Foeniculum – Bitter Fennel Fruit Oil (Foeniculi amari fructus aetheroleum)
|Latin name of the genus:||Foeniculum|
|Latin name of herbal substance:||Foeniculi amari fructus aetheroleum|
|Botanical name of plant:||Foeniculum vulgare miller subsp. vulgare var. vulgare|
|English common name of herbal substance:||Bitter fennel fruit oil|
Latin name of the genus: Foeniculum
Latin name of herbal substance: Foeniculi amari fructus aetheroleum
Botanical name of plant: Foeniculum vulgare Miller subsp. vulgare var. vulgare
English common name of herbal substance: Bitter Fennel Fruit Oil
- Assessment Report
- FOENICULUM VULGARE
- II. Clinical Pharmacology
- II.1.Phyto-chemical characterization
- Table 1- Compounds identified in essential oils obtained by steam distillation from ripe fruits of bitter and sweet fennels
- Table 2 – Relative amounts of main components extracted from fennel fruit by simultaneous distillation–extraction (SDE) or supercritical fluid extraction (SFE) (+)
- II.2 Absorption, metabolism and excretion
- II.3. Pharmacodynamics
- II.3.1 Mode of action
- II.3.2 Other studies
- III. Clinical efficacy
- III.1 Preparations marketed in Europe
- Herbal teas
- Czech Republic
- Fennel powder
- Bitter Fennel fruit oil
- III.2 Posology, duration of use, method of administration
- Fennel fruit
- multiple divided
- Fennel tincture
- Fennel oil
- Duration of use
- Method of administration: Oral use.
- III.3 Clinical studies
- III.4 Clinical studies in special populations
- III.4.1 Use in children
- III.4.2 Use during pregnancy and lactation
- III.5 Traditional use
- IV. Safety
- IV.1 Genotoxic and carcinogenic risk
- IV.1.1 Preclinical data
- IV.1.2 Clinical data
- IV.1.3 Conclusion
- IV.2. Toxicity
- IV.2.1 Acute toxicity
- IV.2.2 Subchronic toxicity
- IV.2.3 Reproductive toxicity
- IV.3 Contraindications
- IV.4 Special warnings and precautions for use
- IV.5 Undesirable effects
- IV.6 Interactions
- IV.7 Overdose
- V.Overall Conclusion
- significant relaxing
FOENICULUM VULGARE MILLER (bitter fennel, sweet fennel)
This assessment report reviews the available scientific data for bitter fennel and sweet fennel (i.e.
Foeniculum vulgare Miller sp. vulgare var. vulgare and Foeniculum vulgare Miller sp. vulgare var. dulce (Miller) Thellung, respectively) and particularly clinical data. Bitter and sweet fennels belong to the Apiaceae botanical family and to the capillaceum botanical subspecies. The material of interest for medicinal use is the fruit (i.e. whole cremocarp and mericarp), sweet fennel being more broadly used. This herbal substance is administered after crushing in solid or liquid dosages (Niesel, 1992). The essential oil obtained by steam distillation from the dry ripe fruits is also used.
In preparing this report, a number of data sources were reviewed. The main ones are as follows:
•The ESCOP monographs published in 2003;
•The results of a literature search carried out in mid 2005 by the Italian National Institute of Health in Pubmed;
•The results of a data search carried out in mid 2005 by the Italian National Institute of Health in several electronic archives (i.e. Napralert, Caplus, Dart, Toxcenter, Embase and Medline);
•The bibliographic references made available by the Association of the European Self- Medication Industry (AESGP) at the end of 2005;
•The monographs of “Foeniculi amari fructus”, of “Foeniculi dulcis fructus” and of “Bitter- fennel fruit oil” present in the current (5th edition) of the European Pharmacopoeia and of
•The Council of Europe monograph on Foeniculum vulgare as a cosmetic ingredient (2002);
•The monograph on Foeniculum vulgare Mill. published in Teuscher et al. (2005);
•The results of a data search carried out at the end of 2005 on Micromedex (including Martindale, Drugdex, Posindex, Altmedex, Reprotox, Herbal Medicines: A Guide for Health- Care Professionals);
•The results of a data search carried out at the end of 2005 on phytovigilance data banks available on internet (i.e. www/farmacovigilanza.org; www.epicentro.iss.it/focus/erbe/sorv_piante_officinali.htm);
•The result of the update in literature search carried out in Pubmed until the end of June 2007 by the Department of Clinical and Experimental Medicine and Pharmacology of Messina University.
