Agency Response Letter
GRAS Notice No. GRN 000156

George A. Burdock, Ph.D.
Burdock Group
780 U.S. HWY 1
Suite 300
Vero Beach, FL 32962

Re: GRAS Notice No. GRN 000156

Dear Dr. Burdock:

The Food and Drug Administration (FDA) is responding to the notice, dated August 4, 2004 that you submitted on behalf of LycoRed Natural Products Industries, Ltd. (LycoRed), 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 August 6, 2004, filed it on August 11, 2004, and designated it as GRAS Notice No. GRN 000156. FDA also received a submission dated September 29, 2004, on October 18, 2004, and added it as an amendment to GRN 000156.

The subjects of the notice are tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract. The notice informs FDA of LycoRed's view that tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract, are GRAS, through scientific procedures, for use as ingredients in a number of food categories (baked goods, breakfast cereals, cheeses, condiments and relishes, confections, dairy product analogs, frozen dairy desserts, gelatins, puddings and fillings, grain products, gravies and sauces, jams and jellies, meat products, milk products, processed vegetables and vegetable juices, snack foods, soft candies, soups and soup mixes), at a maximum final concentration of lycopene in food of 10 milligrams/kilogram (mg/kg). For clarity, in the remainder of this letter FDA uses the term "lycopene" to denote the principal carotenoid of these three ingredients.

Our use of the terms "tomato lycopene extract 6 percent, tomato lycopene extract 1.5 percent, and crystallized tomato lycopene extract" in this letter should not be considered an endorsement or recommendation of these terms as appropriate common or usual names for the purpose of declaring these substances in the ingredient statement of foods that contain these ingredients. 21 CFR 101.4 states that all ingredients must be declared by their common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for non-standardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS).

As part of its notice, LycoRed includes a summary of conclusions of a panel of individuals (LycoRed's GRAS panel) who evaluated the data and information that are the basis for LycoRed's GRAS determination. LycoRed considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. LycoRed's GRAS panel evaluated the following: estimated dietary exposure; method of production of tomato lycopene extract and crystallized tomato lycopene extract; nature and quantity of impurities; product specifications; and data and information available from human clinical studies and pre-clinical toxicity studies including acute and subchronic animal studies and in vitro assays of genotoxicity. LycoRed's GRAS panel concluded that tomato lycopene extract and crystallized tomato lycopene extract are GRAS for their intended uses.

LycoRed describes the chemical composition of the tomato lycopene extract (1.5 percent or 6 percent), which contains a standardized concentration of lycopene (1.5 or 6 percent respectively), with the balance consisting of other tomato lipids including total fatty acids,⁽¹⁾ phytosterols, tocopherols, and other carotenoids such as phytoene, phytofluene, and beta-carotene. Typical values for compositional analyses of the tomato lycopene extract are provided in the notice. The fatty acids present in the tomato lycopene extracts are identified as follows: myristic acid (14:0); palmitic acid (16:0); stearic acid (18:0); oleic acid (18:1); linoleic acid (18:2); linolenic acid (18:3); arachidic acid (20:0); behenic acid (22:0). LycoRed also describes the chemical composition of a crystallized tomato lycopene extract, an ingredient obtained by isolation or fractionation of lycopene crystals from tomato lycopene extract 6 percent, that contains a high lycopene content (approximately 70 percent), with lower levels of total fatty acids and trace amounts of phytosterols, tocopherols, and other carotenoids.

LycoRed describes generally available information about the chemical identity of lycopene, the predominant carotenoid in the tomato lycopene extract (1.5 percent and 6 percent) and crystallized tomato lycopene extract. In foods such as red ripe tomato, lycopene is the most abundant carotenoid and the all trans isomer of lycopene predominates. Similarly, in the tomato lycopene extracts and crystallized tomato lycopene extract, lycopene exists predominantly in the trans form (80 percent) with the remainder as various cis isomers.⁽²⁾ All trans lycopene is denoted by the Chemical Abstract Service Registry Number 502-65-8.

LycoRed describes the method of manufacture of tomato lycopene extracts and crystallized tomato lycopene extract, prepared by a patented ethyl acetate extraction process. Tomato lycopene extract is prepared from a hybrid, high lycopene variety of tomato (Lycopersicon esculentum (L.) Karst Ex. Farwell). Production of tomato extract involves two steps: production of tomato pulp and an ethyl acetate extraction of fat-soluble components from tomato pulp. Ethyl acetate is removed in a 3-stage vacuum stripping process, and the resultant tomato extract is standardized to a specific lycopene concentration (typically 6 percent lycopene), and stored under nitrogen at 4 degrees Celsius. Tomato lycopene extract 6 percent may be used as such or may be further fractionated into two components, as described in the September 29 amendment. Briefly, these two fractions are formed by isolation of crystalline lycopene from the tomato lycopene extract, either by de-oiling of the extract to remove the bulk of non-lycopene tomato lipids or extraction with ethyl acetate. The latter process relies on the limited solubility of lycopene (relative to other tomato lipids) in ethyl acetate. The resulting fractions are crystallized tomato lycopene extract containing 70 percent lycopene (i.e., "crystallized tomato lycopene extract") and tomato lycopene extract containing 1.5 percent lycopene (i.e., "tomato lycopene extract 1.5 percent").

