Oromucosal use or cutaneous use
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- Bu səhifədəki naviqasiya:
- Indication Referenc e Method Participants Posology Interventions
- Clinical studies conducted with combinations containing TTO: Mycosis
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- Table 5: Skin irritation potential of TTO in humans Test substance No of subjects Results Study
- Table 12: Summary of human patch test studies Test substance Number of subjects Results Study
- 5.2. Patient exposure
- 5.4. Laboratory findings 5.5.
- 5.6. Overall conclusions on clinical safety
- Annex List of references
Participants
Posology Interventions Outcomes Comments ml of control solution and standard dentifrice. Week 3: 1 min mouthwashes for 7 days using 10 ml of one of the treatment solutions (G1, G2 and G3) 30 mins after the last tooth brushing of the day. Week 4 and 5: treatment discontinued 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. Receive either 6% TTO in aqueous gel base or placebo gel organisms was observed only for garlic and TTO during the two consecutive weeks (4
th and 5
th ). 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. Prevention of dental plaque growth
Arweiler et al. 2000 Three arm cross over study,
non- randomise d 8 subjects 23-34 years Rinse twice daily for 2 minutes with 15ml of solution using no mechanical brushing warm water
Week 1: water (placebo) Week 2: 0.1% Chlorhexidine (positive control) Week 3: 0.34% TTO dispersed in milk and diluted with water TTO reduced neither the plaque index nor the plaque area relative to the placebo, although reduction of vital bacteria compared to placebo. Chlorhexidine significantly reduced plaque area Adverse reactions: All subjects complained about intensive and unpleasant taste of TTO. Study may have dropped off particularly as in 3 rd
week patients had to mix the TTO solution themselves. No significant efficacy of TTO was detected on the amount of vital bacteria although there was a reduction compared to placebo.
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Indication Referenc e Method Participants Posology Interventions Outcomes Comments Effect on plaque and chronic
gingivitis Soukoulis & Hirsch 2004
3 arm, double-
blind, longitudin al, non- cross-over study. Gels
randomly distributed 58 subjects recruited with 49 subjects evaluated (24F/25M; 18-60 years) with moderate to severe gingivitis, non- smokers. For 8 weeks, gel applied along entire length of toothbrush and twice daily used as dentifrice in contact with gingival tissues adjacent to teeth for min of 2 mins. No rinsing, eating, drinking for 30 mins following gel application. Treatment: 2.5% TTO gel Positive control: 0.2%
chlorhexidine gel Negative control: Placebo gel TTO had significant reduction in Papillary Bleeding Index (PBI) and Gingival Index (GI) but did not reduce plaque scores which tended to increase towards end of study No adverse reactions
Clearance of MRSA colonisation Dryden et
Randomis
ed controlled trial; Balanced randomisa tion using software allocation 236 colonised with MRSA (224 evaluable) Standard treatment: 114 patients TTO treatment: 110 patients Nasal application 3 times per day for 5 days; Body wash applied all over body at least once per day for 5 days; Application to skin lesions, wounds and ulcers once per day for 5 days Standard treatment: Mupirocin 2% to anterior nares; chlorhexidine gluconate 4% soap over body; silver sulfadiazine 1% cream to skin lesions, wounds, leg ulcers. TTO Treatment: 10% TTO cream to anterior nares; 5% TTO body wash over body; 10% TTO cream to skin No significant difference between treatments for clearing MRSA. Mupirocin significantly more effective at clearing nasal carriage. TTO more effective at clearing superficial skin sites and skin lesions. TTO preparations were safe and well tolerated.
