**3. General aspects of essential oil toxicity**

Essential oils are easily available in pharmacies, supermarkets or online, being used by large segments of the general public. A recent study found that 11% of Australians have used essential oils in 2016, for medicinal purposes, usually self-prescribed [11]. Despite their popularity and extensive use, the safety profile of essential oils has not been fully determined to date. Chemical complexity of essential oils is challenging when investigating which individual components are responsible for certain unwanted effects. Nevertheless, some necessary steps have already been undertaken.

Potential toxic effects of some essential oils and their components were tested on laboratory animals, usually rodents. Acute toxicity was evaluated by LD50 test (median lethal dose) in rats, which revealed that most essential oils have a LD50 of 1–20 g/kg, indicating a low toxicity. In humans, some essential oils like lemon oil have an LD50 of above 5 g/kg. Thus, the lethal dose would be 350 g for an adult of 70 kg, difficult to reach in normal circumstances [12, 13].

A few notable exceptions are EOs from *Boldo* leaf, *Chenopodium*, *Mentha pulegium* (pennyroyal), *Satureja hortensis* (savory) and *Thuja* who presented an LD50 between 0.1 and 1 g/kg in rats, signaling a significant toxicity which recommends necessary precautions for their use [12].

Essential oils are susceptible to oxidative degradation, some of the resulting molecules like oxidation products of limonene being potential skin sensitizers [14]. Therefore, a proper storage of essential oils is necessary to conserve their effectiveness and reduce the risk of adverse reactions. Essential oils should be stored in a refrigerator or in a cool, dark place in tightly sealed recipients (brown bottles).

Although most essential oils received the GRAS (generally recognized as safe) status, granted by Flavor and Extract Manufacturers Association (FEMA), it should be pointed out that they were evaluated as flavors with a very low concentration in the tested products. For a concentrated essential oil, certain toxic effects, local or systemic, could develop in specific circumstances [12].

## **4. Acute intoxication with essential oils**

Acute intoxication (poisoning) with essential oils almost invariably results from an oral ingestion of large quantities of undiluted oil, usually accidental. The intoxicated person may present polypnea, convulsions, nausea and vomiting or even death in rare cases. Tea tree oil and the oils of wintergreen, clove, cinnamon and eucalyptus are responsible for most cases, although acute intoxication with other essential oils is possible [13].

In the US, 966 intoxication cases due to tea tree oil ingestion were recorded in 2006, most subjects being represented by children up to 6 years old [13]. In Australia, a recent study identified 1387 cases of essential oil poisoning between 2014 and 2018 [15]. The exposures were accidental or due to a confusion between liquid cough medicines and essential oils. In young children, oral ingestion of 0.6–5 mL of pure eucalyptus oil is sufficient to cause severe symptoms, a fatal case being reported after the ingestion of 30 mL of the oil by an 8-month-old infant [16]. In acute intoxication, infants and young children are particularly at risk due to their reduced body weight combined with the immaturity of enzymatic systems capable of metabolizing essential oils.

Essential oil poisoning was reported also in dogs and cats treated topically with tea tree oil used in large doses for dermatological conditions. The animals presented depression, weakness, motor incoordination and tremors but they recovered after supportive treatment was given [17].

In order to reduce acute intoxication risk, it is recommended that essential oils are kept in child proof recipients, with droppers, separated from oral medication, to avoid confusion.
