U. S. Food and Drug Administration
Center for Food Safety and Applied Nutrition
Office of Nutritional Products, Labeling, and Dietary Supplements
May 16, 2000

Letter to Industry -
FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid

To:	American Botanical Council, American Herbal Products Association Council for Responsible Nutrition Consumer Healthcare Products Association National Nutritional Foods Association, and, Utah Natural Products Alliance.

The Food and Drug Administration (FDA) is issuing this letter to communicate to you our concern about the marketing of dietary supplements that may contain aristolochic acid. We also wish to communicate to you actions that manufacturers and distributors of dietary supplements containing certain botanical ingredients should consider in light of reports that aristolochic acid has been found in some dietary supplements or other products that may be marketed as traditional herbal medicines. FDA asks that you share this information with your members.

In the past several months, public warnings have been issued by Health Canada and the Medicine Controls Agency (United Kingdom) because of findings of aristolochic acid in several botanical products marketed as traditional medicines. The use of products containing aristolochic acid has resulted in several life-threatening adverse incidents. Aristolochic acids are potent carcinogens and nephrotoxins that are present, primarily, in plants of the family Aristolochiaceae. There are at least 14 aristolochic acids known. In recent years, there have been several reported instances of severe nephropathy in consumers consuming products containing aristolochic acid. The incidents range from a few cases to, in one incident in Belgium, over 100 cases of nephropathy linked to the use of an herbal product containing aristolochic acids. In each incident the source of the aristolochic acids was determined to be from an ingredient in the herbal product which is a member of this plant family. The plant material used in the suspect products was either mis- identified or the name of the plant ingredient was confused with that of another plant.

Attached to this letter are lists of plants known to contain aristolochic acid and of plants which may become adulterated with Aristolochia spp. These lists, however, should not be considered a comprehensive listing of all plants which may contain aristolochic acid; the family Aristolochiaceae has about 600 species.

In light of known association between products containing these plants and incidents of nephropathy, the FDA believes that manufacturers need to take steps to positively confirm that botanical ingredients are not inadvertently contaminated with plant material which contains aristolochic acid. As you know, under the Federal Food, Drug, and Cosmetic Act (the Act), as amended by the Dietary Supplement Health and Education Act of 1994, the manufacturer bears the primary responsibility for ensuring that its dietary supplement products are safe. FDA believes that manufacturers can do several things to ensure that their products are not inadvertently adulterated.

First, FDA advises manufacturers to review their current manufacturing practices. Their manufacturing practices should include procedures that ensure comprehensive and rigorous testing of ingredients and finished products to prevent the sale to consumers of products that contain potentially harmful impurities. At a minimum, we believe that it is absolutely necessary that manufacturers who produce products that contain ingredients that may be contaminated with aristolochic acid test their products to confirm the absence of aristolochic acids.

Second, FDA believes that manufacturers need to take adequate steps to identify and report adverse events, especially adverse events that may include renal system disorders, associated with any product that contains an ingredient on the enclosed list of ingredients. FDA recommends that firms promptly notify FDA's MEDWATCH program of reports of adverse events associated with the use of products containing any of the listed botanicals.

Regardless of the reason for the presence of aristolochic acid in different products, it is important that products that contain aristolochic acid not be allowed to enter the U.S. marketplace. Aristolochic acid is a potent carcinogen and nephrotoxin. While a product that contains a large amount of it may result in the rapid onset of acute toxicity symptoms in a consumer using the product, a product containing a small amount could be used for years with no apparent adverse effects, until serious, irreversible effects, such as renal failure, has occurred. Because there is evidence that aristolochic acid-containing products are in international commerce, FDA intends to issue, in the very near future, an import alert that will provide for the automatic detention without physical examination of any product containing a plant listed in the enclosure to this letter. Detained product will be released when the responsible party can provide direct analytical evidence that it is free of aristolochic acid. FDA considers any FDA-regulated product containing aristolochic acid to be unsafe and to be adulterated.

In conclusion, FDA urges manufacturers and distributors of dietary supplements and other botanical-containing products containing any ingredient identified in the attachment to this letter, if they plan to continue marketing these products, to: (1) review their current manufacturing practices to ensure that they do not contain aristolochic acid; and (2) ensure that adequate procedures are in place to collect and report to FDA adverse events that may be associated with the use of products.

FDA is available and prepared to assist the industry on these matters. Firms are encouraged to contact FDA if they have any questions or concerns about this important public health issue. Inquiries should be directed to Dr. Robert Moore in the Office of Nutritional Products, Labeling, and Dietary Supplements (202-205-4605; email rmoore2@cfsan.fda.gov).

April 9, 2001 updated attachments: Listing of Botanical Ingredients of Concern

Consolidated Information on Aristolochic Acids: FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid