Melaleuca – Tea-tree oil (Melaleucae aetheroleum)
|Latin name of the genus:||Melaleuca|
|Latin name of herbal substance:||Melaleucae aetheroleum|
|Botanical name of plant:||Melaleuca alternifolia (maiden and betche) cheel|
|English common name of herbal substance:||Tea-tree oil|
Latin name of the genus: Melaleuca
Latin name of herbal substance: Melaleucae aetheroleum
Botanical name of plant: Melaleuca alternifolia (Maiden and Betche) Cheel, and/or other spieces of Melaleuca
English common name of herbal substance: Tea-tree oil
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.1.1. Primary pharmacodynamics
- 3.1.2. Secondary pharmacodynamics
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- 3.3.1. Single dose toxicity
- 3.3.2. Repeated dose toxicity
- 3.3.3. Genotoxicity
- 3.3.4. Carcinogenicity
- 3.3.5. Reproductive and developmental toxicity
- 3.3.6. Local tolerance
- 3.3.7. Other special studies
- 3.4. Overall conclusions on non-clinical data
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.3. Clinical studies in special populations (e.g. elderly and children)
- 4.4. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 5.1. Overview of toxicological/safety data from clinical trials in humans
- 5.2. Patient exposure
- 5.3. Adverse events and serious adverse events and deaths
- 5.4. Laboratory findings
- 5.5. Safety in special populations and situations
- 5.5.1. Use in children and adolescents
- 5.5.2. Contraindications
- 5.5.3. Special Warnings and precautions for use
- 5.5.4. Drug interactions and other forms of interaction
- 5.5.5. Fertility, pregnancy and lactation
- 5.5.6. Overdose
- 5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
- 5.5.8. Safety in other special situations
- 5.6. Overall conclusions on clinical safety
- 6. Overall conclusions
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Melaleuca alternifolia tree is a member of the botanical family Myrtaceae. The name tea tree was established for the plant because the leaves were used to prepare an aromatic tea.
The term “Tea Tree” includes species of the genus Leptospermum and Melaleuca (more than 150 species) of the family Myrtaceae. The best known and economically most important species is the Australian Tea Tree (Saller et al. 1998).
The preparation with pharmacological interest is the oil from the leaves (called tea tree oil, TTO), because it has been reported as having
There are several historical terms for TTO, including ‘‘melaleuca oil’’ and ‘‘ti tree oil’’, ‘‘ti tree’’ being a
Maori and Samoan common name for plants in the genus Cordyline. The term ‘‘Melaleuca oil’’ has been selected as the official approved name by the Therapeutic Goods Administration of Australia (Carson & Riley 2001).
About 2% essential oil can be obtained from the leaves of the Australian Tea Tree by extraction with lipophilic organic solvent or by steam distillation. According to the European Pharmacopoeia TTO is obtained by steam distillation from the foliage and terminal branchlets of Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca. It is a clear, mobile, colourless or pale yellow liquid with no visible trace of water and has a distinct pleasant odour like turpentine with a high content of terpenes (> 50 to 60%) and a specific weight of 0.89. It is almost insoluble in water, but mixes well with most organic solvents (Saller et al. 1998).
TTO is produced mainly from Melaleuca alternifolia on
(Carson & Riley 2001).
TTO is composed of terpene hydrocarbons, mainly monoterpenes, sesquiterpenes and their associated alcohols. According to Carson et al. (2006), the early reports on the number of components TTO was put at up to 48, however in 1989 a paper was published reporting on the examination of over 800 samples of TTO and concluded that there were approximately 100 components (Brophy 1989). This wide variation and the potential for
The chemical composition of TTO consists largely of cyclic monoterpenes of which about 50% are oxygenated and about 50% are hydrocarbons (Cox et al. 2000).
The oil contains 42.35%
Since the exact composition of TTO is variable, according to the Australian and International Standards Organizations, the substance known as TTO from Melaleuca alternifolia has a chromatographic profile within given ranges (Halcón & Milkus 2004).
The European Pharmacopoeia and the International Standard ISO 4730 require TTO to have a minimum content of 30% of
Table 1: Main constituents of tea tree oil
TTO is incorporated in topical formulations for the treatment of cutaneous infections (Carson et al. 2006; Hammer et al. 2006). The concentrations of TTO found in commercially available products range from 2 to 5%.
TTO has to be stored in
TTO has been used for many years as a component in cosmetic products. It has also been used as an ingredient in medicinal products for its antimicrobial properties especially in treating cutaneous infections. It has been listed in various reference books including the British Pharmaceutical Codex
1949 and books on Essential Oils (Penfold & Morrison 1950) and the World Health Organisation in 2004 has published a monograph on “Aetheroleum Melaleucae Alternifoliae”.
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2. nformation about products on the market in the Member States
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
1.3. Search and assessment methodology
This assessment report reviews the scientific literature data available for Melaleuca alternifolia essential oil, and from the WHO monograph, European Pharmacopoeia monograph, British Pharmaceutical Codex monograph, ESCOP monograph, PubMed, EMA library and the internet, as well as available information on products marketed in the European Community, including pharmaceutical forms, indications, posology and methods of administration.
The keywords “Melaleuca alternifolia”, “tea tree oil”, in all text fields were used. The information ad references provided by the Australian Tea Tree Industry (ATTIA Ltd.) following the call for submission of scientific data were also taken into consideration. Only clinical studies with tea tree oil were included in the assessment report.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Melaleuca alternifolia oil has been used as medicinal by Australian Bundjabung Aborigines for several millennia for bruises, insect bites, and skin infections. European colonists soon recognized the therapeutic properties and began to distil oil from its leaves (Carson & Riley 2001). Members of the crew of James Cook described at the end of the eighteenth century the use of the TTO. It was rediscovered in the 1920s as a topical antiseptic with more effective activity than phenol (Bozzuto et al. 2011).
The essential oil was distilled for the first time in 1925 and due to its antiseptic, antibacterial and antifungal effects became a standard antiseptic agent for surgery, especially for dental surgery (Saller et al. 1998).
The monograph on TTO of the British Pharmaceutical Codex of 1949 reports that TTO has germicidal properties and has been used as a local application in the treatment of furunculosis, tinea, paronychia,
impetigo, trush and stomatitis, and as inhalant in coryza. In veterinary practice it has been used in the treatment of mange and eczema and in sores and skin diseases of parasitic origin.
TTO has been used for its bactericidal and fungicidal properties as a disinfectant component in several medicinal combination products with
A cutaneous liquid containing TTO has been authorised in Denmark from 1993 to 2009 for disinfection in acne and in fungal infections on the foot.
In Sweden a cutaneous liquid is marketed since 1988 and a oromucosal and cutaneous solution is registered in Hungary since 2004.
In Australia, the Complementary Medicines Evaluation Committee (CMEC) recommended in 1999 to the TGA that registration applications for uncompounded TTO products, intended for topical use and with low level claims of a first aid nature, can be approved by the TGA without requiring prior consideration and recommendation by CMEC (CMEC extracted ratified minutes).
There is a significant number of 100% TTO medicinal products authorised in Australia to date.
Table 2 shows a consistent and long standing use of TTO demonstrated for more than 30 years, since 1930, internationally and for more than 15 years, since 1933, in the European Community. A wide range of traditional indications have been described for local application including the nasal, mouth and throat regions.
TTO has been used as an antiseptic for special and general dental surgery and in denture and mouth washes (MacDonald 1930, Anonymous 1933, Penfold & Morrison 1937, Penfold & Morrison 1950). It has also been indicated for a variety of skin conditions including bacterial and fungal infections of the skin such as acne, furunculosis, dermatophytosis (tinea pedis, tinea cruris, tinea barbae), pityriasis versicolor (tinea versicolor), parionychia, impetigo, empyema, dermatitis, eczema, psoriasis, skin rashes, impetigo contagiosa, pediculosis, ringworm, thrush, infected pustules, intertrigo and nail infections (caused by Candida albicans), parasitic skin diseases (Penfold & Morrison 1937, Penfold & Morrison 1950, Humphery 1930, Martindale 1993, British Pharmaceutical Codex 1949, Walker 1972, WHO 2004, Williamson 2003, Lawless 1994, Drury 1991).
Many different foot problems have been treated by TTO including onychomycosis infections of toenails, bromidrosis, malodour, cracks, fissures, peeling, callused heels, inflammation of corns, calluses, bunions, hammertoes,
Throat, nasal and mouth conditions including acute nasopharyngitis, catarrh, thrush, stomatitis, tonsillitis, mouth ulcers, sore throat, coughs and colds, nasopharyngitis, sinus congestion, tonsillitis, pyorrhoea, gingivitis are traditional indications for use of TTO (Penfold & Morrison 1937, Penfold & Morrison 1950, Humphery 1930, British Pharmaceutical Codex 1949, WHO 2004).
TTO has been used for vaginal infections and gynaecological conditions including vaginitis, cystitis and cervicitis (Penfold & Morrison 1937, Penfold & Morrison 1950, Humphery 1930, WHO 2004), irrigation of bladder and urethra (Anonymous 1933), symptomatic treatment of colitis (WHO 2004) and as an inhalant in coryza (British Pharmaceutical Codex 1949).
Table 2: Traditional use of tea tree oil
2.2. Information on traditional/current indications and specified substances/preparations
The leaves were macerated in water for a long period (hours or even days) and then used as infusion or impregnated dressing especially in treating common cold, sore throat, insect bites, wounds or fungal skin infections as well as in delousing (Saller et al. 1998).