Fennel crushed fruits as infusions, tincture, syrups and honey are traditionally used (see section III.5 Traditional use) for the treatment of a variety of symptoms including:
•Dyspeptic complaints, a broad range of adverse symptoms including, among others, spasmodic ailments involving altered functional motility of local smooth muscles induced by anomalous hormonal secretions, Helicobacter infections, stress and psychological disturbances and other idiopathic causes;
•Bloating and flatulence, symptoms associated with an altered composition of intestinal flora mainly caused by food borne infections or physiological alterations causing a slowing down of the intestinal content transit;
•Infantile colic, a
•Primary dysmenorrhea, a condition associated with ovulatory cycles, caused by myometrial contractions induced by prostaglandins originating in secretory endometrium, which results in uterine ischemia and pain; and
•Catarrh, an excessive secretion of epithelial cells due to respiratory tract infections generally also inducing
These uses are substantiated mainly by empirical data deriving from investigations carried out into the constituents and their pharmacology, while only poor clinical data are available.
II. Clinical Pharmacology
Bitter fennel is characterized by a content of essential oil not lower than 40 ml per kg anhydrous fruit, whereas sweet fennel only contains not less than 20 ml of essential oil per kg anhydrous fruit.
The oil in bitter fennel fruits has been reported to contain not less than 60% anethole and 15% fenchone and not more than 6% estragole, whereas in sweet fennel fruits the oil contains not less than 80% anethole (as determined with reference to anethol R that consists of at least 99% trans– anethole) and not more than 7.5% fenchone and 10% estragole (European Pharmacopoeia, 1/2005:824; European Pharmacopoeia, 1/2005:825; Brand, 1993; Tóth, 1967; Trenkle K 1969, 1971 and 1972). The essential oils of bitter and sweet fennels also contain relatively small amounts of
Table 1- Compounds identified in essential oils obtained by steam distillation from ripe fruits of bitter and sweet fennels
(+) Monograph on bitter fennel fruit oil (European
(++)Monograph on sweet fennel fruit oil (Italian
Crushed or powdered fennel fruits gradually lose their volatile constituents upon aging (Czygan, 1989). Teabags examined 30 days after opening showed in general a loss of essential oil ranging from 4 to 10%; moreover, in these samples a decrease of anethole content and an increase of anisaldehyde content (considered as the degradation product of the former) was also evident (Bilia et al., 2002).
Some chemotypes are known for their lower content of
The essential oil contents of 10 samples of dry, ripe fennel fruits of different origin, obtained by hydrodistillation, were analysed by gas
A considerable variability among relative proportions of different compounds in fennel fruits has been observed in relation to the methodology used to extract the essential oil. Table 2 shows the differences observed among relative amounts of the main components extracted from the same sample (unknown variety) of fennel fruits by simultaneous
Table 2 – Relative amounts of main components extracted from fennel fruit by simultaneous
distillation–extraction (SDE) or supercritical fluid extraction (SFE) (+)
Chemical compositions of volatiles in infusions or microwave decoctions prepared from crushed fruits or in teas from
The fennel fruits also contain
This AR supports the establishment of individual Community herbal monographs and/or Community list entries on bitter fennel fruit, sweet fennel fruit and bitter fennel fruit oil that comply with the European Pharmacopoeia monographs 5th Ed.
II.2 Absorption, metabolism and excretion
No data available for fennel in human beings or animals.
After oral administration of
irrespective of the dose level, the principal metabolite (more than 90% of urinary 14C) was 4- methoxyhippuric acid (Caldwell and Sutton, 1988).
In mice and rats
II.3.1 Mode of action
The medicinal use of fennel is largely due to antispasmodic, secretolytic, secretomotor and antibacterial effects of its essential oil.
•Spasmolytic effect on contracted smooth muscles
Fennel fruit alcoholic extracts and oil exerted a relaxing effect on in vitro
The relaxant effect of fennel aqueous extract, ethanolic extract and essential oil on methacholine
Fennel oil significantly and
Fennel essential oil (5 to 25 ml of distillate administered to dogs by means of a catheter inserted into an intestinal fistula) (Plant and Miller, 1926) and anethole (10 to 25 ml/l of physiological solution in which an isolated mouse intestinal jejunum is plunged) (Imaseki et al., 1962) induced intestinal motility at low concentrations, but an intestinal relaxation was observed at concentrations higher than 50 mg/l.
