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İstanbul Journal of Pharmacy
Istanbul J Pharm2024
DOI: 10.26650/IstanbulJPharm.2024.1434421
Review Article
Safety and possible risks of tea tree oil from a toxicological perspective
Sonia Sanajou2, Rana Ülker Özkan1,3, Pınar Erkekoğlu1, Gözde Girgin1, Terken Baydar1
1Hacettepe University, Faculty of Pharmacy, Department of Toxicology, Ankara, Türkiye
2İstanbul Aydın University, Faculty of Pharmacy, Department of Toxicology, İstanbul, Türkiye
3Turkish Medicines and Medical Devices Agency, Ankara, Türkiye
ABSTRACT
Tea tree oil (TTO) is a sophisticated essential oil extracted from the Melaleuca alternifolia plant. It comprises around 1,000
components with a significant presence of monoterpenes and their alcohols. Terpinen-4-ol, the monoterpene that makes up 30%
to 48% of TTO essential oil, is the main factor responsible for its strong antibacterial properties. TTO has been extensively used
in skin care products to treat many problems, including acne, eczema, and dandruff. TTO is included in products used by children
and adults. Nevertheless, the reliability of TTO in cosmetic and dermatological or derma cosmetic formulations is contingent
upon numerous influential aspects, underscoring the pivotal significance of formulation and production procedures. TTO can
be taken orally, topically, or ocularly. However, it is important to exercise caution, as high levels of TTO may cause phytotoxic
effects and result in negative consequences such as contact allergy, inflammation, irritation, and dermatitis. Though natural, this
essential oil can be harmful if not used correctly, considering factors like the route of application, exposure dose, and poor-quality
contents. This review thoroughly examines the negative consequences, considerations for safety, and regulatory factors related to
the usage of TTO. The study emphasizes the importance of conducting thorough research to better understand the safe use of
essential oils, especially TTO. It also calls for a full assessment of the possible negative effects on vulnerable populations. Given
the increasing demand for products containing TTO, it is crucial to conduct ongoing research to improve recommendations and
ensure the informed and safe use of this precious essential oil.
Keywords: tea tree oil, risk, safety, adverse effects, essential oil
INTRODUCTION
Tea tree oil (TTO) is the essential oil obtained by distill-
ing the leaves and terminal branchlets of the narrow-leaf
tea tree Melaleuca alternifolia, which grows in New South
Wales and Queensland in Australia. It is a pale-yellow liquid
with a terpenic, coniferous, and minty–camphoraceous odor.
TTO is present in many cosmetics and personal care prod-
ucts, including ointments, skin cleansers, and shampoos (de
Groot & Schmidt 2016). TTO acts as a natural bactericide
against methicillin-resistant Staphylococcus aureus at 0.002-
2% concentrations and is also suggested to have antiviral, anti-
inflammatory, and analgesic effects (Vatanen et al., 2016). The
European Medicines Agency (EMA) has approved TTO to treat
minor superficial wounds, insect bites, tiny boils, irritation in
athlete’s foot cases, and minor oral mucosa inflammation. It is
mainly used against skin problems such as contact allergy, irri-
tation, eczema, dandruff, and dermatitis (de Groot & Schmidt
2016). Figure 1 summarizes the dermatological applications,
biological activities, and composition of TTO.
TTO includes about 1000 ingredients, most of which are
monoterpenes and their alcohols. Terpinen-4-ol is a monoter-
pene and the most prevalent constituent (with a minimum of
30% and a maximum of 48%) and is responsible for most
of TTO’s antibacterial activity (Oliva et al. 2018). TTO also
contains high amounts of 𝛾-terpinene and 1,8-cineole (euca-
lyptol), both of which cause skin irritation (Zeiner, Michaela &
Stingeder, 2018)Sabinene, aromadendrene, 𝛿-cadinene, ledene
(viridiflorene), limonene, globulol, and viridiflorol are also
present in TTO but in lower amounts. The other high ingredi-
ents are 𝛾-terpinene, 𝛼-terpineol, p-cymene, 𝛼-pinene, and ter-
pinolene, with maximum levels of 13%, 8%, 8%, 6%, and 5%,
respectively. The minimum and maximum amounts of these
chemical components are given in Table 1.
This review primarily aims to gather and summarize the
findings on the safety and regulations on the use of TTO in cos-
metics and dermatological pharmaceuticals. It will also provide
data on accurate and relevant information regarding the toxicity
of TTO.