The essential oil had been used during the Second World War as a general antimicrobial agent and insect repellent, and provided in the first aid kits of serving Australian soldiers. The essential oil is nowadays used as a strong antimicrobial and antifungal agent in creams, soaps, toothpastes and other preparations and it has been used both externally and internally by both herbalists and aromatherapists
In modern times, TTO is reputed to have several medicinal properties including antibacterial, antifungal, antiviral,
TTO enjoys remarkable popularity as a topical antimicrobial agent and, although it is marketed mainly for its
TTO has a number of characteristics which suggest potential for its use in wound treatments or protectants against fly strike. It has documented insecticidal effects, which could be of use in the treatment of larvae in strikes, and repellent effects (Callander & James 2011).
In Australia, it has also a long history of clinical use in the treatment of foot problems such as tinea pedis and toenail onychomycosis. Dermatologic studies have been conducted in the treatment of acne, dandruff, head lice, and recurrent herpes labialis, in which effects were found to be either similar or better than traditional treatment, and often with fewer side effects. A few published studies report the successful use of TTO in treating mucous membrane infections, including Trichomonas vaginalis, and against oral bacteria and oropharyngeal candidiasis (Halcón & Milkus 2004). 100% TTO is listed by the Australian Therapeutic Goods Administration. A wide range of claims for use are permitted [Quoted at Austteam Tea Tree Oil Conference, 1995].
In Denmark it has been authorised for disinfection in acne and in fungal infections on the foot (1993- 2009).
In Sweden TTO is used against itch at mild athlete´s foot, for uncomplicated insect bites and for treatment of mild acne, in Hungary for treatment of skin infection, stomatitis, gingivitis, cut wounds, excoriation and acne.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
TTO is usually topically applied at concentrations
Tea tree preparations containing 10% and 100% TTO have been used in clinical trials to treat tinea pedis and onychomycosis, respectively (Buck et al. 1994; Tong et al. 1992).
For treating athlete’s foot, it is advised to dilute the concentrated oil with an equal amount of water or vegetable oil and apply to the affected area three times a day with a cotton ball (Combest 1999).
A topically applied 5% solution appears to be effective in treating acne (Bassett et al. 1990).
Several published reports have addressed minimum inhibitory and bactericidal concentrations of TTO against clinical isolates of Staphylococcus aureus. A study of 105 clinical isolates of Staphylococcus aureus using a broth microdilution method found the MIC90 (Minimal Inhibitory Concentration required to inhibit the growth of 90% of organisms) of TTO to be 0.5%. A later study of 100 clinical isolates of
In Australia, in 1995 the Medicines Evaluation Committee approved undiluted TTO as a “mild antiseptic for minor cuts, abrasions, bites and stings and minor burns”. [Quoted at Austteam Tea Tree Oil
According to the posology of medicinal products licensed in Europe for application on the skin TTO should always be diluted before use. In Sweden it is diluted in olive oil or baby oil 1:9 and dabbed on the afflicted areas of the skin
In Hungary the daily dose for cutaneous use is
A number of papers, documents and letter on the sales of TTO in Europe, provided by Interested Parties, represent a body of data that, as a whole, substantiates the medicinal use of undiluted TTO in Europe for at least 15 years (Drury 1991, Drury 1995, Lawless 1994, Lawless 1996). In these papers and documents the use of undiluted TTO is specified and posology is given. In addition this was supported by wide spread evidence of use by way of magazine articles, sales figures and books.
Table 3: Information on preparations of TTO grouped according to the traditional use
* a preparation containing 40% of TTO in a soap base called Melasol in Australia and Ti.Trol solution in England (Anonimous 1933)
1)Liquid preparation containing 0.5% to 10% of essential oil to be applied to the affected area
2)Oily liquid or
3)Oily liquid or
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Based on results of laboratory and animal studies, there are several likely mechanisms by which a topical TTO preparation may facilitate healing in chronic
3.1.1. Primary pharmacodynamics
The oil exhibits a broad spectrum of antimicrobial activity in vitro although its efficacy in vivo remains relatively unsubstantiated. Antibacterial activity against Staphylococcus aureus, both methicillin- susceptible (MSSA) and
Minimum inhibitory concentrations (MICs) have been determined for many organisms including
MICs of TTO range from 0.06 to 0.5% (v/v) for Escherichia coli, Staphylococcus aureus and
Streptococcus spp., and 2 to 8% (v/v) for Pseudomonas aeruginosa (Longbottom et al. 2004).
A study was carried out to evaluate the activities of TTO against lactobacilli and a range of organisms associated with bacterial vaginosis. MIC data indicated that a variety of anaerobic and aerobic bacteria are susceptible to TTO. The data also show that all lactobacilli tested were appreciably more resistant to TTO than organisms known to be associated with bacterial vaginosis, with at least a twofold difference in MIC90 results. Therefore, authors suggested that previous clinical success reported by Blackwell may be due, in part, to the susceptibility of bacterial
In vitro studies established that MIC and MBC (minimum bactericidal concentration) of TTO range from 0.003 to 2% (v/v). Studies indicate that several oral bacteria are susceptible, suggesting that TTO may be used in oral healthcare products and in maintenance of oral hygiene (Hammer et al. 2003a).
The in vitro activity of TTO against MRSA has been shown many times with minimum inhibitory concentrations ranging from 0.25% to 2% (Edmondson et al. 2011).
McMahon et al. (2007) has suggested that the treatment of both
The effect of
MRSA⁄MSSA cultures also displayed decreased susceptibility to TTO. Conclusions of the authors were that TTO habituation
Results suggested that application of TTO at
Carson (2009), Thomsen et al. (2009) and Hammer & Riley (2009) attempted to reproduce the results of McMahon et al. (2007), but were unsuccessful. The authors have suggested that exposure to sub- inhibitory concentrations of TTO does not appear to affect the susceptibility or resistance to conventional antibiotics.
Carson et al. (2002) investigated the mechanisms of action of TTO and three of its components, 1,8- cineole,
When the compounds were tested at
In their review paper Carson et al. (1996) stated that the antiviral activity of TTO was first shown using tobacco mosaic virus and tobacco plants. In field trials TTO (spray concentration 0, 100, 250 or 500 ppm) was sprayed on plants that were then experimentally infected with tobacco mosaic virus. After 10 days, there were significantly fewer lesions per square centimetre of leaf in plants treated with TTO than in controls.
Another study has been conducted in 2001 by Schnitzler et al. with herpes simplex viruses that were incubated with various concentrations of TTO; these treated viruses were then used to infect cell
TTO has an interesting antiviral activity against influenza A⁄PR⁄8 virus subtype H1N1 in
The mechanism of action of TTO and its active components against Influenza A/PR/8 virus subtype H1N1 was investigated in MDCK cells. The effect of TTO and its active components on different steps of the replicative cycle of influenza virus was studied by adding the test compounds at various times after infection. These experiments revealed that viral replication was significantly inhibited if TTO was added within 2 h of infection, indicating an interference with an early step of the viral replicative cycle of influenza virus and suggesting that TTO could inhibit viral uncoating by an interference with acidification of
The antifungal activity of TTO was known anecdotally especially amongst the aboriginal people of Australia.
In 1998 Hammer et al. studied the in vitro TTO activity against Candida albicans and
Candida albicans and
Mondello et al. (2003) investigated the in vitro antifungal activity of TTO (ISO
TTO was active against all tested strains, with MICs ranging from 0.03% (for Cryptococcus neoformans) to 0.25% (for some strains of Candida albicans and other Candida spp.). Fluconazole- and/or
The results of the in vivo investigations on the animal model (oophorectomized – ovary removal surgery female rats of the Wistar strain) of vaginal candidiasis demonstrated that TTO administered intravaginally using a dose volume of 0.1 ml at concentrations of 1%, 2.5% and 5% is effective in resolving experimental Candida albicans infection, with both
In a follow up study, Mondello et al. (2006) confirmed the previous result with the animal experimental model as reported on the in vivo activity of
TTO. Using the same methodology as detailed in their previous paper they concluded that
Antimycotic properties of TTO and its principal components were compared with the activity of 5- fluorocytosine and amphotericin B. The majority of the organisms were sensitive to the essential oil, with TTO and
The in vitro activities of TTO against Malassezia yeast species were shown. Ketoconazole was the most active of the imidazoles in the agar dilution assay, followed by miconazole and econazole, which were similar in activity. Malassezia furfur was the least susceptible species. Malassezia sympodialis,
Malassezia slooffiae, Malassezia globosa, and Malassezia obtusa showed similar susceptibilities. Tea tree oil was active against all Malassezia species, for which the MICs were similar. Ketoconazole was also the most active of the imidazoles in the broth dilution assay. Miconazole and econazole showed similar activities against each species, but demonstrated differences in activity between species. The MICs of tea tree oil were similar for M. furfur and M. sympodialis, but the minimum fungicidal concentrations (MFCs) were several dilutions lower for M. furfur. The authors concluded that individual Malassezia species vary in their susceptibility to several antifungal agents, with M. furfur being the least susceptible of the species tested, whereby TTO may be a suitable alternative topical agent (Hammer et al. 2000).
In another study investigating in vitro antifungal activity of TTO components, the highest activity, with minimum inhibitory concentrations and minimum fungicidal concentrations of
Carson et al. (2006) summarised the antifungal activity of TTO against a range of fungal species published by a number of researchers obtained from over 15 papers: MICs were in the range between 0.03 and 0.5% and fungicidal concentrations from 0.12 to 2%. The exception to these ranges was Aspergillus niger with MFC values up to 8%. However the authors noted that these assays were conducted with fungal conidia that are known to be relatively impervious to chemical agents. Subsequent assays show that germinated conidia are significantly more susceptible to TTO than non- germinated conidia. They also noted that TTO vapours have also been demonstrated to inhibit fungal growth and affect sporulation.