•Secretolytic and expectorant effects
Anethole and fenchone vapour were given by inhalation to urethanized rabbits as doses of 1 to 243 mg/kg b.w. added to the steam vaporizer (the amount actually absorbed by the animals being considerably less, estimated as not more than 1% of that added to the vaporizer). Inhalation of anethole did not affect the volume but produced a
An increase of about 12% in mucociliary transport velocity was observed in isolated ciliated epithelium from the frog oesophagus 90 seconds after application of 200 µl of an infusion from bitter fennel (4.6 g per 100 ml of water)
Fennel aqueous extracts, in a concentration of 10% weight/volume, increased gastric acid secretion in the stomach of anesthetized rats from the basal level of 0.12 to 0.42 ml (p<0.02). It has been shown that fennel increases gastric acid secretion. An experiment showed that following administration of an fennel aqueous extract, the increase in acid production in
Subacute oral administration of an acetonic extract from fennel to adult female ovarectomized rats at
Estrogenic activity of
Fennel fruit extracts and oil as well as some oil components, exhibited in vitro strong inhibitory activities against the growth of a wide spectrum of bacteria and fungi known to be pathogenic for man and other species.
Fennel oil inhibited the growth of Escherichia coli (Minimal inhibitory concentration (MIC): 0.5% V/V), Staphylococcus aureus (MIC: 0.25%), Salmonella typhimurium (MIC: 1.0%) and Candida albicans (MIC: 0.5%) using the agar dilution method (Hammer et al, 1999). Significant antibacterial activity of the oil (10 μl of undiluted oil added to wells in the agar plates) was demonstrated against Brevibacterium linens, Clostridium perfringens, Leuconostoc cremoris and
Staphylococcus aureus (Ruberto et al., 2000). Earlier studies also demonstrated the antibacterial activity of the oil (Afzal and Akhtar, 1981, Ramadan et al., 1972).
In vitro growth of Candida albicans strain ATCC 10261 was inhibited by fennel essential oil (Ezzat, 2001).
Bactericidal activities of a number of plant essential oils, including fennel fruit oil, and of their isolated constituents were tested against Campylobacter jejuni, Escherichia coli, Listeria monocytogenes and Salmonella enterica (Friedman et al., 2002). Fennel fruit oil was shown to reduce bacterial activity of all tested bacteria (C. jejuni > S. enterica > E. coli > L. monocytogenes). As far as the antibacterial activity of isolated compounds is concerned, estragole had an inhibitory pattern close to that of the fennel oil; limonene showed an inhibitory activity only on C. jejuni and L. monocytogenes and
An essential oil, extracted by
Essential oil, extracted by steam distillation from fennel fruits and containing 83%
Growth of 4 Streptococcus strains (i.e. KCTC 3065, NHS 1DD, UBF GTFC, and
The essential oils of anise (500 ppm), fennel (2,000 ppm) and other olants showed a dose- dependent inhibitory effect on the growth of tested fungi including Aspergillus flavus, A. parasiticus, A. ochraceus and Fusarium moniliformis (Farag et al., 1989; Hasan, 1994; Soher, 1999; Soliman and Badeaa, 2002).
The aniseed and fennel oils were found to have a high antibacterial activity against Staphylococcus aureus (responsible for bases, sepses and skin infections), Streptococcus haemoliticus (causing infection of the throat and nose), Bacillus subtilis (infection in immunecompromised patients),
Pseudomonas aeruginosa (causing hospital acquired infection), Escherichia coli (responsible for urogenital tract infections and diarrhoea), Klebsella species and Proteus vulgaris (Singh et al., 2002).
II.3.2 Other studies
See section IV.1.1. Preclinical data
The hepatoprotective activity of steam distilled essential oil from fennel fruit was studied by Ozbek et al. (2003a) by using the carbon tetrachloride induced acute liver injury model in rats. When simultaneously administered with carbon tetrachloride, the fennel oil significantly reduced hepatotoxicity as shown by the decreased levels (p<0.01) of serum aspartate
These results were confirmed by Ozbek et al. (2004) with a steam distilled essential oil from fennel fruit (main components:
No such activity was detected by Ozbek et al. (2003b) in the diethyl ether extract obtained by maceration of fennel fruit for two hours, separation of the liquid phase and evaporation of the solvent
A lyophilized aqueous extract of fennel administered orally at 190 mg/kg b.w. (equivalent to crude herbal substance at 1,000 mg/kg) for 5 days significantly lowered the systolic blood pressure of spontaneously hypertensive (SH) rats (p<0.05), but had no effect on normotensive rats. The extract also significantly increased the urine output of SH rats, by 80% at day 3 (p<0.05), and increased renal excretion of sodium and potassium (p<0.05), suggesting that fennel acts mainly as a diuretic and natriuretic in the SH rats (El Bardai et al., 2001).