Corresponding Author: Sonia Sanajou E-mail: sanajou19@hotmail.com
Submitted: 10.02.2024 •Revision Requested: 18.03.2024 •Last Revision Received:23.03.2024 •Accepted: 17.04.2024
This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0)
12
Sanajou, S. et al., Safety and possible risks of tea tree oil from a toxicological perspective
Figure 1. Summary of TTO’s composition, activities, and situations where it can be applied
Table 1. TTO’s Constituents, Chemical Structures, and Percentage of Overall Content (SCCP, 2008)
Constituent
Content (%)
Min. Max.
Terpinen-4-ol 30 48
γ-terpinene 10 28
1,8-cineole (eucalyptol) Trace 15
α-terpinene 5 13
p-cymene 0.5 8
α-terpineol 1.5 8
α-pinene 1 6
Terpinolene 1.5 5
13
İstanbul Journal of Pharmacy
Search Strategy
The study conducts a literature search with the intent to collate,
synthesize, and integrate the reports that have been published on
TTO. Data have been gathered from three databases: PubMed,
Web of Science, and Scopus. The searches have been restricted
to papers published in English between 2015-2024, with re-
search articles and comprehensive reviews both being chosen.
The most common search terms have been chosen as “tea tree
oil,” safety of tea tree oil,” regulations for tea tree oil,” and
“toxicity of tea tree oil.” After searching in the databases, the
exclusion criteria for the papers are articles (i) with no abstract,
(ii) in languages other than English, or (iii) with no reliable
data and statistics.
Safety Regarding Exposure to TTO
With regard to all the available data, TTO is considered gen-
erally safe and might help treat acne and other superficial skin
infections when used topically. An earlier Scientific Commit-
tee on Consumer Products (SCCP, 2008) report calculated daily
exposure to TTO for rinse-off and leave-on products. Systemic
exposure levels between 1.7 and 3.33 μg/kg per day were es-
timated for various types of cosmetics. The SCCP report con-
cluded that considerable systemic exposure could occur with
topical application of TTO-containing products and TTO itself
if used daily. The report also calculated worst-case estimations
for general systemic and reproductive toxicity. However, the
margin of safety (MoS) could not be calculated, as a lack of
data is found regarding the bioavailability of TTO. A rate of
3% was calculated for the subcutaneous absorbance of TTO
(Cross, Russell, & Roberts, 2008) . However, no data could be
found on the oral bioavailability of TTO. Hence, converting
between exposure routes is challenging.
Evaluating TTO Toxicity
With rising reports of TTO’s therapeutic benefits, multiple TTO
toxicity reviews have also been published. According to manu-
facturing companies, adverse effects of TTO are infrequent (less
than 0.0016%) and only involve mild complaints. TTO causes
numerous local adverse effects, including contact allergy (de
Groot & Schmidt 2016), irritation (Zeiner et al., 2018) and
dermatitis (Ambrogio et al., 2022) . However, most evidence
suggests that diluting TTO can decrease these reactions.
Some components of TTO oxidize in ambient air and light,
creating peroxides, epoxides, and endoperoxides, which have
sensitizing properties and may cause allergic skin reactions
(Ambrogio et al., 2022). These oxidation products are suggested
to increase the toxicity of TTO. Although TTO is a modest skin
sensitizer in susceptible individuals, oxidized TTO has stronger
oxidizing effects. Manufacturers of TTO warn users against ex-
posure to oxidized TTO (Thomas et al., 2016). According to
the International Fragrance Association (IFRA), concentrated
TTO is hazardous and bears the R-codes R-22 (harmful if in-
gested), R38 (skin irritant), and R65 (may cause lung damage
if ingested), as well as the symbol Xn (harmful). These health
threat indicators are also included in the safety data sheets of
raw material suppliers (IFRA, 2022).
Cytotoxicity of TTO
Initially, studies were conducted to assess the cytotoxicity of
TTO on cultured cells to ascertain its possible harmful effects.
The toxicity of TTO was assessed over a diverse range of human
cell cultures, including HeLa cervical cancer cells, MOLT-4
acute lymphoblastic leukemia cells, K562 erythromyeloblas-
toid leukemia cells, CTVR-1 B cells obtained from the bone
marrow of a patient with acute myeloid leukemia, and fibrob-
last and epithelial cells. The experiments showed that TTO
exhibited an inhibitory concentration 50 (IC50) value for cell
growth ranging from 20 to 2,700 μg/mL (Russo, Corasaniti,
& Morrone, 2015). Terpinen-4-ol was shown to cause toxic-
ity in meibomian gland epithelial cells based on dosage and
exposure route (Chen, Wang & Liu, 2020) . At high concen-
trations, both TTO and its major ingredient terpinen-4-ol have
long been known to cause cytotoxicity in human cells, includ-
ing epithelial cells and fibroblasts. Moreover, TTO can exert
antimicrobial activity. TTO does not directly induce cell wall
alterations; however, it causes the release of autolytic enzymes
associated with the cell membrane, which may induce lysis
and subsequent leakage of nucleic acids across the damaged
cytoplasmic membrane in bacteria (Low, Kenward & Martin,
2017).