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Indication Referenc e Method Participants Posology Interventions Outcomes Comments lesions, wounds, leg ulcers and as alternative to body wash for axillae, groins
Clearance of colonised or infected MRSA
Caelli et al. 2000 Randomiz
ed, controlled pilot study 30 hospital inpatients colonised or infected with MRSA (15 in each study arm; 32-82 years for TTO group) Minimum three days treatment 4% TTO nasal ointment + 5% TTO body wash vs. Standard treatment: 2% mupirocin nasal ointment + triclosan body wash TTO; 33% cleared, 20% chronic, 47% incomplete; for standard treatment 13% cleared, 53% chronic, 33% incomplete (not significant) Adverse reactions: No adverse events. Mild swelling of nasal mucosa to acute burning reported for TTO nasal ointment (number not reported). One patient in standard treatment reported skin tightness Pilot study. Small number of patients Treatment of mild to
moderate dandruff Satchell et
RCT,
investigat or blinded 126 patients with mild to moderate dandruff (> 14 yrs); 63 TTO group, 62 placebo group For 4 weeks, wash hair daily, leaving shampoo in for 3 mins before rinsing 5% TTO shampoo; placebo shampoo Whole scalp lesion score significantly improved in TTO group (41.2%) compared to placebo group (11.2%). Total area of involvement score, total severity score and itchiness and greasiness had statistically significant improvement in TTO group compared to placebo.
Treatment of ocular Demodex Gao et al. 2007 Case
series 11 patients (6F/6M: 60.2±11.6yrs) with ocular Demodex not using topical or systemic anti- inflammatory and antibacterial Weekly lid scrub: 3 times a cotton tip wetted in 50% TTO to scrub lash roots from one end to other as 1 stroke. 6 strokes applied. Dry Weekly lid scrub: 50% TTO diluted with mineral oil Daily lid scrub: 0.5ml TTO shampoo mixed with tap water Demodex count dropped to zero for 2 consecutive visits in less than 4 weeks in 8 patients. 10/11 patients showed different degrees of symptomatic relief and notable reduction of inflammatory signs. Significant visual improvement in 6 of 22 eyes was associated with stable Small number of patients
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Indication Referenc e Method Participants Posology Interventions Outcomes Comments medications before TTO scrub. cotton tip used to remove excess 5 mins later. Reapplication after 5 mins. Daily lid scrub: With eyes closed, lids massaged with TTO shampoo and water for 3-5 minutes, medium pressure then rinsed with water. Twice daily for 1 month, then once daily. (Kato Sales, Florida). lipid tear film
Adverse reactions: The weekly office lid scrub with 50% TTO resulted in mild irritation in 6 patients and moderate irritation in 3 patients. Patients’ symptoms were relieved, ocular surface inflammation resolved and lipid tears film stability improved. Treatment of various
gynaecologica l conditions Peña 1962
Open, uncontroll ed 96 trichomonal vaginitis, 4 C. albicans vaginitis, 20 nulliparous cervicitis from Trichomonas vaginalis, 10 chronic endocervicitis vaginal canal washed for 30 sec then tampon left in place for 24 hours – weekly treatment Treatment: TTO 40% in solution Cured and healed cervicitis in 10 patients after 4 weekly treatments Effective concentration found to be 20% solution of TTO Adverse reactions: No irritation, mild drying effect.
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Indication Referenc e Method Participants Posology Interventions Outcomes Comments Treatment of vaginal discharge typical of anaerobic vaginosis Blackwell 1991 2 1
Case study
40 year old woman 5 day application in form of TTO vaginal pessaries Vaginal pessary containing TTO in a vegetable oil base
Vaginal secretions normal
Vaginal infections associated with C. albicans Belaiche 1985a Open,
non- controlled
90 days daily application in form of a TTO vaginal capsule every night before sleeping; Vaginal capsule containing TTO 0.2 g 23 out of 27 patients showed a complete cure. Remaining patients had moderate improvement of discharge. C. albicans disappeared in 21 patients 4 of them had to continue the treatment due to the persistence of leucorrhea. Biological examinations showed the disappearance of C. albicans in 21 patients Adverse reactions: One out of 28 patients experienced vaginal burning sensation and withdrew from study.
Treatment of warts on finger
Millar & Moore
2008 Case
study Seven yr old girl TTO applied with sterile cotton wool swabs to each lesion, each evening after bathing and prior to sleep. 100% TTO. Previously used salicylic acid (12%w/w) and lactic acid (4% w/w) resulting in temporary removal of warts but they recurred in greater numbers After 5 days, all warts reduced in size. After a further 7 days, no evidence of warts and complete re-epithelialisation. No recurrence to date.
