Beruflich Dokumente
Kultur Dokumente
(HMPWG)
1.
GENERAL DATA.........................................................................................................................3
1.1.
1.2.
1.3.
1.4.
2.
3.
TOXICOLOGICAL DATA.......................................................................................................................................7
ANNEX I.............................................................................................................................................................................9
1.
GENERAL DATA
2.
o PDE
o TTC
(Please proceed to 5. Toxicological Data)
Toxicity data unavailable with sufficient phytochemical or chemical characterisation provided
o
TTC
CH 12/ DH 24
3.
4.
AUTHORISED ALLOPATHIC
TERATOGENIC
MEDICINAL PRODUCT
Community Herbal Monograph on Rheum palmatum L. and Rheum officinale Baillon, radix
5.
TOXICOLOGICAL DATA
Acute toxicity:
1,8-dihydroxyanthraquinone derivates*:
Rhein:
Lowest toxic dose for man is 600mg/kg for a period of 3 days (intermittent): Intestinal hypermotility
and diarrhoea were observed (USXXAM United States Patent Document. U.S. Patent Office, Box 9,
Washington, DC 20231, Volume (issue)/page/year: #6197818)
Total rhubarb (rhizomes of Rheum palmatum L.) anthraquinones (TRAs) were orally administered for 13 weeks to
Sprague Dawley rats at a dose of 0, 140, 794, 4,500mg/kg bw. In the highest dose group, nephrotoxicity was discernible
at 13 weeks.
Genotoxicity
In vitro studies
In the Salmonella/microsome assay an ethanolic root extract of Rheum officinale Baillon was weakly mutagenic in strain
TA 1537 with and without metabolic activation.
No further toxicological data are available for rhubarb itself or preparations thereof. Experimental data, mainly in vitro tests
showed a genotoxic risk of several anthranoids in the Salmonella/microsome assay, aloe-emodin, emodin, chrysophanol
and physcion were weakly mutagenic. No mutagenic effects were observed in the V79-HGPRT mutation assay and in the
unscheduled DNA synthesis (UDS) assay for chrysophanol and physcion. Emodin was highly mutagenic in the V79HGPRT mutation assay. In the UDS assay emodin was a string inducer of UDS in primary hepatocytes. Aloe-emodin
showed a significant increase in net grains/nucleus. Emodin was also tested with respect to its transforming activity in
C3H/M2 mouse fibroblasts in vitro. In the in vitro Salmonella/microsome mutagen test and the deoxyribonucleic acid
(DNA) repair test of primary rat hepatocytes emodin and frangulin showed a dose-dependent increase in the mutation rate
or the induction of DNA repair.
In vivo studies
However, in vivo studies of other anthranoid-containing herbal substance (senna) in rat hepatocytes (chromosome
aberration test, mouse spot test, in vivo/in vitro UDS (unscheduled DNA synthesis) showed no evidence of any genetic
effects.
In in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow
cells of Wistar rats; mouse spot test [DBA/2J x NMRI]) no indication of a mutagenic activity of aloe emodin was found.
Sennoside B and rhein did not induce significant numbers of chromosomal aberrations or aberrant cells in bone marrow
cells of Swiss mice.
Experimental data, mainly in vitro tests showed a genotoxic risk of several anthranoids. However, most of the in-vivo
studies showed no effect or only equivocal effects (Westendorf, 1990; Sandnes, 1992; Heidemann, 1993; Heidemann A et
al. 1996; Helmholz H et al., 1993; Paneitz A et al., 1999).
Heidemann A et al. undertook in vitro and in vivo experiments to clarify the genotoxic potential of the
hydroxyanthraquinone aloe-emodin. The results confirmed that aloe-emodin is able to induce mutagenic effects in vitro. In
in vivo studies (micronucleus assay in bone marrow cells of NMRI mice; chromosome aberration assay in bone marrow
cells of Wistar rats; mouse spot test [DBA/2J x NMRI]) no indication of a mutagenic activity of aloe emodin was found.
Information about a possible reaction of aloe-emodin with DNA was derived from an in vivo unscheduled DNA synthesis
(UDS) assay. Hepatocytes of aloe-emodin treated male Wistar rats did not show DNA damage via repair synthesis. These
data suggest that aloe-emodin is able to interact with DNA under certain in vitro conditions.
However, in vivo the results did not indicate a genotoxic potential.
Therefore the authors assume that a genotoxic risk for man might be unlikely.
Carcinogenicity
Jahnke GD et al. (2004) evaluated emodin for potential effects on pregnancy outcome. Emodin was administered in feed
to timed-mated Sprague-Dawley (CD) rats (0, 425, 850, and 1700 ppm) at gestational day (GD) 6-20 (day 20 termination).