Acute and Chronic Toxicity of TTO
TTO has an oral median lethal dose (LD50) of 1,900 mg/kg
in rats. According to the SCCP, undiluted TTO should not be
consumed orally, as it is dangerous (Mertas et al., 2015). The
LD50 value for 𝛾-terpinene in orally exposed rats was found
to be 5,000 mg/kg (Tabarraei, Hadi, & Mosavi, 2019). The
Committee of Experts on Flavouring Substances of the Council
of Europe evaluated eucalyptol as a natural flavoring content,
and using a minimum lethal dose of 60 mg/kg/day with a safety
factor of 300, they predicted 0.2 mg/kg/bw as tolerable daily
intake (TDI) (SCCP, 2008).
No oral or dermal repeated dose toxicity studies regarding
pure TTO were found in the literature. However, read-across
considerations regarding the systemic toxicity of some ingre-
dients have been performed. For terpinen-4-ol, 𝛾-terpinene,
1,8-cineole, 𝛼-terpinene, p-cymene, 𝛼-terpineol, 𝛼-pinene, and
terpinolene, the established or estimated LD50 and no observed
adverse effect level (NOAEL) values are presented in Table 2
(European Medicines Agency, 2013).
14
Sanajou, S. et al., Safety and possible risks of tea tree oil from a toxicological perspective
Table 2. Doses in Relation to TTO Constituent Toxicity and Safety (European Medicines Agency, 2013)
TTO constituent LD50
(mg/kg bw) Animal species Application route NOAEL
(mg/kg bw/day) Animal species, period, toxicity
Terpinen-4-ol 1,300 rat Oral
250 rabbit dermal 400 rat, oral, 28-day study, kidney toxicity
γ-Terpinene 5,000 rat dermal
1,8-Cineole 430 rat oral 300 rats and mice, subchronic toxicity study,
hepatic and renal toxicity
>2,000 dermal
α-Terpinene 1,680 rat oral
60 pregnant Wistar rats, oral, maternal
systemic toxicity
75 (as cumene/p-cymene) rat, oral, renal
toxicity
α-Terpineol
2,900-5,170 rat oral
500 male and female Wistar rats, oral, 28-
day study
2,000 dermal
2,830 mouse oral
2,000 intramuscular
α-Pinene >2,000 rat oral 250 weanling Osborne-Mendel male rats,
oral, 28-day study, nephrotoxicity
Terpinolene 3,740 rat oral
4,300 rabbit Dermal
TTO Toxicity Related to Exposure Routes
Essential oils enter the blood circulation in 30 seconds via mu-
cosa and 4-12 minutes dermally. They reach internal organs and
the nervous system within 20 min, resulting in systemic effects,
and are excreted from the body through the kidneys (Pazyar,
Yaghoobi &Kazerouni, 2013). Oral intake of the essential oil
TTO lead to diarrhea, abdominal pain, rash, incoordination, and
muscle weakness at relatively high doses, with these symptoms
generally able to resolve within 36 hours. Oral TTO adminis-
tration is not advised until more scientific investigations on its
toxicity are completed (Özfenerci &Çalışkan, 2018).
Table 3 summarizes the poisoning cases in the literature.
The literature does not mention cases of human death linked
to TTO. A few studies have been published on accidental TTO
poisoning in humans. The literature shows accidental ingestion
of TTO to have varied from less than 10 mL to half a cup. Little
information is found on the renal toxicity of TTO (Özfenerci
&Çalışkan, 2018).
TTO is commonly administered to the skin as an essential oil.
In addition, it is present in many cosmetics and personal care
products, such as moisturizers, soaps, and shampoos. There-
fore, dermal toxicity studies have great importance (Özfenerci
&Çalışkan, 2018). After extrapolating the LD50 values on hu-
mans, dermally administered TTO through cosmetic products
or as an essential oil can be concluded to not be assessable
as harmful. Because up to 90% of TTO is a volatile liquid,
it swiftly evaporates from the skin’s surface. Its dermal ab-
sorption rate depends on factors such as body temperature, the
integrity and age of the skin, the environment temperature and
dilution rate, the amount covering the skin’s surface, the chem-
ical composition of the oil, and the application method used.