1 Not peer reviewed
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TTO – Tea Tree Oil RCT – Randomised Controlled Trial F – female M – male
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Clinical studies conducted with combinations containing TTO: Mycosis Treatment of toenail onychomycosis with 2% butenafine and 5% TTO in cream The objective of a randomised, double-blind, placebo-controlled study was to examine the clinical efficacy and tolerability of 2% butenafine hydrochloride and 5% TTO incorporated in a cream to manage toenail onychomycosis in a cohort. Sixty outpatients (39 M, 21 F) aged 18–80 years (mean 29.6) with 6–36 months duration of disease were randomised to two groups (40 and 20), active and placebo. Patients were shown how to apply the trial medication at home three times a day topically for 7 days. After 16 weeks, 80% of patients using medicated cream were cured, as opposed to none in the placebo group. Four patients in the active treatment group experienced subjective mild inflammation without discontinuing treatment. During follow-up, no relapse occurred in cured patients and no improvement was seen in medication-resistant and placebo participants (Syed et al. 1999).
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
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
probes. ANCOVA was used at the p = 0.05 level of significance. Two subjects reported a minor adverse event. One subject withdrew from the study. Several subjects objected to the taste of the test rinse
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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).
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, pre-treatment and post-treatment, from subjects with different types of hair, different coloured hair and hair of different length. Subjects with at least 20 live eggs of Pediculus capitis (head lice) were randomised to one of three treatment-groups: a TTO and lavender oil pediculicide (TTO/LO); an eucalyptus oil and lemon TTO pediculicide (EO/LTTO); or a “suffocation” pediculicide. Pre-treatment: 10 to 22 live eggs were taken from the head by cutting the single hair with the live egg attached, before the treatment (total of 1,062 eggs). Treatment: The subjects then received a single treatment of one of the three pediculicides, according to the manufacturers’ instructions. Post-treatment: 10 to 41 treated live eggs were taken from the head by cutting the single hair with the egg attached (total of 1,183 eggs). Eggs were incubated for 14 days. The proportion of eggs that had hatched after 14 days in the pre- treatment group was compared with the proportion of eggs that hatched in the post-treatment group. The primary outcome measure was % ovicidal efficacy for each of the three pediculicides. 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 crawling-stages. Thus, the “suffocation” pediculicide and TTO/LO should be recommended as first line treatments (Barker & Altman 2011). Assessor’s comment: this study shows the efficacy of a combination of TTO with lavender oil as pediculicide. 4.2.3. Clinical studies in special populations (e.g. elderly and children) No significant study has been performed in special populations
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4.3. 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 (Catalan 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, Catalan 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) provide 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
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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 5. 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.
Ten different samples of undiluted TTO applied under occlusive conditions for 48 hours. 219
The prevalence of marked irritancy to 100% TTO ranged from 2.4% to 4.3%. Any level of irritancy (mild and marked) ranged from 7.2 to 10.1%. Greig et al. 1999 Undiluted TTO and 25% TTO in cream, 25% TTO in ointment, 25% TTO in gel, 5% TTO in cream and 5% TTO + 5% synergist in cream. Applied under occlusive conditions for 48 hours. 311 Subjects were treated daily for a three week period during the induction phase of a sensitisation study. Mean irritancy score of 0.25 for undiluted TTO. The incidence of irritation with undiluted TTO was 5.5%. Formulations containing 25% or lower of TTO were non-irritating. Altman 1991 Aspres & Freeman 2003 TTO at 10% (in pet.) and 5% in a commercial lotion and 4 other formulations. Applied under occlusive conditions for 48 hours. 217 10% TTO (in pet.) did not cause irritation. The 5% lotion caused irritation in 44 subjects (20%). The 4 formulations tested on 160 subjects caused 5 weak reactions (3.1%). All test samples contained the same source of TTO. The other components in the formulation influence the incidence and severity of irritation. Veien et al. 2004
