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⚠️ Toxicology

TOXICOLOGY

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⚠️ Animal data to humans ⚠️ Eucalyptus oil acute toxicity ⚠️ Cineole acute toxicity ⚠️ Poisonings in humans ⚠️ Other documented effects ⚠️ Thujone toxicity ⚠️ Pulegone and menthofuran ⚠️ Salicylate toxicity ⚠️ References
Introduction
Toxicology of essential oils

How do assessors extrapolate from animal data to humans?

According to the 2012 guidance document of the EFSA Scientific Committee, in the absence of chemical-specific data on kinetics and/or dynamics, the Committee recommends an overall default uncertainty factor of 100 (10 for inter-species variability × 10 for intra-human variability). The same guidance gives the default sub-factors to be applied when chemical-specific data are missing for some components: 4.0 for inter-species variability in toxicokinetics, 2.5 for inter-species variability in toxicodynamics, 3.16 for intra-human variability in toxicokinetics and 3.16 for intra-human variability in toxicodynamics. For extrapolating from a subchronic to a chronic study duration in rodents, the guidance recommends an uncertainty factor of 2.

What acute toxicity values are reported for eucalyptus oil?

According to the 2024 EMA/HMPC assessment report on eucalyptus essential oil, citing ESCOP (2003), which quotes von Skramlik (1959) and Ohsumi et al. (1984), animal studies give an oral LD50 for eucalyptus oil of 4.4 g/kg body weight in rats and 3.3 g/kg in mice. The same report states that Zhao et al. (2021) analysed the acute toxicity of a eucalyptus oil of unknown quality and found by the modified Karber method an oral LD50 in mice of 3065 mg/kg.

The 2024 EMA/HMPC assessment report also states that Hu et al. (2014) studied in rats, following OECD Guideline 425, the acute toxicity of an emulsion in water of eucalyptus oil of unknown quality, in five experimental groups of 10 rats each with equal numbers of males and females; the oral LD50 of this emulsion was 3811.5 mg/kg (Karber method), and at high doses the liver was the target organ.

What acute toxicity values are reported for 1,8-cineole?

The 2024 EMA/HMPC assessment report on eucalyptus essential oil states that Jenner et al. (1964) found for 1,8-cineole an oral LD50 of 2,480 mg/kg body weight in Osborne-Mendel rats. Citing Opdyke (1975), the same report gives an LD50 for 1,8-cineole of 2.5 g/kg in rats, the route not being stated in that sentence. Also citing Opdyke (1975), the report gives a dermal LD50 for 1,8-cineole in rabbits of more than 5 g/kg body weight.

Which poisonings after ingestion of eucalyptus oil are reported in humans?

According to the 2024 EMA/HMPC assessment report, the SCF (2002), quoting Webb and Pitt (1993), summarised that accidental intoxications have been reported following ingestion of eucalyptus oil, that the lowest lethal doses reported were 4-5 ml in adults, and that in other cases ingestion of higher doses caused less severe effects or remained asymptomatic. The same report states that Saller et al. (1988) cited a lethal dose of only 4-5 ml of eucalyptus oil in adults. Darben et al. (1998), cited in the report, reported a death from central nervous system depression after ingestion of 30 ml of oil. De Vincenzi et al. (2002), cited in the report, listed adverse case reports after ingestion of eucalyptus oil in amounts ranging from 1 ml to 220 ml, among which 2 patients died after ingesting only 3.5-5 ml.

Cases reported in India

Ittyachen et al. (2019), cited in the 2024 EMA/HMPC assessment report, reported the cases of two adult patients in India who unintentionally consumed eucalyptus oil and developed seizures; the authors detected camphor in the “eucalyptus oil” the patients had consumed. Mathew et al. (2021a), cited in the report, described from an observational study in a hospital in south India (January 2018 to December 2019) 3 young adults with essential oil-related status epilepticus, the first 2 of whom had a history of excessive ingestion of eucalyptus oil, 5 ml in one case and 10-15 ml in the other.

What do the assessors say about these case reports?

In their comments, the assessors of the 2024 EMA/HMPC report state that the case reports give no information on the products or on the quality of the oil involved, and that the case of Ittyachen et al. (2019) showed that adulterations are possible.