TTO’s lipophilic property allows it to enter the skin’s surface
layer; it boosts antimicrobial effects and may lead to moder-
ate dermal toxicity (Mertas et al., 2015). However, only small
amounts of the components of TTO enter the subdermal layers
and into the bloodstream, with human skin not being readily
able to absorb higher amounts of TTO to generate acute toxic
effects (Caliskan & Karakus 2020).
In rabbits, the Draize irritation index for undiluted TTO is
5.0. This means TTO is a severe skin irritant. Human studies
have presented conflicting results, such as no irritation with
diluted and undiluted TTO, as well as skin irritation with undi-
luted TTO or cosmetic formulations containing 5% TTO. Such
inconsistent results may be due to differences delivery meth-
ods, exposure routes, and exposure periods (SCCP, 2008). One
Hen’s Egg-Chorioallantoic Membrane Text (HET-CAM) as-
say found undiluted TTO and its 25% and 10% solutions in a
surfactant to cause severe irritation, with TTO being a slight
irritant at 5% dilution (Capasso, Abbinante & De Vernardo,
2022).
Topical administration of TTO is associated with few side
effects, including irritation and allergic reactions. Irritant re-
actions can be reduced significantly by utilizing products with
lower oil concentrations. Patch tests confirm allergic reactions
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İstanbul Journal of Pharmacy
Table 3. TTO Poisoning Case Reports in Humans
Ingested amount Gender and age Clinical symptoms Reference
½ teaspoonful 60-year-old male
a dramatic rash accompanied by
leukocytosis; swollen face, hands,
and feet
(Elliott, 1993)
2 teaspoons 4-year-old male ataxia, shortly after progressed to
unresponsiveness
(Morris, Donoghue, &
Osterhoudt, 2003)
< 10 mL 23-mo-old male
confusion, unable to maintain
balance; tripping and falling over;
disorientation
(Jacobs & Hornfeldt, 1994)
< 10 mL 17-mo-old male ataxia and drowsiness (Del Beccaro, 1995)
to TTO can even occur at very low concentrations. Terpinen-
4-ol and 𝛼-terpineol can penetrate the skin’s epidermal layer
and exert antibacterial, anti-inflammatory, and acaricidal ef-
fects. When testing a 20% TTO formulation in ethanol, only
terpinen-4-ol (0.05% of the applied formulation) was able to
completely permeate the epidermis (Thomas et al., 2016). A
retrospective assessment of 41 instances of positive patch test-
ing in Australia over 4.5 years concluded only 1.8% of the study
population to be allergic to TTO (Chen et al., 2020).
Meanwhile, allergic contact dermatitis, systemic contact der-
matitis, linear immunoglobulin-A disease, multiform erythema
reactions, systemic hypersensitivity reactions, and idiopathic
male prepubertal gynecomastia have also been observed (Mer-
tas et al., 2015). Another study found the patch test findings of
311 volunteers to reveal an average irritancy score of 0.25. Yet
another study that applied a patch test with 10% TTO to 217
people observed no irritation reaction in the volunteers, with
the researchers suggesting that skin irritation could be avoided
by using lower concentrations. Although many ingredients in
TTO have been claimed to be able to lead to allergic reactions,
the most important claim also stated that these result from ox-
idation products formed from outdated or badly preserved oils
(Bekhof, Hunsel & Woerdenbag, 2023).
Lee et al. (2013) investigated the acute dermal toxicity of
TTO using multiple dilution doses. According to their findings,
skin irritation was reduced dramatically for TTO concentrations
< 2.5%. They also further researched the major and minor TTO
components that produce skin irritation, investigating Terpinen-
4-ol, and 1,8-cineole mainly to determine whether they were the
primary causes of skin irritation at a 5% concentration, TTO
caused substantial skin irritation, with terpinen-4-ol compris-
ing up to 30% of the mixture. Moreover, when examined at a
concentration of 1.5%, terpinen-4-ol was determined to be non-
irritating. In the Local Lymph Node Assay (LLNA), both whole
TTO and its polyethylene glycol (PEG) solution (at ISO4730
quality) were found to be moderate sensitizers in mice (SCCP,
2008) .TTO is also suggested for sensitizing humans, with sev-
eral patch test studies indicating an allergic contact dermatitis
prevalence rate of 4.8% (European Medicines Agency, 2013)
. Despite this, there is no clear data on the skin sensitization
potentials of the individual constituents of TTO. Suggestions
point towards the terpenoid fraction, limonene, and/or oxida-
tive degradation products as possible culprits. Notably, oxidized
TTO demonstrates three times more potent sensitization than
fresh TTO. The increase in levels of p-cymene and 1,8-cineole
over time may also contribute to the heightened sensitizing
potency of TTO. Conversely, skin oxidative bioactivation of
prohaptens to haptens is plausible. 𝛼-terpinene, a major con-
stituent of TTO, can oxidize over time and become a hapten,
potentially leading to skin sensitization (European Medicines
Agency, 2013). However, further studies are necessary to deter-
mine definitively which constituent(s) of TTO are responsible
for human skin sensitization.
