i.p. (300 mg/kg) to female rats on gestational days 7-9, it prevented 77% of pregnancies, and when administered intravaginally to female rabbits, it prevented 16% and 100% of pregnancies at 60 or 400 mg/kg/day on gestational days 5-9 and 2-4, respectively [125]. It was suggested that the embryotoxic effect of zedoary EO might be caused by its sesquiterpenoids that can block VEGF-mediated angiogenesis [109]. However, no direct evidence was found to link any of the oil components to its antifertility effect. Decoctions and ethanol extracts of zedoary rhizomes also have antifertility effects [241].
No hazards, acute toxicity, or adverse reactions were reported for the wild turmeric (C. aromatica), the mango ginger (C. amada), and the pink-and-black curcuma (C. aeruginosa) rhizome oils [125,206]. No information found for the toxicity and safety of other Curcuma oils.
Curdione, the main component in C. aromatica, C. nankunshanensis, and C. trichosantha EOs significantly suppressed the proliferation of human breast-cancer cells (MCF-7) via inducing cell apoptosis and impairing mitochondrial-membrane potential [252]. Curdione, from zedoary EO, inhibited PGE2 production in LPS-stimulated mouse macrophage RAW 264.7 cells (IC 50 = 1.1 µM) through suppressing COX-2 expression [253]. Curdione is also known for its outstanding antibacterial and antifungal activities [72]. As far as we are aware, there are no known hazards associated with curdione.

Conflicts of Interest:
The authors declare no conflicts of interest. The funding sponsor, dōTERRA International, played no role in the design of the study; in the collection, analysis, or interpretation of the data; conclusions of the study; or in the decision to publish the results.