Hammer et al. (2004) investigated the mechanism of action of TTO and its components against
Candida albicans, C. glabrata and Saccharomyces cerevisiae. Yeast cells were treated with TTO or components, at one or more concentrations, for up to 6 hours. During that time, alterations in permeability were assessed by measuring the leakage of 260 nm absorbing materials and by the uptake of methylene blue dye. Membrane fluidity was measured by
concluded that the data from the study supported the hypothesis that TTO and components exert their antifungal actions by altering membrane properties and compromising
Antiseptic and disinfectant activity
Effective skin antisepsis and disinfection are key factors in preventing many
A study was conducted to determine the frequencies at which
An investigation was carried out to determine the effect of Burnaid, a commercial TTO preparation, against Enterococcus faecalis ATCC29212, Staphylococcus aureus ATCC29213, Escherichia coli
ATCC25922 and Pseudomonas aeruginosa ATCC27853.The organisms were suspended in sterile saline (density of 0.5 McFarland Standard) and inoculated onto horse blood agar (E. faecalis and
Staphylococcus aureus) or
Assessor’s comment: This study suggests not using TTO preparations for the care of burn wounds.
Carson et al. (2006) reported that results have been published showing that TTO has antiprotozoal activity. TTO caused a 50% reduction in growth (compared to controls) of the protozoa Leishmania major and Trypanosoma brucei at concentrations of 403 mg/ml and 0.5 mg/ml, respectively. TTO at high concentration corresponding to 300 mg/ml killed all cells of Trichomonas vaginalis and there is also anecdotal in vivo evidence that TTO may be effective in treating T. vaginalis infections.
3.1.2. Secondary pharmacodynamics
Human melanoma cells (M14 WT) grown in the presence of the antitumor drug adriamycin (M14 ADR) express the multidrug transporter
Liu et al. (2009) reported that TTO showed strong in vitro cytotoxicity towards human lung cancer cell line (A549), human breast cancer cell line
The antioxidant activity of Australian TTO was determined using two different assays. In the 2,2-
Following 3 case reports of gynecomastia in prepubertal boys (4, 7, and 10 years old) after repeated topical use of products containing lavender, one of them in combination with TTO, in vitro studies on estrogenic and
The estrogenic potential of TTO was confirmed with a similar in vitro experimental model. However, the only three constituents of TTO which demonstrated through an in vitro dermal penetration study to be able to penetrate human skin to any measurable degree
skin. It was concluded that the components of TTO which responsible of the estrogenic potential in vitro may not be bioavailable (Nielsen 2008).
Also the SCCP in its opinion concluded that the estrogenic potential of TTO shown in vitro is not supported by in vivo studies to elucidate the relevance of this finding for the in vivo situation. Moreover, since the hormonal active ingredients of TTO were shown not to penetrate the skin, the hypothesized correlation of the finding of 3 cases of gynecomastia to the topical use of TTO is considered implausible (SCCP 2008).
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
TTO contains terpenes, sesquiterpenes, hydrocarbons, and related alcohols. Because of the high lipophilicity of its components it has been postulated that TTO is likely to be rapidly and completely absorbed from the skin and mucous membranes (ESCOP 2009). On the other hand, in vitro experiments indicated that, after application of TTO to human epidermal membranes mounted in diffusion cells in the pure form and as a 20% solution in ethanol, only a small proportion of the applied amount
The major compound of TTO,
Considerable research has been done on the metabolism of monoterpenes. After dermal and/or oral absorption, liver P450
Cal and Krzyaniak (2006), Cal et al. (2006) and Cal (2008) studied the penetration behaviour of TTO and pure constituents using a
Assessor’s comment: In conclusion, the process of terpene penetration into the skin and through the skin can be considered to be strongly dependent on the experimental model used (choice of
membrane, hydration level and dose) and on the carrier for the penetrating terpene, while in vivo the effect of evaporation – shown to be 98% needs to be considered.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
The acute oral LD50 in rats has been reported as
No acute inhalation toxicity was evident in response to exposure with TTO/ethanol/CO2 in rats, but methodological weaknesses with the study were noted (SCCP, 2008).
Postulated lethal dose for a
The dermal LD50 in rabbits is > 5 g/kg (Council of Europe Committee of Experts on Cosmetic Products 2001).
3.3.2. Repeated dose toxicity
No deaths or toxic effects were reported in a 30
Renal toxicity has been observed in separate studies following oral administration of
This conclusion could be substantiated by available information on repeated dose systemic toxicity of TTO constituents. Based on
Cineole given to B6C3F1 mice by gavage for 28 days at doses up to 1200 mg/kg/day did not result in any changes. When given encapsulated at doses corresponding to 600 – 5607 mg/kg/day, some hypertrophy of hepatocytes was seen, but was not considered significant (National Toxicology
Program, cited in De Vincenzi et al. 2002). Cineole (8 or 32 mg/kg b.w. was given by gavage to male SPF CFLP mice 6 days per week for 80 weeks. No changes were evident in mice given cineole when compared to control mice (Roe et al. 1979). Based on the studies on hepatic and renal toxicity evaluated by BIBRA (British Industrial Biological Research Association), a NOAEL for cineole might be estimated as 300 mg/kg b.w., which is in agreement with the evaluation from the Norwegian Food Control Authorities in 1999 (EFSA 2012).
Based on the available information on repeated dose systemic toxicity of TTO constituents, the SCCP opinion estimated a derived NOAEL for TTO of 117 mg /kg b.w. /day for renal effects (SCCP 2008, Norwegian Food Safety Authority (Matthylsyne) 2012).
Several reports of oral toxicity can be found in the literature. Data indicate that due to its systemic toxicity, TTO should only be used as a topical agent.
General toxicology profile of TTO indicates that severe reactions would be extremely rare if TTO is not ingested (Halcón & Milkus 2004).
TTO produced a negative result in the in vitro Ames test (Saller et al. 1998). In December 2004 the Scientific Committee on Consumer Products (SCCP) noted that TTO is not mutagenic in the Ames test although they stated that there were insufficient details of the study and the study was deemed inadequate. They further noted that, as TTO has antimicrobial properties, an Ames test would be of limited value (SCCP 2004).
In 2005 Evandri et al. evaluated the mutagenic and antimutagenic activity of essential oils TTO and Lavandula angustifolia (lavender oil) the bacterial reverse mutation assay in Salmonella typhimurium TA98 and TA100 strains and in Escherichia coli WP2 uvrA strain, with and without an extrinsic metabolic activation system. The results showed that neither essential oil had mutagenic activity on the two tested Salmonella strains or on Escherichia coli, with or without the metabolic activation system, providing further evidence of the lack of mutagenic potential of TTO.
These results were also supported by a paper published by Fletcher et al. (2005) using Salmonella strains TA102, TA100 and TA98 in the Histidine Reversion Assay Ames test: neither TTO nor terpinen-
Two papers were found evaluating the mutagenic potential of TTO components:
Hammer et al. (2006) in a review noted that the following components were
In tests with mammalian cells (comet assay),
They concluded that, overall, the available data on the mutagenicity of TTO and its individual constituents indicate low mutagenic potential, using both bacterial and mammalian test systems (Hammer et al. 2006).
An in vivo Mouse Micronucleus Assay (ICP Firefly Pty Ltd. 2005) was conducted according to OECD Test Guideline No. 474, which was conducted under GL. TTO was administered by gavage at 1000, 1350 and 1750 mg/kg b.w. TTO. There were no increases in the frequency of micronucleated cells in any of the dose groups. There was a statistically significant depression of PCE viability and PCE+NCE ratio (P<0.001) in the high dose group in both sexes when compared with the vehicle control groups at 48 hours. This finding is an indication that there was sufficient exposure of the bone marrow to the test substance to elicit a response. Clinical signs in the high dose group included depressed weight gain, wobbly gait, laboured breathing and rough coat.
TTO in concentrations ranging from 95 μg/ml to 365 μg/ml increased neither the frequencies of micronuclei nor the frequencies of chromosomal aberrations in human lymphocytes. Higher concentrations could not be tested, since at higher concentrations cell viability was significantly reduced. Within that limitation, these results suggest that TTO does not induce chromosome aberration (Pereira et al. 2014).
No available data.
The Scientific Committee on Consumer Products in its updated “Opinion on Tea Tree Oil” in 2008 stated that since methyleugenol was reported as a minor constituent of TTO “the content should be indicated. According to the opinion SCCNFP/0373/00 on methyleugenol in fragrances the content in finished
This statement follows the EMEA “Public statement on the use of herbal medicinal products containing methyleugenol” (2005) reporting a content of 0.28 to 0.9% of the natural potential carcinogen methyleugenol in TTO. However HMPC has concluded that “the present exposure to methyleugenol resulting from consumption of herbal medicinal products (short time use in adults at recommended posology) does not pose a significant cancer risk.”
The Australian TTO industry reports that these levels of methyleugenol refer to Melaleuca bracteata, whereas commercial TTO is derived solely from Melaleuca alternifolia; analytical surveys conducted by Australian TTO industry show that Melaleuca alternifolia contains only trace levels of methyleugenol.
Southwell et al. (2011) quantified the traces of methyleugenol previously reported in TTO ranging from less than 0.01% to 0.06% (mean 0.02%).
3.3.5. Reproductive and developmental toxicity
No data available on TTO.
