Agency Response Letter GRAS Notice No. GRN 000066
CFSAN/Office of Premarket Approval*
April 23, 2001
26216 Alizia Cyn. Drive
Calabasas, CA 91302
Re: GRAS Notice No. GRN 000066
Dear Mr. Hill:
The Food and Drug Administration (FDA) is responding to the notice, dated December 14, 2000, that you submitted in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS)). FDA received your notice on January 3, 2001 and designated it as GRAS Notice No. GRN 000066.
The subject of the notice is milk thistle extract. The notice informs FDA of the view of JHB Inc. that milk thistle extract is GRAS, through scientific procedures, for use as a bittering agent in a malt-based beverage, where a 355 milliliter glass bottle will contain approximately 2.5 milliliter of the extract.
As discussed more fully below, the notice does not provide a basis to conclude that milk thistle extract is GRAS for use in food. Rather, the notice provides evidence that milk thistle extract may produce effects in the liver.
Data and information that JHB presents to support its GRAS determination
In GRN 000066, JHB describes milk thistle extract as a standardized extract containing 100 milligrams silymarin (a collective name for the three flavonolignans; silybin, silychristin, and silidianin) per 5 milliliter of 66 percent ethanol. The extract is not otherwise characterized. Because a 355 milliliter glass bottle will contain approximately 2.5 milliliters of the extract, the 355 milliliter glass bottle will contain approximately 50 milligrams of silymarin. JHB does not estimate dietary exposure to milk thistle extract.
JHB states that milk thistle extract is made from isolated crushed seed husks and pure grain alcohol. No specific manufacturing conditions are provided other than saying that it is produced in accordance with good manufacturing practices of herbal medicinal products. JHB indicates that milk thistle extract will be obtained from Brucia Plant Extracts, Inc., a firm that has produced botanical preparations since 1975. JHB does not provide specifications to describe a food grade material.
GRN 000066 is, in large part, a transcription of a review about milk thistle extract that was posted on the Internet (i.e., www.onhealth.com). The article from the Internet discusses several clinical studies that focused on whether milk thistle extract has protective effects on the liver.
FDA's evaluation of the data and information in JHB's notice
FDA has evaluated the data and information in GRN 000066 as well as other available data and information. Given the minimal description of the method of manufacture and composition of the extract, as well as the lack of specifications for food grade milk thistle extract, it is not evident that food safety experts, generally, have a basis for knowing the composition of milk thistle extract to a degree sufficient to evaluate its safety for use as a direct food ingredient. Likewise, there is no evidence that the review that JHB transcribed from the Internet has been published in a peer-reviewed scientific journal. Moreover, we know of no reason to conclude that food safety experts would read, and accept the conclusions of, this article. Thus, we cannot conclude that the information described on this Internet site is generally known and accepted by food safety experts.
As described in the notice, a bottle of beer (355 ml) with 2.5 ml of milk thistle extract would have 50 mg of silymarin, a substance known to produce effects in the liver. Given this exposure, we would expect the notice to be based on the results of extensive safety tests in animals (e.g., genotoxicity studies and chronic feeding studies in more than one species of laboratory animal) (Ref. 1). We also would expect the notice to address the absorption, metabolism, distribution, and elimination of milk thistle extract and its potential to interfere with human metabolism. These studies typically are conducted to assess toxicity for the purpose of extrapolating the results to the general population. As appropriate, the results of such tests could be used to establish a No-Observed-Effect-Level (NOEL) in order to determine the acceptable daily intake (ADI), or level of consumption of milk thistle extract that would be safe for the general population.
The notice neither provides information about a NOEL established in any oral toxicological study nor provides reference to an ADI that has been established through such a study. Rather, the notice relies on clinical studies that focus on the efficacy of milk thistle as a drug to treat patients with liver disease. These clinical studies are inappropriate for the purpose of extrapolating the results to the general population. Moreover, under the Federal Food, Drug, and Cosmetic Act, FDA's evaluation of a drug considers both benefits and risks to patients, while FDA's evaluation of a food ingredient considers only potential risks. For these reasons, the studies that JHB describes in GRN 000066 are inadequate to evaluate the safety of milk thistle as a food ingredient.
JHB's assertion that there are no reports of adverse effects regarding the medicinal uses of milk thistle extract does not provide sufficient evidence to conclude that the use of milk thistle extract in malt-based beverages is safe. For example, we identified a published report of a 57-year-old woman with a two-month history of intermittent episodes of sweating, nausea, colicky abdominal pain, fluid diarrhea, vomiting, weakness and collapse, associated with the use of milk thistle capsules (Ref. 2). According to that article, a recent report published in the British Journal of Clinical Pharmacology indicates that adverse drug reactions to herbal medicines are more likely to be under-reported than those to conventional over-the-counter medicines (Ref. 3).
FDA has evaluated the data and information in GRAS Notice No. GRN 000066 as well as other available information. The notice does not provide a sufficient basis for a determination that milk thistle extract is GRAS under the conditions of its intended use.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter, as well as a copy of the information in your notice that conforms to the information in proposed 21 CFR 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the Internet (at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Alan M. Rulis, Ph.D.
Office of Premarket Approval
Center for Food Safety and Applied Nutrition
1. Toxicological Testing of Food Additives, which is available at http://www.cfsan.fda.gov/~dms/opa-tg1.html
2. Adverse Drug Reactions Advisory Committee, "An Adverse Reaction to the Herbal Medication Milk Thistle," Medical Journal of Australia, 170, 218-219 (1999).
3. Barnes et al., "Different Standards for Reporting ADRs to Herbal Remedies and Conventional OTC Medicines," British Journal of Clinical Pharmacology, 45, 496-500 (1998).
* The Office of Premarket Approval became the Office of Food Additive Safety on June 18, 2001.
References to FDA's web site in the text are out-of-date.