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 1-3 response in the other volunteers fell between these: 1% (one person), 2% (three people) and 5% (two people). In the same subjects, 11 individual components of TTO were also tested. The TTO components that caused reactions in pre-sensitised individuals were p-cymene, terpinolene, α-terpinene and γ- terpinene. The authors commented that they had concerns that the oil samples may have become oxidised within the duration of the study. Elicitation
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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. Induction 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 alternate-day 48-hour periods. The patch site was pre- treated for 24 hours with 5% aqueous SLS under occlusion for the initial patch only. Following a 10-14 day rest period, a challenge patch of the test material was applied to a fresh site for a 48-hour period under occlusion. Prior to challenge, 5% SLS was applied to the test site for 30 minutes under occlusion on the left side of the back whereas the test materials were applied without SLS treatment on the right side. A fifth site challenged with petrolatum served as a control (RIFM 1802). Clinical Diagnostic Studies Two cases of contact dermatitis associated with the application of TTO have been reported by Apted et al. (1991). The use of a vehicle and other aspects of the patch testing were not discussed however, positive patch tests were apparently obtained. A TTO hand-wash was provided for staff in the intensive care unit of a major hospital. A 45-year-old nurse developed raised red lesions at sites of contact within 5 min of application. This reaction occurred on 3 separate occasions, the lesions persisting for at least 36 h. Previously, she had regularly used a shampoo containing TTO at home without adverse effects. Patch testing was performed (using IQ chambers) on 3 separate occasions over several months, firstly on the outer upper arm and then on the upper back. There was no response to 10 different samples of 10% TTO tested at 10%. When the 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). A 46-yr-old man applied pure TTO to a superficial abrasion on his left leg. Within a few days, the treated area became red and itchy. Applications of TTO were stopped, but the eruption became generalized, with urticarial plaques and atypical targets. A skin biopsy from a target-like lesion showed a spongiotic dermatitis. The patient then developed dermatitis under an Elastoplast® dressing used on the biopsy site. The lesions cleared with oral prednisone. Five months later, patch tests were done with the North American standard series and with TTO, hydroabietyl alcohol, abietic acid and turpentine peroxides. The patient was also tested to a drop of his own, old TTO. At day 4, the patient reacted to both TTO samples, with a stronger reaction to his own than to the fresh preparation. Positive reactions to colophony, hydroabietyl alcohol and Balsam of Peru were also noted (Khanna et al. 2000).
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Open and closed tests on TTO at different concentrations in water were conducted on a 74-year-old man after the occurrence of blistering dermatitis from the use of a TTO containing wart paint. The patient reacted to a concentration of 1% at the closed site and at 100% at the open site. No effects were seen in 50 controls at 1% or 5% (Bhushan & Beck 1997). 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 Euopean 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 33-year-old woman after the occurrence of dermatitis from the use of undiluted TTO. Finn chambers and Scanpor tape were used. Reactions were assessed day 3. A positive reaction was observed (Selvaag et al. 1994). 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 R, et al. 2000). A crystalline compound was isolated from oxidized TTO identified as 1,2,4-trihydroxymenthane by mass spectroscopy. Fifteen patients sensitive to TTO were tested epicutaneously with seven typical constituents of and two degradation products of TTO. Positive effects, 1,2,4-trihydroxymenthane was shown to be an important allergen as well as ascaridol, another degradation product of TTO. Besides 1,2,4-trihydroxymenthane and ascaridol, alpha-phellandrene, alpha-terpinene, and terpinolene were found to give positive reactions as well. The authors noted that TTO kept under practical daily conditions undergoes photo-oxidation within a short time, leading to the formation of peroxides and subsequently to the generation of degradation products. Compounds like ascaridol and 1,2,4- trihydroxymenthane are formed. These degradation products are moderate to strong sensitisers 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 3-year period in an outpatient dermatology clinic. They had been treating pre-existing skin conditions, which included foot fungus, dog scratches, "pimples" of the legs, insect bites and hand rashes. All patients initially had an eczematous dermatitis consisting of ill-defined plaques of erythema, oedema and scaling. In 3 patients vesciculation was also present. The patients were patch tested on their upper backs with Finn Chambers to a 1% solution TTO and solutions of 11 constituent compounds. The application time was 48 hours. Reactions were assessed at 50 hours. Control patches of ethanol, olive oil and a blank Finn Chamber were also applied. A total of 20 control patients with unrelated dermatoses were patch tested to the 1% TTO solution and 10 control patients were patch tested to solutions of 11 constituent compounds. 