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HOMEOPATHIC MEDICINAL PRODUCT WORKING GROUP

(HMPWG)

ASSESSMENT REPORT FIRST SAFE DILUTION: Rheum officinale Baillon or Rheum palmatum L. :European Pharmacopoeia (Ph. Eur.) in force monograph 2371: Method of preparation Ph. Eur. 1.1.10 of Homoeopathic Stocks and PotentisationMethod of preparation Ph. Eur. 1.1.8 of Homoeopathic Stocks and Potentisation31.General data

31.1.Name of the Stock/Raw/Starting Material, and Synonyms if applicable

31.2.Definition of the Stock /Raw /Starting Material

41.3.Monograph European Pharmacopoeia/ official national pharmacopoeias if available:

41.4.Other specifications:

62.Criteria for the establishment of a first safe dilution

63.Allowed as food or constituent of food

64.Authorised allopathic medicinal product (Non-genotoxic, Non-carcinogenic, Non-Teratogenic

75.Toxicological data

86.Integrated risk assessment of the stock/raw/starting material and/or of the major components and components that have been shown in literature to be toxic

87.acceptable amount (mg/kg/day) based on stock/raw /starting material/compound

88.First Safe Dilution

9ANNEX I

ASSESSMENT REPORT TEMPLATE FIRST SAFE DILUTION1. General data1.1. Name of the Stock/Raw/Starting Material, and Synonyms if applicable

Raw material: Rheum officinale Baillon or Rheum palmatum L for homoeopathic preparations (France)

Preparation of mother tincture according to method 1.1.10 (Ph. Fr.) of the Ph. Eur.

Raw material: RheumPreparation of mother tincture from the powdered herbal drug (710) and liquid dilutions according to method 1.1.8 (formerly method 4a of the GHP) 1.2. Definition of the Stock /Raw /Starting Material

- Name of the plant (binomial name (genus, species, author) and synonyms):

Rheum officinale Baillon or Rheum palmatum L.Synonyms: N/A- Part(s) of the plant used:

Dried underground parts- State of the plant (dry or fresh):

Dried

- Homeopathic Manufacturing Method/Method of preparation:

-European Pharmacopoeia (Ph. Eur.) in force monograph 2371: Methods of preparation of

Homoeopathic Stocks and Potentisation (Ph. Eur. 1.1.10)

- Ph. Eur. monograph 2029: Mother Tinctures for Homoeopathic Preparations.

- Toxic Components:Whole plant: Rhubarb: LD50 90400mg/kg (CCHST-RTECS, Rhubarb, MDL Information Systems Inc., 2009) Dried underground parts:hydroxyanthracene derivates make up 3-12% of the dried underground parts of which only a small amount consists of rhein, chrysophanol, aloe-emodin, physcion and emodin (aglycones), the biggest proportion are the mono-and diglucosides of the abovementioned substances (60-80%)(ESCOP-Second edition p419).

1,8-dihydroxyanthraquinone derivates*: Emodin, Rhein, Physcion.1.3. Monograph European Pharmacopoeia/ official national pharmacopoeias if available:

European: European Pharmacopoeia 6.0 (01/2008:0291)National: French Pharmacopoeia (10th Edition): Rhubarb for homoeopathic preparationsRheum for homoeopathic preparations

EMA monograph: EMEA/HMPC/189624/2007Corr.1.4. Other specifications2. Criteria for the establishment of a first safe dilution

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Allowed as food or constituent of food (Please proceed to 3. Allowed as food or constituent of food)

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Maximum amount of raw material 0.15.10-3 mg/60 kg BW/day (TTC) and phytochemical or chemical characterization available

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Authorised allopathic medicinal product (non-genotoxic, non-carcinogenic, non-teratogenic)

(Please proceed to 4: Authorised allopathic medicinal product)

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Toxicity data available (Toxicological monograph, Pharmacopoeia monograph, Scientific literature) PDE

TTC

(Please proceed to 5. Toxicological Data)

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Toxicity data unavailable with sufficient phytochemical or chemical characterisation provided TTC

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Toxicity data unavailable without sufficient phytochemical or chemical characterisation provided CH 12/ DH 24

3. Allowed as food or constituent of food

4. Authorised allopathic medicinal product (Non-genotoxic, Non-carcinogenic, Non-Teratogenic

Community Herbal Monograph on Rheum palmatum L. and Rheum officinale Baillon, radix

5. Toxicological dataAcute toxicity:

1,8-dihydroxyanthraquinone derivates*:

Emodin:LD50 : 35mg/kg : Impaired gastrointestinal system(CCHST-RTECS, Emodin, MDL Information Systems Inc., 2009)

No carcinogenic activity was found after doses up to 1000mg/kg in male rats (ESCOP-Second edition p422)

No carcinogenic activity was found after doses up to 120mg/kg in female mice (ESCOP-Second edition p422)

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)

Physcion:LD50: 10mg/kg: Impaired gastrointestinal system(CCHST-RTECS, Physcion, MDL Information Systems Inc., 2009)

Repeated Dose Toxicity

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 V79-HGPRT 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

In vivo long term studiesFurther 2-year studies on male and female rats and mice with emodin gave no evidence of carcinogenic activity for male rats and female mice, and equivocal evidence for female rats and male mice.

A long-term study over 2 years on male and female rats with a senna pods preparation (anthranoid-containing herbal substance as well) gave no evidence of carcinogenic activity.

Reproductive Toxicity

Potential effects on pregnancy outcome, developmental toxicity:

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. Integrated risk assessment of the stock/raw/starting material and/or of the major components and components that have been shown in literature to be toxicRaw 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. acceptable amount (mg/kg/day) based on stock/raw /starting material/compound TTC = 0,15 *10-3 mg/day8. First Safe DilutionTo 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.

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.

9. Safe dilution with contraindications (SDCI)

Contraindications: children under 12 years, pregnant and lactating womenLHRD = 20 mg of hydroxyanthracene derivatesRelative content (R.C.) of hydroxyanthracne derivates in the dried underground parts = up to 3-12% (EMEA/HMPC/189626/2007)

9.1. Preparation of mother tincture according to method 1.1.10 (Ph. Fr) of the Ph. Eur.

Dilution factor to prepare the MT = 10

9.2. Preparation of mother tincture according to method according to method 1.1.8 (formerly method 4a of the GHP) of the Ph. EurDilution factor to prepare the = 10As = D1, a factor + 1 is added

ANNEX IReferences

EMEA/HMPC/189626/2007 ASSESSMENT REPORT FOR Rhubarb (Rhei radix)

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: 1-1222

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