Food

Agency Response Letter GRAS Notice No. GRN 000517

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CFSAN/Office of Food Additive Safety

November 21, 2014

Gary Yingling
Morgan, Lewis & Bockius, LLP
1111 Pennsylvania Avenue, NW
Washington, DC 20004

Re: GRAS Notice No. GRN 000517

Dear Mr. Yingling:

The Food and Drug Administration (FDA) is responding to the notice, dated May 6, 2014, that you submitted on behalf of DSM Food Specialties (DSM), 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 May 7, 2014, filed it on May 29, 2014, and designated it as GRAS Notice No. GRN 000517.

The subject of the notice is natamycin. The notice informs FDA of the view of DSM that natamycin is GRAS, through scientific procedures, for use as an antimycotic to prevent the growth of molds and yeasts in yogurt at use levels not to exceed 5 milligrams per kilogram (mg/kg).(1)

Natamycin is a polyene macrolide antimycotic with a molecular weight of 665.7; the CAS Registry Number is 7681-93-8. DSM states that natamycin is a white to creamy-white crystalline powder that is almost tasteless and odorless. Natamycin may contain up to three molecules of crystal water.

DSM describes the manufacturing process for natamycin. A pure culture of Streptomyces natalensis CBS 700.57 is grown in a submerged batch fermentation process under controlled conditions. During fermentation, natamycin is secreted to the broth. After fermentation, the broth is centrifuged to separate insoluble natamycin from most of the residual mycelium. For purification purposes, natamycin is then resuspended, re-crystallized, filtered, and washed. Natamycin is then dried and milled into a powder for packaging. DSM states that the manufacturing process complies with good manufacturing practices.

DSM provides specifications for natamycin that include limits on sulphated ash (≤ 0.5%), arsenic (≤ 1 mg/kg), lead (≤ 2 mg/kg), and mercury (≤ 1 mg/kg). Water is limited to between 6.0% and 9.0% (includes both crystal and free water). DSM also provides limits for microbial contaminants. DSM describes the analytical tests performed to verify that natamycin meets the specifications in the Food Chemicals Codex (FCC, 8th Edition).

DSM estimates the dietary exposure to natamycin based on current uses of natamycin combined with the intended use in yogurt. Natamycin is currently approved under 21 CFR 172.155 for use on cheese surfaces, as well as in grated and shredded cheeses at levels not to exceed 20 mg/kg in the finished products. DSM calculates the current mean and corresponding 90th percentile intakes of natamycin to be 0.009 mg/kg body weight per day (bw/d) and 0.020 mg/kg bw/d, respectively, for the total U.S. population. DSM calculates the cumulative (intended use in addition to current use) total per user mean daily intake for natamycin to be 0.011 mg/kg body weight per day (bw/d), and the corresponding 90th percentile intake to be 0.023 mg/kg bw/d for the total U.S. population.

DSM states that S. natalensis is a nonpathogenic and nontoxigenic organism. DSM notes that the company has used S. natalensis CBS 700.57 and isolates derived from this strain for large scale fermentation since 1960.

DSM discusses the metabolism of natamycin, as well as toxicological studies conducted with natamycin. Citing published as well as unpublished studies evaluated by the WHO/FAO Joint Expert Committee on Food Additives (JECFA), DSM states that natamycin is not absorbed from the gut in animals or humans to a significant extent. DSM also states that natamycin is inactivated by bacteria in the cecum and colon of rats. DSM discusses a published subchronic toxicity study conducted in rats fed up to 8000 mg natamycin/kg diet for 94-96 days. DSM also discusses a published subchronic toxicity study conducted in beagle dogs fed up to 750 mg natamycin/kg diet for 3 months. DSM notes that some instances of diarrhea in dogs were observed only in the highest dose groups. DSM does not consider the diarrhea to be a systemic toxicological effect. DSM concludes that no treatment-related toxicological effects were observed in either study, even at the highest dietary concentrations of natamycin.

DSM discusses a published chronic toxicity study conducted in rats fed 0, 125, 250, 500, or 1000 mg natamycin/kg diet for 2 years. DSM notes that no treatment-related adverse effects were seen in animals fed up to 500 mg/kg dietary concentration of natamycin, equivalent to a natamycin intake of 25 mg/kg bw/d. DSM further notes that the numbers and types of tumors found in natamycin-treated rats were not significantly different from those in untreated animals. In a published chronic toxicity study conducted in beagle dogs fed 0, 125, 250, or 500 mg natamycin/kg diet for 2 years, no treatment-related adverse effects were seen in animals fed up to 250 mg natamycin/kg diet, equivalent to a natamycin intake of 6 mg/kg bw/d.

In unpublished studies evaluated by JECFA, natamycin was found to have no reproductive or developmental toxicity in rats and rabbits, and was found to be non-genotoxic in an in vivo chromosomal aberration assay.

In a published human study, ten individuals consumed up to 1000 mg natamycin/d for 13-180 days. DSM states that the level of natamycin causing no adverse effects was estimated to be 200 mg/d, equivalent to 3 mg natamycin/kg bw/d. DSM notes that the available information evaluated by JECFA did not reveal any evidence of human allergic reactions to natamycin.

Based on the information discussed above, DSM concludes that natamycin is GRAS for the intended use.

Standards of Identity

In the notice, DSM states its intention to use natamycin in yogurt, for which standards of identity exist, located in 21 CFR 131.200 (yogurt), 131.203 (lowfat yogurt), and 131.206 (nonfat yogurt). We note that an ingredient that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable standard of identity. The standards of identity for yogurt do not permit the use of preservatives; however, the provisions that exclude the addition of preservatives have been stayed since 1982 (47 FR 41522). FDA has not fully revolved this issue. As such, FDA has not taken enforcement actions against the use of preservatives in yogurt, lowfat yogurt, or nonfat yogurt. As a preservative, natamycin must be declared in the ingredient statement (21 CFR 101.4(a)(1)) and the name must be followed by a statement indicating its preservative function (21 CFR 101.22 (j)).

Potential Labeling Issues

Section 403(k) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provides that a food shall be deemed to be misbranded if it bears or contains any chemical preservative, unless it bears labeling stating that fact. Section 403(i)(2) of the FD&C Act provides that a food shall be deemed to be misbranded unless its label bears the common or usual name of each ingredient. Section 403(a) of the FD&C Act provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. DMS’s use of natamycin constitutes use as a preservative. Therefore, the ingredient statement on labels of food products that contain natamycin must comply with the labeling regulations that implement sections 403(k) and 403(i)(2) of the FD&C Act. For example, 21 CFR 101.22(j) requires that the food to which a chemical preservative is added bear a label declaration stating both the common or usual name of the ingredient and a separate description of its function. Further, food that is subjected to any form of preservation, except as provided in 21 CFR 101.95(c), may not be labeled as “fresh.” If DSM has any questions about the appropriate labeling of this food ingredient, DSM should contact the staff in the Office of Nutrition, Labeling, and Dietary Supplements.

Section 301(ll) of the FD&C Act

The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of DSM’s notice that natamycin is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing natamycin. Accordingly, this response should not be construed to be a statement that foods that contain natamycin, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).

Conclusions

Based on the information provided by DSM, as well as other information available to FDA, the agency has no questions at this time regarding DSM’s conclusion that natamycin is 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 natamycin. As always, it is the continuing responsibility of DSM 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 responding to GRN 000517, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.

Sincerely,

Dennis M. Keefe, Ph.D.
Director
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition

(1)DSM discusses published studies showing that natamycin prevents the growth of food spoilage molds when used in yogurt at a minimum level of 5 mg/kg.

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