7 control patients were patch tested to the higher concentrations of the constituent compounds. The patch test vehicle was ethyl alcohol in all cases. All seven patients reacted to TTO at 1%. No effects were seen in 20 control subjects. Positive reactions were also seen with d-limonene, α-terpinene, aromadendrene, terpinen-4-ol, α-phellandrene, p- cymene, α-pinene and terpinolene (Knight & Hausen 1994). Human Patch Tests There are several human patch test studies with TTO reported in the literature. These have been summarised in Table 12. In total, patch tests have identified 151 subjects with positive reactions to
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
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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 pre-sensitised dermatological patients in the clinical studies to TTO is generally around 0.4%-0.6% (Hammer et al. 2006). Thus, TTO has only a weak sensitising potential among pre-sensitised people, though the present known number may be an overestimate due to problems with aged TTO (unknown peroxide levels) and selection bias in some clinical studies. 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 cross-reactions where patients react to a substance which is not the substance which initially induced the allergic state. TTO is an essential oil with components that are also found in other natural substances. The phenomenon of “excited skin syndrome” has also been suggested to contribute to false positives (Maibach In Ring & Burg 1981). This phenomenon occurs when a subject shows multiple positive patch tests which cannot be reproduced when the subject is retested. It should also be noted that many of the Dermatological units obtain their samples of TTO from Chemotechnique Diagnostics3. Chemotechnique Diagnostics have confirmed that their oil has been deliberately oxidised.
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
EMA/HMPC/320932/2012 Page 69/73
Table 12: Summary of human patch test studies Test substance Number of subjects Results Study Products containing TTO were tested concentrated or diluted 1216 Seven patients (0.6%) with an allergic contact dermatitis due to TTO were identified. Two of them also exhibited delayed type IV hypersensitivity towards fragrance-mix or colophony Fritz et al. 2001 TTO formulations ranging from 5 to 100% 28 21-day RIPT resulted in 3 subjects (11%) showing allergic reactions to mixtures containing oxidised oils Southwell et al. 1997 Undiluted TTO and 25% TTO in cream, 25% TTO in ointment, 25% TTO in gel, 5% TTO in cream and 5% TTO + 5% synergist in cream
311 Three (1%) subjects were sensitised to TTO. Aspres & Freeman 2003 Ten different samples of undiluted TTO. 219 Five subjects (2.3%) exhibited confirmed sensitisation reactions. Greig et al. 1999 Undiluted TTO, and 5%, 1% and 0.1% of TTO in petrolatum Stabilised by microencapsulation 725
Six subjects (0.8%) gave a definite reaction with undiluted TTO. Another 37 subjects presented equivocal to minimal reactions. Serial dilutions were positive until 1% concentration (one subject). There were no reactions at 0.1% concentration. The authors concluded that the sensitisation potential to TTO was “poor”. Lisi et al. 2000 Undiluted TTO which was deliberately oxidised 550 Thirteen (2.4%) subjects with 4 considered of relevance and 5 with possible relevance. Coutts et al. 2002 (Abstract only)
TTO may be regarded as only a weak allergen, where it has any sensitising potential. Thus, normal in- use exposure may induce a sub-clinical allergic state which will not be elicited under normal exposure conditions but may become apparent only under occlusive patch test conditions. This is supported by the absence of any clearly documented epidemic of consumer complaints associated with TTO containing cosmetic products. This hypothesis has been proposed to explain some of the allergic responses seen in clinical studies for some fragrance ingredients (Hostynek & Maibach 2004). Furthermore, the relatively high volatility of TTO and the low dermal penetration may also explain the difference in the result obtained with diagnostic patch testing, where the dermal penetration is expected to be increased due to occlusion, and the lack of consumer complaints as demonstrated by company data.
