SUMMARY OF DATA FOR CHEMICAL SELECTION

Milk Thistle Extract / Silymarin / Silybin

84604-20-6 / 65666-07-1 / 22888-70-6

August 1998

Basis for Nomination

Chemical Identification

Production Information

Use Pattern

Human Exposure

Regulatory Status

Evidence for Possible Carcinogenic Activity

Human Data

Animal Data

Metabolism

Other Biological Effects

Structure-Activity Relationships

References

Milk thistle extract is presented to the CSWG as part of a review of botanicals being used as dietary supplements in the United States. Alternative herbal medicines are projected to be a $5 billion market by the turn of the century. Milk thistle extract is consistently one of the more widely used alternative medicines.

A review of the available literature suggests that milk thistle extract has beneficial effects on the liver, helping reverse the damage caused by organic solvent exposure or alcoholism. The active flavolignan isomers in milk thistle extract, termed silymarin, also appear to possess anticarcinogenic activity. In contrast, no reports of severe side effects from the use of milk thistle extract or silymarin were reported in the available literature. However, many reports of beneficial effects may be from intravenous administration of a dosage form not available in the US The lack of reports on side effects for dietary supplements in use in the US may simply indicate a lack of bioavailability of the active ingredients.

The American Botanical Council provided a report on milk thistle from their Botanical Series publications.

ACTION BY CSWG: 9/16/98

Studies requested:

- Toxicological characterization (90-day) including reproductive testing

- Metabolism studies

- Genotoxicity

Priority: Moderate

- Significant human exposure

-Popular dietary supplement thought to have beneficial effects on the liver

-Metabolism studies needed to resolve questions regarding bioavailability of orally administered milk thistle extract

- Examined as a hepatoprotectant, but limited information on safety

- NCI will conduct mouse lymphoma assay

- Consideration for further testing pending evaluation of results of 90-day toxicity study

Milk Thistle Extract

CAS Registry Number:	84604-20-6
Chemical Abstracts Service Name:	Silybum marianum extract
Synonyms and Trade Names:	Lady's thistle extract
Structural Class:	Botanical mixture; phytopharmaceutical

Silymarin

CAS Registry Number:	65666-07-1
Chemical Abstracts Service Name:	Silymarin
Synonyms and Trade Names:	Apihepar; Laragon; Legalon; Pluropon; Silarine; Silepar; Silirex; Silliver; Silmar
Structural Class:	Mixture of flavonolignans including silidianin, silicristin, and the major compound, silybin

Silybin

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CAS Registry Number:	22888-70-6
Chemical Abstracts Service Name:	4H-1-Benzopyran-4-one, 2-[2,3-dihydro-3-(4- hydroxy-3-methoxyphenyl)-2-(hydroxymethyl) -1,4-benzodioxin-6-yl]-2,3-dihydro-3,5,7-trihydroxy-, [2R[2α -3β, 6(2R*, 3R*)]]- (9 CI)
Synonyms and Trade Names:	4-Chromanone, 3,5,7-trihydroxy-2-[3-(4-hydroxy- 3-methoxyphenyl)-2-hydroxymethyl)-1,4-benzodioxan-6-yl]-; silibinin; silibinine; silybum substance E; silymarin I
Structural Class:	Flavonolignan

Structure, Molecular Formula and Molecular Weight:

 

 

Silybin

C₂₅H₂₂O₁₀ Mol. wt.: 482.4

Chemical and Physical Properties (Silybin):
Melting Point:	158o C (anhydrous substance); 167o C (monohydrate) (Budavari, 1996)
Solubility:	Practically insoluble in water; soluble in acetone, ethyl acetate, methanol, ethanol; sparingly soluble in chloroform (Budavari, 1996)

Milk thistle (Silybum marianum), a member of the Aster family, is a tall herb with large prickly white-veined green leaves and a reddish-purple flower that ends in sharp spines. Milk thistle fruits (often erroneously referred to as seeds) contain up to 6 percent silymarin, the active flavonoid constituent. Silymarin's principal components are silybin, silycristin, and silydianin. The primary investigational focus has been on silybin, which is the most biologically active. A number of other flavonolignans have also been found in the seeds including dehydrosilybin, desoxysilycristin, desoxysilydianin, silandrin, silybinome, silyhermin, and neosilyhermin. In addition apigenin, silybonol, and myristic, palmitic, stearic, and oleic acids have been reported (Foster, 1991; Awang, 1993; Brown, 1996; Grauds, 1996).