TTO is currently being used successfully to eradicate ocu-
lar Demodex. However, an in vitro study showed the doses of
TTO that exert demodicidal activity to be able to lead to toxic
effects in human hepatic cells, cervical cells, breast epithelial
cells, T cells, B cells, bone marrow cells, fibroblasts, and pe-
ripheral blood monocytes (Chen et al., 2020). A primary eye
irritation study classified 1% and 5% TTO solutions as mini-
mally irritating in rabbits. TTO concentrations less than 10%
substantially reduced ocular discomfort and inflammation of
the eyelids and conjunctiva (Messaoud et al., 2019) . On the
other hand, TTO produces eye discomfort in certain patients
when administered at high concentrations. Contact dermatitis,
allergic reactions, and eye irritation are frequent consequences
of TTO preparations (Ergun et al., 2020) .
Undiluted TTO was found to not cause phototoxicity in hair-
less mice (Infante et al., 2022). No other phototoxicity studies
on TTO or its ingredients are present in the literature.
TTO’s Potential for Reproductive and Developmental
Toxicity
Data on the reproductive toxicity of the constituents of TTO
are also limited, and the oral NOAEL values for reproductive
16
Sanajou, S. et al., Safety and possible risks of tea tree oil from a toxicological perspective
toxicity were found to be between 250-365 mg/kg/day. When
applying 𝛼-terpinene at 30, 60, 125, and 250 mg/kg doses to
female Wistar rats during their 6th-15th days of pregnancy, ma-
ternal toxicity was observed in both the 125 and 250 mg/kg/day
dosage groups, with these two highest dosage groups showing
reduced fetal body weights and increased kidney weights. Ab-
normal ossification of bones and minor skeletal abnormalities
in fetuses were evident in the 60, 125, and 250 mg/kg dosage
groups. The oral NOAEL values for embryotoxicity and feto-
toxicity were suggested to be 30 mg/kg, and this value was 60
mg/kg for maternal toxicity (Cross et al., 2008; SCCP, 2008).
Genotoxicity of TTO
Testing the genotoxicity of essential oils and their components
is critical for assessing their safety. The genotoxic effects of
TTO and its components have been evaluated in vitro (Casalle
& Andrade, 2020). Several mutagenicity tests in their study
also examined the mutagenic potentials of TTO and its com-
ponents. Salmonella typhimurium strains were used to test the
mutagenic effects of commercially available TTOs. None of
the TTO brands were found to exert a mutagenic effect on the
Salmonella strains examined with and without metabolic acti-
vation in the Ames test. Terpinen-4-ol application also ended
up with the same negative results. However, at higher doses,
clear evidence of toxicity was observed in all Salmonella strains
regarding all TTOs and terpinen-4-ol (Fletcher, Cassella & Cas-
sella, 2005). Therefore, terpinen-4-ol was suggested as being
the main constituent responsible for the significant antibacterial
activity of TTO.
A genotoxicity study (Gomes-Carneiro, Felzenszwalb &
Paumgartten, 1998) using Salmonella typhimurium strains with
and without S9-mix reported no effect for TTO applications
ranging from 100-1,500 μg/plate, Although TTO and most
of its constituents are non-mutagenic, 𝛼-terpineol was found
to cause a slight mutagenic effect related to dosage (0-2,500
μg/plate) in Salmonella typhimurium strain TA102 with or
without metabolic activation. The other bacterial mutagenic-
ity test strains in their study showed no mutagenic effects.
Moreover, several constituents of TTO were found to ex-
ert no mutagenic activity in various mammalian cells (SCCP,
2008). For example, Australian TTO (Batch ATTIA/0501) was
tested to induce micronuclei in mouse bone marrow. Applica-
tion doses were selected according to the preliminary study on
mice conducted at oral doses between 500-2,000 mg/kg. All
animals in the highest dose group showed wobbly gait, prostra-
tion, and labored breathing between 30 min-5 h after dosing.
Polychromatic erythrocytes prepared from the bone marrow
of each animal were counted for the incidence of micronu-
cleated polychromatic erythrocytes. As a result, SCCP’s study
suggested Australian TTO to be non-clastogenic regarding the
mouse micronucleus test.
