Community herbal monograph on
Rosmarinus officinalis
L.,
folium
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Rosmarinus officinalis
L., folium (rosemary leaf)
i) Herbal substance
Whole or fragmented, dried leaf
ii) Herbal preparations
a) Comminuted herbal substance
b) Extract (DER 1:17.5-18.9), extraction solvent:
liqueur wine
c) Extract (DER 1:12.5-13.5), extraction solvent:
liqueur wine
d) Expressed juice (DER 1:1.8-2.2) from
Rosmarini herba recens
e) Liquid extract (DER 1:1), extraction
solvent ethanol 45% V/V
Well-established use
Traditional use
Herbal substance and/or comminuted herbal
substance as herbal tea for oral use and use as
bath additive.
Herbal preparations in solid or liquid dosage forms
for oral use.
Herbal preparations in liquid dosage forms for use
as bath additive.
The pharmaceutical form should be described by
1 The material complies with the Ph. Eur. monograph (ref.: 01/2008: 1560).
2 The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
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Well-established use
Traditional use
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Adolescents, adults
Oral use
Indication 1)
Traditional herbal medicinal product for
symptomatic relief of dyspepsia and mild
spasmodic disorders of the gastrointestinal tract.
Use as bath additive
Indication 2)
Traditional herbal medicinal product as an
adjuvant in the relief of minor muscular and
articular pain and in minor peripheral circulatory
disorders.
The product is a traditional herbal medicinal
product for use in specified indications exclusively
based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adolescents
,
adults, elderly
Oral use
Indication 1)
a) Herbal substance as herbal tea preparation:
Daily dose: 2-6 g
Single dose: 1-2 g in 150-250 ml of boiling
water
To be taken 2-3 times daily
b) Extract (DER 1:17.5-18.9), extraction solvent:
liqueur wine:
10 to 20 ml 2-3 times daily
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c) Extract (DER 1:12.5-13.5), extraction solvent:
liqueur wine:
20 ml 1-2 times daily
d) Expressed juice (DER 1:1.8-2.2):
5 ml containing 100% expressed juice
2-3 times daily
e) Liquid extract (DER 1:1, 45% ethanol V/V):
2-4 ml daily
Use as bath additive
Indication 2)
f) 1 litre of decoction of herbal
substance/comminuted herbal substance (1:20)
added to bath water (twice weekly)
g) 50 g of herbal substance for a full bath (once
daily)
The use in children under 12 years of age is not
recommended (see section 4.4 ‘Special warnings
and precautions for use’).
Duration of use
Indication 1)
If the symptoms persist longer than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Indication 2)
If the symptoms persist longer than 4 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Indication 1)
Oral use.
Indication 2)
Use as bath additive.
Recommended bath temperature is 35 – 38°C, for
10 to 20 minutes.
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4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Oral use
Obstruction of bile duct, cholangitis, liver
disease, gallstones and any other biliary
disorders that require medical supervision and
advice.
Use as bath additive
Full baths are contraindicated in cases of large
skin injuries and open wounds, acute skin
diseases, high fever, severe infections, severe
circulatory disturbances and cardiac failure.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children under 12 years of age is not
recommended due to lack of adequate data and
because medical advice should be sought.
If symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
practitioner should be consulted.
Use as bath additive
In cases of hypertension, a full hot bath should be
used with caution.
Articular pain accompanied by swelling of joint,
redness or fever should be examined by a doctor.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established. In the absence of sufficient
data, the use during pregnancy and lactation is
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not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Hypersensitivity (contact dermatitis and
occupational asthma) has been reported. The
frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
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Adequate tests on reproductive toxicity,
genotoxicity and carcinogenicity have not been
performed.
Well-established use
Traditional use
Not applicable.
15 July 2010
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
7
2. Historical data on medicinal use ........................................................................................ 7
2.1. Information on period of medicinal use in the Community ........................................
7
preparations and indications.......................................................................................
7
3. Non-Clinical Data ............................................................................................................. 10
preparation(s) and relevant constituents thereof ......................................................... 1
0
3.1.1. Assessor’s overall conclusions on pharmacology................................................. 2
0
preparation(s) and relevant constituents thereof ......................................................... 2
1
3.2.1. Assessor’s overall conclusions on pharmacokinetics ............................................ 2
1
preparation(s) and constituents thereof ..................................................................... 2
2
3.3.1. Assessor’s overall conclusions on toxicology ...................................................... 2
5
4. Clinical Data ..................................................................................................................... 25
4.1. Clinical Pharmacology ....................................................................................... 2
5
including data on relevant constituents ...................................................................... 2
5
4.1.1.1. Assessor’s overall conclusions on pharmacodynamics....................................... 2
6
including data on relevant constituents ...................................................................... 2
6
4.2. Clinical Efficacy ................................................................................................ 2
6
4.2.1. Dose response studies.................................................................................... 2
6
4.2.2. Clinical studies (case studies and clinical trials).................................................. 2
6
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 2
7
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 2
7
5. Clinical Safety/Pharmacovigilance................................................................................... 27
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 2
7
5.2. Patient exposure .............................................................................................. 2
7
5.3. Adverse events and serious adverse events and deaths ......................................... 2
8
5.4. Laboratory findings .......................................................................................... 2
9
5.5. Safety in special populations and situations ......................................................... 2
9
5.6. Overall conclusions on clinical safety ................................................................... 3
0
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1.
Introduction
Rosemary (
Rosmarinus officinalis
L.) belongs to the family Lamiaceae (Labiatae) and has been an
important medicinal plant since earliest times. It is also a commonly used spice and flavouring agent.
Its essential oil is used therapeutically, in particular in balneology.
It was recognised for its medicinal and cosmetic properties in ancient Greece and by the Romans. In
the middle ages, Rosemary oil was distilled for medical purposes and the alcoholic distillate was
probably the first popular perfume.
The plant is native to the Mediterranean regions but has spread to all parts of the world. The leaves
are sessile, tough, linear to linear-lanceolate, 10 mm to 40 mm long and 2 mm to 4 mm wide, and
have recurved edges. The upper surface is dark green and glabrous, the lower surface is greyish-green
and densely tomentose with a prominent midrib (Ph Eur 2001).
There is extensive consumption of the plant. It is mentioned in the literatures that, for the period
1980-1984, 400 to 500 tons were used, with most of this in Western Europe and USA (Chandler,
1995).
The name is derived from the Latin ros (roris), meaning dew, and marinus, meaning the sea, being
known as the ‘dew of the sea’.
In the Mediterranean area, it blooms throughout the year and flowering is most abundant in spring.
Rosemary is mentioned in Anglo-Saxon herbals at the 11
th
century and it is believed that it was grown
in Britain prior to the Norman Conquest. It is widely held to be a single species with several subspecies
and varieties, but there are claims for additional species. The structure of the carbon skeleton of the
main constituents of the essential oils point to three biogenetic types: the eucalyptol type (Italy,
Morocco and Tunisia), the camphor-borneol type (Spain) and the alpha-pinene-verbenone type
(France, Corsica). Bog rosemary (
Andromeda
species) and wild or March rosemary (
Ledum palustre
L.)
are members of the family Ericacea and not related to rosemary (Chandler, 1995).
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Whole or cut dried leaf of
Rosmarinus officinalis
L. (Ph. Eur. monograph ref.:01/2008:1560)
Herbal preparation(s)
Comminuted herbal substance
Liquid extracts
Expressed juice
Essential oil
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
N/A
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1.2.
Information about products on the market in the Member States
Rosmarinus Aetheroleum (Rosemary Essential oil)
Countries Year Preparations Indications
Posology
Germany 1976
Trad.use
Bath additive Traditional use to
support the function of
the skin
If necessary 1 x daily:
10 ml bath additive /100 ml
water for 10-20 min at 34-37ºC
13,5 g rosemary oil /100 ml
(=104 g) bath additive
Every 2-3 days:
3 ml bath additive/150 ml water
for 10-30 min at 35-39ºC
13 g rosemary oil/100 ml
(=104 g) bath additive
1976
WEU
Bath additive Auxiliary treatment in
conditions of exhaustion
If necessary 3-4 x / weekly
10 ml bath additive / 150 ml
water for 10-20 min at 34-37 ºC
48 g rosemary oil / 120 ml bath
additive
If necessary 2-4 x / weekly
10 ml bath additive / 100 ml
water for 10-20 min at 34-37 ºC
20.8 g rosemary oil / 100 ml
(=104 g) bath additive
If necessary 3-4 x / weekly
20 ml bath additive/100 water for
10-20 min at 34-37 ºC
10 g rosemary oil /100 g bath
additive
Maximal 1 x daily
20 ml bath additive/150 ml water
for 10-20 min at 35-38 ºC
25 g rosemary oil /100 g bath
additive
1990
WEU
Bath additive Same indications as
previous
Same
Ointment
3 cm ointment
containing 6 g
rosemary oil/
100 g
ointment.
For the symptomatic
treatment of muscle and
joint pain and in
circulatory disturbance.
2-3 x daily
Contraindications - Not
to be used in bronchial
asthma, whooping
cough, pseudo-croup.
Adverse reactions –
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Countries Year Preparations Indications
Posology
urge to cough, bronchial
and laryngeal spasm
Austria
1994
Tradition
al use
100 g solution
contain 5 g
essential oil as
bath additive
Stimulation of
circulation
For a full bath 30 ml
Rosmarinus folium (Rosemary leaf)
Countries Year Preparations Indications
Posology
Spain
1976
Comminuted
herbal
substance for
herbal tea
Improvement of
digestion
1-2 g/250 ml, 2-3 times/day (2-
4 g/day)
1990
Powdered
herbal
substance
(capsules)
Dispepsia, improvement
of digestion
2 caps (250 mg) 3 times/day
Poland
30 years Infusion
Dyspeptic complaints
Improvement of hepatic
and biliary function and
in dyspeptic complaints
2 g, 1-2 times/day
Decoction
(External use)
Adjuvant therapy in
rheumatic conditions
and peripheral
circulatory disorders.
Adjuvant therapy in
rheumatic conditions,
myalgia and peripheral
circulatory disorders
1 liter of decoction (1:20) added
to bath water (twice weekly)
Germany 1976
Oral use
Extract
(1:17.5-18.9),
extraction
solvent:
liqueur wine
Traditional use to
support the cardiac and
circulatory function
2-3 x daily 20 ml; 100 g liquid
contain 94.816 g extract; 700 ml
= 721 g liquid
2-3 x daily 10 ml
Extract
(1:12.5-13.5),
extraction
solvent:
liqueur wine
Same
1-2 x daily 20 ml
Expressed
juice (1:1.8-
2.2) - Rosm
herba recens
Same
2-3 x/daily, 5 ml containing
100% expressed juice
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Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify:
Belgium
MA
TRAD
Other TRAD
Other Specify: only in combinations
Bulgaria
MA
TRAD
Other TRAD
Other Specify: only in combinations
Cyprus
MA
TRAD
Other TRAD
Other Specify: No RP
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No RP
Denmark
MA
TRAD
Other TRAD
Other Specify: No RP
Estonia
MA
TRAD
Other TRAD
Other Specify: No RP
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify:
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify: only in combinations
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No RP
Italy
MA
TRAD
Other TRAD
Other Specify: No RP
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No RP
Norway
MA
TRAD
Other TRAD
Other Specify: No RP
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No RP
Slovenia
MA
TRAD
Other TRAD
Other Specify: No RP
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify: No RP
United Kingdom
MA
TRAD
Other TRAD
Other Specify: Only in combinations
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
RP: registered products
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1.3.