However, exposure to
Hammer et al. (2006), noted that the embryofoetotoxicity of
3.3.6. Local tolerance
Two studies were conducted on groups of 3 female rabbits of the New Zealand strain according to the methodology detailed in OECD guideline 404 and were GLP compliant. In the first study TTO (100%) was applied undiluted on 4×4 cm patches. In the second study, dilutions of
Draize skin irritancy index was found to be 5.0, based on application of 100% TTO to intact and abraded skin of albino rabbits, thus signifying that TTO could cause dermatitis in some users (Halcón & Milkus 2004).
The acute dermal LD50 in rabbits was recorded as in excess of 5.0 g/kg since this dose resulted in 2/10 deaths in rabbits. Furthermore, it was observed at necropsy that neat TTO produced irritant effects and skin abnormalities in rabbits patch tested at this dose for 24 h with occlusion. Pure (100%) TTO applied to the skin of albino rabbits and maintained at 2 g/kg for 24 hours resulted in no signs of toxicity (Halcón & Milkus 2004).
The primary eye irritation of TTO was also studied in the rabbit (female, Japanese White) under GLP conditions. Two groups of three rabbits were given a single ocular dose (0.1 ml) of TTO (1% or 5% in liquid paraffin). After instillation of the test substance, no abnormal signs in the clinical conditions were observed among the rabbits. Ocular responses using Draize’s criteria demonstrated a conjunctival
discharge lasting for up to six hours following instillation of 1% TTO and conjunctival redness and discharge for up to 24 hours following instillation of 5% TTO. In both groups, the maximal response was observed after one hour. Based on these observations, the author concludes, that both TTO solutions can be classified as “minimally irritating” (SCCP 2008).
TTO was found to produce ototoxicity when applied in the ears of guinea pigs at 100% concentration, but no ototoxicity was found for 2% solutions (Halcón & Milkus 2004).
Skin sensitisation potential
In order to test the potential of TTO to cause skin sensitisation guinea pigs were
A guinea pig maximization assay using the Magnusson and Kligman method (Pharmaceutical Consulting Service 1989) and albino guinea pigs (20 per group) has been conducted with TTO. During the induction phase, two 0.1 ml intradermal injections were given to the animals. One week later, 5% TTO was applied to the skin at the injection site under occlusion for 48 hours. After a two week period, a 30% TTO challenge dose was applied to the skin under occlusion for 48 hours. There was no evidence of sensitisation in this assay. In a published report, TTO of unknown quality was tested in 10 guinea pigs using an adjuvant maximization protocol. The induction concentration was not given. At an elicitation concentration of 30%, 3/10 guinea pigs gave positive reactions at the
Three samples of TTO were tested in the Mouse Local Lymph Node Assay (LLNA) (RCC Ltd. Study A69041, Study A78682, Study A78816 2006). Two of the samples were
The peroxide value and
Southwell (2006) examined 26 TTO samples and demonstrated that the presence of 1,2,4- trihydroxymenthane in TTO is a rare event and in the cases where this breakdown product was found, the oils were extremely old and severely degraded to the extent where the oils would not be compliant to the ISO Standard. Even in extremely degraded oils,
For many years,
Oxidation products are the likely allergens. Since oxidized TTO appears to be a more potent allergen than fresh TTO, human adverse reactions may be minimized by reducing exposure to aged, oxidized oil (Carson & Riley 2001).
Although some irritation was observed, undiluted TTO did not produce phototoxic effects on the skin of hairless mice (Carson et al. 1998).
3.3.7. Other special studies
A case report documented TTO poisoning after a single dermal application of 120 ml of undiluted TTO to 3 adult intact female purebred Angora cats, one of which died. The cats were severely infested with fleas, so they were shaved and the oil was applied directly to the cats’ skin. The shaving produced no nicks on the skin; however, numerous flea bites were visible. The product used to eliminate fleas was labelled for use as a spot treatment for skin lesions, but a catalogue advertised that it would repel fleas when diluted and used as a dip. All animals exhibited hypothermia, incoordination, dehydration and trembling. The surviving 2 cats recovered after
Villar et al. (1994) reported that cases of TTO toxicosis have been reported by American veterinarians to the National Animal Poison Control Centre when the oil was applied on derma of dogs and cats. They noted that, in most cases, the oil was used to treat dermatologic conditions at inappropriate high doses. The typical signs observed were depression, weakness, incoordination and muscle tremors. Treatment of clinical signs and supportive care was sufficient to achieve recovery without sequelae within
TTO and components of TTO was tested on several human cell lines in vitro. Cytotoxicity with 100% TTO ranged from 0.02 to 2.8 g/l, with
3.4. Overall conclusions on
Studies on TTO demonstrate that adequate doses have broad spectrum antimicrobial activity with little evidence for inducing tolerance and resistance. There is also some evidence of TTO possessing anti- inflammatory activity.
The cytotoxic activity towards a range of cancer cell types shown by means of in vitro studies is not considered relevant for the purpose of this assessment.
The published pharmacokinetic data on TTO are minimal. In vitro skin permeation studies using human skin preparations demonstrate that the extent of penetrating of TTO components is very low, with the more polar
TTO has been reported to cause mild to moderate skin irritation in rabbit studies. Local lymph node assay (LLNA) studies indicate that TTO has mild skin sensitisation potential. Highly degraded TTO has a greater potential for skin sensitisation due to the presences of oxidation
There are no oral repeated dose toxicity studies available for TTO. However, there are no known indications which require oral administration of TTO. The main route of administration is by dermal application. Repeated dose data are available on some of the main components of TTO. Renal toxicity has been observed in separate studies following oral administration of
TTO was negative in the Ames assay using Salmonella typhimurium TA102, TA100 and TA98 examined with or without metabolic activation and not genotoxic in in vitro mammalian cells in concentrations ranging from 95 μg/ml to 365 μg/ml (Pereira et al. 2014). It did not induce clastogenicity in the in vivo mouse micronucleus assay (Fletcher et al. 2005).
Available data on the genotoxicity indicate low genotoxic potential of its major constituents,
The slight genotoxic potential of
There are no experimental data on the mutagenic and clastogenic potential of terpinolene (= δ- terpinene, cas nr
While TTO contains trace levels of methyleugenol, the typical use pattern in adults, being
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
The mechanisms of antimicrobial action elucidated so far reflect the terpenic hydrocarbon composition and indicate that cytoplasmic membrane integrity is compromised by treatment with TTO or some of its major components. Alterations in eukaryotic cell membranes have also been observed with TTO and
Pharmacological studies in humans
Pharmacological studies conducted in humans have been discussed in the ESCOP Monograph Supplement 2009. Messager et al. 2005 reported on the antimicrobial activity of TTO for hand cleansing. Koh et al. 2002 and Pearce et al. 2005 reported on the
Khalil et al. 2004 have also investigated the regulation of wheal and flare by undiluted TTO on
Canyon & Speare 2007 conducted head lice (Pediculus humanus var. capitis) avoidance experiments on the arm of the researcher. Circles of skin (2.5 cm in diameter) were marked out and test materials were applied to a test area. These test materials consisted of 100% TTO, a variety of other oils, neem insect repellent,
A summary of these studies is presented in Table 4.
Table 4: Pharmacological studies in humans
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Considerable research has been done on the metabolism of monoterpenes. After rapid dermal and/or oral absorption, liver P450
Cal and Krzyaniak (2006), Cal et al. (2006) and Cal (2008) studied the penetration behaviour of TTO and pure constituents using a
The process of terpene penetration into the skin and through the skin can be considered to be strongly dependent on the experimental model used (choice of membrane, hydration level and dose) and on the carrier for the penetrating terpene, while in vivo the effect of evaporation – shown to be 98% needs to be considered.
Human pharmacokinetic data are not available for tea tree oil. In vitro dermal penetration studies using human skin preparations indicate that dermal absorption of TTO components is relatively low, up
4.2. Clinical Efficacy
Clinical trials have been performed to test the efficacy of topical TTO products for a range of conditions including acne, wound healing, mycosis (oral candidiasis, denture stomatitis, onychomycosis, tinea and tinea pedis), protozoan infections, herpes labialis, dandruff, tinea.
4.2.1. Dose response studies
4.2.2. Clinical studies (case studies and clinical trials)
Clinical studies on effects of TTO were conducted for the following indications (presented in
–Minor skin lesions
Clinical studies conducted with combinations containing TTO (presented in 22.214.171.124):
126.96.36.199. Clinical studies conducted with TTO
Bassett et al. 1990 and Enshaieh et al. 2007 conducted randomised controlled trials and reported on the use of TTO for the treatment of mild to moderate acne.
A comparative study of
The efficacy of 5% topical TTO gel in mild to moderate acne vulgaris: A randomised,
One study has been conducted on the possible efficacy of TTO in treatment of the acne vulgaris. It was a randomised
Assessor’s Comment: 5% TTO gel showed to ameliorate acne lesions in two studies.
Feinblatt 1960 reported on the use of TTO for the treatment of furunculosis (boils). Thirty five patients (26 males and 9 females) with furuncles located in various sites (18 in the neck, 8 on the back, 6 in the axilla areas, 1 on the scalp, 4 on the face and forehead, 4 on the forearm, 1 on the calf and 1 on the external ear) many of them at multiple sites were enrolled in the study. Ten patients were given expectant treatment and 25 were treated with TTO painting the surface over the furuncle freely with the oil two or three times daily, after thoroughly cleaning the site. Results showed that, of the 10 untreated controls, five of the boils were finally incised and in five cases the infected site of the furuncle was still apparent after eight days. In the 25 cases treated with TTO, only one boil required
incision and in 15 cases the infected site of the furuncle was removed completely in eight days. In six cases the infected site of the furuncle, while still present after eight days, was reduced more than one- half and in three cases the infected site was reduced less than half in eight days. As to local reactions, three patients complained of slight temporary stinging.