A hypoglycemic effect was observed in
•Local anaesthetic activity
In the rabbit conjunctival reflex test, solutions of
Fennel essential oil had a spasmogenic effect on smooth muscle of isolated
Anethole was reported to have a contractile effect on smooth muscle (Reiter and Brandt, 1985).
It was also reported to increase the
Addition of 0.5% of fennel to the diet of rats for 6 weeks shortened food transit time by 12% (p<0.05) (Platel and Srinivasan, 2001). Fennel oil increased the
Fennel administered orally at 24 mg/kg b.w. increased spontaneous movement of the stomach in unanaesthetized rabbits and reduced the inhibition of stomach movement induced by sodium pentobarbitone (Niiho et al., 1977).
An aqueous extract of fennel (10% w/v), perfused through the stomach of anaesthetized rats at 0.15 ml/minute and collected over periods of 20 minutes, significantly increased gastric acid secretion (p<0.02) to more than
III. Clinical efficacy
III.1 Preparations marketed in Europe
Fennel fruit, sweet (
Foeniculi, Species) is marketed in
Latvia since 1970 with the following indications: Orally as a carminative, for gastrointestinal disorders and spasms, as galactagogue increases
Sweet fennel herbal tea is authorised in
France since February 1990, traditionally used in the symptomatic treatment of digestive upsets such as epigastric distension, slow digestion, eructation, flatulence, with the following posology: 1.8 g 2 to 3 times daily.
Germany the authorised indications since 1996 for bitter fennel herbal tea are: symptomatic treatment of dyspeptic complaints such as minor gastrointestinal spasms, repletion and flatulence. For the relief of symptoms in coughs and colds with viscous mucilage. Posology: 2.5 g herbal substance/150 ml water
The indications authorised in
Austria for the herbal tea are the following:
Dyspeptic complaints such as mild, spasmodic
Posology: Adult daily dose:
Children, average daily dose:
Herbal tea is also authorised in the
Czech Republic as an adjuvant in mild gastrointestinal complaints such as bloating, flatulence and minor spasms and in catarrhs of the upper respiratory tract; posology: 1.5 g poured with 0.25 l of boiling water (extracted for 15 minutes) three times daily (no restrictions).
Poland herbal tea has been traditionally used over 30 years in digestive disorders, spastic complaints, feeling of fullness and flatulence, as spasmolytic and cholagogic. It is also used as expectorant in inflammations of upper respiratory tract and in lactagogue mixtures. Posology: Infusion made of 1 teaspoon of fruits in a glass of boiling water. Drink 1/3 – 1/2 of portion 3 – 2 times a day. For children in single doses of one teaspoon. Not abuse during pregnancy and lactation.
Hard capsules containing sweet fennel powder are authorised in
France since November 1990 with the following indications:
–Traditionally used in the symptomatic treatment of digestive upsets such as: epigastric distension, slow digestion, eructation, flatulence.
–Traditionally used as an adjuvant treatment for the painful component of functional digestive disorders.
Posology: 390 mg 3 times a day (if necessary: until 1,950 mg daily)
Bitter Fennel fruit oil
Bitter fennel fruit oil is authorised as a syrup in Germany since 1978 for the relief of symptoms in coughs and colds with viscous mucilage in children over one year. Posology: 3 times daily 1 cup, equivalent 0.003 g fennel oil
No authorised/registered products are on the market in the following European countries: Belgium, Ireland, Italy, The Netherlands, Portugal, Finland and Norway.
Various fixed combinations containing fennel are authorised/registered in different European countries.
Food supplements containing fennel are on the market.
III.2 Posology, duration of use, method of administration
There are no
The recommended dosage for adults and children over 12 years of age is supported by clinical experience and expert opinions (Brand, 1993; Czygan and Hiller, 2002; Dorsch et al., 2002; Leclerc, 1983; Valnet, 1990).
Fennel fruit (Blumenthal et al., 1998)
Adult and children over 12 years:
dose per day or in
multiple divided doses as a herbal tea or similar preparations.
Fennel tincture (Blumenthal et al., 2000): 5 to 7.5 ml two to three times daily
Fennel oil (Blumenthal et al., 1998): 0.2 ml essential oil, as single dose per day or in multiple divided doses.
The use in the paediatric age (see section III.4.1 Use in children) is not recommended for the presence of estragole, whose exposure should be minimised in young children.
The posology recommended by the HMPC per age category and in the different indications can be found in the corresponding Community herbal monographs/Community list entries.
