March 15, 2001

Mr. Robert H. Sindt
Attorney at Law
1850 M Street, N.W.
Suite 400
Washington, DC 20036

Re: GRAS Notice No. GRN 000063

Dear Mr. Sindt:

The Food and Drug Administration (FDA) is responding to the notice, dated December 19, 2000, that you submitted on behalf of Rhodia, Inc., 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 this notice on December 20, 2000 and designated it as GRAS Notice No. GRN 000063.

The subject of the notice is hops beta acids. The notice informs FDA of the view of Rhodia that hops beta acids are GRAS, through both scientific procedures and experience based on common use in food, for use as an antimicrobial agent in casings for frankfurters and in cooked meats. In a telephone conversation on February 6, 2001, you agreed that FDA would evaluate this notice based on scientific procedures, corroborated by evidence of the related history of use of hops beta acids.

Rhodia's notice provides a report of a specially convened panel of individuals (Rhodia's GRAS panel) who evaluated the data and information that are the basis for Rhodia's GRAS determination. Rhodia considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Rhodia's GRAS panel states that essential oils, oleoresins (solvent-free) and natural extractives (including distillates) from hops (Humulus lupulus L) are listed as GRAS in 21 CFR 182.20, and that the safety of hops and the component acids extracted therefrom is supported by a long history of safe use in foods, especially beer, throughout recorded history. Based on the data and information reviewed, Rhodia's GRAS panel concludes that hops beta acids, when produced in accordance with current good manufacturing practice and meeting appropriate food grade specifications, are GRAS for use as an antimicrobial agent in casings for frankfurters and in cooked meats.

Rhodia's notice describes published information pertaining to the chemical identity of hops beta acids. The primary hops beta acids are lupulone (C₂₇H₃₈O₄), colupulone (C₂₆H₃₇O₄), and adlupulone (C₂₇H₃₈O₄). The notice states that hops resin obtained from the yellow vesicles in the petals of hops flower is the source of hops beta acids. The manufacturing process involves the extraction of hops resin utilizing commonly accepted extraction methodology with such solvents as hexane or ethyl alcohol, to give hops alpha acids and hops beta acids, followed by the separation of these two fractions using liquid carbon dioxide under super critical conditions or by chromatography. Purified hops beta acids are usually 80-90 percent pure in a liquid form dried on a carrier, such as maltodextrin. The notice provides specifications for hops beta acids, including a lead specification of less than 2 parts per million.

Rhodia's notice states that the intended use of hops beta acids is as an antimicrobial agent in casings for frankfurters at a concentration of 2.5 milligrams (mg) per pound of frankfurter (equivalent to 5.5 mg per kilogram of frankfurter) and in cooked meats sold ready-to-eat at a concentration of 2.0 mg per pound of meat (equivalent to 4.4 mg per kilogram of meat). The notice discusses Rhodia's view that hops beta acids have antimicrobial activity against select Gram positive spoilage bacteria, and inhibit the growth of L. monocytogenes in foods. Rhodia's notice provides intake estimates for hops beta acids from the proposed use based on the 1994-1996 Continuing Survey of Food Intakes by Individuals (CSFII) two-day survey: 0.09 mg/person/day (mg/p/d) for the mean per capita exposure and 0.27 mg/p/d at the 90th percentile.

Rhodia's notice states that estrogenic activity associated with hops harvesting and brewing has been reported in the scientific literature since the 1950s. Extraordinary levels of estrogenic activity were found in beer, hops or hops extract. However, there were also published reports which found no estrogenic activity in hops essential oil, hops extract, hops alpha acids, hops beta acids, and hops resin. The notice states that the variability of these reports may be due to the extracts and the specific assays used. A more recent study (Milligan, 1999) reported that the estrogenic activity was concentrated in the polar, polyphenol-containing fractions of hops extracts and no estrogenic activity was detected in the less polar fractions of hops extract, which include hops alpha acids and hops beta acids.

Based on the information provided by Rhodia as well as other information available to FDA, the agency has no questions at this time regarding Rhodia's conclusion that hops beta acids are GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of hops beta acids. As always, it is the continuing responsibility of Rhodia to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

During its evaluation of GRN 000063, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service of the United States Department of Agriculture (FSIS). FSIS requests that Rhodia be advised that it may be necessary to modify regulatory standards where a standard of identity prohibits or limits the use of an ingredient. At this time, FSIS is not initiating any substance-specific rulemaking activities to amend food standards until its ongoing standards modernization activities are completed. However, FSIS will be able to address requests for the use of any antimicrobial formulations containing hops beta acids on meat and poultry products with prevailing standards of identity provided they are descriptively labeled to clearly distinguish them from the traditional standardized products. It is our understanding that you will seek regulatory guidance from FSIS concerning the use of these antimicrobial formulations in standardized meat and poultry products. You should direct your inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program Development and Evaluation, Food Safety and Inspection Service, 300 12th Street, SW, Room 602, Washington, DC 20250-3700. The telephone number of his office is (202) 205-0279 and the FAX number is (202)205-3625.

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 the 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).

References

1. Milligan, S. R., et al, "Identification of a Potent Phytoestrogen in Hops (Humulus lupulus L.) And Beer," Journal of Clinical and Endocrinological Metabolism, 84, 2249-2252, 1999.

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