No carcinogenicity studies have been performed with TTO
or its constituents in the literature.
CONCLUSION
Many essential oils do not possess harmful effects and can be
used safely via dermal application. However, concerns exist that
some of these oils can be inhaled after dermal absorption, and
inhalation may lead to systemic toxicity. Current scientific pub-
lications are limited, with most data having been obtained from
observational in vitro studies. Therefore, the mechanisms un-
derlying the toxicity of essential oils are not well documented.
The past decade has seen increased interest in non-traditional
and non-prescription natural medicines. Also, new approaches
need to be found for treating skin diseases. When used and
stored correctly (i.e., well-sealed and away from light and heat),
TTO poses no danger to human health. Therefore, after review-
ing the literature, this study can suggest TTO to be safe for
treating dermatologic illnesses.
The stability of TTO in cosmetics and personal care products
is affected by several factors. Undiluted TTO should not be
used, as it clearly can cause skin reactions. Good formulation
design and production techniques are critical. Moreover, users
should store prepared products properly. They should be kept
away from direct sunlight and avoid excessive exposure to heat
and air. Antioxidants can be added to TTO formulations to
prevent terpene oxidation, which causes skin sensitization. For
example, one study collected storage stability data on different
formulated items and monitored product stability using TTO’s
p-cymene content (European Medicines Agency 2013). The p-
cymene content generally increased with storage duration but
remained below the International Organization for Standards’
upper limits.
Concluding whether or not herbal remedies pose a danger
to human health is usually a complicated issue, as they are
composed of various components. The effects and toxicities of
herbal remedies arise as a combined effect of different chemical
compounds with different characteristics. In the case of TTO,
the components can make up anywhere from 1% to 48% of the
total oil. Meanwhile, with their varying structures and physic-
ochemical properties, these constituents have different kinetics
and oxidation rates, thus adding another challenging and im-
portant issue regarding the further toxicological evaluation of
TTO.
In conclusion, this study suggests that fresh products con-
taining TTO are able to treat certain skin conditions at proper
concentrations. As oxidation of certain constituents occurs over
time, TTO should not be used after a certain date. Meanwhile,
oral administration should be avoided. More in vitro and in vivo
studies are needed to reveal the full safety profile of TTO and
its constituents.
17
İstanbul Journal of Pharmacy
Peer-review: Externally peer-reviewed.
Author Contributions: Conception/Design of Study-
T.B., G.G.; Data Acquisition- R.Ü.Ö., S.S.; Data
Analysis/Interpretation- G.G., P.E., R.Ü.Ö., S.S.; Draft-
ing Manuscript- G.G., P.E., R.Ü.Ö., S.S.; Critical Revi-
sion of Manuscript- T.B., S.S., P.E.; Final Approval and
Accountability- S.S., R.Ü.Ö., P.E., G.G., T.B.
Conflict of Interest: The authors have no conflict of interest to
declare.
Financial Disclosure: The authors declared no financial sup-
port.
ORCID IDs of the authors
Sonia Sanajou 0000-0002-6751-5266
Rana Ülker Özkan 0000-0001-6812-581X
Pınar Erkekoğlu 0000-0003-4713-7672
Gözde Girgin 0000-0002-7051-0490
Terken Baydar 0000-0002-5497-9600
REFERENCES
Ambrogio, F., Foti, C., Cazzato, G., Mortato, E., Mazzoccoli,
S., De Caro, A. P., Cassano, N., Vena, G. A., Calogiuri,
G., & Romita, P. (2022). Spreading allergic contact der-
matitis to tea tree oil in an over-the-counter product ap-
plied on a wart. Medicina (Kaunas, Lithuania), 58(5), 561.
https://doi.org/10.3390/medicina58050561
Bekhof, A. M. W., van Hunsel, F. P. A. M., van de Koppel, S., & Woer-
denbag, H. J. (2023). Safety assessment and adverse drug reaction
reporting of tea tree oil (Melaleuca aetheroleum). Phytotherapy
Research, 37(4), 1309–1318. https://doi.org/10.1002/ptr.7687
Caliskan, U. K., & Karakus M. M. (2020). Essential Oils as Skin Per-
meation Boosters and Their Predicted Effect Mechanisms. Journal
of Dermatology and Skin Science 2(3).