Duration of use
Unless otherwise advised by a physician or pharmacist, one should not consume fennel oil for an extended period (several weeks) (Blumenthal et al., 1998).
Because of the poor evidence of clinical trials, considering the lack of available safety data on long- term use of fennel preparations and due to the potential toxicity of
If the symptoms persist during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
Method of administration: Oral use.
III.3 Clinical studies
Primary dysmenorrhoea, a condition associated with ovulatory cycle, is due to myometrial contractions induced by prostaglandins originating in secretory endometrium, which results in pain. Intensity of pain of thirty patients with moderate to severe dysmenorrhoea was recorded by using a linear analog technique for 5 days in three consecutive cycles (first cycle: no treatment; second cycle: treatment with mefenamic
Investigations available in human beings on the role of fennel in reducing pain in primary dysmenorrhoeal are very preliminary. However, the likelihood of the postulated effect is considerably increased by several in vitro studies showing that fennel fruit alcoholic extracts and oil exerted a relaxing effect on in vitro
III.4 Clinical studies in special populations
III.4.1 Use in children
The efficacy of fennel tea for treating infantile colic was addressed by Weizman et al. (1993).
Relief of colic symptoms was assessed as a decrease of cumulative crying to less than 9 hours per week. No side effects were noted in the treated infants with colic (Alexandrovich et al., 2003). As the postulated mechanism in the pathogenesis of colic is a spasm of the intestinal smooth muscles, the therapeutic effect of fennel fruit oil was interpreted as possibly secondary to a spasmolytic action.
Matricariae recutita L., Foeniculum vulgare M. var dulce and Melissa officinalis L. in the treatment of 93 breastfed colicky infants. The results showed that colicky infants treated with the extract improved within 1 week of treatment (Savino F et al., 2005).
Iten and Saller in 2004 published a comment to the statement of the German ‘Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin’ (BgVV, May 2001), where consumers are advised to reduce their intake of foods or fruits containing estragole for reasons of health. The crucial points of criticism concerned the transfer of data obtained in animal models to the human situation as well as the high doses of the applied monosubstance and difference in estragole metabolism between mice and men. The authors concluded admitting the lack of epidemiological and clinical studies on use of fennel tea but, at the same time, declared that in their opinion the probability of a serious cancerogenic potential risk connected with the consumption of fennel tea seems to be negligibly small.
Investigations available in human beings on the role of fennel in reducing pain in infantile colic are very preliminary. However, the likelihood of the postulated effect is considerably increased by several in vitro studies showing that fennel fruit alcoholic extracts and oil exerted a relaxing effect on in vitro
The missing data cannot be extrapolated from the use in adults and available data cannot be accepted for supporting the use in children for safety reasons, on the basis of Eur. Ph requirements for the content of estragole (no more than 5.0% in bitter fennel and no more than 10.0 % in sweet fennel). Considering that even authors, who are in favour of the use of fennel without limits in children admit the lack of epidemiological studies (the type of studies that could give more information on safety), according to the recommendations of the HMPC ‘Public statement on the use of herbal medicinal products containing estragole’, “the exposure of estragole to sensitive groups such young children, pregnant and breastfeeding women should be minimised.”
The use of fennel oil in children and adolescents under 18 years of age is therefore contraindicated (lack of data and presence of estragole).
The prescription of fennel tea in infants and children under 4 years of age should be restricted to the paediatrician and no general recommendation for the use without any medical advice should be given.
The indicative average daily dose for symptomatic treatment of mild, spasmodic
In children between 4 and 12 years of age, with the aim to minimise the exposure to estragole, a
III.4.2 Use during pregnancy and lactation
There are no clinical studies available.
According to Madaus (1938), fennel oil produces an excitation of the gravid uterus and can lead to abortion. An estrogenic activity (see section II.3.1) and
Moreover, a descriptive retrospective survey on 86 consultations due to ingestion of herbal infusion with abortive intent received at the Toxicological Information and Advisory Centre of Montevideo between 1986 and 1999 (Ciganda and Laborde, 2001) indicated that
In view of the
Despite the fact that the European Scientific Cooperative on Phytotherapy reports that the herbal substance and preparations of fennel at the recommended dosage may be used during pregnancy and lactation (ESCOP, 2003), no data are available in relation to the use of fennel during pregnancy and lactation at the recommended dosages. According to the recommendations of the HMPC ‘Public statement on the use of herbal medicinal products containing estragole’, “the exposure of estragole
to sensitive groups such young children, pregnant and breastfeeding women should be minimised.”
It is unknown if fennel constituents are excreted in human breast milk.