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
EMA/HMPC/320932/2012 Page 70/73
5.2. Patient exposure No data available. 5.3. Adverse events and serious adverse events and deaths Allergic reactions Very rarely allergic dermatitis may occur during the use of the essential oil without any dilution. Allergic skin reactions reported in Denmark are not common (≥1/1.000 and < 1/100). At the Skin and Cancer Foundation (Sydney, NSW, Australia), three of 28 normal volunteers tested strongly positive to patch testing with TTO. Following further patch testing with TTO constituents, all three patients reacted strongly to two preparations containing sesquiterpenoid fractions of the oil (Rubel et al. 1998).
Several cases of human TTO poisoning have been reported, mostly involving the ingestion of modest volumes (N 10-25 ml) of oil. In two cases, ingestion of TTO resulted in what appeared to be systemic contact dermatitis (Carson & Riley 1998). It has been reported the case of a patient comatose for the first 12 h and then semi-conscious for the following 36 h after ingestion of approximately half a cup of TTO. Other cases reported that two children who ingested less than 10 ml TTO became ataxic and drowsy or disorientated. Both were treated supportively and recovered fully without further complications (Carson & Riley 1998). Ingestion of significant quantities of TTO has been described in a 17-month-old male who ingested less than 10 ml of the pure oil (100%) and developed ataxia and drowsiness (Halcon & Milkus 2004). 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. Cutaneous and mucosal reactions Adverse skin reactions like smarting pain, itch, and allergic reactions have been reported. The frequency is not known (Sweden). Burn-like skin reaction has been reported in Denmark. The frequency is rare (<1/1.000). There have been case reports of dermal sensitivity, contact dermatitis related to TTO. Varma et al. reported a case of vaginal application of TTO and lavender oil in a patient with concurrent severe eczema (Halcon & 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 (Halcon & Milkus 2004). It has been reported the case of a 18 year female patient in whom linear Immunoglobulin A (IgA) disease appears to have been precipitated by a contact reaction to TTO. Linear IgA disease is a rare acquired subepidermal blistering disorder, characterized by basement membrane zone IgA deposition (Perrett et al. 2003).
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
EMA/HMPC/320932/2012 Page 71/73
Not to be used orally use or as inhalation. Not to be used in eyes, ears or in the mouth. The patient should be advised to consult a doctor in cases with severe acne. To decrease the risk for side effects it is important to follow the instruction to dilute the product before use.
(ciprofloxacin⁄amphotericin B) when used in combination were investigated. Interactions of TTO when combined with ciprofloxacin against S. aureus indicate mainly antagonistic profiles. The interactions of TTO with amphotericin B indicate mainly antagonistic profiles when tested against C. 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. 5.6. Overall conclusions on clinical safety Clinical studies and traditional use show that short-term use (not more than 1 month) of diluted TTO on skin or mucosa is safe, but it is not suitable to be used in the eye or ear. 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 should avoid the development of these by-products and reduce the risk of skin irritation and sensitisation in sensitive individuals. Oral use results in poisoning. Accidental ingestion of 10-25 ml, demonstrates that at these relatively high doses, TTO causes Central Nervous System depression and muscle weakness. However, these symptoms had generally resolved within 36 hours. 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.
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 since a least 10 years and therefore the “well-established medicinal use” cannot be supported. However results of clinical studies reinforce the plausibility of the traditional uses of TTO preparations. 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
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
EMA/HMPC/320932/2012 Page 72/73
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 use. Overall, a monograph on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M.
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 on the affected area 1-3 times daily. 2) Traditional herbal medicinal product for treatment of small boils (furuncles and mild acne): oily liquid or semi-solid preparations containing 10% of essential oil, to be applied on the affected area 1-3 times daily or 0,7-1 ml of essential oil stirred in 100 ml of lukewarm water to be applied as an impregnated dressing to the affected areas of the skin. 3) Traditional herbal medicinal product for the relief of itching and irritation in cases of mild athlete´s foot: oily liquid or semi-solid preparations containing 10% of essential oil, to be applied on the affected area 1-3 times daily. 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 like smarting pain, mild pruritus, burning sensation, irritation, itching, stinging, erythema, oedema and allergic reactions have been reported. The frequency is not known. Burn-like skin reaction has been reported. The frequency is rare (<1/1.000). 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.
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum EMA/HMPC/320932/2012 Page 73/73 Document Outline
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