Eugenol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Eugenol is expected to be absorbed via the oral, dermal, and inhalation routes; eugenol is rapidly distributed to various organs including (but not limited to) the small and large intestines, kidneys, liver, adrenal gland, stomach, and brain. Eugenol is rapidly metabolised primarily via phase-II conjugation, to form glucuronide and sulphate conjugates. The major route of elimination is the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Considering the physicochemical properties of eugenol, [i.e.,low molecular weight (164.2 g/mol) and moderate log K_owvalue (2.2) indicating lipophilicity that would make eugenol more susceptible to permeation across lipid membranes [1,2]], absorption of eugenol from various routes of exposure, such as oral, dermal or inhalation, is expected. The finding of a greater fraction of eugenol in red blood cells compared to plasma at early time points after oral dosing is considered to be consistent with eugenol's lipophilic properties [3]. For the oral route, this assumption is supported by the results of toxicokinetic studies in rats and humans, which demonstrate that eugenol is readily absorbed and excreted in the conjugated form in the urine or faeces [3, 4]. Although no clinical signs of toxicity or adverse effects were noted in the acute or repeated-dose oral toxicity studies in rats or mice [5], the lack of systemic effects is likely attributed to the rapid first pass metabolism and the short residence time of eugenol in the body, which is supported by the excretion of up to 90% of an ingested dose in the urine and faeces within 24 hours [3]. For the inhalation route, the trace amounts of eugenol identified in the serum of mice, along with the motility effects and clinical signs following acute inhalation are indicative of systemic absorption [6,7]. For the dermal route, the skin irritancy effects observed with eugenol [8], in addition to its favourable physicochemical properties for penetration into the stratum corneum indicate that eugenol is likely to be absorbed from the dermal route. 

Following intraperitoneal injection, eugenol was shown to be rapidly distributed to various organs including small and large intestines, kidneys, liver, adrenal gland, stomach, testes, lung, pancreas, heart, erythrocytes and brain reaching levels of 1 ng/mg tissue [4]. Evidence for eugenol crossing the BBB can be obtained from the results of a toxicokinetic study in rats demonstrating sedative effects following intravenous administration of eugenol (20 mg/kg body weight), the effects of eugenol on motility of mice following acute inhalation exposure, as well as the anaesthetic effects noted in rats orally exposed to isoeugenol (an isomer of eugenol) in a reproductive toxicity study [2,6,9]. Blood and plasma concentrations peak rapidly (i.e., 0.25 hours) following oral dosing, as shown in rats; the rapid peak is followed by a slow decline [3]. A secondary peak appearing in plasma at 4 hours was considered possibly related to enterohepatic recirculation of eugenol [3].

 

Metabolic data in humans and rats indicate that orally administered eugenol is rapidly metabolised, primarily via phase-II conjugation, to form mainly glucuronide and sulphate conjugates [10, 11, 12, 13 ]. The minor metabolic pathways of eugenol include the epoxide-diol pathway, isomerisation of the double bond, allylic hydroxylation, and GSH conjugation resulting in the formation of the following metabolites:cis- and trans-isoeugenol; 4-hydoxy-3 -methoxyphenyl-propane; 3-(4-hydroxy-3-methoxyphenyl)-propylene-1,2-oxide; 3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol; and 3-(4-hydroxy-3 -methoxy-phenyl)-propionic acid. 

Eugenol is considered to be non-carcinogenic whereas methyl eugenol has consistently been shown to be carcinogenic in animal studies. Methyl eugenol has been shown to be metabolised by allylic 1'-hydroxylation followed by sulphation leading to an unstable genotoxic metabolite. The 1'-hydroxy metabolite is considered to be the proximate carcinogen. Studies using rat, mouse and human liver microsomes have shown that eugenol is less likely to form its' 1'-hydroxy metabolite than is methyl eugenol. Furthermore, in the presence of glucoronide the 1'-hydroxy metabolite of eugenol is so rapidly detoxified that it's presence could not be detected in human or mouse liver S9 and only a very small amount in rat liver S9. However, for methyl eugenol significant amounts of the 1'hydroxy metabolite were detected both in the presence and absence of glucoronide. Therefore, it may be concluded that methyl eugenol metabolism leads to the formation of the 1'hydroxy proximate carcinogen whereas eugenol metabolism leads predominantly to a non-genotoxic glucuronide conjugate. Consequently, methyl eugenol is not a valid analogue of eugenol.