III.5 Traditional use
Fennel fruit has also been reported as useful in the treatment of dyspeptic complaints such as mild, spasmodic
Fennel fruit has also been reported to be in use in some areas for many years to relieve painful menstruation, symptoms of female climacteric and other purposes (Hare et al., 1916; Albert- Puleo, 1980; Zargari, 1991; Mills et al., 2000; Jahromi et al., 2003).
Fennel fruit (Xiaohuixiang) has been in use for many centuries in Chinese Medicine, generally as decoction with other herbs (L’Italia Agricola, 1989, Chinese Herbal Medicine 1999, p.203- 204) and the Chinese Herbal Medicine (1999,
For oral use in Traditional Chinese Medicine (TCM) the dosage is
According to the TCM, fennel fruit can be ‘hotted’ and wrapped in a bag (10 grams) for ironing the lower abdomen to treat abdominal pain of cold type (Liu Gan Zhong et al., 2003).
Fructus Foeniculi processed with salt acts to dispel “cold” from the interior and relieve pain. It is used for lower abdominal pain with cold sensation, dysmenorrhoea. This magisterial preparation described in appendix II D of the Chinese Pharmacopoeia, is traditionally prescribed by physicians when kidneys or renal function are involved.
Otherwise, according to the TCM criteria, fennel fruit should not be taken in the following conditions:
Internal “Heat” due to Yin Deficit (SATCM 2002)
–Febrile disease with persistent high fever (internal “Heat” in the Qi System) (Chinese Materia Medica , TianJin. 2001 )
–Late stage of febrile disease (“Heat” syndrome due to Yin deficiency) (SATCM 2002)
–Acute infections of the gastro – enteric tract (internal “Fire” and toxins) (SATCM 2002)
–Acute inflammation of the gastro – enteric tract such as gastritis, gastric or duodenal ulcer, irritable bowels disease, etc. (Endogenous “Heat” in Stomach and Intestine) (SATCM 2002)
–Constipation due to dryness (Deficit of body fluid due to Yin Deficiency) (SATCM 2002)
Fennel has been used as lactagogue since antiquity with no side effects reported (Keller, 1992).
The Treaty “Farmacologia Teorica e Pratica”, also named “Farmacopea Italiana” of Giuseppe Orosi (1851- Vincenzo Mansi
IV.1 Genotoxic and carcinogenic risk
IV.1.1 Preclinical data
•Mutagenicity and carcinogenicity
Aqueous and methanolic extracts of fennel did not show any mutagenic activity in the Ames test using Salmonella typhimurium strains TA 98 and TA 100, with or without metabolic activation (Morimoto et al., 1982; Yamamoto et al., 1982), whereas fennel oil (2.5 mg/plate) was mutagenic (Marcus and Lichtenstein, 1982). The two extracts showed no activity also in the Bacillus subtilis
Sweet fennel oil was found to be mutagenic in the Bacillus subtilis
From a series of studies in mice, Miller et al. (1983) concluded that anethole fed to female
Another bioassay carried out in
In nine Salmonella studies to detect
Anethole was found to be mutagenic in the mouse lymphoma assay which is known for its extreme sensitivity and poor selectivity for genotoxicity (Gorelik, 1995; Heck et al., 1989; Caldwell, 1993; Casciano et al., 1992).
Other results showing the absence of mutagenic potential of anethole include assays in Escherichia coli (Sekizawa and Shibamoto, 1982) and in Saccharomyces cerevisiae (Nestmann and Lee, 1983).
A mouse micronucleus assay was negative, with no micronuclei found at 6 and 30 hours after anethole administration (Marzin, 1979). Similarly, in the mouse bone marrow micronucleus test, oral
Very low levels of DNA adducts were evidenced after administration of anethole to mice, whereas 150 and 220 times as many adducts were detected following administration of safrole and estragole, respectively (Phillips et al., 1984).
Unscheduled DNA synthesis (UDS) assays in rat hepatocytes did not indicate any mutagenic potential of anethole (Howes et al., 1990; Muller et al., 1994).
Anethole has three primary metabolites in the rat and the pathway of toxicological concern is that of epoxidation of the 1,2 double bond at the side chain; in fact,
To date very little is known about the metabolism of
In 1999, the USA Expert Panel of FEMA (Flavour and Extract Manufacturers’ Association) released a review of scientific data relevant to the safety evaluation of
In the 51st meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) a document on safety evaluation of
Estragole, a minor constituent of fennel oil, has shown its ability to produce genotoxic effects in bacteria, yeasts and mammalian cells, while no mutagenic activity was observed in Salmonella typhimurium probably because of the absence of the complex metabolism needed for bioactivation (EMEA/HMPC, 2005).