Search and assessment methodology
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
Rosemary was used in traditional Greek and European medicine as a tonic, stimulant, and carminative
for dyspepsia, headache, and nervous tension. The ancient Greeks used rosemary to strengthen the
memory.
In different regions of the world, the use varies.
In traditional Chinese medicine, rosemary was used for headaches.
In the Indian Materia Medica (Nadkarni, 1999), rosemary oil it is described to have a carminative and
stimulant action.
Rosemary was used topically to treat cancer in ancient Greece and South America (Hartwell, 1982).
The Eclectic physicians used the oil of rosemary in 2 to 10 drop doses for colic, nervous disorders, and
painful or delayed menses (Felter and Lloyd, 1983). Women have used rosemary for minor menstrual
complaints.
Rosemary is used as an abortive agent in Brazilian folk medicine. It is traditionally referred to as an
emmenagogue and is generally avoided during pregnancy. It is claimed to stimulate bile. Rosemary is
said to prevent baldness when used as a hair tonic.
The following uses are reported in the literature: as an antiseptic, diuretic, antidepressant and
antispasmodic, as well as for cold, influenza, rheumatic pain. The oil is reported to have antimicrobial
properties and to have a relaxing effect on tracheal smooth muscles. (Erenmemisoglu, 1997; Chandler,
1995).
In folk medicine, rosemary is put on dressings for healing wounds and for eczema. It is also used as an
insecticide, as a preservative and antioxidant for meals and fats (Wichtl, 2004).
Regulatory status
Rosemary oil
Rosemary oil was notified for Generally Recognized as Safe (GRAS) status by the Fragrance and
Essence Manufacturers Association of the USA (FEMA) in 1965 and has been listed by the U.S. Food
and Drug Administration (FDA) for food use (GRAS). In 1970 the Council of Europe included rosemary
oil in the list of substances, spices and seasonings deemed admissible for use, with a possible
limitation of the active principles in the final product (EFSA, 2008 citing Opdyke, 1974).
2.2.
Information on traditional/current indications and specified
substances/preparations
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
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Bibliographic sources:
A) Pharmacopée Française - Préparation Officinale, 1980 (Romarin)
Justified by the use:
Oral use:
1.
Spasmolytic
Infusion or decoction – 5 to 10 g/l; Infusion for 15 m. Decoction for 30 min 200 to 400 ml/day
Liquid extract – 3 to 5 g/day
Essential oil – 3 to 4 drops, 3-4 times/day
Local application
2.
Antiseptic and wound healing
Alcoholic solution 2 % V/V essential oil
Justified by the pharmacological properties:
3.
Spasmolytic, cholagogic, choleretic
Extracts, tinctures, essential oil: several pharmaceutical specialties
Contra-indications: Pregnancy, prostatic affections and dermatosis
B) British Herbal Pharmacopoeia - 1983
Action
1.
Carminative, spasmolytic, Thymoletic, Sedative, Diuretic, Antimicrobial
2.
Topically: rubefacient, mild analgesic, parasiticide
3.
Specific indications: Depressive states with general debility and indications of cardio-vascular
weakness
4.
Combinations used – May be used with Avena, Cola and Verbena in depression; with Salvia,
Gelsemium and Valerian in migraine
5.
Preparations and dosage: dried leaves and twigs
6.
Dose: 2-4 g or by infusion. Liquid extract 1:1 in 45 % alcohol. Dose 2-4 ml
C) ESCOP – 1997
Indications
Oral use
Improvement of hepatic and biliary function and in dyspeptic complaints.
External use
Adjuvant therapy in rheumatic conditions and in peripheral circulatory disorders.
Promotion of wound healing and as a mild antiseptic.
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Preparations and posology
Oral use
Infusion: 2-4 g of rosemary daily
Fluid extracts (1:1, 45 % ethanol v/v): 1.5-3 ml daily
Tincture (1:5, 70 % ethanol): 3-8.5 ml daily
External use
Ethanolic extract (1:20)
Essential oil (2 % V/V) in ethanol, as an antiseptic
1 litre of decoction (1:20) added to bath water (twice weekly)
D) Blumenthal (The Complete German Commission E Monographs, 1998)
Indications
Oral use – Dyspeptic complaints
External use - Supportive treatment for rheumatic diseases; Circulatory problems
Dosage
Internally – Daily dose
4-6 g drug, 10-20 drops essential oil; equivalent preparations
Ed. Note:
The essential oil dosage appears excessive and possibly unsafe. A more reasonable dosage
for internal use would be 2 drops (1 ml).
Externally
50 g to a full bath; 6-10 % essential oil in semi-solid and liquid preparations; equivalent preparations
Assessor’s comments (oral use):
Comparing both proposals for the posology, the editor’s note seems more reasonable:
Daily dosage: 4 – 6 g herb containing 1.2 % (V/m) essential oil; Corresponding: 48 – 72 µl essential
oil/day (equal to 0.048 – 0.072 ml essential oil).
In the European Pharmacopoeia, the density of rosemary essential oil is reported as 0.895 to 0.920
(M/V) -> approximately 0.90.
Considering that comparable essential oils weigh 19 mg per drop, the following calculation should be
correct:
Minimum: 48 µL x 0.9 (dens.) = 43.2 mg -> 43.2 mg/19 mg = 2.27 drops, rounded: 2 drops
Maximum: 72 µL x 0.9 (dens.) = 64.8 mg -> 64.8 mg/19 mg = 3.41 drops, rounded: 3 drops
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3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
(e.g. primary pharmacodynamics, secondary pharmacodynamics, safety pharmacology,
pharmacodynamic interactions)
Composition
Rosemary leaves contain 1,2-cineole, α-pinene, apigenin, betulin, betulinic acid, caffeic acid, camphor,
carnosic acid, carnosol, carnosol isomer, methyl carnosate, cirsimaritin, diosmin, hesperidin, limonene,
luteolin 3'-O-beta-D-glucuronide, luteolin 3'-O-(3"-O-acetyl)-beta-D-glucuronide, oleanolic acid,
rosmadial, rosmanol, rosmarinic acid, scutellarein, thymol, ursolic acid (Senorans et al., 2000;
Okamura et al., 1994).
A diterpene, rosmariquinone, has been isolated from a methanolic extract of
Rosmarinus officinalis
L.
(Houlihan et al., 1985).
The leaves contain 0.5 to 2.5 % of a volatile oil, consisting of 0.8-6 % esters and 8-20 % free alcohols
(Chandler, 1995).
The essential oil is a colourless or pale yellow liquid with a camphoraceous taste and contains
monoterpenes, phenols, sesquiterpenes, monoterpenoid ethers, monoterpenoid ketones,
monoterpernoid alcohols, and monoterpenoid esters, camphor, eucalyptol, α-pinene, borneol (Fahim et
al., 1999; Steinmetz et al., 1987).
It contains 1,8-cineole (20–50 %), α-pinene (15-25 %), camphor (10-25 %), bornyl acetate (1-5 %),
borneol (1-6 %), camphene (5-10 %) and α-terpineol (12-24 %), limonene, β-pinene, β-caryophyllene
and myrcene (ESCOP, 1997).
The 40-day-old
in vitro
proliferating shoots of
Rosmarinus officinalis
L. var.
genuine
forma
erectus
produced an appreciable quantity of essential oil, i.e., 1.8 % fresh weight, which was similar in its
constituents to that obtained from 1-year-old plants, whether naturally grown or
in vitro
-raised potted
plants. The quantity of the various constituents identified was marginally less in the former case than
the latter two kinds, with the exception of bornyl acetate and 1,8 cineole, where the concentration was
higher (Jain et al., 1991).
During an investigation period of 17 months, the shoot culture of rosemary accumulated varying
amounts of carnosic acid and carnosol, which were also present in callus culture but about 20- to 80-
fold lower than in the shoot culture. In suspension culture, only carnosic acid and no carnosol could be
detected. The level of carnosic acid in suspension culture was threefold less than detected for the
callus culture on average. The amount of rosmarinic acid produced in shoot culture and callus culture
were comparable, whereas in suspension culture higher concentrations of rosmarinic acid could be
measured than in shoot and callus culture. Thus, the content of carnosic acid, carnosol, and rosmarinic
acid in the extracts depended on the differentiation grade of the cell culture type (Kuhlmann et al.,
2006).
Methanolic extracts from the leaves of
Rosmarinus officinalis
harvested from different locations
of
Turkey at four different times of the year were
analyzed by HPLC, and their radical scavenging
capacities
and antioxidant activities were studied by various
assays. The amounts of carnosol, carnosic
acid and rosmarinic
acid, active constituents of rosemary, varied in different
geographical regions of
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 10/31
growth, and also showed
a seasonal variation. The levels of the constituents were
higher in the warm
months of June 2004 and September
2004 (Yesil-Celiktas et al., 2007).
Carnosol
Carnosic acid
R
osmarinic acid
T
fo
he principal antioxidative components of the extracts are the phenolic diterpenes carnosol (molecular
rmula C
20
H
28
O
4
) and carnosic acid (molecular formula C
20
H
28
O
4
).
The amount and nature of the oil
s
may also
(del
vary with the subspecies, part of the plant used, the geographic
ource and the method of preparation. Phenolic diterpenes, flavones and rosmarinic acid distribution
vary during the development of leaves, flowers, stems and roots of
Rosmarinus officinalis
Baño et al., 2006).
1.
In vitro
stu
dies
Spasmolytic activity
some medicinal plants, including Rosemary, prepared from 1 part of the plant and 3.3 parts of etha
(31% w/w). The guinea pig ileum was employed and acetylcholine and histamine were used as
spasmogens. In histamine–induced contractions all plants, except Melissa exhibited a significant
increase of the DE
50
and
and Niklas, 1980).
decreased the maximal possible contractility induced by histamine (Forster
tha piperita
L.,
Salvia officinalis
L.,
Rosmarinus
officinalis
L.) were investigated
for their spasmolytic action on the longitudinal musculature of guinea-pig ileum. The concentration of
the components of the oils influences their action. The three essential oils show a spasmolytic action.