Technical Products and Impurities: Milk thistle is available at health food stores and pharmacies as well as through direct-mail companies. Extracts are supplied as capsules, tablets, liquids, powders and creams. Some of these milk thistle preparations are sold in combination formulas with other herbs. In Europe, a water-soluble silybin compound is available for use in intravenous infusion treatments (Ferenci et al., 1989; Foster, 1991; Awang, 1993).

Capsules. Capsules range in strength from 100 to 250 mg and most are standardized to contain 80 percent silymarin. Herbal Resources offers milk thistle extract in 150 mg capsules standardized to contain 70 percent silymarin (as silybin). Solgar's Vegicaps contain 100 mg of milk thistle extract (standardized to 80% silymarin) in a base of milk thistle herb and seed powder (Herbal Resources, Inc., 1995a; Global Nutrients, 1997; Smart Basics, 1997; Ripplecreek, 1998; Solgar Herbal Supplements, 1998). Time release capsules of milk thistle extract are also available (Dialog, 1998a).

Tablets. Source Natural's Silymarin 80 tablets are 210 mg standardized to deliver 168 mg of the three flavonolignans silybin, silydianin and silycristin. In addition, the tablets contain 50 mg of whole milk thistle seed (Dialog, 1998a).

Liquid. A blend of the liquid extracts of milk thistle mature seed (20%); dandelion root, leaf and flower (20%), Oregon grape root (20%), artichoke leaf (16%), beet leaf (16%), and fennel seed (8%) is available from Herbal Resources (Herbal Resources, Inc. 1995b).

Powder. Each 5 ml of a tonic powder from the Women's Health Advisory Service contains milk thistle (330 mg), psyllium husk powder (924 mg), dandelion root powder (330 mg), globe artichoke (165 mg), taurine (165 mg), and slippery elm bark (82.5 mg) (Women's Health Advisory Service, 1997).

Cream. A moisturizing cream, available from Abra Therapeutic Skin Care, contains milk thistle, green tea, and white willowbark; Derma E produces a skin lightening cream which combines milk thistle, licorice and vitamin C (Dialog, 1998a).

Silymarin is available from Aldrich and Sigma. The Aldrich product is a mixture of toxifolin, silicristin, silidianin, silybin A, silybin B, isosilybin A, and isosilybin B. The Sigma product is described as a mixture of anti-hepatotoxic flavonolignans from the fruit of Silybum marianum. Sigma also supplies silybin (Aldrich Chemical Co., Inc., 1996; Sigma, 1998).

EXPOSURE INFORMATION

Production and Producers: Silybum marianum, commonly known as milk thistle, is distributed throughout Southern Europe, Australia, North and South American, and parts of Asia (Ikram et al., 1984). Although milk thistle has been used medicinally for over 2000 years, the active hepatoprotective constituent, silymarin, was first isolated from the seeds (fruit) in 1968 (Brown, 1996).

The total synthesis of silybin, which constitutes about 60 percent of the silymarin complex, has been reported (Tanaka et al., 1985; Budavari, 1996; Boigk et al., 1997). Tanaka and coworkers (1985) achieved synthesis via a key intermediate, 3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-1,4-benzodioxan-6-carbaldehyde. This aldehyde was converted to the methoxymethyl ether which was condensed with an acetophenone derivative to yield the chalcone. Oxidation of the chalcone with alkaline hydrogen peroxide followed by treatment of the resulting epoxide with hydrochloric acid in methanol afforded racemic silybin in 63 percent yield.

Milk thistle extract is available from Acta Pharmacal, American Ingredients, Inc., Anmar International, Ltd., Ashland Chemical Co., Belmont Chemicals, Inc., Bio-Botanica, Inc., China Tech, Inc., G.C.I. Nutrients, Marcor Development Corp., Mini Star International, Inc., Motherland Herb-Pharm, Inc., Pharmline, Inc., QBI (Quality Botanicals Ingredients, Inc.), RIA International, Schweizerhall, Inc., F.H. Taussig, Inc., and P.L. Thomas & Co., Inc. (McCoy, 1997).