It has been shown that estragole and its
Estragole or its metabolite,
The EMEA/HMPC (2005) assessment is that the profiles of metabolism, metabolic activation and covalent binding of estragole are
The major metabolic pathway of low doses of estragole as established in rats and mice is
In conclusion, fennel oil extracts were found to be mutagenic in vitro and studies carried out in laboratory animals showed a weak mutagenic potential of anethole. However,
Several studies have shown the carcinogenic effects of estragole and some of its metabolites in mice (mainly malignant liver tumours). The EMEA/HMPC (2005) assessment is that the profiles of metabolism, metabolic activation and covalent binding of estragole are
IV.1.2 Clinical data
No data available.
In Swiss albino mice with Ehrlich ascites tumour (EAT) in the paw, anethole administered orally at 500 or 1,000 mg/kg on alternate days for 60 days significantly and
Anethole at a concentration below 1 mM has been shown to be in vitro a potent inhibitor of tumour necrosis factor
In the mouse bone marrow micronucleus test, oral
•Antioxidant activity of fennel extracts
The inhibitory effects of some constituents isolated from a methanolic extract of fennel fruit were investigated on the oxidation of linoleic acid and on the activation of inactive hyaluronidase. Among the test compounds, six stilbene trimers, miyabenol C,
Antioxidant activity of fennel oil against lipid peroxidation was demonstrated in the thiobarbituric acid reactive species assay and in a micellar model system (Ruberto et al., 2000).
The antioxidant activities of fennel fruit aqueous and ethanolic extracts were compared in vitro to those of standard antioxidants such as BHA, butylated hydroxutoluene and tocopherols in various antioxidant assays including total antioxidant, free radical scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, metal chelating activities and reducing power (Oktay et al., 2003). Both fennel extracts showed effective reducing power, free radical scavenging, hydrogen peroxide scavenging and metal chelating activities.
Antioxidant activity of an aqueous extract from fennel fruit (as evaluated in vitro from amounts needed for 50% scavenging of superoxide radicals or for 50% inhibition of lipid peroxide or for 50% inhibition of hydroxyl radicals) was found to be higher than that of ascorbic acid and comparable to those of 4 other umbelliferous fruits (Satyanarayana et al., 2004).
IV.2.1 Acute toxicity
Oral administration of an ethanolic extract of fennel to mice at 0.5, 1 and 3 g/kg b.w. caused no mortality and no significant difference in body and vital organ weights or in external morphological, haematological or spermatogenic parameters in comparison with the control group over a period of 24 hours (Shah et al., 1991).
Values of the oral LD50 corresponding to 3.8 g/kg b.w. (Opdyke, 1974) and 3.12 g/kg b.w. (von Skramlik, 1959) had been reported for fennel oil in rats, but in a more recent study the oral LD50 was estimated to be 1.326 g/kg b.w. (Ostad et al., 2001). In this last study, animals treated with the highest dose showed prostration, sedation, respiratory distress, movement disorders, unresponsiveness to external stimulation, hind limb weakness, tremor and fasciculation in dorsal muscles during the first 24 h from single dose ingestion. In treated animal groups with lower doses the most evident adverse effect was sedation. In all groups, the amount of 24h urine increased parallel to the amount of fennel oil administered.
The dermal LD50 in rabbits was estimated to be higher than 5,000 mg/kg (Opdyke, 1974).
Fennel extracts in high dosages resulted in abnormal movements, tremor, fasciculation and drowsiness in experimental animals (Ostad et al., 2000).
Oral LD50 values per kg b.w. were determined for
Anethole activates the central nervous system and its excessive use may lead to convulsions (Zagari, 1991).
IV.2.2 Subchronic toxicity
Male rats receiving 0.25% of anethole in their diet for 1 year showed no toxic effects, while other receiving 1% for 15 weeks had slight oedematous changes in liver cells (Hagan et al., 1967).
Oral administration in drinking water of an ethanolic extract of fennel to mice at 100 mg/kg b.w. and day for 3 months caused significant body weight gain in male mice and weight loss in females. Alopecia was observed in 3/10 males, swollen testes in 1/10 males and penile erection in 2/10 males. No toxic symptoms were observed in females. It caused no significant differences in mortality or in haematological and spermatogenic parameters in comparison with the control group (Shah et al., 1991).