Pinene always induces spasms and the other components give rise to the double spasmogen-
spasmolytic effect. The stimulating action of pinene, which is present at a higher content in rose
(21.4 %), can be observed (Taddei et al., 1988).
mary
ese three plant emulsions were tested in doses between 0.1 and 1 mg/kg i.v., in
male guinea pig, using the experimental method of Boissier and Chivot’s. Oddi’s sphincter, contracted
by morphine hydrochloride (1 mg/kg i.v.) prolapses following injection of the three plants. The time to
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 11/31
A study was performed to test the antispasmodic activity of 2.5 and 10.0 ml/l of alcoholic extracts of
nol
Three essential oils (
Men
In another study, th
return to normal of Oddi’s sphincter is accelerated in relation to the dose of the various essences
(Giachetti et al., 1988).
The spasmolytic activity (against BaCl2 and acetylcholine) of the major components of the essential
oils of several aromatic plants was studied. Camph
two spasmogens studied (Cabo et al., 1986).
or revealed no agonistic activity against either of the
Antioxidant activity
A mixture of α-tocopherol and rosemary extract, as additives each at 0.035 % (total 0.07 %)
expressed very strong an
at 5ºC (Wada and Fang, 1994).
tioxidant activity in sardine oil stored at 30ºC, 50ºC and dried sardine meat
Four diterpenoids (carnosic acid, rosmanol, carnosol and epirosmanol) isolated from the leaves of
Rosmarinus officinalis
by bioassay-directed fra
xanthine/xanthine oxidase system, showi
al., 1995).
ctionation, inhibited superoxide anion production in the
ng to be protective against oxidative stresses (Haraguchi et
Inhibition of the growth of 6 strains of food associated bacteria and yeasts by carnosol and ursolic acid
was achieved at concentrations of 150
g ml
-1
for carnosol to the greatest extent. Butylated
Hydroxyanisole (BHA) proved a superi
Butylated Hydroxytoluen (BHT) (Collins and Charles, 1987).
,
or inhibitor to ursolic acid which itself was more effective than
A study on the variability of rosemary and sage and their volatile oils on the British market has been
performed. The antioxidative properties of the various samples were determined and found to be
variable based on the geo
graphical location and type of processing (Svoboda, 1992).
The concentration of phenolic diterpenes in commercially available extracts of
Rosmarinus officinalis
determined by HPLC with electrochemical detection ranged from 2.8 to 22.5 %. Antioxidant activity of
extracts under simultaneous storage and thermal stress depended directly on the concentration of
phenolic diterpenes. Differences in rates of degradation of in
temperatures were obtained (Schwarz et al., 1992).
dividual phenolic diterpenes at different
In a sardine oil model system, a mixture of α-tocopherol and rosemary extract showed a significantl
stronger antioxidant effect, as it prolonged the induction period for 10 and 16 days longer than
tocopherol alone and rosemary extract alone, respectively. Treatment of samples with this mixture al
led to a lower rate of decomposition of highly unsaturated fatty acids, myoglobin and haemoglobin,
and triglyceride compared to samples treated with tocopherol or rosemary extract alone (Fang and
Wada, 1993).
y
α-
so
To test
in vitro
conditions the action of
R. officinalis
L. i
hydroxyl radicals, which may be implicated directly or indirectly in cell damage, two different methods
were performed and the results expressed as IC
50.
Both the infusion and ethyl acetate extract have
lower activity as a scavenger of OH
+
. The antioxidant activity of the infusion is probably related to the
content in flavonoids, as a major group of the polyphenols. In the ethyl acetate extract, this activity
probably related to the enrichment in phenolic acids, namely rosmarinic acid, as major group of
polyphenols (G
nfusion and ethyl acetate extract against
a
is
uerreiro and Cunha, 1994).
Tateo et al. (1988) made the comparison of the antioxidant power between two dry rosemary ext
obtained by a simplified extraction process, a commercial rosemary extract and BHA, and an
evaluation of the mutagenic effect of four different dry rosemary extracts. Four conclusions were
reached by the authors: the antioxidant activity of the extracts was comparable; the extraction
treatment by supercritical CO
2
, which is as efficient for deodorizing as the traditional method of steam
racts
flow distillation, gives an antioxidant product with an activity comparable to the product deoleated by
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 12/31
steam flow distillation; the antioxidant activity of rosemary extracts in general is less evident in
regards to soy oil, even at considerably high
antimutagenic activity is higher for the rosemary extract obtained by hydroalcoholic extraction (ethyl
alcohol 50 % v/v).
er concentrations than those active in solid fat; the
Various experimental models were used for the characterisation of the antioxidant activity of four
commonly consumed herbs belonging to the Lamiaceae family, i.e. oregano (
Origanum vulgaris
L.
rosemary (
Rosmarinus officinalis
L.), sage (
Salvia officinalis
L.
)
and thyme (
Thymus vulgaris
L.),
including iron reduction capacity, 2.2-diphenyl-1-picrylhydrazyl DPPH_ , ABTS_+ and _OH radical-
scavenging activities and the capacity of the extracts to inhibit copper-induced oxidation of huma
density lipoproteins (LDL)
ex vivo
. The extracts showed varying degrees of reductive and radical
scavenging capacity, and were capable of a marked prolongation of the lag-time in the LDL oxidation
assay. The hierarch
assay used. The observed antioxidant characteristics were not fully related to the total phenolic
contents of the extracts in any of the assays, but were presumably strongly dependent on rosmarinic
acid, the major phenolic component present in this type of Lamiaceae extract (Dorman et al., 2003).
),
n low-
y of the observed antioxidant activity of the extracts was dependent on the type of
The DPPH radical scavenging method, Folin–Ciocaulteu method and HPLC chromatography were us
to study the distribution and levels of antioxidants (AOXs). A good correlation between the AOX
activities and total phenol content in the extracts was found. All rosemary extracts showed a high
radical scavenging activity (Moreno et al., 2006).
ed
On other study, Kuhlmann et al. (2006) were able to demonstrate that the DPPH radical-scavenging
activity of the extracts of rosemary depended on the amount of all three phytochemicals, carnosic acid
carnosol, and rosmarinic acid, in particular the last one. The anti-inflammatory character of the
extracts was mainly based on their carnosic acid content.
,
R. officinalis
L. essential oil showed greater activity than three of its main components (1,8-cineole, α-
pinene, β-pinene) by means of DPPH assay and β-carotene bleaching test. The antioxidant activities of
all the tested samples were mostly related to their concentrations (Wang et al., 2008).
The results of a study performed with methanolic extracts from the leaves of
Rosmarinus officinalis
harvested from different locations
of Turkey at four different times of the year, were
analyzed by
HPLC, and their radical scavenging capacities
and antioxidant activities were studied by various
assays.
The results indicated that the plants harvested in September possess higher levels of active
constituents and had superior antioxidant capacities compared to
Celiktas et al., 2007).
those collected at other times (Yesil-
Relaxation activity
The effects of the volatile oil of
R. officinalis
on the tracheal smooth muscle of rabbit and guinea pig
were tested in vitro using tracheal strips. The contractions of rabbit tracheal smooth muscles induced
by acetylcholine were inhibited as well the contractions of guinea pig tracheal muscle, induced by
histamine stimulation. The oil also inhibited contractions of both tracheal muscles induced by high
potassium solution, which was dose dependent and reversible. It inhibited the contractions of both
tracheal muscles induced by acetylcholine and histamine in Ca
2+
free solution. This result suggests
possible calcium antagonisti
c properties of rosemary oil (Aqel, 1991).
Chemopreventive effect
Rosemary extract, carnosol, carnosic acid
Some of the molecular mechanisms involved in the chemopreventive action were investigated usin
vitro
human liver and bronchial cell models. Rosemary extract and some of its active components,
g
in
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 13/31
carnosol and carnosic acid, are potent inhibitors of DNA adduct formation induced by benzo(α)pyren
or aflatoxin B
1
. According to the authors, two mechanisms among others are involved in the
anticarcinogenic action: the inhibition of the metabolic activation of the
the phase I cytochrome P450 enzymes
the phase II enzymes such as gl
e
procarcinogens catalysed by
and the induction of the detoxification pathway catalysed by
utathione S-transferase (Offord et al., 1997).
Cardiovascular activity
Rosemary oil
A study has been performed to investigate if rosemary and its constituents affect the contractility of
isolated guinea pig atria and if there are quantitative differences when compared with the gui
ileum. The rosemary oil used consisted of 40.9 % 1,8-cineole, 5.2 % bornyl acetate, 13.9 % α-pinene
and 7.1 % β-pinene. The method consisted of a modification of the one of Magnus. In guinea pig
ileum, half-maximal inhibition of acetylcholine–induced contractions was achiev
cineole (2.5 x 10 M), 112 nl
the non-stimulated atria was observe
400 nl/ml borny
guinea pig ileum. The contractility of the heart was not influenced up to 300 nl/ml, for both
substances. The authors concluded that rosemary oil, 1,8-cineole and bornyl acetate depress
contractility of the cardiac muscle and inhibit acetylcholine–induced contractions of guinea pig ileum
(Hof and Ammon, 1989).
nea pig
ed by 465 nl/ml 1,8-
/ml bornyl acetate (5.7 x 10
-4
M). Half maximal inhibition of contractility of
d at 250 nl/ml rosemary oil, 100 nl/ml 1,8-cineole (6 x 10
-4
M),
l acetate (2 x 10
-3
M). α-pinene and β-pinene increased contractility of the isolated
In another study, the effect of the oil was investigated on the vascular smooth muscle of rabbit, usin
isolated aortic segments (rings). The oil inhibited the contractions induced by norepinephrine
stimulation in Ca
2+
containing and free solution and high K
+
solutions. The effects were shown to be
dose-dependent and reversible. It suggests that the oil has a direct vascular smooth muscle relaxan
effect (Aqel, 1992).
g
t
Aqueous extract
The potential effects of an
parameters on isolated rabbit heart, such as left ventricular pressure, coronary flow and heart rate,
were investigated. In conclusion, some of the active constituents were shown to be associated with
coronary vasodilatation and positive inotropic effects (Khatib et al., 1998).
aqueous extract of the leaves of
R.
officinalis
on certain cardiovascular
Immunological effects
Rosmarinic acid
The effects of caffeetannins and rel
on the arachidonate metabolism in human peripheral polymorphonuclear leukocytes (PMN-L).
Rosmarinic acid strongly inhibited the formation of 5-hydroxy-6, 8, 11, 14 – eicosatetraenoic acid (5
HETE) and leukotrienes B
4
(LTB
4
) (5-lipoxygenase products) at concentrations of 10
-5
- 10
-3
M. The
formation of LTB
4
, induced by calcium ionophore A 23 187 in human PMN-L
, and 3.4-di-
0
-caffeoylquin
(Kimura and Okuda, 1987).
ated compounds isolated from medicinal plants were investigated
-
was inhibited by 3.5-, 4.5-
ic acid, caffeoylmalic acid, caffeoyltartric, rosmarinic acid and caffeic acid
The phenolic comp
acid and the other from tyrosine via dihydroxyphenyl-lactid acid. It is well absorbed from the
gastrointestinal tract and from the skin. It increases the production of prostaglandin E2 and red
the production of LTB
4
in human PMN-L and inhibits the complement system (Al-Sereiti et al., 1999).
ound, rosmarinic acid, obtains one of phenolic rings from phenylalanine via caffeic
uces
Rosmarinic acid and fragments of human gamma globulins, an inhibitor of complement activation,
were tested on endotoxin-induced hemodynamic and haematological changes in the rabbit. Their
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 14/31
-3
effects were compared with complement depletion by cobra venom factor (CVF) pre-treatment.
Rosmarinic acid (20 mg/kg) i
70 %. The complement–dependent features of endotoxin, i.e. the stimulation of prostacyclin and
tromboxane biosynthesis, both hypotensive phases and the primary thrombocytopenia, were largely
reduced after treatment with rosmarinic acid. The complement-independent effects of endotoxin
(leucopoenia, formation of lung oedema) were hardly influenced by rosmarinic acid (Bult et al., 1985).
nhibited the activation of complement after endotoxin injection by about
Kidney action
Rosmarinic acid
An
in vitro
study suggested that rosmarinic acid, a constituent of rosemary, may prevent mesangial
cell proliferation. Glomerular mesangial cell proliferation is one of the major histological findings in
various renal diseases and is mediated by various humoral factors. Murine mesangial cells were
isolated from mice glomeruli and incubated. Quiescent cells were stimulated for 24 hours with 10
nanograms per millilitre platelet-derived growth factor (PDGF) or 100 units per millilitre of tumour
necrosis factor-alpha (TNFα) together with one of several different concentrations of rosmarinic acid.
After stimulation, a
measuring the extent of 3-(4.
reduction by the cel
Rosmarinic acid significantly reduced the basal deoxyribonucleic acid (DNA) synthesis (p< 0.001).
Rosmarinic acid significantly and dose-dependently inhibited PDGF- and TNFα-induced DNA synthesi
(p< 0.01 to 0.05). Rosmarinic acid at 1.5 µg/ml inhibited 50 % of the PDGF-induced proliferation,
at 3.8 µg inhibited 50 % of the TNFα-induced proliferation. A time course study showed that rosma
acid was effective when added up to 8 hours after the growth stimulus and suggested that rosmarin
acid suppressed the entry of mesangial cells into the S phase. The authors note that the concentrations
of rosmarinic acid used in this
in vitro
study can be achieved by moderate ingestion of plants in the
Lamiaceae family and may be a promising way to protect against the chronic aggravation of ren
diseases (Makino et al., 2000).
pulse of [3H] thymidine was added to the culture. Cell viability was assessed by
5-dimethylthiazol-2- yl)-2.5-diphenyl tetrazolium bromide (MTT)
ls and by the amount of lactate dehydrogenase (LDH) released by the cells.
s
and
rinic
ic
al
Anti-viral effect
Carnosic acid, carnosol, rosmanol
Two compounds, carnosic acid and carnosol isolated from rosemary and rosmanol, as well semi
synthetic derivatives (7-O-methylrosmanol, 7-O-ethylrosmanol and 11, 12-O, O-dimethylcarnosol)
were tested in order to find HIV protease inhibitors. The carnosic acid showed the strongest inhibitory
effect (IC90=0.08
g/ml). The cytotoxic TC90 on H9 lymphocytes was 0.36
g/ml for the same
compound, very close to the effective antiviral dose (Paris et al., 1993).
The activity of some rosemary extracts and fo
replication by plaque
extract. The results indicate that one fr
cytotoxicity in tissue cultures (Romero et al., 1989).
ur fractions derived from rosemary against HVS
2
reduction assay, showed 50 % of inhibition of virus plaque formation for the
action has antiviral activity without significant signs of
Antimicrobial, fungicide and insecticidal action
Essential oil
Essential oils from
Satureja montana
L.,
Rosmarinus officinalis
L.,
Thymu
nepeta
were chemically analysed and their antimicrobial and fungicide activities evaluated on the basi
of their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC).
Rosmarinus was the least effective, but all showed a wide spectrum of action (Panizzi et al., 1993).
s vulgaris
L. and
Calamintha
s
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 15/31
A modified method of Beylier-Maurel was applied to
from thyme, rosemary,
rosemary and eucal
study the antimicrobial properties of essential oils
eucalyptus and mugwort. Thyme was the most effective, followed by mugwort,
yptus oil (Benjilali et al., 1986).
Rosmarinus officinalis
oil showed an appreciable activity in inhibiting bacterial growth in a study using
also
Inula helenium
oil, which possesses a higher activity compared to
Rosmarinus
, against Gram-
positive
Staphylococcus aureus and Streptococcus pyogenes
(Boatto et al., 1994).
The chemical composition of 10 essential oils (including rosemary oil) and their antimicrobial activity
have been investigated. The antimicrobial activity was evaluated by agar diffusion and atmospheric
methods with respect to Gram+ and Gram- bacteria, hypomycetes and Saccharomyces (a total of 40
microorganisms). It was found that the oils were Gram+ sel
type 19 of
Tanacetum vulgare
,
T. patula
and one of
Rosmarinus officinalis
oils resulted in 100 %
inhibition in the multiplication of strains (Héthelyi et al., 1989).
ective, as the oil of
Artemisia dranunculus
,
Essential oils from eleven aromatic plants belonging to the Lamiaceae family were exami
different development stages of
Drosophila auraria
. All showed insecticidal effects, either by preventin
egg hatching, or by causing the death of larvae and adult flies. Malformation and/or prohibition of
puparium formation were also observed (Konstantopoulou et al., 1992).
ned on three
g
The effect of essential oils from three common herbs of the family Lamiaceae,
Lavandula
officinalis
,
Melissa
officinalis
and
Rosmarinus
officinalis
, on the morphology of
Candida albicans
was examined by
scanning electron microscopy. The results showed significant inhi
Melissa officinalis
(100 %) but
Rosmarinus officinalis
oil did not inhibit
C. albicans
(Larrondo and Calvo
1991).
bitory effects on
Candida albicans
by
,
Methanol extract
A methanol extract containing 30 % of carnosic acid, 16 % of carnosol and 5 % of rosmarinic acid was
found to be the most effective antimicrobial against Gram positive bacteria (MIC between 2 and 15
mg/ml), Gram negative bacteria (MIC between 2 and 60 mg/ml) and yeast (MIC of 4 mg/ml). By
contrast, a water extract containing only 15 % of rosmarinic acid showed a narrow activity. MIC value
of the methanol and water extracts is in a good correlation with the values obtained with pure carnosic
acid and rosmari
Antimutagenic and hepato
protective effect
Administration of rosemary ethanolic extract (0.15 g/100 g body weight –BW–) to rats for 3 weeks
produced a hepatoprotective effect, using carbon tetrachloride and cyclophosphamide as mutagenic
and hepatotoxic compounds. This effect was comparable to silymarin (reference), and there were
amelioration of the serum and liver parameters, confirmed by histopathological examination of the
liver tissue. Rosemary oil (1.1 mg/g BW) used as pre-treatment for 7 days, followed by i.p. injection
with cyclophosphamide reduced the mitodepression in the bone marrow. Ac
effect is due to the high percentage of phenolic com
1999).
cording to the author, this
pounds with antioxidant activity (Fahim et al.,
Tert
-butyl hydroperoxide induces in freshly isolated rat hepatocytes malonaldehyde formation and
lacticodehydrogenase and aspartate aminotransferase leakage. The demonstration of both anti-
lipoperoxidant and antihepatotoxic activity of reference products such as quercetin and silymarin an
plant extracts such as
Rosmarinus officinalis
and
Escholtzia californica
was possible using this model,
adapted to the crude extracts. The results confirm the antihepatotoxic action of
Rosmarinus officinalis
young sprouts,
in vivo
, on carbon tetrachloride-induced toxicity in rats (Joyeux et al., 1990)
d
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
Page 16/31
nic acid, respectively (Moreno et al., 2006).
Carnosic acid and carnosol against chromosomal damage induced by
γ
-rays, were compared with
those of L-ascorbic acid and the S-containing compound dimethyl sulfoxide (DMSO), and demon
to be the only compounds that showed a significant antimutagenic activity both before and after
γ
-
irradiation treatments. These results are closely related to those reported by other authors on the
antioxidant activity of the same compounds, and the degree of effectiveness depends on their
structure (del Baño et al., 2006).
strated
2.
In vivo
studies
Choleretic and diuretic action
One of the main traditional indications of rosemary is related with the hepato and kidney axes,
particularly the hepatobiliary problems. A study was performed to evaluate the influence of rose
and compare its different parts on
conclude that Rosemary pr
are choleretic at doses of 500,
alcoholic is needed for the diuretic
entire plant at 1500 mg/kg didn’t show hepatic protection or diuretic effect (Fleurentin et al., 1986).
mary
the rat bile secretion and its hepatoprotective effect. The authors
esents choleretic, diuretic and hepatoprotective activity. The new sprouts
1000 and 2000 mg/kg and diuretic at 50 mg/kg. The solvent hydro-
effect. The others parts of the plant stimulates the biliary flux. The
After the administration of the essential oil (donated by the company of Drey’s Italia of Calderara di
Reno-Bologna), the increase of the secreted bile and of the cholates present in it did not produce in
rats the expected dose-effect linearity (Taddei and Giachetti, 1993).
Two medicinal plants used in Morocco,
Rosmarinus officinalis
L. and
Centaurium erythraea
L., reported
for the treatment of urinary ailments, were tested for their diuretic effect. Aqueous extracts of both
plants were administered orally to Wistar rats for 1 week. The urinary volume, the excretion of sodium,
potassium and chloride were determined, as well the concentration of electrolytes and urea in plasma
and creatinine clearance. The dose of 10 mg/kg of 8 or 16 % extract in distilled water enhanced
diuresis in rats compared with the control group from the day five.
R.
reached at the day six the peak of urinary excretion of sodium, potassium and chloride (p<0.01). At 16
%, it induced slight increases of sodium and chloride excretion on day seven and potassium on day six
(p<0.05) (Haloui. et al., 2000).
officinalis
at the dose of 8 %
For the evaluation of the choleretic and protective activities in the rat, lyophilised and aqueous extracts
of
Rosmarinus officinalis
young sprouts and total plant were tested.
R. officinalis
ethanol extracts
prepared from young sprouts and total plant show a significant dose-related choleretic activity and a
more active than the total plant extract. Aqueous extract of young sprouts show a significant
hepatoprotective effect on plasma GTP levels when given as pre-treatment before tetrachloride
intoxication, while the whole plan
re
t extract was inactive (Hoefler et al., 1987).
