October 12, 1999

Brian M. Coyle
Manager, Pharaoh Palmier
155 Wilson Street
Albany, CA 94710

Re: GRAS Notice No. GRN 000025

Dear Mr. Coyle:

The Food and Drug Administration (FDA) is responding to the notice, dated June 19, 1999 , 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 June 25, 1999 and designated it as GRAS Notice No. GRN 000025.

The subject of your notice is Garcinia kola (commonly called bitter cola). The notice informs FDA of your view that the extract of G. kola seeds is GRAS, through scientific procedures, for use as a flavor enhancer in the beverage Pharaoh Palmier (a distillate of palmwine).

Your notice includes information regarding the production of the liquor Pharaoh Palmier, the components of the extract of G. kola seeds, and studies on the potential use of G. kola as a liver prophylaxis and as a hop substitute.

FDA has evaluated the information in GRAS Notice No. GRN 000025 as well as other available data and information and has identified certain issues, discussed in more detail below, regarding the safety of the extract of G. kola seeds for its intended use in the liquor Pharaoh Palmier. In light of these issues, your notice does not provide a sufficient basis for a determination that the extract of G. kola seeds is GRAS under the proposed conditions of use.

Data and information that you present to support the GRAS determination

Your notice states that Pharaoh Palmier is composed of distillate of palmwine, distillate of grain, and distilled water, which are combined in equal portions to produce a liquor of 40% alcohol. Approximately one gram of G. kola seeds is infused in 100 milliliters of grain alcohol and two milliliters of this infusion is added to every liter of Pharaoh Palmier. The notice indicates that the extract of G. kola seeds contains protein, lipid, sugar, plus small quantities of kolaviron (a mixture of biflavonoids GB-1, GB-2 and kolaflavone). You state that the extract is used as a flavor enhancer, imparting an astringent and pleasing aftertaste, and that the seeds are widely eaten in the areas in West Africa where the tree grows.

Your notice states that many scientific studies suggest that G. kola plays a pharmacological role as a liver prophylaxis. The seeds contain a family of biflavonoids that inhibit liver lipid peroxidation. However, the notice is silent about whether there will be an attempt to promote the liquor with such a claim.

Your notice also states that many studies report that G. kola can be a replacement for hops in the brewing of large quantities of beer in Africa. However, the use of G. kola in beer is outside the scope of your notice.

Your notice mentions the high acidity (that may cause ulcers) and methylating property (that may cause cancers) of the G. kola seeds as potential adverse effects, but dismisses them as a safety concern because of lack of evidence.

Your notice claims that the notified use of the extract of G. kola seeds is GRAS based on the facts that the seeds are edible and have virtually no toxic effect, that they may have an important physiological effect protecting against liver disease, and that they are used as a traditional African medicine.

FDA's evaluation of the data and information regarding your GRAS determination

FDA has evaluated the information that you discuss in your notice as well as other data and information that are available to the agency. We have identified several issues that your notice does not address. We briefly discuss some of these issues below. For simplicity, we have organized these issues according to the applicable sections of the GRAS notice.

(1) Under proposed 21 CFR 170.36(c)(2), a GRAS notice shall provide detailed information about the identity of the notified substance, that includes, among other things, quantitative composition, method of manufacture, characteristic properties, any content of potential human toxicants, and specifications for food grade material.

Your notice does not describe (1) the quantitative composition of the extract, including the amounts of biologically active components, such as kolaviron; (2) the physical properties of the extract; (3) the manufacturing conditions, such as the time and temperature, under which extraction is performed; and (4) the specifications for the extract.

Information about the quantitative composition of the extract is important, because the extract may contain minor components that are human toxicants or are biologically active. This is particularly true, since G. kola is used as a medicinal plant (Ref. 1) and its seeds are consumed in some countries for their stimulant properties. (Ref. 2) Information about the physical properties and manufacturing conditions is important to fully identify the extract. Information about the specifications of the extract is important to set reproducible standards for a food-grade extract.

(2) Under proposed 21 CFR 170.36(c)(4)(i)(B), a GRAS notice shall include a comprehensive discussion of any reports of investigations or other information that may appear to be inconsistent with the GRAS determination.

These potential adverse effects are not discussed in your notice. These effects may affect your claim that the notified use of the extract is GRAS, unless you can provide appropriate explanations in relation to these, or any other, reports concerning the safety of G. kola or its extract.

Because of these issues, it is our view that your notice does not provide a sufficient basis for a determination that the extract of G. kola seeds is GRAS under the proposed conditions of use.

In accordance with proposed 21 CFR 170.36(f), a copy of this letter, as well as a copy of the information in your notice that conforms to the information in proposed § 170.36(c)(1), is available for public review and copying on the Office of Premarket Approval's homepage on the World Wide Web.

References

1. Iwu, M. M., O. A. Igboko, O. K. Elekwa, and M. S. Tempesta, "Prevention of Thioacetamide-induced Hepatotoxicity by Biflavanones of Garcinia kola," Phytotherapy Research, 4:157-159, 1990.

2. Atawodi, S. E., et al., "Nitrosatable Amines and Nitrosamide Formation in Natural Stimulants: Cola acuminata, C. nitida, and Garcinia kola," Food and Chemical Toxicology, 33:625-630, 1995.

3. Braide, V. B., and V. Grill, "Histological Alterations by a Diet Containing Seeds of Garcinia kola: Effect on Liver, Kidney, and Intestine in the Rat," Gegenbaurs Morphol Jahrb, 136:95-101, 1990.

4. Akintonwa, A., and A. R. Essien, "Protective Effects of Garcinia kola Seed Extract against Paracetamol-induced Hepatotoxicity in Rats," Journal of Ethnopharmacology, 29:207-211, 1990.

5. Nwafor, A., and I. E. Ogheneaga, "Influence of Garcinia kola on in-vivo Secretion of Gastric Acid," African Journal of Pharmacology, 22:107-109, 1992.

6. Iwu, M. M., O. A. Igboko, C. O. Okunji, and M. S. Tempesta, "Antidiabetic and Aldose Reductase Activities of Biflavanones of Garcinia kola," Journal of Pharmaceutical Pharmacology, 42:290-292, 1990.

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