Capasso, L., Abbinante, G., Coppola, A., Salerno, G., & De Bernardo,
M. (2022). Recent evidence of tea tree oil effectiveness in blephar-
itis treatment. BioMed Research International, 2022, 9204251.
https://doi.org/10.1155/2022/9204251
Casalle, N., & de Andrade C.R. (2020). Cytotoxic and mutagenic ca-
pacity of TTO and terpinen-4-ol in oral squamous cell carcinoma.
BioRxiv.https://doi.org/10.1101/2020.01.03.893735.
Chen, D., Wang, J., Sullivan, D. A., Kam, W. R., &
Liu, Y. (2020). Effects of terpinen-4-ol on meibomian
gland epithelial cells in vitro. Cornea, 39(12), 1541–1546.
https://doi.org/10.1097/ICO.0000000000002506
Cross, S. E., Russell, M., Southwell, I., & Roberts, M. S. (2008). Hu-
man skin penetration of the major components of Australian tea
tree oil applied in its pure form and as a 20 solution in vitro. Eu-
ropean Journal of Pharmaceutics and Biopharmaceutics, 69(1),
214–222. https://doi.org/10.1016/j.ejpb.2007.10.002
de Groot, A. C., & Schmidt, E. (2016). Tea tree oil: contact allergy
and chemical composition. Contact Dermatitis, 75(3), 129–143.
https://doi.org/10.1111/cod.12591
Del Beccaro M. A. (1995). Melaleuca oil poisoning in a 17-month-old.
Veterinary and Human Toxicology, 37(6), 557–558.
Elliott C. (1993). Tea tree oil poisoning. The Medical Journal of
Australia, 159(11-12), 830–831. https://doi.org/10.5694/j.1326-
5377.1993.tb141370.x
Ergun, S. B., Saribas, G. S., Yarayici, S., Elmazoglu, Z., Cardak,
A., Ozogul, C., Ilhan, M. N., Karasu, C., & Evren Kemer, O.
(2020). Comparison of efficacy and safety of two tea tree oil-based
formulations in patients with chronic blepharitis: a double-blinded
randomized clinical trial. Ocular Immunology and Inflammation,
28(6), 888–897. https://doi.org/10.1080/09273948.2019.1644349
European Medicines Agency (2013). Assessment Report on Melaleuca
Alternifolia (Maiden and Betch) Cheel, M. Linariifolia Smith,
M. Dissitiflora F. Mueller and/or Other Species of Melaleuca,
Aetheroleum. European Medicines Agency 44(July):73.
Fletcher, J. P., Cassella J. P., Hughes D., and Cassella S. (2005). An
Evaluation of the mutagenic potential of commercially available
tea tree oil in the United Kingdom. International Journal of Aro-
matherapy, 15(2):81–86. doi: 10.1016/j.ijat.2005.03.004.
Gomes-Carneiro, M. R., Felzenszwalb, I., & Paumgartten,
F. J. (1998). Mutagenicity testing (+/-)-camphor, 1,8-
cineole, citral, citronellal, (-)-menthol and terpineol with the
Salmonella/microsome assay. Mutation Research, 416(1-2),
129–136. https://doi.org/10.1016/s1383-5718(98)00077-1
IFRA (2022). The Complete IFRA Standards.
https://ifrafragrance.org/docs/default-source/ifra-
code-of-practice-and-standards/ifra-standards—50th-
amendment/standards-compiled.pdf
Infante, V. H. P., Maia Campos, P. M. B. G., Gaspar, L. R., Darvin,
M. E., Schleusener, J., Rangel, K. C., Meinke, M. C., & Lade-
mann, J. (2022). Safety and efficacy of combined essential oils
for the skin barrier properties: In vitro, ex vivo and clinical stud-
ies. International Journal of Cosmetic Science, 44(1), 118–130.
https://doi.org/10.1111/ics.12761
Jacobs, M. R., & Hornfeldt, C. S. (1994). Melaleuca oil poison-
ing. Journal of toxicology. Clinical Toxicology, 32(4), 461–464.
https://doi.org/10.3109/15563659409011050
Lee C.J., Chen L.W., Chen L.G., Chang T.L., Huang C.W., Huang
M.C., Wang C.C. (2013). Correlations of the components
of tea tree oil with its antibacterial effects and skin irrita-
tion. Journal of Food and Drug Analysis, 21 (2), 169-176.
https://doi.org/10.1016/j.jfda.2013.05.007
Low, W. L., Kenward, K., Britland, S. T., Amin, M. C., & Martin, C.
