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U.S. Department of Health and Human Services

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Agency Response Letter GRAS Notice No. GRN 000135

CFSAN/Office of Food Additive Safety
January 16, 2004

Edward A. Steele
AAC Consulting
7361 Calhoun Place
Rockville,
MD, 20855-2765

Re: GRAS Notice No. GRN 000135

Dear Mr. Steele:

The Food and Drug Administration (FDA) is responding to the notice, dated July 10, 2003, that you submitted on behalf of Chisso Corporation (Chisso) 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); the GRAS proposal). FDA received the notice on July 10, 2003, filed it on July 15, 2003, and designated it as GRAS Notice No. GRN 000135.

The subject of the notice is epsilon-polylysine (polylysine). The notice informs FDA of the view of Chisso that polylysine is GRAS, through scientific procedures, for use as an antimicrobial agent in cooked rice or sushi rice at levels up to 50 milligrams per kilogram (mg/kg) of rice. Chisso estimates that intake of polylysine from its intended use would be 15 mg per person per day at the 90th percentile.

As part of its notice, Chisso includes the report of a panel of individuals (Chisso's GRAS panel) who evaluated the data and information that are the basis for Chisso's GRAS determination. Chisso considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. The report of Chisso's GRAS panel discusses the identity of polylysine, its method of manufacture, specifications, exposure, and safety studies. Chisso's GRAS panel concludes that polylysine, meeting appropriate specifications, is GRAS when used as an antimicrobial ingredient in rice and sushi rice at levels up to 50 mg polylysine per kilogram of rice.

Chisso describes generally available information about the identity and composition of polylysine (Chemical Abstracts Service Registry Number 28211-04-3). Polylysine is a homopolymer of L-lysine, an amino acid that is a common component of protein. The polymer consists of approximately 30 L-lysine units linked by amide bonds between the carboxyl groups and the epsilon-amino groups. The systematic name for polylysine is poly(imino(2-amino-1-oxo-1,6-hexanediyl)). The 30-unit homopolymer has a molecular weight of 4700 and an empirical formula of C180H362N60O31.

Chisso describes the manufacturing process for polylysine. Polylysine is manufactured by fermentation using a nonpathogenic and nontoxigenic strain of Streptomyces albulus subspecies lysinopolymerus under aerobic conditions. The fermentation is conducted according to current good manufacturing practice, and the raw materials used are those that are commonly used in bacterial production of food ingredients. Following fermentation, microorganisms are removed by membrane filtration. The polylysine in the filtrate is further purified by passing it through an ion exchange resin, treatment with activated charcoal, and sequentially passing it through three ion exchange resins and then concentrated by evaporation. The resulting polylysine solids are powdered or atomized to produce the desired fine powder. Chisso provides specifications for polylysine with limits on purity, appearance, solubility, moisture, ash, heavy metals, arsenic, and lead.

Chisso provides a publication that presented a summary of the toxicological studies on polylysine that have been published in Japanese journals, as well as additional studies and described new data on the absorption, distribution, metabolism and excretion of polylysine.

Chisso provides a publication that reports the results of a study of absorption, distribution, metabolism and excretion of polylysine in rats using radio-labeled polylysine. Based on this study, Chisso concludes that approximately 94 percent of the polylysine passed unabsorbed through the gastrointestinal tract and was eliminated in the feces. Chisso further concludes that polylysine is not accumulated in any tissue or organ. Chisso concludes that L-lysine is cleaved from polylysine and that there is low level fragmentation into 4 and 6 unit polymers in the lower gut and absorbed L-lysine is incorporated into protein or further metabolized.

The publication provided by Chisso describes the results of an acute toxicity study and bacterial assays for mutagenicity. Chisso concludes that polylysine was non-toxic up to 5g/kg body weight in the acute oral study. Chisso further reports that there was no evidence for mutagenic activity of polylysine.

Chisso describes the results and conclusions of a subchronic and chronic toxicity and carcinogenicity study. Chisso concludes that reductions in body and organ weights associated with poor palatability were observed in the sub-chronic study at the high dose level and up to midpoint in the chronic study, but these effects were not sustained through the end of the chronic study and no notable histopathological effects were observed.

Based on the information provided by Chisso, as well as other information available to FDA, the agency has no questions at this time regarding Chisso's conclusion that polylysine is GRAS for use as an antimicrobial agent in cooked rice or sushi rice at levels up to 50 mg/kg. The agency has not, however, made its own determination regarding the GRAS status of the subject use of polylysine. As always, it is the continuing responsibility of Chisso to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.

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 homepage of the Office of Food Additive Safety (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).

Sincerely,
Laura M. Tarantino, Ph.D.
Acting Director
Office of Food Additive Safety
Center for Food Safety
     and Applied Nutrition