In the same paper Feinblatt (1960) described a typical case report of a male patient aged 40 under treatment for diabetes mellitus, who complained of recurrent boils. TTO was applied directly over a large boil (3 x 3 cm), swollen, reddened and painful boil on his neck two or three times daily after thorough cleansing. There was definite improvement within two days, most of the inflammation had disappeared after four days and the skin healed after eight days with no untoward effects or local reactions. The patient repeated the use of TTO whenever a new boil developed and every time the further boils development aborted. The Author concluded that, due to its high germicidal activity against Staphylococcus aureus and on the basis of rapid healing without scarring achieved in the study, TTO may be used as an alternative option before surgical intervention in furunculosis.
The primary aim of an uncontrolled case series study was to assess whether a TTO solution used in a wound cleansing procedure could decolonise MRSA from acute and chronic wounds of mixed aetiology. The secondary aim was to determine if the TTO solution influenced wound healing outcomes. The product used was a
Two adverse events of pain were reported by participants who experienced pain during the cleansing procedure that may or may not have been because of the irrigation with the TTO solution (Edmondson et al. 2011).
Assessor’s comment: this study shows that treatment with TTO can influence positively wound healing through its antimicrobial activity; limit of the study is the small number of participants.
The Effect of Tea Tree Oil (Melaleuca alternifolia) on Wound Healing Using a Dressing Model (Chin & Cordell 2013)
not controlled as well as other variables such as the age and the immune system function (Chin & Cordell 2013).
An Integrated Approach to
A study was performed in a
Residents of the 5 nursing homes were screened for MRSA at baseline and 1 year later to detect the microbial quality improvement. Active surveillance cultures were performed on subsequently admitted nursing home residents,
The author concluded that the use of active surveillance cultures and decolonization therapy was effective in decreasing the prevalence of asymptomatic carriage, the incidence of nosocomial infection, and the overall prevalence of MRSA. However it has to be noted that the number of patients lost to the
Chronic Wound Treatment with Topical Tea Tree Oil (Culliton & Halcon 2011)
A case study has been reported on the healing of a chronic
A clinical investigation to determine the efficacy and safety of TTO use for vaginal douche and topical application in the treatment of trichomonal vaginitis, Candida albicans vaginitis and other vaginal infections was performed. The medication studied was a special emulsified 40% solution of Australian TTO with isopropropyl alcohol 13%. Hundred thirty cases of vaginal infections were investigated: trichomonal vaginitis (n=96), Candida albicans vaginitis (n=4), nulliparous cervicitis from Trichomonas vaginalis (n=20), chronic endocervicitis (n=10). Australian TTO was found to be highly effective in
treatment of tricomonal vaginitis, Candida albicans vaginitis, cervicitis and chronic endocervicitis (Peña 1962).
Onychomycosis is a superficial fungal infection that destroys the entire nail unit. It is the most frequent cause of nail disease, ranging from 2% to 13%. Standard treatments include debridement, topical medications, and systemic therapies.
Comparison of two topical preparations for the treatment of onychomycosis: TTO and clotrimazole (Buck et al. 1994).
The participants included 117 patients with distal subungual onychomycosis proven by culture. Patients received
The baseline characteristics of the treatment groups did not differ significantly. After 6 months of therapy, the two treatment groups were comparable based on culture cure (clotrimazole = 11%, TTO = 18%) and clinical assessment documenting partial or full resolution (clotrimazole = 61%, TTO = 60%). Three months later, about one half of each group reported continued improvement or resolution (clotrimazole = 55%; TTO = 56%).
Topical therapy, including the two preparations presented in this paper, provide improvement in nail appearance and symptomatology. The study shows that use of a topical preparation in conjunction with debridement is an appropriate initial treatment strategy (Buck et al. 1994).
Assessor’s comment: the study shows efficacy of 100% TTO solution comparable to clotrimazole in the treatment of onychomycosis.
Syed et al. 1999 conducted a double blind randomised controlled trial investigating the treatment of onychomycosis. 40 patients were randomly allocated to the Treatment group of 2% butenafine hydrochloride and 5% TTO and 20 patients were randomly allocated to the control group consisting of a TTO cream of unspecified concentration. After 16 weeks of topical application three times daily and covering with an occlusive plastic dressing, 80% in the treatment group were cured and no patients in the control group were cured. TTO in the control cream did not show the expected response and TTO was mixed with butenafine hydrochloride in the treatment group, it is difficult to determine whether the TTO produced any effect in this group. Treatment in the control group was discontinued after 8 weeks so it is possible that the control treatment did not have sufficient time to render its full potency.
Oropharyngeal candidiasis. Oropharyngeal candidiasis is the most common opportunistic infection observed in the patients with HIV/AIDS.
Efficacy of melaleuca oral solution for the treatment of fluconazole refractory oral candidiasis in AIDS patients (Jandourek et al. 1998, Vazquez & Zawawi 2002).
Efficacy of Melaleuca oral solution, an USA branded
A prospective, single centre,
Patients were given 15 ml Melaleuca oral solution four times daily to swish and expel for
Resolution of clinical lesions of oral pseudomembranous candidiasis lesions evaluations were performed weekly for 4 weeks and at the end of therapy for clinical signs of oral candidiasis. Quantitative yeast cultures were performed at each evaluation.
A total of 13 patients were entered into the study, 12 were evaluable. At the
The authors concluded that melaleuca oral solution appeared to be effective as an alternative regimen for AIDS patients with oropharyngeal candidiasis refractory to fluconazole (Jandourek et al. 1998).
The efficacy of
All Candida albicans isolates showed some degree of in in vitro resistance to fluconazole. Overall, using a modified
The authors concluded that both formulations of the TTO mouthwash appeared to be effective alternative regimens for patients with AIDS suffering from oropharyngeal candidiasis refractory to fluconazole (Vazquez & Zawawi 2002).
Assessor’s comment: These studies show a positive effect of TTO commercial preparations in patients with AIDS affected by oropharyngeal candidiasis. No information on the concentration of TTO in the preparations used in the studies is available. Moreover the studies were conducted on a small number of patients.
In vitro and in vivo activity of Melaleuca alternifolia mixed with tissue conditioner on Candida albicans
(Catalán et al. 2008).
Denture stomatitis is an inflammatory reaction of the palatal and alveolar mucosa underlying removable dental prostheses. Denture stomatitis is more commonly seen in the maxillary mucosa than in the mandibular mucosa.
A study was performed to identify in vitro and in vivo activity of TTO mixed with different tissue conditioners on the Candida albicans strain. Microbiological tests were used to isolate Candida albicans from patients with denture stomatitis. The in vitro antifungal activity of TTO against Candida albicans was determined when it was applied directly and when it was mixed with tissue conditioners (Fitt, Lynal,
In the in vitro study,
Assessor’s comment: This study has been conducted on a small number of patients, but suggests that TTO can be useful as an adjuvant in the care of denture stomatitis.
Treatment of tinea pedis
Satchell et al. 2002a and Tong et al. 1992 conducted randomised controlled trials and reported on the use of TTO for the treatment of tinea pedis.
Treatment of interdigital tinea pedis with 25% and 50% TTO solution: A randomised, placebo- controlled, blinded study (Satchell et al. 2002a).
A randomised, controlled,
Assessor’s comment: This randomised, controlled,
TTO in the treatment of tinea pedis (Tong et al. 1992).
One hundred and four patients completed a randomised,
Assessor’s comment: This RCT shows efficacy of cream containing 10% TTO in improving symptoms of tinea pedis but without significant effects against the basic cause of pathology.
Treatment of vaginal infections of Candida albicans with TTO (Belaiche 1985a).
A clinical study with TTO on 28 patients (average age 34), in full
Treatment of skin infections with TTO (Belaiche 1985b).
A clinical study with TTO was conducted in 27 patients affected by different dermatological disorders with the following results:
3 cases of intertrigo infected with Candida albicans: application of pure TTO for 6 weeks – 2 months showed positive effects.
4 cases of angular stomatitis infected with Candida albicans and streptococci: twice a day application of TTO was successful in 3 out of 4 patients.
2 cases of staphylococcal and streptococcal impetigo in children: twice a day application of TTO caused improvement in
6 cases of staphylococcal acne: local treatment determined amelioration of the lesions, without a complete healing, acting on the infection and not on the sebaceous glands activity.
11 cases of nail infections by Candida albicans: treatment with pure TTO twice a day for 3 months, was successful in 8 patients with the first positive result in the first week; no significant improvement in 3 patients.
1 case of pytiriasis versicolor [tinea versicolour caused by Malassezia and/or Trichophytum]: twice a day application of TTO controlled the event after 20 hours (Belaiche 1985b).
Australian TTO: a natural antiseptic fungicidal agent (Shemesh & Mayo 1991)
A clinical trial with Australian TTO was undertaken for the treatment of various dermatological disorders for six months in 50 patients. Several forms of TTO preparations were used: pure oil (100%), lozenges with 1% TTO plus 2.5 mg ground leaf; and a 5% cream. 50 patients were supplied TTO for a
period of 1 to 4 weeks, depending on the severity of the condition being treated. All patients who completed treatment were either cured, all showed remarkable improvement in their presenting condition. One patient stopped the treatment after one day because of mild erythematous skin sensitivity to the 100% TTO (Shemesh & Mayo 1991).
Recurrent herpes labialis
Use of deception to achieve
In a randomised,
Antimicrobial activity of garlic, TTO, and chlorhexidine against oral microorganisms (Groppo et al. 2002).