IV.2.3 Reproductive toxicity
Malini et al. (1985) showed estrogenic activity of the seed extract in both male and female rats. The protein concentration was found to be significantly decreased in testes and vas deferens and increased in seminal vesicles and prostate gland, following oral administration of an acetone extract of Foeniculum vulgare seeds at the doses of 150 μg/kg and 250 μg/kg for 15 days in male rats. Moreover, the activity of acid and alkaline phosphatase decreased in all these tissues. Only the alkaline phosphatase was unchanged in vasa. The same doses of the extract, after oral administration for 10 days in female rats, caused vaginal cornification and estrus cycle. The lower doses caused increase in weight of mammary glands and the higher doses increased the weight of oviduct, endometrium, myometrium, cervix and vagina.
Ostad et al. (2004) exposed cultivated limb bud cells obtained from day 13 rat embryo to concentrations of fennel essential oil between 0.0186 and 9.3 mg/ml for 5 days at 37°C. A significant reduction in the number of stained differentiated foci due to cell loss rather than decreased cell differentiation was observed in the presence of fennel essential oil. These findings were interpreted as a toxic effect of fennel essential oil on foetal cells with no evidence of teratogenicity.
The body of the data indicates that reproductive system is a target for the action of fennel extracts and its principal constituent
Persons with hypersensitivity to the active substance or to Apiaceae (Umbelliferae) (aniseed, caraway, celery, coriander and dill) or to anethole should avoid the use of fennel preparations and fennel oil. A
The use of fennel oil in children and adolescents under 18 years of age is contraindicated because of the lack of data and because of the presence of estragole.
IV.4 Special warnings and precautions for use
The use of fennel tea is not recommended in children under 4 years of age due to the lack of adequate data and paediatrician advice should be sought.
Preparation with high fennel content (> 7 g of herbal substance) should not be taken for more than two weeks without medical advice.
If excessive doses are ingested, the estrogenic activity of fennel oil may affect hormone therapy, including the oral contraception and hormone replacement therapy (see sections IV.6 Interactions and II.3.1. Mode of action – Estrogenic effects).
Patients should seek medical advice if symptoms persist for more two weeks or worsen upon administration of the medicinal product.
IV.5 Undesirable effects
Allergic reactions to fennel, affecting the skin or the respiratory system, occur rarely (Levy, 1948; Schwartz et al., 1997; Blumenthal et al., 1998).
Enzyme immunoassay inhibition studies with one patient’s serum revealed
Rare cases of contact dermatitis to anethole containing preparations (Andersen, 1978; Franks, 1998) have been reported.
It has been observed that fennel contains
Fennel contains small amounts of bergapten, a linear furocoumarin that might be responsible for phototoxicity (Kwon et al., 2002).
Fennel contains a high amount of minerals, mainly calcium, magnesium, iron, zinc, manganese, and copper. It has been shown in the rat that
fennel led to a 83% reduction in ciprofloxacin Cmax while Tmax remained virtually unaffected resulting in a significant reduction in area under the curve. This interaction has not been observed in humans (Zhu et al., 1999).
Investigations showing liver
In fact, experiments in which rats were injected
Limonene was found to increase levels of reduced glutathione in mouse liver (Reicks and Crankshaw, 1993) and
Excessive doses of preparations containing fennel oil may affect hormone therapy or oral contraception (see section IV.4 Special warnings and precautions for use). If the patient is on other medications, he/she should seek medical advice.
No data available.
The traditional uses of fennel for “dyspeptic complaints such as mild, spasmodic
Clinical trials showing the efficacy of fennel as a smooth muscles spasmolytic remedy are limited and preliminary, but pharmacological data show a
significant relaxing effect of fennel alcoholic extracts and essential oil on tracheal, ileal and uterine smooth muscles contracted by several
Moreover, the ability to counteract prostaglandins actions may also explain the
It has been shown that both anethole and estragole given intravenously (10 mg/kg) elicit in the laboratory animal vagal effects causing a transitory bradycardic and depressor effect (de Siqueira, 2006).
Lastly, when considering the plausibility of the above indications, particularly with reference to inflammation of mucous membranes of upper respiratory tract, bloating and flatulence, the likely role of a number of compounds detected in fennel fruit and very active in inhibiting growth of pathogenic bacteria and fungi should not be underestimated.
On the basis of
i)for symptomatic treatment of mild, spasmodic
ii)for symptomatic treatment of minor spasm associated with menstrual periods;
iii)used as an expectorant in cough associated with cold.”
No other traditional medicinal uses of fennel are supported by adequate data.
For bitter fennel oil, traditional use is known only as “an expectorant in cough associated with cold” and is recommended by the HMPC.
For fennel fruit,