An aqueous alcoholic extract (15 %) of
R. officinalis
in blossom has been investigated by experimental
biliary fistula in guinea pig. The increase of the biliary flux happens because of a rapid cholagogic
activity and a slowest choleretic activity. An acute toxicity in mice and rats did not reveal any signs of
toxicity at the dose used (2 g/kg i.p.) (Mongold et al., 1991).
Liver action
Rosemary extract exhibited an antioxidative effect in mice. The hexane extract of rosemary (containing
about 1.5 % carnosol) was fed to a group of 18 mice. Another 18 mice (eating a normal diet) served
as controls. At the end of one week, the animals were fasted overnight and heparinized blood was
withdrawn from 6 mice in each group. The animal's livers were weighed and homogenized.
Phosphatidylcholine hydroperoxide and phosphatidylethanolami
blood cells (RBC)
Assessment report on
Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
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ne hydroperoxide in the plasma, red
, and livers were determined by chemiluminescence’s-high performance liquid
chromatography. Phospholipid hydroperoxides (PLOOH) were assessed to reflect products of oxidative
injury in membranous phospholipids layer in the plasma, RBC, and liver of mice. An aliquot of the liver
homogenate was incubated with ferrous sulphate and ascorbic acid and PLOOH and thiobarbituric acid
reactive substances (TBARS) measured. The addition of rosemary did not affect food intake or liver
weight and did not change the
in vitro
liver lipid peroxidizability compared to controls. Howe
tocopherol concentrations in plasma, RBC, and liver were significantly lower in mice fed rosemary.
Rosemary resulted in a lower level of PLOOH in RBC but did not affect PLOOH levels in plasma or
liver compared to controls. The authors stated that the decrease in α-tocopherol concentrations was
unexpected and is unexplained; however, the PLOOH levels remained similar to that of controls,
suggesting that some component in rosemary had an antioxidant effect in the liver and partially made
up for the loss of α-tocopherol (Asai et al., 1999).
ver, the α-
the
Antiulcerogenic effect
The crude hydroalcoholic (70 %) extract (CHE) of
Rosmarinus officinalis
L. decreased the ulcerative
lesion index in different experimental models in rats, produced by some ulcerogenic products like
indomethacin, ethanol and reserpine. The pharmacological mechanism seemed not related with n
oxide, or with prostaglandins. The results of the experiments suggested that the CHE increases the
mucosal nonprotein sulphydryl group’s content or, as another hypothesi
antioxidant compounds of the CHE react wi
itric
s, the activity of the
th N-ethyl-maleimide (Dias et al., 2000).
Anti-inflammatory activity
Rosmarinic acid
In preliminary studies, at short term, ebselen and rosmarinic acid were effective by reducing both
gingival inflammation and plaque accumulation when topically applied in the Rhesus monkey model
(Van Dyke et al., 1986).
Hypoglycaemic effect
In a study on normo- and hypergl
handful of leaves in
cooled to the temperature room and 200 ml was drunk 30-60 min before each meal. The normo- a
alloxan-induced hyperglycaemic group taking the infusion presented lower levels of glucose plasma
levels than the control (p<
insulin release inhibitory r
Hader et al. The interpreta
volatile oil on the leaves infusion and the presence of other components (Erenmemisoglu et al., 1997).
ycaemic mice, the effect of a hot infusion of
R. officinalis
leaves (two
1 l of boiling water) was investigated, as well the chronic toxicity. The mixture was
nd
0.05, 0.01 respectively). The author mentions the hyperglycaemic and
esults in alloxan-diabetic rabbits, using the volatile oil, from the study of Al-
tion of the author about this controversial effect is the small content of
In alloxan diabetic rabbits,
R. officinalis
volatile oil increased fasting plasma glucose levels by 17 %
(p<0.05) above those of untreated animals 6 h after administration. The author concludes that these
data suggest that the volatile oil of
R. officinalis
has hyperglycaemic and insulin inhibitory effects in
rabbits (Al-Hader et al., 1994).
Immunological effect
Rosemary may only have an immune enhancing effect in vivo in stressed conditions, such as protein or
antioxidant deficiency. Male rats were fed an experimental diet for 8 weeks. Test diets contained eith
10 % or 20 % casein with rosemary (0, 100, 200, or 400 parts per million (ppm)) or BHT, 400 ppm, a
a positive control. The mitogenic reactivity of isolated splenic mononuclear cells from the test animal
against concanavalin A (Con A),
assessed as were plasma u
effect on feed consumption or growth
er
s
s
phytohemagglutinin (PHA), and lipopolysaccharide (LPS) were
ric acid and tocopherol levels in blood and liver. Rosemary treatment had no
of the animals and did not affect uric acid or tocopherol levels.
Rosemary only had a significant effect on mitogenic reactivity to Con A and PHA in rats fed a 10 %
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
EMA/HMPC/13631/2009
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casein diet with 200 ppm rosemary (p<0.05 compared to controls). Rosemary had no impact on
mitogenic reactivity to LPS. The authors conclude that rosemary may not have any significant
immunopotentiation in healthy situations but that its effectiveness in a more oxidative stressed model,
such as decreased dietary antioxidants and/or severe protein insufficiency, deserves further study
(Babu et al., 1998).
Antitumorigenic activity
This study was performed to evaluate the activity of rosemary extract, carnosol and ursolic acid in
inhibiting the
in vivo
formation of mammary 7, 12-dimethylbenz
α
anthracene (DMBA)-DNA adduc
and the initiation of DMBA-induced mammary tumorigenesis in female rats. A significant decrea
the
in vivo
formation of rat mammary DMBA-DNA adducts, compared to controls resulted after the
supplementation of diets for two weeks with rosemary extract (0.5 % by weight), but not with carn
(1.0 %) or ursolic aci
and carnosol, but not ursolic ac
respectively, compared to control
induced mammary adenocarcinomas per rat was associated with injection of this dose of rosemary
carnosol, respectively. Ursolic acid had no effect (Singletary et al., 1986).
ts
se in
osol
d (0.5 %). After injecting intraperitoneally for 5 days at 200 mg/kg BW, rosemary
ids, significantly inhibited adduct formation by 44 % and 40 %,
s. A significant decrease of 74 % and 65 % in the number of DMBA-
and
An extract of rosemary was given to female A/J mice for 4 weeks at concentrations of 0.3-0.6 % (by
weight) prior to determination of the activities of detoxification enzymes glutathione S-transferase
(GST) and NAD(P)H:quinone reductase (QR) in lung, liver and stomach. Liver activities of GST and QR,
and stomach GST activity were significantly increased in animals fed diets containing rosemary extract
but did not affect lung GST and QR activities (Singletary and Rokusek, 1997).
A methanol extract of the leaves of
Rosmarinus officinalis
L. was evaluated for its effects on promotion
and initiation of mouse skin tumour. Rosemary extract application to the m
covalent biding of benzo
(
α
)
pyrene
B
(a)
P
to epidermal DNA and inhibited tumour initiation by B
(a)
P and DMBA. It also inhibited TPA-induced ornithine decarboxylase activity (Ho et al., 1994).
ouse skin inhibited the
Topical application of carnosol or ursolic acid isolated from rosemary inhibited TPA-induced ear
inflammation, ornithine decarboxylase activity and tumour promotion (Huang et al., 1994).
According to Ho et al. (Ho et al., 1994), studies of the effects of a fraction of green tea pol
extract of leaves of rosemary and the pure phytochemicals on the carcinogenic process in short-term
animal studies (biochemical markers) and long term animal tumour studies, indicate that they have
potent inhibitory effects on biochemical marker changes associated with tumour initiation and
promotion, and anticarcinogenic activity in several animal models.
yphenols, an
After 13 weeks, post-DMBA tumour incidence for rats fed the 1.0 % rosemary diet (33.3 %) wa
significantly lower than for rats fed the control diet (53.6 %). But by 20 weeks, incidence for
0, 0.5 and 1.0 % rosemary was 72.2, 69.6 and 58.3 % respectively (p<0.5). Rosemary extract can
inhibit DMBA-induced mammary tumorigenesis when fed prior to and after DMBA dosing (Singletary,
1992).
s
rats fed
Antimutagenic and hepatoprotective effect
Administration of rosemary ethanolic extract (0.15 g/100 g BW) to rats duri
hepatoprotective effect, using carbon tetrachloride and cyclophosphamide as mutagenic and
hepatotoxic compounds. This effect was comparable to silymarin (reference), and there were
amelioration of the serum and liver parameters, confirmed by histopathological examination of the
liver tissue. Rosemary oil (1.1 mg/g BW) used as pre-treatment for 7 days, followed by i.p. injection
with cyc
ng 3 weeks produced a
lophosphamide reduced the mitodepression in the bone marrow. According to the authors, this
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L., aetheroleum
and Rosmarinus
officinalis
L., folium
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effect is due to the high percentage of phenolic com
1999).
pounds with antioxidant activity (Fahim et al.,
Tert
-butyl hydroperoxide induces in freshly isolated rat hepatocytes malonaldehyde formation
lacticodehydrogenase and aspartate aminotransferase leakage. The demonstration of both ant
lipoperoxidant and antihepatotoxic activity of reference products such as quercetin and sylimarin an
plant extracts such as
Rosmarinus officinalis
and
Escholtzia californica
was possible using this model,
adapted to the crude extracts. The results confirm the antihepatotoxic action of
Rosmarinus officinalis
young sprouts,
in vivo
, on carbon tetrachloride-induced toxicity in rats (Joyeux et al., 1990).
and
i-
d
Cytotoxi
c effect
A well expressed direct cytotoxic effect on L1210 leukaemia cells in hybrid-BDF1 mice was
demonstrated by Ilarionova et al. (1992), on a study about the essential oils extracted from
Rosmarinus officinalis, Geranium macrorrhisum
and
Urtica dioica
grown in Bulgaria. It was
concentration and time of incubation dependent.
Anticonvulsivant activity
To study the effects
anisum, Matricaria chamomilla, Artemisia vulgaris, Origanum vulgare, Lapinus albus
and
Ol
on the Picrotoxon-induced seizures in mice, this test were performed. The mortality rate, onset of
convulsion and GABA content were monitored. The extracts of these plants were found to del
onset of picrotoxin-induced seizures and to decrease the mortality rate. Extracts of
Origanum vulgare,
Lapinus albus
and
Olea europea
had no effect on the onset of convul
(Abdul-Ghani et al., 1987).
of the aqueous extracts of leaves and stems of
Rosmarinus officinalis, Pimpinella
ea europea
,
ay the
sions or on the mortality rate
Antinociceptive activity
The effect of the aqueous and ethanol extracts of
Rosmarinus officinalis
aerial parts on morphine
withdrawal syndrome was investigated in mice. The aqueous and ethanol extracts induced a significant
antinociceptive activity in the writhing test. This activity was inhibited by naloxone pretreatment.
