Agency Response Letter
GRAS Notice No. GRN 000185

Melvin S. Drozen
Keller and Heckman
1001 G Street
Suite 500 West
Washington, DC 20001

Re: GRAS Notice No. GRN 000185

Dear Mr. Drozen:

The Food and Drug Administration (FDA) is responding to the notice, dated November 23, 2005, that you submitted on behalf of San-Ei Gen F.F.I. Inc. (San-Ei), 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 November 28, 2005, filed it on November 30, 2005, and designated it as GRAS Notice No. GRN 000185.

The subject of the notice is concentrated tomato lycopene extract. The notice informs FDA of the view of San-Ei that concentrated tomato lycopene extract is GRAS, through scientific procedures, for use as an ingredient in non-alcoholic beverages (21 CFR 170.3 (n) (3)), including carbonated beverages at levels up to 20 parts per million (ppm) of lycopene.

San-Ei's concentrated tomato lycopene extract is prepared from tomato lycopene extract manufactured by LycoRed Natural Products Industries, Ltd. (LycoRed), which is the subject of GRN 000156. The method of manufacture of LycoRed's tomato lycopene extract is detailed in GRN 000156. San-Ei describes generally available information about the chemical identity of lycopene, the predominant carotenoid in concentrated tomato lycopene extract.

San-Ei describes the method of manufacture and provides specifications for its concentrated tomato lycopene extract. San-Ei extracts LycoRed's tomato lycopene extract with ethanol to form a concentrated product containing at least 90% lycopene. The data in the notice indicate that ethanol extraction increases the percentage of all-trans-lycopene, while decreasing the percentages of cis-lycopene and beta-carotene. To increase the stability of lycopene, San-Ei formulates its product with ascorbic acid. San-Ei provides specifications for contaminants, including lead, arsenic, and heavy metals for its ingredient. San-Ei also provides the results of analyses of several lots of its concentrated tomato lycopene extract that conform with these specifications.

San-Ei discusses safety studies conducted with lycopene, the principal carotenoid of the concentrated tomato lycopene extract. San-Ei discusses published and unpublished acute and subchronic animal toxicity studies, reproductive, developmental and genotoxicity studies, and describes generally available information about the absorption, distribution, metabolism, and elimination of dietary lycopene.

Also, San-Ei describes published human clinical studies conducted with tomato lycopene extracts. San-Ei concludes that these studies indicate that long-term consumption of tomato lycopene extract is well-tolerated.

San-Ei discusses additional safety studies conducted with both synthetic lycopene and lycopene from Blakeslea trispora.. Synthetic lycopene is the subject of GRAS Notice 000119 and lycopene from B. trispora is the subject of GRAS Notice 000173.

Consideration of the potential use as a color additive

FDA notes that San-Ei's concentrated tomato lycopene extract has the potential to impart color in food products that contain it. As such, their use in food products may constitute the use of a color additive under section 201(t)(1) of the Federal Food, Drug, and Cosmetic Act (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 concentrated tomato lycopene extract 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 a color additive is deemed adulterated unless its use conforms with a regulation ⁽²⁾ issued under 721(b) listing it for such use.⁽³⁾

Conclusions

Based on the information provided by San-Ei, as well as other information available to FDA, the agency has no questions at this time regarding San-Ei's conclusion that concentrated tomato lycopene extract is GRAS under the intended conditions of use, as an ingredient in non-alcoholic beverages (21 CFR 170.3 (n) (3)), including carbonated beverages. The agency has not, however, made its own determination regarding the GRAS status of the subject use of concentrated tomato lycopene extract. As always, it is the continuing responsibility of San-Ei 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 000185, as well as a copy of the information in this notice that conforms to the information in the proposed GRAS exemption claim (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

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⁽¹⁾The Secretary of the Department of Health and Human Services (DHHS). The Secretary of DHHS has delegated the authority for this provision of the FFDCA to FDA.

⁽²⁾FDA is aware that 21 CFR 73.585 lists tomato lycopene extract and tomato lycopene concentrate as color additives that are exempt from certification.

⁽³⁾FDA notes 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 000185 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FFDCA.