Silymarin is available from Amax Industries, Inc., CPB International, Inc., DNP International Co., Inc., Kaden Biochemicals GMBH, M.M.P., Inc., Marcor Development Corp., Maypro Industries, Inc., Mini Star International, Inc., Motherland Herb-Pharm, Inc., Pharmline, Inc., and F.H. Taussig, Inc. (McCoy, 1997).

For the 12-month period ending April 1998, milk thistle formulas were among the strongest sellers in natural product stores with a growth rate of 83.2 percent (Scimone & Scimone, 1998).

In the 6-month period from October 1997 to April 1998, the Port Import/Export Reporting Service (PIERS) reported milk thistle seed and silymarin imports of 73,082 and 27,645 pounds, respectively (Dialog, 1998b).

Neither milk thistle nor silymarin are listed in the EPA's Toxic Substances Control Act (TSCA) Inventory.

Use Pattern: Milk thistle has a long history of European cultivation for food. Young leaves can be used in salads and as a substitute for spinach; stalks can be eaten like asparagus; roots are eaten like salsify; and boiled flower heads used like artichoke. Milk thistle fruit has also been used as a coffee substitute (Awang, 1993).

Various preparations of milk thistle, especially the seeds, have been used medicinally for over 2000 years. It was taken as a tonic, demulcent, anti-depressant, and stimulant for milk production in nursing mothers. In homeopathy, a tincture of the fruits is used to treat bronchitis, cough, gallstones, hemorrhage, jaundice, peritonitis, uterine congestion, and varicose veins. Its use as a liver-protecting agent dates to early Greek references. The plant is not mentioned in most American works on medicinal plants until the end of the nineteenth century (Foster, 1991; Awang, 1993).

Currently the most important medicinal application of milk thistle is its use as an hepatoprotectant and as supportive treatment of chronic inflammatory liver disorders such as cirrhosis, hepatitis, and fatty infiltration due to alcohol and toxic chemicals. It has also been used in the treatment of liver damage by poisonous mushrooms. Following the isolation of silymarin and the development of standardized extracts in 1968, over 200 clinical studies involving over 4,000 patients have been completed with milk thistle extracts. Modern clinical research on the hepatobiliary effects of milk thistle began in Germany under the guidance of Madaus AG over thirty years ago (Foster, 1991; Awang, 1993; Brown, 1996).

For the treatment of liver disease (hepatitis, cirrhosis, toxin damage), the recommended dose of milk thistle extract is 420 mg (silymarin) a day taken in three divided doses. Suggested treatment periods range from 4 weeks to 9 months. When milk thistle is used as a nutritional supplement or for preventive purposes, 210 to 280 mg (silymarin) a day is recommended (Brown, 1996; Takao Co., 1996).

Human Exposure: The primary exposure of humans to milk thistle occurs through its use as an herbal supplement. Approximately one third of the US adult population or approximately 60 million consumers, have increasingly used alternative pharmaceutical preparations to prevent or treat illnesses (Tanaka, 1997).

There is potential for worker exposure to milk thistle during the growing, harvesting and processing of the plants. For the purposes of quantifying the costs of food labeling regulations, the FDA (1997) estimated that there were 250 herbal/botanical firms; the number of firms producing milk thistle products was not identified

No listing was found for milk thistle or silymarin in the National Occupational Exposure Survey (NOES), which was conducted by the National Institute for Occupational Safety and Health (NIOSH) between 1981 and 1983.

Environmental Occurrence: Milk thistle (Silybum marianum), a member of the Aster family, is a widespread wayside herb of uncultivated ground and wasteplaces throughout much of Europe. The plant is naturalized in the Eastern United States, California, and South America (Foster, 1991).

Regulatory Status: Since 1994, dietary supplements have been regulated under the Dietary Supplement Health and Education Act (DSHEA). For dietary supplements on the market prior to October 15, 1994, the DSHEA requires no proof of safety in order for them to remain on the market. The labeling requirements for supplements allow warnings and dosage recommendations as well as substantiated "structure or function" claims. All claims must prominently note that they have not been evaluated by the FDA, and they must bear the statement "This product is not intended to diagnose, treat, cure, or prevent any disease" (Croom & Walker, 1995).