Antimicrobial activities of TTO, garlic, and chlorhexidine solutions against oral microorganisms were compared in a five week study consisting of thirty subjects. The first week was considered baseline. All subjects used a control solution (second week), and were randomly divided into the three groups (third week): G1- 0.12% chlorhexidine in a vehicle solution; G2 – 2.5% solution of a garlic (Allium sativum L.) aqueous extract 1:1; and G3 – 0.2% TTO in vehicle solution and 0.5% Tween 80. Dishes containing blood agar and Mitis Salivarius Bacitracin agar (MSB) were inoculated with the subjects’ saliva (collected twice a week). Total microorganisms and mutans streptococci were counted in blood agar and MSB, respectively.
Chlorhexidine and garlic groups showed antimicrobial activity against mutans streptococci, but not against other oral microorganisms. The TTO group showed antimicrobial activity against mutans streptococci and other oral microorganisms. Maintenance of reduced levels of microorganisms was observed only for garlic and TTO during the two consecutive weeks (fourth and fifth). Unpleasant taste (chlorhexidine 40%, TTO 30%, garlic 100%), burning sensation (chlorhexidine 40%, TTO 60%, garlic 100%), bad breath (chlorhexidine 40%, TTO 20%, garlic 90%), and nausea (chlorhexidine 0%, TTO 10%, garlic 30%) were reported. The authors concluded that garlic and TTO might be an alternative to chlorhexidine (Groppo et al. 2002).
Clinical and antibacterial effect of tea tree oil – a pilot study (Arweiler et al. 2000)
Arweiler et al. 2000 reported the results from a pilot,
water solution with milk as emulsifier in a third test week. Every test week was followed by a
The effects of a tea tree
The use of TTO for oral conditions such severe gingivitis was studied in a
Minor skin lesions
A randomised, controlled trial of TTO topical preparations versus a standard topical regimen for the clearance of MRSA colonisation (Dryden et al. 2004)
Two topical MRSA eradication regimes were compared in hospital patients: a standard treatment included mupirocin 2% nasal ointment, chlorhexidine gluconate 4% soap, silver sulfadiazine 1% cream versus a TTO regimen. The TTO regimen comprised TTO 10% cream applied to the anterior nostrils three times a day for five days; TTO 5% body wash all over the body at least once a day for five days; TTO 10% cream to skin lesions, wounds and ulcers, and also to axillae or groins as an alternative to the body wash. One hundred and fourteen patients received standard treatment and 56 (49%) were cleared of MRSA carriage. One hundred and ten received TTO regimen and 46 (41%) were cleared.
There was no significant difference between treatment regimens (Fisher’s exact test; P ¼ 0:0286).
Mupirocin was significantly more effective at clearing nasal carriage (78%) than TTO cream (47%; P ¼ 0:0001), but TTO treatment was more effective than chlorhexidine or silver sulfadiazine at clearing superficial skin sites and skin lesions. The TTO preparations were effective, safe and well tolerated and could be considered in regimens for eradication of MRSA carriage (Dryden et al. 2004).
Assessor’s comment: this study shows the efficacy of a cream containing TTO 10% to clean skin lesions, wounds and ulcers.
TTO as an alternative topical decolonisation agent for
Clearance of MRSA was also investigated by Caelli et al. 2000 who conducted a pilot randomised controlled trial on 30 hospital inpatients aged between 32 and 82 years. Fifteen patients were randomised to the TTO treatment group consisting of 4% TTO nasal ointment and 5% TTO body wash. Fifteen patients were randomised to the standard treatment group consisting of 2% mupirocin nasal ointment and triclosan body wash. The TTO treatment combination appeared to perform better than the standard treatment of mupirocin and triclosan although the difference was not statistically significant.
Assessor’s comment: this is a pilot study with a too small number of patients.
Treatment of dandruff with 5% TTO shampoo (Satchell et al. 2002b).
The efficacy and tolerability of 5% TTO on mild to moderate dandruff vs. placebo was investigated in a randomised,
Assessor’s comment: this study shows efficacy and good tolerability of a 5% TTO shampoo in the treatment of dandruff.
Finally a case study describing a
Clinical Treatment of Ocular Demodecosis by Lid Scrub With Tea Tree Oil (Gao et al. 2007)
Gao et al. 2007, following an in vitro observation that Demodex is resistant to a wide range of antiseptic solutions but susceptible to TTO in a
Finally the results of a case study were described by Millar 2008 where 100% TTO was used for the topical treatment of multiple warts, due to human papilloma virus, on the hand of a seven year old girl. Salicylic acid (12%) and lactic acid (4%) was previously used on this condition but only resulted in the temporary removal of the warts and they recurred in greater numbers. After five days treatment with undiluted TTO, all warts were reduced in size. After a further 7 days, there was no evidence of warts and complete reepithelialisation of the area. No recurrence has been reported.
A summary of these studies is presented in Table 5.
Table 5: Clinical studies on humans
188.8.131.52. Clinical studies conducted with combinations containing TTO
Treatment of toenail onychomycosis with 2% butenafine and 5% TTO in cream
The objective of a randomised,
Assessor’s comment: this is randomised,
Reduction of Mouth Malodour and Volatile Sulphur Compounds in Intensive Care Patients using an Essential Oil Mouthwash
A study was carried out to explore the effect of an essential oil solution on levels of malodour and production of volatile sulphur compounds (VSC) in patients nursed in intensive care unit. Thirty two patients received 3 min of oral cleaning using an essential oil solution (mixture of TTO, peppermint, Mentha piperita and lemon, Citrus limon) on the first day, and benzydamine hydrochloride on the second day. Two trained nurses measured the level of malodour with a 10 cm visual analogue scale (VAS) and VSC with a Halimeter before (Pre), 5 min after (Post I) and 1 h following treatment (Post II). The level of oral malodour was significantly different following the essential oil session, and differed significantly between two sessions at Post I (p < 0.005) and Post II ( p < 0.001). Differences between the two sessions were significant (benzydamine hydrochloride, p < 0.001; essential oil, p < 0.001) in the level of VSC and significantly lower in the essential oil session than benzydamine hydrochloride at the Post II (p < 0.05). These findings suggest that mouth care using an essential oil mixture of diluted TTO, peppermint and lemon may be an effective method to reduce malodour and VSC in intensive care unit patients (Hur et al. 2007).
Assessor’s comment: These studies suggests that TTO, alone or in combination, probably due to its antimicrobial activity against oral microorganisms, can be useful to fight halitosis.
A Clinical Study: Melaleuca, Manuka, Calendula and Green Tea Mouth Rinse
A mouthwash (IND 61,164) containing essential oils and extracts from four plant species (Melaleuca alternifolia, Leptospermum scoparium, Calendula officinalis and Camellia sinensis) was tested. The study aimed to evaluate the safety, palatability and preliminary efficacy of the rinse. Fifteen subjects completed the Phase I safety study. Seventeen subjects completed the Phase II randomised placebo- controlled study. Plaque was collected, gingival and plaque indices were recorded (baseline, 6 weeks, and 12 weeks). The relative abundance of two periodontal pathogens (Actinobacillus actinomycetemcomitans, Tanerella forsythensis) was determined utilizing
but continued treatment. Differences between gingival index, plaque index or relative abundance of either bacterial species did not reach statistical significance when comparing nine placebo subjects with eight test rinse subjects. Subjects exposed to the test rinse experienced no abnormal oral lesions, altered vital signs, changes in liver, kidney, or bone marrow function. The authors concluded that larger scale studies would be necessary to determine the efficacy and oral health benefits of the test rinse (Lauten et al. 2005).
Assessor’s comment: a preliminary study on a small number of patients showing positive effects of mouth rinse containing TTO in combination with Manuka, Calendula and Green Tea.
An ex vivo, assessor blind, randomised, parallel group, comparative efficacy trial of the ovicidal activity of three pediculicides after a single application – TTO and lavender oil, eucalyptus oil and lemon TTO, and a “suffocation” pediculicide
Components to the clinical efficacy of pediculicides are: (i) efficacy against the crawling stages (lousicidal efficacy); and (ii) efficacy against the eggs (ovicidal efficacy). Lousicidal efficacy and ovicidal efficacy are confounded in clinical trials. A trial was specially designed to rank the clinical ovicidal efficacy of pediculicides. Eggs were collected,
Subjects with at least 20 live eggs of Pediculus capitis (head lice) were randomised to one of three
Seven hundred twenty two subjects were examined for the presence of eggs of head lice. Ninety two of these subjects were recruited and randomly assigned to: the “suffocation” pediculicide (n = 31); the
TTO/LO (n = 31); and the EO/LTTO (n = 30 subjects). The group treated with EO/LTTO had an ovicidal efficacy of 3.3% (SD 16%) whereas the group treated with TTO/LO had an ovicidal efficacy of 44.4%
(SD 23%) and the group treated with the “suffocation” pediculicide had an ovicidal efficacy of 68.3% (SD 38%).
Ovicidal efficacy varied substantially among treatments, from 3.3% to 68.3%. The “suffocation” pediculicide (68.3% efficacy against eggs) and the TTO/LO (44.4% efficacy against eggs) were significantly more ovicidal than EO/LTTO (3.3%) (P < 0.0001). The “suffocation” pediculicide and TTO/LO are also highly efficacious against the
Assessor’s comment: this study shows the efficacy of a combination of TTO with lavender oil as pediculicide.
4.3. Clinical studies in special populations (e.g. elderly and children)
No significant study has been performed in special populations.
Combination of Essential Oil of Melaleuca alternifolia and Iodine in the treatment of Molluscum Contagiosum in children.