Phytochemical study indicated that only the aqueous extract of
R. officinalis
has an alkaloid
component. The authors concluded that the aqueous and ethanol extracts of
R. officinalis
aerial parts
could diminish morphine withdrawal
syndrome (Hosseinzadeh and Nourbakhsh, 2003).
Enzymes induction
Rodent studies suggest the possibility of the induction of CYP1A, CYP2B, CYP2E1, and CYP3A along
with some phase II enzymes (e.g. glutathione S-transferase, UDP-glucuronosyltransferase) (Barceloux,
2008).
3.1.1.
Assessor’s overall conclusions on pharmacology
of rosemary and the pharmacological effects of the constituents support the
claims for carminative and digestive ailments, such as flatulence and feelings of distension.
Documented antibacterial and anti-inflammatory effects are also attributable to the essential oil.
totoxic action and diuretic activity have been shown with young sprouts of
Rosmarinus
officinalis
,
in vivo
. The diuretic action was achieved with traditional doses but the hepatoprotection
needed very high doses.
The antioxidant properties of rosemary results primarily from the actions of phenolic diterpenes, such
as carnosic acid, carnosol and rosmanol. The
in vitro
studies indicate that the main diterpene
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
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The essential oil content
Antihepa
antioxidant is carnosic acid. The concentration of carnosic and rosmarinic ac
id depends on drying
techniques and distillation processes.
exert an
se
the accumulation of chemotherapeutic agents in drug resistant mammary tumour cells
in vivo
and
in
vitro.
3.2.
Overview of av
substance(s), herbal preparation(s) and relevant constituents thereof
ailable pharmacokinetic data regarding the herbal
(e.g. absorption, distribution, metabolism, elimination, pharmacokinetic interactions with other
medicinal products)
Rosmarinic acid
In
ex vivo
experiments, permeation of rosmarinic acid (RA) across excised rat skin was about 8 times
higher from alcoholic solution than from water. After topical application, RA concentration in muscle
and bo
followed, given the indication for extensive peripheral tissue distribution, which becomes 7 to 13
higher in the soft tissue than in blood concentrations (Ritschel et al., 1989).
times
e and
tic. The compound is rapidly eliminated from the circulation (i.v. T
1/2
=9 min) and
has a low toxicity (LD
50
in mice=561 mg/kg i.v.), transient cardiovascular actions becoming
g/kg i.v. (Parnham and Kesselring, 1985).
pronounced at ≥ 50 m
Rosemary oil
In mice, inhalation of 0.5 ml of volatile oil released into the breathing air resulted in detectable levels
of 1,8-cineole in the blood and was biphasic, with a short half-life of about 45 min during a second
phase, indicating elimination by a two compartment model (Kovar et al., 1987).
Camphor
Camphor’s cyclic terpene structure makes it highly lipophilic, explaining both its rapid movement
across mucous membranes and large volume of distribution. Once absorbed, it is rapidly oxidized to
camphorol, which is then conjugated in the liver to the glucuronide form. As a result of their
nature, active metabolites are stored in fat deposits and cleared o
camphor is ultimat
lipophilic
ver a prolonged period of time. Most
ely excreted in the urine (Sage leaf AR, HMPC, 2008).
Breastfeeding
Scientific evidence for the safe use of rosemary during lactation is not available. Neither the German
Commission E nor the American Herbal Products Association note any contraindic
during lactatio
ations to its use
n (Blumenthal et al., 2000; McGuffin et al., 1997).
3.2.1.
Assessor’s overall conclusions on pharmacokinetics
Just some aspects of the pharmacokinetics of rosmarinic acid, rosemary oil and camphor are known
depending on the preparation used.
There are no data on the transfer into human milk.
,
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L., aetheroleum
and Rosmarinus
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L., folium
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Rosemary leaf diterpenes have been shown to have lipid peroxidase inhibiting activity and to
influence on glucose levels in mice. They also appear to have an antitumour effect and may increa
ne tissue beneath the application site was comparable to those after systemic administration.
Upon intravenous administration, the classical two-compartment open pharmacokinetic model is
Rosmarinic acid (i.v.) produced moderate inhibition of plaque-forming cell (B-cell) activity in mic
was mildly antiherpe
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
(e.g. single/repeat dose toxicity, genotoxicity, carcinogenicity and reproductive and developmental
toxicity, local tolerance, other special studies)
1.
Acute and sub-chronic toxicity
Rosemary extracts
In a study to evaluate the acute toxicity, in Wistar rats, two representative rosemary leaf extracts were
ues found
or negative clinical
signs were observed during the 2 weeks observational period, with no significant differences in weight
gain, food and water consumption, clinical chemistry parameters or histological changes (Anadón et
al., 2008).
Alcoholic extract
A 15 % alcoholic extract
kg (Wichtl, 1994).
showed no signs of toxicity when i.p. administered to rats at doses of 2 g, 7
Antioxidant rosemary extracts have low acute and sub-chronic toxicity in the rat. Sub-chronic studies
on five solvent extracts (rosemary extract produced from dried rosemary leaves by acetone extraction;
rosemary extract prepared by extraction of dried rosemary leaves by means of supercritical carbon
dioxide; rosemary extract prepared from a partially deodorized ethanolic extract of rosemary; extrac
prepared fro
deodorized rosemary extract obtai
the only effect at high
effect has been shown to be reversible and may be the result of Phase I and II enzyme induction. The
effect was not accom
aminotransferase (ALT), and alkaline phosphatase (AP). Considering the low magnitude, reversibility
and the nature of the hepatic changes, and the absence of increases in plasma ALT, AST and AP, the
Panel concluded that the minor increase in the liver weight reported, accompanied by minimal
centrilobular hypertrophy and microsomal enzyme induction, represent an adaptive response and are
not of toxicological concern. Overall, the 90-day feeding studies in rats with the different rosemary
extracts tested, reveal NOAEL values in the range of 180 to 400 mg extract/kg BW/day equivalent,
depending on the carnosol and carnosic acid content of the respective extracts, to 20-60 mg/kg
BW/day of carnosol plus carnosic acid (EFSA, 2008).
t
m a deodorized ethanolic extract of rosemary; extract which is a decolorized and
ned by a two-step extraction using hexane and ethanol) reveal that
doses of these rosemary extracts is a slight increase in relative liver weight. This
panied by increases in plasma levels of aspartate aminotransferase (AST), alanine
Essential oil
The results from the study of the action of rosemary essential oil, eucalyptol and camphor on the
cortex of mice
in vitro
showed an inhibition of O2 consumption and the lost of electrolytic gradient of
Na+ and K+ (Steinmetz et al., 1987).
With the ingestion of large amounts of rosemary oil, there is a danger of gastroenteritis and nephriti
(Wichtl, 1994)
s
Rosemary extract showed no mortality at intragastric doses up to 1.2 g/100 g of BW in rats, class
as a very low lethality. Essential oil of rosemary had a
intragastrically in
ified
lethal dose 50 (LD
50
) of 5.5 g/kg BW
rats, and a lethal effect on all animals at an intragastric dose of 0.9 g/100 g BW
(Fahim et al., 1999).
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L., aetheroleum
and Rosmarinus
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used, with different concentrations of phenolic diterpenes, representing medium and high val
in commercial supercritical extracts. At a single dose of 2.0 mg/kg of BW, no deaths
2.
Genotoxicity
Rosemary extract, carnosic acid and carnosol
A rosemary extract with carnosic acid and carnosol as the two major active ingredients were shown to
exhibit strong antimutagenic effects in Ames tester strain TA102. This property was attributed to their
antioxidant capaci
1992).
ty. Carnosic acid was held responsible for the antimutagenic effect (Minnunni et al.,
According to EFSA report (EFSA, 2008) four of the five rosemary extracts considered (rosemary extract
produced from dried rosemary leaves by acetone extraction; rosemary extract prepared by extracti
of dried rosemary leaves
p
extract of rosema
two-step extracti
genotoxicity studies were performed in both proka
mouse micronucleus test performed with the last above-mentioned rosemary extract. The Panel
concluded that these do not give rise to safety concerns with respect to genotoxicity of the rosemary
extracts.
Cam
phor
Camphor did not show mutagenic activity in
Salmonella typhimurium
strains TA 1535, TA 1538, TA 98
and TA 100 with and without S9 activation. No mutagenic effect was found with d,l-camphor in strains
TA 97a, TA 98, TA 100 and TA 102 with and without metabolic activation (Sage leaf AR, HMPC, 2008).
3.
Carcinogenicity
Several studies reported that rosemary may be protective at various stages of carcinogenesis
models
in vivo.
in animal
Camphor
No oral stu
tumour respon
and females) three ti
in primary lung tumours and was not considered by the authors to be carcinogenic for lung (Sage leaf
AR, HMPC, 2008).
dies on chronic toxicity or carcinogenicity from camphor are available. In a pulmonary
se test
d
-camphor injected intraperitoneally into strain A/He mice (groups of 15 males
mes a week for 8 weeks in total doses of 3.6 and 18 g/kg BW induced no increase
4.
Reproductive toxicity
Aqueous extract
In Central America, a tea prepared with
R. officinalis
and “ocean Artemisia” is used to control fertility,
producing tempo
development o
the preimplantation period, as the same dose as used by women to induce abortion (doses of 26 mg of
a 30% w/v aqueous extract – 13 mg solids/ml, made with leaves, flowers and stems, administered by
gavage during two different periods of Wistar rats pregnancy). One group (N=12) received the extract
from days 1 to 6 of pregnancy (preimplantation period) and another group (N=14) received the same
extract from days 6 to 15 of pregnancy (organogenic period), against control groups (N=12) which
received saline solu
extract may present an an
control), without interferi
et al., 1996).
rary sterility. To assess if rosemary induces abortion or interferes with the normal
f the conception, an aqueous extract of
R. officinalis
was given to pregnant rats during
tion. The animals were sacrificed at term. The results suggest that rosemary
ti-implantation effect (the difference was not significant compared to the
ng with the normal development of the concept after implantation (Lemonica
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
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on
by means of supercritical carbon dioxide; rosemary extract prepared from a
artially deodorized ethanolic extract of rosemary; extract prepared from a deodorized ethanolic
ry; extract which is a decolorized and deodorized rosemary extract obtained by a
on using hexane and ethanol) were tested for genotoxicity. Several
in vitro
ryotic and eukaryotic test systems and an
in vivo
Methanolic extract
A methanolic extract (2 %) from the leaves of
Rosmarinus officinalis
L. was given to female CD-1 mice,
in AIN-76A diet for 3 weeks. The liver microsomal 2-hydroxylation of estradiol and estrone were
increased 140-180 %, 6-hydroxylation was increased by 30 % and 16α-hydroxylation of estradiol was
inhibited by 50 %. It also stimulated the liver microsomal glucoronidation of estradiol by 54-67 % and
estrone by 37-56 %. In ovariectomized CD-1 mice, it inhibited the uterotropic action of estradiol and
estrone by 30-50 % compared with the group control (Zhu et al., 1998).