What other effects of eucalyptus oil are documented?

In the conclusions on clinical safety of the 2024 EMA/HMPC assessment report, eye contact with unwashed hands after application of eucalyptus oil or use of the preparation may potentially cause irritation.

What is known about the toxicity of thujone?

What do animal studies report?

According to the 2012 EMA/HMPC public statement on thujone, the most prominent symptoms associated with acute intoxication are epileptiform convulsions, in line with the proposed mechanism of action. The same statement gives, from Rice and Wilson (1976), a subcutaneous LD50 in mice of 134 mg/kg for α-thujone and of 442 mg/kg for β-thujone. Citing Pinto-Scognamiglio (1967) and the SCF (2002), the statement reports that in rats, intraperitoneal administration of thujone led to both convulsant and lethal effects at a dose of 180 mg/kg body weight. From Höld et al. (2000), the statement gives an intraperitoneal LD50 of α-thujone in mice of 45 mg/kg body weight.

The statement reports, from Margaria (1963), an oral LD50 of a mixture of α- and β-thujone of 192 mg/kg in rats, 230 mg/kg in mice and 396 mg/kg in guinea pigs.

What is reported for humans?

Noting that exposure doses are difficult to determine in the human cases it discusses, the SCF (2002), cited in the 2012 EMA/HMPC public statement, concluded that humans are at least as sensitive to thujone neurotoxicity as experimental animals.

Which reference values and limits apply to thujone?

According to the 2012 EMA/HMPC public statement, the Council of Europe (1999) allocated to thujone a tolerable daily intake (TDI) of 10 µg/kg body weight/day, based on a NOEL for convulsions of 5 mg/kg body weight in the female rat, dosed by gavage 6 days per week for 14 weeks, to which a safety factor of 500 was applied. The same statement reports that the Scientific Committee on Food (SCF, 2002) “considered the available data inadequate to establish a TDI/ADI”. Under Directive 88/388/EEC as amended by Regulation (EC) No 1334/2008, as reported by the statement, the maximum thujone levels allowed are 10 mg/kg in alcoholic beverages other than those produced from Artemisia species, 35 mg/kg in alcoholic beverages produced from Artemisia species, and 0.5 mg/kg in non-alcoholic beverages produced from Artemisia species. The statement adds that the use of thujone as such as a flavouring substance is not authorised in Europe (Regulation (EC) No 1334/2008), nor for such a use in the United States.

What is known about pulegone and menthofuran?

According to the 2016 EMA/HMPC public statement on pulegone and menthofuran, a tolerable daily intake (TDI) for pulegone and menthofuran has been set for food at 0.1 mg/kg body weight. The same statement reports that under Regulation (EC) No 1334/2008 a joint maximum daily intake (MDI) for pulegone and menthofuran of 0.1 mg/kg body weight is set, and that the limit for pulegone in foods and beverages in general is 20 mg/kg.

According to the 2016 EMA/HMPC public statement on pulegone and menthofuran, pulegone is the major component of the volatile oils of European pennyroyal (Mentha pulegium L.) and American pennyroyal (Hedeoma pulegioides (L.) Pers.), where it comprises 85–97 % (w/v) and about 30 % (w/v) of the respective oil. According to the 2016 EMA/HMPC public statement on pulegone and menthofuran, a literature review of cases of human intoxication with pennyroyal oil (pulegone content 62–97 %) indicates that ingestion of 10 ml (about 5.4–9 g of pulegone, about 90–150 mg/kg body weight for a 60 kg person, calculated with a relative density of 0.9 “as for peppermint oil”) resulted in moderate to severe toxicity, and ingestion of more than 15 ml (about 8–13 g of pulegone, about 130–215 mg/kg body weight for a 60 kg person) resulted in death; the clinical pathology was characterised by massive centrilobular necrosis of the liver, pulmonary oedema and internal haemorrhage, a passage the statement closes with the reference “(SCF, 2002)”.

What is reported about salicylate toxicity?

According to Chin, Olson and Dempsey (2007), the primary effects of salicylate toxicity are complex and include direct stimulation of the respiratory centre of the central nervous system, leading to a respiratory alkalosis.

References