A randomized double blinded placebo controlled three arm study, with intention to treat analysis, was performed in children for the treatment of molluscum contagiosum viral infection, which is a common benign childhood condition and is increasingly found as a sexual transmitted disease in adults. Fifty- three children (mean age 6.3+5.1 years) were randomised and treated with twice a day topical application of either a combination of 75% V/V TTO, canola oil and organically bound iodine in a proprietary formulation
4.4. Overall conclusions on clinical pharmacology and efficacy
TTO has been widely investigated in several clinical studies, which showed its efficacy as an antiseptic in various conditions.
Two RCT conducted in different countries support the ability of a 5% TTO gel to ameliorate lesions in the treatment of mild to moderate acne vulgaris (Enshaieh et al. 2007, Bassett et al. 1990). Another study conducted by Feinblatt (1960) is insufficient to show the efficacy of 100% TTO for the treatment of furunculosis (boils) despite the positive findings.
Clinical trials support the efficacy versus placebo of 50% and 25% TTO solutions in the treatment of interdigital tinea pedis (Satchell et al. 2002a) and the traditional use of a cream containing 10% TTO to improve symptoms of tinea pedis, but with no significant effects against the basic cause of the pathology (Tong et al. 1992).
A RCT showed that 100% TTO has an effect comparable to that of clotrimazole for the treatment of onychomycosis (Buck et al. 1994). Another RCT (Syed et al. 1999) did not show effects of TTO in onychomycosis, but information are lacking on the TTO concentration of the cream used in the study.
The use of TTO for the reduction of yeast and fungal infections was studied in various clinical trials conducted by different investigators, but in some studies information on the TTO content of the preparation used is not provided (Jandourek et al. 1998, Vazquez & Zawawi 2002) and in the other studies the number of patients or the study design cannot be considered supportive for the well- established use (Catalán et al. 2008, Belaiche 1985a, Belaiche 1985b).
Two RCT (Dryden 2004, Caelli et al. 2000) and one open controlled pilot study (Enshaieh et al. 2007, Bassett et al. 1990) conducted by different investigators showed that different concentrations (3.3- 10%) of TTO may influence positively wound healing through its antimicrobial activity and clearance of MRSA.
Clinical studies for the relief of the symptoms associated with a variety of oral cavity diseases or for the prevention of dental plaque growth support the use and antimicrobial activity of various TTO preparations (TTO commercial oral solutions, 6% TTO in aqueous gel, 0.34% TTO dispersed in milk and diluted with water, 2.5% TTO gel) but they were performed in a too small number of patients or showed no significant results (Jandourek et al. 1998, Vazquez & Zawawi 2002, Catálan et al. 2008, Groppo et al. 2002, Arweiler et al. 2000, Soukoulis & Hirsch 2004).
The clinical study on the use of TTO for the treatment of ocular Demodex (Gao et al. 2007) provides an interesting hypotesis for further investigation.
Clinical investigations on the use in vaginitis, cervicitis and endocervicitis gives only a very low level of evidence, insufficient to support the use of any formulation tested (Peña 1962, Blackwell 1991, Belaiche 1985a).
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
Most of the clinical studies in which skin irritations and allergies were demonstrated utilized 1% TTO preparations thus indicating that commonly used topical concentrations are likely to elicit allergic responses in susceptible individuals. Because of demonstrated systemic toxic effects, TTO should never be used internally. In 2005, Nielsen reviewed the reported toxicity of TTO and its major components and derived an estimated NOAEL for whole TTO of 330 mg/kg b.w. based on component data with a worst case scenario of 117 mg/kg b.w. (Nielsen 2005).
In a recent review, Hammer et al. (2006) reported the results of a number of publications on human patch testing with TTO. The results of these studies are summarised in the Table 6. Undiluted TTO has been reported to cause skin irritation in a small proportion of subjects (generally <5%). The irritation potential of TTO may be related to the age of the oil, with aged oils (presumably containing higher levels of peroxides and degradation products such as ascaridol) displaying a greater incidence of irritation.
Table 6: Skin irritation potential of TTO in humans
Greig et al. (2002) investigated the allergic reaction threshold using occluded patch testing in eight subjects previously confirmed to be sensitised to TTO. The reaction threshold concentrations for TTO were highly variable and were found to occur at 0.5% in one subject, while still being somewhat doubtful at 10% in one other subject. The lowest concentration able to induce a level
The elicitation studies generally demonstrate that the threshold for elicitation of allergic reactions in subjects sensitised to tea tree are >2% in the majority of sensitised subjects. Friedman & Moss (1985) suggested that when induction conditions are severe then the elicitation threshold is low. When induction occurs under mild conditions (as is the case with TTO) much higher exposures are required to elicit an allergic reaction and allergic reaction may not occur as long as exposure remains low.
A test on human volunteers using a low dose but highly maximized conditions failed to produce sensitisation reactions. A Kligman Human Maximization test was conducted on 1% TTO in petrolatum in 22 healthy male and female volunteers. The test material was applied under occlusion to the same site on the volar forearm of all subjects for 5
Clinical Diagnostic Studies
Two cases of contact dermatitis associated with the application of TTO have been reported by Apted (1991). The use of a vehicle and other aspects of the patch testing were not discussed however, positive patch tests were apparently obtained.
TTO used in the manufacture of the handwash was tested at the concentration in the product (3%) there was no reaction. When tested at 100% however, the 10 samples of TTO produced reactions on 2 occasions. Mild erythema and pruritus also occurred with 6 of the 10 oils on 1 occasion and with 4 on the other. On the 2nd occasion, one oil caused erythema and oedema. She also gave vesicular responses to 3 metals (potassium dichromate, cobalt chloride, and nickel sulfate) (Greig et al. 1999).
Two professional aroma therapists with suspected allergic contact dermatitis after having handled a variety of essential oils in the course of their work were patch tested with a total of 60 and 22 oils, respectively. Occluded patches with the oils including TTO at 2% diluted in white petrolatum, were applied for 48 hours. In one of these patients a positive (+++) reaction was observed to this oil. It is not clear how many other oils produced positive reactions in this patient (Dharmagunawardena et al. 2002).
Open and closed tests on TTO at different concentrations in water were conducted on a
A 64 year old woman with severe eczema of the ears, neck and upper chest following the use of Earex® ear drops was patch tested with the European standard, preservatives, cosmetics and the hairdressing series as well as her own products including Earex® ear drops which was positive. Further testing to the ingredients of Earex drops was conducted including 5% TTO to which she reacted. No further details provided (Stevenson & Finch 2003).
Tests were conducted on a
In a study on the frequency of sensitisation to TTO in consecutive patients, patch tests were conducted in 10 dermatological departments. TTO gave positive reactions in 16/794 patients when tested at 5% in diethylphthalate. Of these 16 reacting patients, 12/16 pts had used TTO in the past, mainly as a treatment for herpes simplex, eczema and onychomycosis. 4/16 subjects denied any contact to TTO. 7/16 subjects also showed a positive patch test to oil of turpentine at 10% in petrolatum (Treudler et al. 2000).
A crystalline compound was isolated from oxidized TTO identified as
trihydroxymenthane are formed. These degradation products are moderate to strong sensitizers and must be considered responsible for the induction of contact allergy developing in individuals having treated themselves with TTO (Harkenthal et al. 2000).
Seven male and female patients who had become sensitised to TTO were examined during a
Human Patch Tests
There are several human patch test studies with TTO reported in the literature. These have been summarised in Table 7. In total, patch tests have identified 151 subjects with positive reactions to TTO among 9367 subjects. The rate of allergic reactions varies from one study to another and is between 0.6% and 2.4% (mean 1.6%). The incidence and strength of the reactions was generally higher with oxidised TTO samples. Rutherford et al. (2007) concluded that oxidised TTO has a sensitising capacity three times stronger than fresh TTO. This is consistent with the finding of Hausen (Hausen et al 1999, Hausen 2004) and the relatively high rate of positive reactions observed in patch testing of a deliberately oxidised TTO sample (Coutts et al. 2002).
Nielsen (2005) concluded that the prevalence of positive findings following exposure of
While patch testing remains a useful diagnostic tool used by Dermatologists, it has some well recognised limitations. In most studies the researchers neglect to demonstrate clinical relevance of any positive patch testing results (Lachapelle 1997). Rutherford et al. (2007) observed positive patch tests with TTO in 41 out of 2320 patients. However when the patients were questioned regarding prior exposure to TTO products, only 17 out of 41 reactions were of possible clinical relevance, but none could be demonstrated to have probable or definite relevance. In other words, out of the 41 patients giving a positive patch test to TTO, 24 subjects had no identified prior exposure to TTO.
False positives in the patch tests are not uncommon. False positives can occur as a result of irritancy rather than a true allergic response, particularly as TTO can cause skin irritation both in animals (Beckmann & Ippen 1998) and humans (Aspres & Freeman 2003). Similarly, false positives may result from
It should also be noted that many of the Dermatological units obtain their samples of TTO from Chemotechnique Diagnostics have confirmed that their oil has been deliberately oxidised.
Table 7: Summary of human patch test studies
TTO may be regarded as only a weak allergen, where it has any sensitising potential. Thus, normal in- use exposure may induce a
5.2. Patient exposure
Aside from market presence and data from studies (see section 4), there are no concrete data concerning patient exposure.
5.3. Adverse events and serious adverse events and deaths
According to the data provided by ATTIA Ltd., since record keeping commenced in 1987, 23 adverse events for TTO have been recorded in Australia, corresponding to 0.8 incidents per year. As the estimated sale from 1987 is 25 million unit of bottle containing 100% TTO, the incidence appear
extremely low. Of the 23 events reported, 6 are of identified 100% TTO, 10 product are related to formulated product of less than 100% concentration of TTO, 7 are unidentified, no concentration is reported, but TTO is ‘suspected’.
Cutaneous and mucosal reactions
Adverse skin reactions like smarting pain, itch, and allergic reactions have been reported. The frequency is not known (Swedish leaflet).
It is likely that the irritation potential of tea tree oil may be related to the age of the oil, with aged oils (presumably containing higher levels of peroxides and degradation products such as ascaridol) displaying a greater incidence of irritation (Australian Government – Rural Industries Research and Development Corporation 2007).
Allergic skin reactions reported in Denmark are not common (≥1/1.000 and < 1/100).
For example Varma et al. reported a case of vaginal application of TTO and lavender oil in a patient with concurrent severe eczema (Halcón & Milkus 2004). Bhushan & Beck (1997) reported a case of blistering dermatitis where a wart paint containing TTO had been used for a period of 4 months. The man had a positive patch test to 1% TTO, while 50 controls were negative on testing with 1% and 5% aqueous tea tree solutions. The case patient was treated with topical corticosteroids and recovered with no known sequelae (Halcón & Milkus 2004).
At the Skin and Cancer Foundation (Sydney, NSW, Australia), three of 28 normal volunteers tested strongly positive to patch testing with 25% TTO. Following further patch testing with TTO constituents, all three patients reacted strongly to two preparations containing sesquiterpenoid fractions of the oil, which supports the indication that sesquiterpenes hydrocarbons may be potent allergens and that the allergenic fraction may be reduced by removal of sesquiterpenes by fractionation and selection of genotypes with lower sesquiterpene contents. These adverse skin reactions were classified as allergic reactions rather than irritant, because erithema with market dermal oedema and itching appeared in the absence of the epidermal reaction usually seen in an irritant patch test reaction, where scaling and wrinkling of epidermis is evident (Rubel et al. 1998). Due to the widespread use of TTO, especially in Australia, prevalence rate for allergic contact dermatitis reactions are difficult to estimate and it seems that in Australia the prevalence is higher than in other Countries, such as for instance United States, due to the previous exposure to TTO (Crawford et al. 2004).
In the evaluation of patients with allergy to TTO it should be considered that they could have been exposed to several other essential oils with common chemical constituents known to be sensitizers (Crawford et al. 2004). Moreover, whereas fresh TTO seems to possess only a weak sensitizing potential, it is well known that oxidized constituents of TTO increase their ability to act as allergens (Harkenthal et al. 2000, Carson & Riley 2001, Norwegian Food Safety Authority 2012).In ten separate human patch test studies involving almost 9400 people, an average of 1.6 per cent of people showed some allergic reaction to TTO. It is known, however, that in several of the patch test studies degraded
tea tree oil was used to test for sensitisation. The incidence of sensitisation in the patch test studies may therefore be an overestimate due to peroxides and their degradation products in the oils tested (Australian Government – Rural Industries Research and Development Corporation 2007).
The studies generally have demonstrated that the TTO concentration at which an allergic response may be elicited is greater than 2% in the majority of sensitised subjects. Data collected by six companies that supply TTO products shows that the incidence of adverse reports is dependent on the concentration of oil, with most of the reports occurring with undiluted TTO. Overall, with records from more than 10 years covering 38 million products – many of which were full strength or high concentration tea tree oil, the incidence of adverse events reported for all tea tree
Several cases of human TTO poisoning have been reported, mostly involving the ingestion of modest volumes (N
It has been reported the case of a patient comatose for the first 12 h and then
Ingestion of significant quantities of TTO has been described in a
Accidental poisonings following TTO ingestion demonstrate that at relatively high doses, TTO causes Central Nervous System depression and muscle weakness (Jacobs & Hornfeldt 1994, Del Beccaro 1995, Morris et al. 2003, Elliott 1993, Villar et al. 1994, Seawright 1993). However, these symptoms had generally resolved within 36 hours.
The 29th Annual Report of the American Association of Poison Control Centers ’ National Poison Data System (NPDS) analyzed the data obtained in the year 2011 from
5.4. Laboratory findings
No data available.
5.5. Safety in special populations and situations
In vitro pharmacological interactions between TTO and conventional antimicrobials
(ciprofloxacin⁄amphotericin B) when used in combination were investigated. Interactions of TTO when combined with ciprofloxacin against Staphylococcus aureus indicate mainly antagonistic profiles. The interactions of TTO with amphotericin B indicate mainly antagonistic profiles when tested against Candida albicans. The authors concluded that the predominant antagonistic interactions noted, suggest that therapies with TTO should be used with caution when combined with antibiotics (van Vuuren et al. 2009).
Safety related to the use in pregnancy and lactation is unknown and therefore the use is not to be recommended.
5.5.1. Use in children and adolescents
The use in children under 12 years of age has not been established due to lack of adequate data.
Hypersensitivity to the active substance or to colophony as TTO
5.5.3. Special Warnings and precautions for use
Not to be used orally or as inhalation. Not to be used in eyes or in ears.
Not to be swallowed in case of use as a gargle or mouth wash.
If a rash develops discontinue use.
If fever or signs of exacerbating skin infection are observed, a doctor or a qualified health care practitioner should be consulted.
In cases of severe acne or for the eradication of fungal infection a doctor or a qualified healthcare practitioner shall be consulted.
If symptoms worsen during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
5.5.4. Drug interactions and other forms of interaction
5.5.5. Fertility, pregnancy and lactation
No fertility data available.
Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the use during pregnancy and lactation is not recommended.
None reported for the cutaneous use.
Accidental ingestion may cause central nervous system depression and muscle weakness. However, in adults these symptoms generally resolve within 36 hours (See “Acute intoxications” in section 5.3)
If ingestion occurs, the patient should be monitored and standard supportive treatment applied as required.
In children, ingestion of tea tree oil is a medical emergency requiring immediate hospital treatment and respiratory support.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effect on the ability to drive and use machines have been performed.
5.5.8. Safety in other special situations
Previous exposure to TTO or to several other essential oils with common chemical constituents known to be sensitizers may increase the possibility of allergic contact dermatitis reactions (Crawford et al. 2004).
Whereas fresh TTO seems to possess only a weak sensitizing potential, oxidized constituents of TTO increase their ability to act as allergens and as irritating agents (Harkenthal et al. 2000, Carson & Riley 2001, Norwegian Food Safety Authority 2012, Australian Government – Rural Industries Research and Development Corporation 2007). See also section Allergic reactions in 5.3 Adverse events and serious adverse events and deaths.
5.6. Overall conclusions on clinical safety
Clinical studies and traditional use show that
Reported adverse events were minor and mostly limited to local irritation. A case of blistering dermatitis has been reported with a wart paint containing TTO used for a period of 4 months.
There is some evidence that 100% TTO can cause allergic reactions in some patients. The rate of allergic reactions reported in the literature in various patch testing studies ranges between 0.6% and 2.4% (mean 1.6%). The incidence and strength of the reactions is generally higher with oxidised TTO samples. Proper storage and handling of TTO and its formulated products are needed to avoid the development of these
Oral use results in poisoning. Accidental ingestion of
TTO was not genotoxic in in vivo mouse micronucleus test (up to 1750 mg/kg). Ames test data are incomplete.
Tests on reproductive toxicity and on carcinogenicity have not been performed.
6. Overall conclusions
Despite several studies show that the antiseptic properties of TTO in various conditions no herbal medicinal product used in clinical trials with positive outcome is currently authorised in Europe for a least 10 years and therefore the
TTO has been used as a traditional medicine for more than 30 years in Europe and worldwide, particularly in Australia for a number of indications. Some of them are supported by pharmacological or clinical data which confirm the antibacterial activity, antifungal activity, antiviral activity and antiprotozoal activity under controlled conditions. TTO has a broad spectrum antimicrobial activity with little evidence for inducing tolerance and resistance. TTO products are a useful addition to the range of
skin hygiene and protection products. This type of product has a known safety profile with a long history of traditional medicinal use.
Overall, a monograph on Melaleuca alternifolia (Maiden and Betch) Cheel, Melaleuca linariifolia Smith, Melaleuca dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum radix is established with the following preparations and therapeutic indications.
1)Traditional herbal medicinal product for treatment of small superficial wounds and insect bites: liquid preparation containing 0.5% to 10% of essential oil to be applied to the affected area
2)Traditional herbal medicinal product for treatment of small boils (furuncles and mild acne): oily liquid or
3)Traditional herbal medicinal product for the relief of itching and irritation in cases of mild athlete´s foot: oily liquid or
4)Traditional herbal medicinal product for symptomatic treatment of minor inflammation of oral mucosa: 0.17 – 0.33 ml of TTO to be mixed in 100 ml of water for rinse or gargle several times daily for symptomatic treatment of minor inflammation of oral mucosa.
Adverse skin reactions including smarting pain, mild pruritus, burning sensation, irritation, itching, stinging, erythema, oedema, allergic reactions and allergic contact dermatitis have been reported. The frequency is not known. Sensitization is more likely to appear with oxidized TTO and therefore human adverse reactions may be minimized by reducing exposure to aged, oxidized oil. Proper storage and handling are needed to avoid the formation of oxidation products which have greater potential for skin sensitisation. Thus TTO should be in
There is insufficient data to support the safety of TTO during pregnancy and lactation or in children under 12 years and therefore the use in this population groups is not recommended as a precautionary measure.
The data on safety are considered sufficient to establish a list entry for the above mentioned preparations and indications.