Ethanolic extract
The EFSA panel (EFSA, 2008) reports the recently Nusier
et al
. (2007) published results from a study
on the effects of a 70 % ethanol: 30 % water extract of rosemary on reproductive function in adult
male Sprague D
mg/kg BW/day for 63 d
but in the highest dose group the average weight of the epididymides, ventral prostates, seminal
vesicles, and preputial glands significantly decreased. A significant decline in spermatogenesis in testes
due to a decrease in the number of primary and secondary spermatocytes and spermatids in the high
dose group was observed and attributed to a significant decrease in testosterone. In rats of the highest
dose group, sperm motility and density were also significantly decreased in the caudal epididymis and
in the testes. For the high dose group the treatment also markedly increased the number of foetal
resorptions in female rats impregnated by the high dose males, thereby reduc
250 mg/kg BW dose g
and it can therefore be concluded that
250 mg extract/kg BW/day is the NOAEL in this study. Analytical details on the extract used in the
study were not provided.
awley rats, ingesting rosemary extracts dissolved in water at levels of 250 and 500
ays. Body weight and absolute and relative testes weights were not affected,
ing their fertility. For the
roups no statistically significant decreases in these parameters were observed
5.
Teratogenicity
D-Camphor
D-Camphor showed no evidence of teratogenicity after oral administration during the foetal period of
organogenesis to pregnant rats at doses up to 1000 mg/kg BW/day, and to pregnant rabbits at doses
up to 681 mg/kg BW/day. The NOEL for the foetal organism of the rat was above 1000 mg/kg BW, and
for the rabbit above 681 mg/kg BW No increased incidence in variations, retardations or malformat
was observed at any of the treated dose levels. The daily maximum therapeutic camphor dose in
humans is 1.43 mg/kg BW. The author concluded that the present test conditions the therapeutic rati
is above 450 for the endpoint embryo to
ions
o
xicity reflecting a wide margin of safety (Leuschner, 1997).
Aqueous extracts
Rosemary did not i
rats were randomly
postimplantation
(stems, leaves, and flowers) or an equal amount of saline solution was administered either from the
1st to 6th day (preimplantation) or the 6th to 15th day (organogenic period). On day 21, the rats were
sacrificed and the foetuses were examined for external malformations. No differences were noted in
the term foetuses and the rate of postimplantation loss was the same in both groups (Lemonica et al.,
1996).
nterfere with normal foetal development after implantation in rats. Mated female
assigned to groups, and treated either during the preimplantation or
period. Either, 26 mg daily of a 30 % (w/v) boiled aqueous extract of rosemary
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
officinalis
L., folium
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3.3.1.
Assessor’s overall conclusions on toxicology
Serious poisoning by rosemary or its oil is not reported. The potential problems of gastroenteritis a
nephritis, after the ingestion of large amounts of the oil are mentioned in the literature, but do not
relate to actual cases. Acute toxicity by rosemary extract was not observed in animal tests.
nd
Teratogenicity data on rosmary oil is not available. One study of rats showed no foetotoxic effects fro
the administration of a rosemary aqueous extract at various stages of pregnancy.
m
Rosemary may have an anti-implantation effect in rats but it does not interfere with normal foetal
elaxing effect on smooth
muscles, may have interfered with the movements of the oviducts and ovum transport or may have
interfered with the uterine conditions related to ovum implantation. These findings may explain the use
of rosemary extract as an abortive in Brazilian folk medicine but the results of the studies were not
conclusive. Nevertheless, it seems prudent to avoid consumption during pregnancy.
The existing data on rosemary extracts are insufficient to establish a numerical ADI. The absence of
effects in the 90-day studies on reproductive organs and lack of genotoxicity do no
concern.
t give reason for
However, as the minimum required data on mutagenicity (Ames’ test) are not available for herba
preparations of rosemary leaf and rosemary oil, inclusion in the Community list of herbal substances,
preparations and combinations thereof for use in traditional herbal medicinal products is not
recommended.
l
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
Essential oil
ts to assess the EEG activity, the alertness and the mood after 3 min
der and rosemary. The lavender group showed increased beta power, less
depressed mood and felt more relaxed performing the math computations faster and accurately. The
ntal alpha and beta power, suggesting increased alertness, lower
t te a xiety scores and was faster but not accurate on the math computations (Diego et al., 1998).
rosemary group showed decreased fro
s a n
Rosemary extract
A study was performed to
nonheme-iron absorpti
–St-Denis, Switzerland). Each extract was diluted (10 % w/v) using an ethanol / water solution (2:1
v/v). Women aged 19-39 years consumed identical test meals on 4 separate occasions, except for the
absence or presence of a phenolic-rich extract from green tea (study 1;
n
=10) or rosemary (study 2;
n
=14). The meals were extrinsically labelled with either
55
Fe or
59
Fe. The presence of phenolic-rich
extracts resulted in decreased nonheme-iron absorption. Absorption decreased from 12.1±4.5 % to
8.9±5.2 % (p<0.01) in
(p<0.05) in the presenc
extracts used as antioxidants in foods reduce the utilization of dietary iron (Samman et al., 2001).
determine the effect of phenolic-rich extracts from green tea or rosemary on
on. The rosemary extract was commercially available (Herbor®; FIS SA, Chatel
the presence of the green tea extract and from 7.5±4 % to 6.4±4.4 %
e of the rosemary extract. The authors concluded that the phenolic-rich
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L., aetheroleum
and Rosmarinus
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development after implantation. Rosemary, which is known to have a r
A study was performed in 40 adul
of aromatherapy, with laven
A hydrophilic fraction (Rosm1) from an alcoholic extract of rosemary had strong antioxidant activity
and inhibited oxidative alterations to skin surface lipids. The effectiveness of Rosm1 was tested in
humans to assess its ability to prevent lipid peroxidation of skin surface lipids with vitamin E used as a
control. Thirty adult males were randomly divided into 5 groups, and a sample of skin surface lipids
was obtained from the forehead of each volunteer as an internal control. Group 1 applied the vehicle
for one week; groups 2 through 5 applied a 3 ml 5 % ethanol solution containing 50, 100 or 500
of Rosm1 fraction. Samples of skin lipids were taken the morning after the last day of treatment
resistance to oxidative stress was assessed by chemiluminescence. The rosemary extract dose-
dependently protected the skin lipids from oxidative stress
in vitro
in a test of the skin samples from
volunteer foreheads. Lipids extracted after topical treatment with the rosemary extract showed a
significantly higher resistance towards lipoperoxidative chain reactions than did lipids from the
controls. The authors suggested that the hydrophilic rosemary extract may be an important natural
antioxidant that may prove beneficial as an anti-aging treatment of the skin (Calabrese et al., 2000).
µg/ml
and
4.1.1.1.
Assessor’s overall conclusions on pharmacodynamics
Some authors conclude that rosemary extract may be an important natural antioxidant that may
beneficial as an anti-aging treatment of the skin.
prove
Some studies conclude that the phenolic-rich extracts used as antioxidants in foods reduce the
utilization of dietary iron.
The lack of human data limits conclusions regarding the clinical relevance of the potential interactions.
the herbal
substance(s)/preparation(s) including data on relevant constituents
There are no clinical pharmacokinetic data.
4.2.
Clinical Efficac
y
4.2.1.
Dose response studies
None.
4.2.2.
Clinical studies (case studies and clinical trials)
Topical application of a combination of essential oils, including rosemary oil, significantly improved the
a randomized, double-blind, controlled trial of 84 patients. The active
test group received a combination of essential oils from
Thymus vulgaris
(88 mg),
Lavandula
inus
officinalis
114 mg), and
Cedrus atlantica
(94 mg) mixed
in a carrier oil of 3 ml jojoba oil and 20 ml grape seed oil. The control group used the carrier oils. The
e massaged into the scalp for 2 min each night and a warm towel was then wrapped around
dependent scoring by two
uential photographs of the
angustifolia
(108 mg), rosemary (
Rosmar
oils wer
the head. Assessments were made initially, at 3 months, and at 7 months. In
dermatologists who were unaware of the treatments and who evaluated seq
volunteers assessed primary outcome. A significant improvement was noted in the treatment group
(p<0.05). The responses were variable but showed a clear and statistical advantage to treatment. A
secondary outcome measure, tracing hair growth where alopecia occurred in patches, and a
computerized image analyzer, was used to calculate changes in the areas of alopecia. This secondary
measure could only be performed in 32 patients but showed a mean reduction of approximately 104
+/- 140 cm
2
in the test group versus -1.8 +/- 155 cm
2
in the control group. The authors noted that th
e
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L., aetheroleum
and Rosmarinus
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L., folium
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4.1.2.
Overview of pharmacokinetic data regarding
symptoms of alopecia areata in
essential oil treatment caused no adverse events and showed a better therapeutic ratio compared to
other available treatments for alopecia (Hay et al., 1998).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
None.
Paediatric use requires a careful assessment as often medical advice and supervision should be sough
for safety reasons.
t,
4.3.
Overall conclusions on clinical pharmacology and efficac
y
A single clinical study suggested that rosemary applied topically may protect skin cells from oxida
tive
stress and another single clinical study showed that rosemary essential oil combined with other
l oils might be a moderately effective treatment for alopecia areata.
These studies are not sufficient to support therapeutic indications on the basis of WEU. The therapeutic
indications can there
fore only be based on traditional use.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
Commission E: Leaf permitted for oral use. No contraindications (CI), adverse
(I)
BAnz nr. 223 30.11.85
.
events (AE), interactions
Standardzulassungen: Leaf permitted as herbal tea. CI: pre
gnancy. No AE, I.
French Guideline: Leaf and flowering top permitted for oral use (toxi
herbal
extracts, tinctures (De Smet, 1993).
cological category 1 for powder,
tea, aqueous extract, low strength aqueous-alcoholic extracts, high strength aqueous-alcoholic
Germany (essential oil) – External use - urges to cough, bronchial and laryngeal spasm, local
hypersensitive reactions.
Regarding the adverse reactions reported by Germany, these can be considered as a form of
hypersensitivity to the medicinal product.
5.2.
Patient exposure
Rosemary has a long history of consumption in the human diet. Rosemary extract is a component of
g for
alami.
Carnosol and carnosic acid
The main potential sources of exposure to rosemary extracts used as antioxidants were reported as
soups and broths’ and ‘seasonings and condiments’ in UK adults and
‘fine bakery wares’ and ‘meat, poultry and fish/seafood products (non-processed)’ in pre-school
children (EFSA, 2008).