The major route of excretion for eugenol following oral administration is via the urine and to a smaller extent the faeces. As determined in rats, about 80% of the administered oral dose of eugenol was rapidly excreted in the urine as conjugated metabolites within 24 hours, while 10% was excreted in the faeces, and less than 1% was excreted unchanged in the urine; data in humans are similar in showing a high urinary excretion [14]. Less than 1% of total radiolabelled eugenol, administered intraperitoneally to rats, was excreted in the expired air as¹⁴CO₂[4]. Based on the available data demonstrating the rapid absorption of eugenol and its efficient metabolism and excretion, and taking into consideration the low molecular weight, moderate log K_ow and water solubility values, eugenol is not expected to bioaccumulate.

References

[1]       TEST REPORT: “7191030824-CHM12-LSM-CR2” -29 MAY 2012

[2]       Guénette SA, Beaudry F, Marier JF, Vachon P. Pharmacokinetics and anesthetic activity of eugenol in male Sprague-Dawley rats. J Vet Pharmacol Ther. 2006 Aug;29(4):265-70.

[3]       Guénette SA, Ross A, Marier JF, Beaudry F, Vachon P. Pharmacokinetics of eugenol and its effects on thermal hypersensitivity in rats. Eur J Pharmacol. 2007 May 7;562(1-2):60-7.

[4]      Weinberg JE, Rabinowitz JL, Zanger M, Gennaro AR. 14C-eugenol: I. Synthesis, polymerization, and use. J Dent Res. 1972 Jul-Aug;51(4):1055-61.

[5] NTP (1983).Carcinogenesis Studies of Eugenol (CAS No. 97-53-0) in F344/Rats andB6C3F₁Mice (Feed Studies). (NTP Technical Report Series, no 223). Research Triangle Park (NC): National Toxicology Program (NTP).

[6] Buchbauer G, Jirovetz L, Jäger W, Plank C, Dietrich H. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci. 1993 Jun;82(6):660-4.

[7] Clark GC. Acute inhalation toxicity of eugenol in rats. Arch Toxicol. 1988;62(5):381-6.

[8] Study report by Toxicol Laboratories Limited, Acute dermal irritation study. 1988

[9] NTP (1999).Final Report on the Developmental Toxicity of Isoeugenol (CAS # 97-54-1) in Sprague-Dawley CD^®Rats Exposed on Gestation Days 6 - 19. (NTP Study No. Ter-97-006, PB2000-105138). Research Triangle Park (NC): National Institute of Environmental Health Sciences (NIEHS), National Toxicology Program (NTP).

[10] Thompson D, Constantin-Teodosiu D, Egestad B, Mickos H, Moldeus P. Formation of glutathione conjugates during oxidation of eugenol by microsomal fractions of rat liver and lung. Biochem Pharmacol 1990;39:1587-1595.

[11] Thompson DC, Constantin-Teodosiu D, Moldeus P. Metabolism and cytotoxicity of eugenol in isolated rat hepatocytes. Chem Biol Interact 1991;77:137-147.

[12] Minet EF, Daniela G, Meredith C, Massey ED. A comparativein vitrokinetic study of [¹⁴C]-eugenol and [¹⁴C]-methyleugenol activation and detoxification in human, mouse, and rat liver and lung fractions. Xenobiotica. 2012; 42(5):429-441.

[13] Fischer IU, von Unruh GE, Dengler HJ. The metabolism of eugenol in man. Xenobiotica. 1990 Feb;20(2):209-22.

[14] Sutton JD, Sangster SA, Caldwell J. Dose-dependent variation in the disposition of eugenol in rat. Biochemical Pharmacology. 1985 34: 465-466.