Ingested dose was 0, 31, 57, and ~80-144 mg emodin/kg/day (rats). The rat maternal lowest observed adverse effect
level (LOAEL) was 1700 ppm; the no observed adverse effect level (NOAEL) was 850 ppm. The rat developmental
toxicity NOAEL was +/- 1700 ppm. A LOAEL was not established.
Human Safety Data
Conflicting results in clinical trials: Chronic laxative use as a risk factor in colorectal cancer (CRC) was investigated in
some clinical trials. Some studies revealed a risk for CRC associated with the use of anthraquinone-containing laxatives,
some studies did not. However, a risk was also revealed for constipation itself and underlying dietary habits. Further
investigations are needed to assess the carcinogenic risk definitely.
The short-term use of Rheum as recommended can be regarded as safe.
6.
Raw material : Rheum is not recommended for children under the age of 12 and for pregnant or lactating women.
Problems mainly occur when people that already have gastro-intestinal problems consume Rheum. If used for an
extensive period, hypokalaemia and other problems can occur. Therefore the recommended period of usage is only 1 or 2
weeks.
There are authorised allopathic medicinal products made from Rheum. The toxicological data show a genotoxicity of the
Rheum. However, the data avaible doesnt allow to take in consideration all patient groups (childeren less than 12 years
old are excluded). Therefore, we consider to take the TTC as daily exposure.
7.
8.
TO CALCULATE A FSD, ALL PATIENT GROUPS MUST BE CONSIDERED. THEREFORE, THE TTC MUST BE USED:
8.1. Preparation of mother tincture according to method 1.1.10 (Ph. Fr.) of the Ph. Eur.
Dilution factor to prepare the MT = 10
As MT = 0D, no factor must be added.
0.15 * 10 6
TTC
FSD log
* dilution _ factor _ MT log
* 10 6.82 7 D
dose _ of _ stock _ in _ 10ml _ or _ 10 g
10
8.2. Preparation of mother tincture according to method according to method 1.1.8 (formerly method 4a of the
GHP)
Dilution factor to prepare the
As = D1, a factor + 1 is added.
0.15 * 10 6
TTC
* dilution _ factor _ 1 log
* 10 7.82 8D
dose _ of _ stock _ in _ 10ml _ or _ 10 g
10
FSD log
9.
0.02
1
1
100 *
100
* dilution _ factor _ MT log
* *10 2.77 3D
12
R.C. dose _ of _ stock _ in _ 10ml _ or _ 10 g
10
100
LHRD
SDCI log
9.2.
Preparation of mother tincture according to method according to method 1.1.8 (formerly method 4a of the GHP) of
the Ph. Eur
0.02
1
1
100 *
100
* dilution _ factor _ 1 log
* *10 1 3.77 4D
12
100
LHRD
SDCI log
ANNEX I
References
EMEA/HMPC/189626/2007 ASSESSMENT REPORT FOR Rhubarb (Rhei radix)
10
Heidemann A et al. The Genotoxicity Status of Senna. Pharmacology 1993; 47, Suppl. 1: 178-86
Heidemann a et al. Genotoxicity of aloeemodin in vitro and in vivo. Mutation Res.1996; 367: 123-3
Helmholz H et al. Genotoxizitt der Faulbaumrinde. Genotoxicity of buckthorn bark. Pharm. Zeit. 1993; 138 (Oct 28):
48-50
Jahnke GD et al. Developmental toxicity evaluation of emodin in rats in mice. Birth Defects Research Part B
Developmental and Reproductive Toxicology 2004; 71 (2): 89-101
NTP Technical Report on the Toxicology and Carcinogenesis Studies of Emodin in F344/N Rats and B6C3F1 Mice.
National Toxicology Programs Board of Scientific Counselors Technical Reports Review Subcommittee, National
Toxicology Programm, June 2001, NTP TR 493, NIH Publication No. 01-3952, U.S. Department of Health and Human
Services
Paneitz A et al. anthranoid contents of rhubarb (Rheum undulatum L.) and other Rheum species and their
toxicological relevance. Eur Food Res Technol 1999; 210: 97-101
Sandnes D et al. Mutagenicity of Crude Senna and Senna Glycosides in Salmonella typhimurium. Pharmacol. Toxicol.
1992; 71: 165-72
Van Gorkom BA et al. Review article: anthranoid laxatives and their potential carcinogenic effects. Alim. Pharm. &
Therap. 1999; 13 (4): 443-52
Westendorf J et al. Genotoxicity of naturally occurring hydroxyanthraquinones. Mutat Res 1990; 240: 1-12
11