ml of control
Week 3: 1 min
mouthwashes for 7
days using 10 ml of
one of the
(G1, G2 and G3) 30
mins after the last
tooth brushing of
Week 4 and 5:
chlorhexidine in a
G2 - 2.5% solution
of a garlic (Allium
1:1; and G3 -
0.2% TTO in
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
). 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.
8 subjects 23-34 years Rinse twice daily for
15ml of solution
Week 2: 0.1%
Week 3: 0.34%
TTO dispersed in
milk and diluted
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
Adverse reactions: All subjects
complained about intensive and
unpleasant taste of TTO. Study may
have dropped off particularly as in 3
efficacy of TTO
on the amount
of vital bacteria
was a reduction
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
58 subjects recruited
with 49 subjects
18-60 years) with
moderate to severe
For 8 weeks, gel
applied along entire
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
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
236 colonised with
MRSA (224 evaluable)
TTO treatment: 110
Nasal application 3
times per day for 5
Body wash applied
least once per day
for 5 days;
Application to skin
lesions, wounds and
ulcers once per day
for 5 days
Mupirocin 2% to
gluconate 4% soap
over body; silver
cream to skin
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
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum
leg ulcers and as
alternative to body
wash for axillae,
30 hospital inpatients
colonised or infected
with MRSA (15 in each
study arm; 32-82
years for TTO group)
4% TTO nasal
ointment + 5%
TTO body wash vs.
TTO; 33% cleared, 20% chronic, 47%
13% cleared, 53% chronic, 33%
incomplete (not significant)
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
126 patients with mild
to moderate dandruff
(> 14 yrs); 63 TTO
group, 62 placebo
For 4 weeks, wash
shampoo in for 3
mins before rinsing
5% TTO 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
Gao et al.
11 patients (6F/6M:
ocular Demodex not
using topical or
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:
with tap water
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
cotton tip used to
remove excess 5
With eyes closed,
lids massaged with
TTO shampoo and
water for 3-5
rinsed with water.
Twice daily for 1
month, then once
lipid tear film
Adverse reactions: The weekly office lid
irritation in 6 patients and moderate
irritation in 3 patients. Patients’
symptoms were relieved, ocular surface
inflammation resolved and lipid tears
film stability improved.
4 C. albicans vaginitis,
washed for 30 sec
then tampon left in
place for 24 hours –
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
5 day application in
form of TTO vaginal
in a vegetable oil
90 days daily
of a TTO vaginal
capsule every night
containing TTO 0.2
23 out of 27 patients showed a
complete cure. Remaining patients had
moderate improvement of discharge. C.
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
One out of 28 patients experienced
vaginal burning sensation and withdrew
Seven yr old girl
TTO applied with
sterile cotton wool
swabs to each
bathing and prior to
lactic acid (4%
w/w) resulting in
of warts but they
recurred in greater
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.
Not peer reviewed
TTO – Tea Tree Oil
RCT – Randomised Controlled Trial
F – female
M – male
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).
Assessor’s comment: this is randomised, double-blind, placebo-controlled study showing efficacy of a
combination of TTO (5%) with 2% butenafine hydrochloride incorporated in a cream in management of
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,
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).
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 digoxigenin-labelled DNA
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
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller
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, 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%
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).
No significant study has been performed in special populations
Assessment report on Melaleuca alternifolia (Maiden and Betch) Cheel, M. linariifolia Smith, M. dissitiflora F. Mueller
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
Clinical studies for the relief of the symptoms associated with a variety of oral cavity diseases or for
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,
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 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
Table 5: Skin irritation potential of TTO in humans
No of subjects Results
Ten different samples of
undiluted TTO applied under
occlusive conditions for 48
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
Subjects were treated daily for a three
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.
Aspres & Freeman
TTO at 10% (in pet.) and 5%
other formulations. Applied
10% TTO (in pet.) did not cause
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
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.
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 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).
Two cases of contact dermatitis associated with the application of TTO have been reported by Apted et
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.
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).
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,
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).
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
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
Products containing TTO
were tested concentrated
Seven patients (0.6%) with an
TTO were identified. Two of them
also exhibited delayed type IV
fragrance-mix or colophony
Fritz et al. 2001
TTO formulations ranging
from 5 to 100%
21-day RIPT resulted in 3
reactions to mixtures containing
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
Three (1%) subjects were
sensitised to TTO.
Aspres & Freeman 2003
Ten different samples of
Five subjects (2.3%) exhibited
Greig et al. 1999
Undiluted TTO, and 5%,
1% and 0.1% of TTO in
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
Lisi et al. 2000
Undiluted TTO which was
Thirteen (2.4%) subjects with 4
with possible relevance.
Coutts et al. 2002
TTO may be regarded as only a weak allergen, where it has any sensitising potential. Thus, normal in-
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
No data available.
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.
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).
Contraindications: Allergy to tea tree oil or to colophonium
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
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 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
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
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
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
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.
dissitiflora F. Mueller and/or other species of Melaleuca, aetheroleum radix is recommended 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 on the affected area 1-3 times
2) Traditional herbal medicinal product for treatment of small boils (furuncles and mild acne): oily
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
The data on safety are considered sufficient to establish a list entry for the above mentioned
preparations and indications.
List of references
and/or other species of Melaleuca, aetheroleum