(2017). Essential oils and metal ions as alternative antimicrobial
agents: a focus on tea tree oil and silver. International Wound
Journal, 14(2), 369–384. https://doi.org/10.1111/iwj.12611
Mertas, A., Garbusińska, A., Szliszka, E., Jureczko, A., Kowalska,
M., & Król, W. (2015). The influence of tea tree oil (Melaleuca
alternifolia) on fluconazole activity against fluconazole-resistant
Candida albicans strains. BioMed Research International, 2015,
590470. https://doi.org/10.1155/2015/590470
Messaoud, R., El Fekih, L., Mahmoud, A., Ben Amor, H., Ban-
nour, R., Doan, S., & Khairallah, M. (2019). Improvement in
ocular symptoms and signs in patients with Demodex anterior
blepharitis using a novel terpinen-4-ol (2.5%) and hyaluronic acid
(0.2%) cleansing wipe. Clinical Ophthalmology, 13, 1043–1054.
https://doi.org/10.2147/OPTH.S198585
Morris, M. C., Donoghue, A., Markowitz, J. A., & Osterhoudt,
K. C. (2003). Ingestion of tea tree oil (Melaleuca oil) by
a 4-year-old boy. Pediatric Emergency Care, 19(3), 169–171.
https://doi.org/10.1097/01.pec.0000081241.98249.7b
Oliva, A., Costantini, S., De Angelis, M., Garzoli, S., Božović, M.,
Mascellino, M. T., Vullo, V., & Ragno, R. (2018). High po-
18
Sanajou, S. et al., Safety and possible risks of tea tree oil from a toxicological perspective
tency of Melaleuca alternifolia essential oil against multi-drug
resistant gram-negative bacteria and methicillin-resistant Staphy-
lococcus aureus. Molecules (Basel, Switzerland), 23(10), 2584.
https://doi.org/10.3390/molecules23102584
Özfenerci, M. & Ufuk Koca Çalışkan U.K. (2018). Tea Tree Oil and
Its Use in Aromatherapy. Current Perspective on Medicinals and
Aromatic Plants. 90–102.
Pazyar, N., Yaghoobi, R., Bagherani, N., & Kazerouni, A.
(2013). A review of applications of tea tree oil in derma-
tology. International Journal of Dermatology, 52(7), 784–790.
https://doi.org/10.1111/j.1365-4632.2012.05654.x
Russo, R., Corasaniti, M. T., Bagetta, G., & Morrone, L. A.
(2015). Exploitation of cytotoxicity of some essential oils
for translation in cancer therapy. Evidence-based Comple-
mentary and Alternative Medicine: eCAM, 2015, 397821.
https://doi.org/10.1155/2015/397821
SCCP. 2008. Scientific Committee on Consumer
Products - OPINION ON Tea Tree Oil.
https://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp
_o_160.pdf
Tabarraei H., Hassan J., Mosavi S.S. (2019). Determination of
LD50 of some essential oils and histopathological changes in
short-term exposure to one of them in rainbow trout (On-
corhynchus mykiss). Toxicology Research and Application,3.
doi:10.1177/2397847318820719
Thomas, J., Carson, C. F., Peterson, G. M., Walton, S. F., Hammer, K.
A., Naunton, M., Davey, R. C., Spelman, T., Dettwiller, P., Kyle,
G., Cooper, G. M., & Baby, K. E. (2016). Therapeutic potential of
tea tree oil for scabies. The American Journal of Tropical Medicine
and Hygiene, 94(2), 258–266. https://doi.org/10.4269/ajtmh.14-
0515
Vatanen, T., Kostic, A. D., d’Hennezel, E., Siljander, H., Franzosa, E.
A., Yassour, M., Kolde, R., Vlamakis, H., Arthur, T. D., Hämäläi-
nen, A. M., Peet, A., Tillmann, V., Uibo, R., Mokurov, S., Dor-
shakova, N., Ilonen, J., Virtanen, S. M., Szabo, S. J., Porter, J. A.,
Lähdesmäki, H., . . . Xavier, R. J. (2016). Variation in microbiome
LPS immunogenicity contributes to autoimmunity in humans.
Cell, 165(4), 842–853. https://doi.org/10.1016/j.cell.2016.04.007
Zeiner, M., Cindrić I.J., Kandler W., and Stingeder G. (2018).
Trace determination of skin-irritating metals in tea tree
oil by GFAAS. Microchemical Journal, 136:101–5. doi:
10.1016/j.microc.2016.12.016.
How cite this article
Sanajou, S., Ülker Özkan, R., Erkekoğlu, P., Girgin, G., &
Baydar, T. (2024). Safety and possible risks of tea tree oil from a
toxicological perspective. İstanbul Journal of Pharmacy, 54(2):
XX-XX. DOI: 10.26650/IstanbulJPharm.2024.1434421
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