Agency Response Letter
GRAS Notice No. GRN 000173

Diane B. McColl
Counsel to Vitatene S.A.
Hyman, Phelps, & McNamara, P.C.
700 Thirteenth Street, NW
Suite 1200
Washington, DC 20005-5929

Re: GRAS Notice No. GRN 000173

Dear Ms. McColl:

The Food and Drug Administration (FDA) is responding to the notice, dated June 20, 2005, that you submitted on behalf of Vitatene S.A. (Vitatene) 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 June 21, 2005, filed it on June 22, 2005, and designated it as GRN No. 000173.

The subject of the notice is lycopene from Blakeslea trispora. The notice informs FDA of the view of Vitatene that lycopene from B. trispora is GRAS, through scientific procedures, for use as an ingredient in a number of food categories (baked goods, baking mixes, beverages and beverage bases, breakfast cereals, cheeses, condiments and relishes, confections and frostings, fats and oils, frozen dairy desserts and mixes, gelatins, puddings and fillings, gravies and sauces, milk products, plant protein products, processed fruits and fruit juices, snack foods) at levels up to 50 parts per million (ppm) and in soups and soup mixes that do not contain tomatoes at levels up to 575 ppm.

Vitatene states that lycopene from B. trispora is a red crystalline powder that is identical to lycopene found in tomatoes. Lycopene from B. trispora is produced through a co-fermentation process using the two sexual mating types of the organism. Vitatene states that both mating types are stable cultures and are preserved under conditions consistent with food good manufacturing practices. Lycopene is extracted from the fungal cells and crystallized. Crystalline lycopene is then formulated into either a suspension in high oleic sunflower oil containing 5% or 20% lycopene or a cold water dispersible product containing modified food starch and 10% or 20% lycopene. Either type of formulation also contains up to 2% tocopherol as an antioxidant. To manufacture the oil suspensions, lycopene crystals are mixed and milled with high oleic sunflower oil and tocopherol. To manufacture the cold water dispersible product, lycopene crystals and tocopherol are first dissolved in a food grade solvent and then this solution is mixed with an aqueous modified food starch solution until a homogenous emulsion is formed. Finally, the solvent is evaporated under vacuum and the remaining liquid is dried. Vitatene provides specifications for their oil suspensions and cold water dispersible products.

Vitatene estimates the total daily intake of lycopene from the consumption of foods containing lycopene from B. trispora as 9.3 milligrams per person per day (mg/p/d) at the mean and as 18.8 mg/p/d at the 90th percentile level.

As part of its notice, Vitatene includes a summary of conclusions of a panel of individuals (Vitatene's GRAS panel) who evaluated the data and information that are the basis for Vitatene's GRAS determination. Vitatene considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Vitatene's GRAS panel reviewed two published rat toxicological studies: a 90-day oral toxicity study of the final product (lycopene 20% oil suspension) and a 28-day sub-chronic toxicity study of non-viable, disrupted Blakeslea biomass. In addition, the panel reviewed published animal and clinical safety studies conducted with lycopene from sources other than Blakeslea (naturally occurring dietary lycopene and supplemental lycopene). Vitatene's GRAS panel concluded that the scientific data support the safety of Vitatene's oil mixtures and cold water dispersible products containing lycopene from B. trispora under Vitatene's intended conditions of use.

Potential Requirement for a Color Additive Petition

FDA notes that Vitatene's lycopene from B. trispora when used in food products has the potential to impart color. As such, the use of lycopene from B. trispora in food products may constitute the use of a color additive under section 201(t)(1) of the FFDCA and FDA's implementing regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted, isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or through reaction with another substance) of imparting color when added or applied to a food; except that such term does not include any material which the Secretary,1 by regulation, determines is used (or intended to be used) solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the definition of color additive can be exempt from that definition on the basis that it is used or intended to be used solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is concerned. Given the construct of section 201(t)(1) of the FFDCA and 21 CFR 70.3(f) and (g), the use of a substance that is capable of imparting color may constitute use as a color additive in addition to use as a food additive or GRAS substance. For example, beta-carotene is both approved for use as a color additive (21 CFR 73.95) and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, beta-carotene is used for both purposes. Importantly, if the use of lycopene from B. trispora constitutes use as a color additive within the meaning of section 201(t)⁽¹⁾ of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food product that contains an unapproved color additive would be deemed adulterated.⁽²⁾

Potential Labeling Issues

Section 403(a) of the FFDCA provides that a food shall be deemed to be misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for health claims. In describing the intended use of Vitatene's oil mixtures and cold water dispersible products containing lycopene from B. trispora and in describing information that the notifier relies on to conclude that the product is GRAS under the conditions of its intended use, Vitatene raises issues under these labeling provisions of the FFDCA. These issues include Vitatene's description of the intended use of oil mixtures and cold water dispersible products containing lycopene from B. trispora as having effects that Vitatene views as beneficial. These issues are the purview of Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS). The Office of Food Additive Safety neither consulted with ONPLDS on these labeling issues nor evaluated the information in Vitatene's notice to determine whether it would support any claims made about lycopene on the label or in labeling.

Standards of Identity

In its notice, Vitatene states its intention to use oil mixtures and cold water dispersible products containing lycopene from B. trispora in several food categories, including milk products and cheeses for which a standard of identity exists. 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.

Conclusions

Based on the information provided by Vitatene, as well as other information available to FDA, the agency has no questions at this time regarding Vitatene's conclusion that lycopene from B. trispora 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 lycopene from B. trispora. As always, it is the continuing responsibility of Vitatene 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.
Director
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition

⁽¹⁾ The Secretary of the Department of Health and Human Services.

⁽²⁾ We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FFDCA while there is in effect a published finding of the Secretary declaring that the substance is exempt from the definition of "food additive" because of its being generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FFDCA. Importantly, FDA's response to GRN 000110 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FFDCA.