Dietary exposure to carnosol plus carnosic acid has been estimated for adults and pre-school children
(aged 1.5 to 4.5 years) and amounts to mean val
carnosic acid/kg bw/day, 0.10 a
ues of respectively 0.04 and 0.11 mg carnosol plus
nd 0.20 mg carnosol plus carnosic acid/kg bw/day at the 95
th
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
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L., folium
EMA/HMPC/13631/2009
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essentia
some perfumes, disinfectants and insecticides. Rosemary leaves are widely used as a seasonin
meat dishes, sauces and s
‘fine bakery wares’, ‘dehydrated
percentiles and 97.5
th
percentile values of 0.12 and 0.23 mg carnosol plus carnosic acid/kg bw/day
(EFSA, 2008).
rt, it is noted that the margin between the NOAEL range in the 90-day rat
studies with all five extracts of 180 to 400 mg extract/kg BW/day equivalent to 20-60 mg/kg BW/day
of carnosol plus carnosic acid, and the dietary exposure estimates for adults would amount between
500-1500 for the mean intake values, between 200-600 for the 95
th
percentile values and between
th
percentile values. For pre-school children these margins would amoun
respectively at least 182-546, 100-300 and 87-261. The Panel noted that these margins of safety ar
worst case estimates si
levels tested, and that the estimates of dietary exposure were conservative.
t to
e
nce the NOAELs from the different studies were generally the highest dose
The EFSA Panel (2008) was of the opinion that the margin of safety is high enough to conclude that
dietary exposure resulting from the proposed uses and use levels are not of safety concern. To achiev
these levels of dietary exposure, high level consumers would need to select a diet that was entirely
composed of foods containing rosemary extracts for those food categories in which it was permitt
reality not all processed foods will contain added antioxidants and it seems unlikely that these extracts
would be used at the maximum usage level in all the proposed food in each category or that some
consumers would systematically always choose all foods containing rosemary
e
ed. In
extract.
Camphor
Dietary exposure to camphor arises from the consumption of foods flavoured by using herbs, their
essential oils or the chemically defined flavouring substance
d
-camphor. The dietary exposure to
camphor was estimated to be 1.5 mg/person/day (Council of Europe, 2001). Assuming an average
body weight of 60 kg, this corresponds to an exposure of 25 µg/kg BW/day. Limits for
d
-camphor,
suggested by the Council of Europe were 10 mg/kg in beverages (including alcoholic drinks), 25 mg
in food in general, 100 mg/kg in candies, 140 mg/kg in fresh cheese, 150 mg/kg in sau
condiments (S
/kg
ces and
age leaf AR, HMPC, 2008).
According to the EFSA report, exposure to camphor should not exceed 2 mg/kg BW on a single day
any age group.
in
5.3.
Adverse events and serious adverse events and deaths
5.3.1.
Adverse events
Carnosol
A case of contact dermatitis to carnosol, the main constituent of Rosmanox®, made from the leaves of
rosemary, develo
ied a rosemary leaf
e. Three days later, he developed an itchy, vesicular exudative
dermatitis that improved within 10 days of withdrawing the plasters. Patch tests were only positive for
authors note that this is the first report of a rosemary-induced case of contact
rosemary. The
dermatitis (Fernandez et al., 1997).
Further case reports related to allergic contact dermatitis show, from patch testing, that carnosol (CAS
RN: 5957-80-2) is a major allergen in rosemary. The chronic use of rosemary as a culinary spice in
food was associated with the development of chronic contact cheilitis. Exposure to rosemary extracts
also has been associated with occupational asthma (Barceloux, 2008).
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
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L., folium
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On the EFSA panel repo
167-500 for the 97.5
ped in a 56-year old man on his hands, forearms and face, after it was introduced in
a food processing factory where he was working. 226 controls were negative (Hjorther et al., 1997).
A rosemary leaf plaster caused contact dermatitis in a 56-year-old man. A man appl
plaster to treat a pain in his kne
Camphor
Rosemary oil contains 20-50 % camphor; orally, camphor readily causes epileptiform convulsi
taken in sufficient quantity (Barnes, 2002).
ons if
According to EFSA (EFSA, 2008), in humans, the intoxication of camphor includes central nervous
stimulation, oral and gastric irritation, nausea and vomiting, excitement, hallucinations, delirium,
muscular excitability, tremors, convulsions and urinary retention. Locally, it can produce irritation of
the skin, eyes and mucous membranes of the respiratory tract.
In the same r
accidental intake of camphorated oil (20 % camphor in cottonseed oil).
eport, it is mentioned that the intoxications present in the literature, in general, involve
No acute toxicity was reported after doses lo
toxicity may be seen in sensitive individuals at doses of 5 mg/kg BW and higher. Clinical manifest s
in these individuals require doses higher than 30 mg/kg BW (EFSA, 2008).
wer than 2 mg/kg BW. Clinically insignificant signs of
igns
5.3.2.
Serious adverse events and deaths
The report of a hepatic abscess secondary to ingestion of a rosemary twig was considered to be serious
(Karamarkovic et al., 2007). However, this case is considered to be not relevant for the safety
assessment of authorised medicinal products containing rosemary.
Camphor
20 children aged 1 to 4 years became ill with seizures, after ingestion of 1 t
camphorated oil equivalent to about 3 to 4.5 g of camphor
o 1.5 tablespoons of
(EFSA, 2008).
In a literature review of 64 cases, 6 reports of death were found. In a 19-month old child, the ingestion
of 1 g of camphor in camphorated oil was fatal (EFSA, 2008).
In a recent published case report, a 10-year old boy presented at the
of lethargy, na
remedy transd
ingredients (EFSA, 2008). Assuming a body weight of 30 kg, this would correspond to 10 mg/kg B
camphor.
emergency room with symptoms
usea, vomiting and rigors. 24 h previously, he had chewed three over-the-counter cold
ermal patches containing 4.7 % (95.4 mg/patch) camphor and 2.6 % menthol as active
W of
The American Academy of Paediatrics concluded that although adults recovered from ingestion of up to
43 g of camphor, the ingestion of 2 g generally produces dang
0.7 to 1.0 g of camphor has proved fatal.
erous effects. In children, ingestion of
On the basis of the data reviewed, a probable lethal dose was estimated to be in the range of 50 to
500 mg/kg BW, with a large variation on the sensitivity of humans to the acute toxicity of camphor.
oratory findings
Not available.
5.5.
Safety in special populatio
ns and situations
Not available.
5.5.1. Intrinsic (including elderly and children)/extrinsic factors
Not to be used in cases of hyperse
nsitivity to the active substance.
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5.4.
Lab
l
Limited data available.
Cineol induction of CYP450 enzymes is possible.
The lack of human data limits conclusions regarding the clinical relevance of these potent
interactions (Barceloux, 2008).
ial
5.5.3.
Use in pregnancy a
nd lactation
Therapeutic doses are not recommended for use during pregnancy (McGu
ffin et al., 1997).
Preparations of rosemary should not be used during pregnancy due to the toxic effects of som
components (Wichtl, 1994).
e
The data available are not sufficient to conclude the s
used during pregnancy and lactation. The only concl
and lactation has not been established and thus rosemary preparations should be avoided.
afety or the danger of rosemary preparations
usion possible is that the safety during pregnancy
Not reported.
5.5.5.
Drug abuse
None.
5.5.6.
Withdrawa
l and rebound
None.
5.5.7.
Effects on ab
mental ability
ility to drive or operate machinery or impairment of
Not available.
5.6.
Overall c
onclusions on clinical safety
In general, it can be concluded that rosemary preparations are safe and devoid of toxic effects if ta
in recommended doses.
ken
Use must be av
contraindicated in hypersensitive patients.
oided during pregnancy and lactation, as the safety has not been established. Use is
Although rosemary preparations contain variable quantities of camphor, there are no human data to
support the development of seizures as a complication of the ingestion of rosemary extracts.
Hot and full baths are contrai
high fever, severe infections, severe circulatory disturbances and cardiac failure.
ndicated in cases of open wounds, large skin injuries, acute skin diseases,
With regard to oral use, rosemary preparati
duct, cholangitis, liver disease, gallstones and any other biliary disorders that require medical
supervision and advice.
ons are contraindicated in cases of obstruction of the bile
With regard to cutaneous use, the warning to avoid contact with the eyes and mucous membranes is
included in the monograph of
Rosmarinus aetheroleum
, due to potential irritation o
f the essential oil.
Where symptoms such as articular pain accompanied by swelling of the joint, redness or fever occur
medical advice should be sought.
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5.5.2.
Drug interactions
Essential oi
6.
Overall conclusions
Rosemary (
Rosmarinus officinalis
L.) belongs to the family Lamiaceae and has been an important
medicinal plant since earliest times. It is also a commonly used spice and flavouring agent for foods
and its essential oil is used therap
eutically, in particular in balneology.
cosmetic properties in ancient Greece and by the Romans. In
the middle ages, rosemary oil was distilled for medical purposes and also used as a perfume.
The pharmacological studies reported in the literature give plausibility to the traditional indications set
out in the monographs:
Oral use
Traditional herbal medicinal product for symptomatic relief of dyspepsia and mild spasmodic di
of the gastrointestinal tract.
sorders
Cutaneous use and u
se as a bath additive
Traditional he
and in minor peripheral circulatory disorders.
rbal medicinal product as an adjuvant in the relief of minor muscular and articular pain
A single clinical study sugges
oxidative stress and another clinical study showed
essential oils might be a moderately effective t
ted that rosemary applied cutaneously may protect skin cells from
that rosemary essential oil combined with other
reatment for alopecia areata.
However, these studies are not enough to support the indication on the basis of WEU. The therapeutic
indications are based solely on the traditional us
medical diagnosis, prescription and supervision.
es and are suitable for use without the need for
Some proposals for therapeutic indications from the interested parties (see the “overview of comments
received during the public consultation”) were not accepted for safety reasons.
Due to the lack of sufficient data to assure the safety, the use in children (Rosmarini folium and
preparations thereof including Rosmarini aetheroleum), in adolescents (Rosmarini aetheroleum) and
during pregnancy and lactation are not recommended.
The preparations proposed in the monograph are based on those which are known to be on the market
for 30 years. Some others are stated in the literature, but either information on the peri
the posology for these preparations are missing or they do not comply with the requirement for 3
years of traditional use evidence.
od of use or
0
As the minimum required data on mutagenicity (Ames’ test) ar
of rosemary leaf and rosemary oil, inclusion in the Community list of herbal substances, preparations
and combinations thereof for use in traditional herbal medicinal products is not recommended.
e not available for herbal preparations
Annex
List of references
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Rosmarinus officinalis
L., aetheroleum
and Rosmarinus
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L., folium
EMA/HMPC/13631/2009
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It was mentioned for its medicinal and
Source: European Medicines Agency
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