LycoRed provides product specifications and analyses for tomato lycopene extract (6.0 percent and 1.5 percent) and crystallized tomato lycopene extract. LycoRed also provides specifications for moisture and contaminants, including pesticides, heavy metals, residual solvent, and microbiological specifications for each ingredient. Both tomato lycopene extracts (6.0 percent and 1.5 percent) are described as clear, dark red, viscous liquids. Tomato lycopene extract 6.0 percent meets the following specifications: 5-8 percent total lycopene (90-95 percent trans), 1.5-3.0 percent tocopherols, 60-75 percent total fatty acids, 13-20 percent unsaponifiable matter, and 6.5-9.0 percent total carotenoids. Tomato lycopene extract 1.5 percent meets the following specifications: 1-2 percent total lycopene (≥ 80 percent trans), 1-3 percent tocopherols, 75-80 percent total fatty acids, 12-13 percent unsaponifiable matter, and 2-4 percent total carotenoids. Crystallized tomato lycopene extract is described as a dark red, free-flowing powder. Crystallized tomato lycopene extract meets the following specifications: 60-80 percent total lycopene (≥ 90 trans), 2.5-11 percent phospholipids, 0.2-1.0 percent waxes, 3-7 percent water soluble matter, 5-12 percent total fatty acids, 60-80 percent total carotenoids, and trace amounts of tocopherols and other carotenoids.

LycoRed specifies the intended use levels of tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract in several food categories. LycoRed proposes the same lycopene levels for each food category: 167 mg/kg tomato lycopene extract 6 percent, 14.3 mg/kg crystallized tomato lycopene extract, and 668 mg/kg tomato lycopene extract 1.5 percent. Each of these use levels results in a lycopene concentration of 10 mg/kg food. LycoRed considers these intended GRAS uses to be in addition to the uses specified in a color additive petition (CAP 1C0273) under review at FDA.⁽³⁾

LycoRed notes that the use of tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract is largely self-limiting. At high levels (e.g., in excess of 800 mg/kg from tomato lycopene extract 6 percent) certain food items may acquire an undesirable taste and/or color. Tomato lycopene extracts and crystallized tomato lycopene extract would not be compatible with all food systems, due in part to technical limitations (e.g., solubility, aesthetics), cost, and to limited or restricted use in standardized foods.

LycoRed provides estimates of the intake of lycopene from its intended GRAS uses of tomato lycopene extract (1.5 percent and 6 percent) and crystallized tomato lycopene extract when added to several food categories. These estimates were derived from the Continuing Survey of Food Intakes by Individuals (CSFII) 1994-6, and 1998 for ages 2 and older. The notifier estimates that users-only intake of lycopene from the intended GRAS uses of tomato lycopene extracts and crystallized tomato lycopene extract would be 10.4 milligrams per person per day (mg/p/d) at the mean and 17.7 mg/p/d at the 90th percentile of intake. For comparison, LycoRed estimates the intake of lycopene for individuals that consume lycopene-containing foods (i.e., fruits and vegetables and foods derived therefrom in which lycopene is a known constituent) would be 8.2 mg/p/d at the mean and 15.7 mg/p/d at the 90th percentile.

LycoRed estimates that combining GRAS and petitioned color additive uses of tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract would result in lycopene intake of 23.9 mg/p/d at the mean and 42.6 mg/p/d at the 90th percentile. LycoRed acknowledges that some individuals will also consume tomato lycopene extract as a dietary supplement, and estimates intake of lycopene from this use as 30 mg/p/d lycopene. LycoRed concludes that the addition of dietary supplement use to the GRAS and petitioned color additive lycopene intake would result in potential total intakes of approximately 54 mg/p/d lycopene at the mean and 103 mg/p/d lycopene at the 90th percentile. LycoRed notes that this estimate is well within their acceptable daily intake (ADI) of 120 mg/d for lycopene from tomato lycopene extract. LycoRed's GRAS panel concluded that tomato lycopene extracts and crystallized tomato lycopene extract were GRAS for their intended uses when daily intake of lycopene from all sources did not exceed 120 mg/p/d.

LycoRed discusses studies conducted with lycopene, the principal carotenoid of the three ingredients, and tomato lycopene extracts (5 percent and 6 percent). For lycopene, LycoRed discusses published and unpublished acute and subchronic animal studies, and describes generally available information about the absorption, distribution, metabolism, and elimination of dietary lycopene. In addition, LycoRed describes preclinical studies conducted with tomato lycopene extracts, concluding that tomato lycopene extracts have been found to be non-toxic in both acute and subchronic animal studies. Furthermore, LycoRed describes published clinical studies conducted with tomato lycopene extracts. LycoRed concludes that all of these studies indicate that long-term consumption of tomato lycopene extract is well-tolerated.⁽⁴⁾

Consideration of the potential use as a color additive

FDA notes that LycoRed's tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract have 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⁽⁵⁾ 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 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 issued under 721(b) listing it for such use.

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 tomato lycopene extract and in describing information that the notifier relies on to conclude that tomato lycopene extract is GRAS under the conditions of its intended use, LycoRed raises issues under these labeling provisions of the FFDCA. These issues include LycoRed's description of the intended use of tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract as having effects that LycoRed views as beneficial. These issues are the purview of ONPLDS. The Office of Food Additive Safety neither consulted with ONPLDS on these labeling issues nor evaluated the information in LycoRed'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, LycoRed states its intention to use tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract 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.

Use in Meat Products

During its evaluation of GRN 000156, FDA consulted with the Labeling and Consumer Protection Staff of the Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA). Under the Federal Meat Inspection Act and the Poultry Products Inspection Act, FSIS is responsible for determining the efficacy and suitability of food ingredients in meat and poultry products as well as prescribing safe conditions of use. Suitability relates to the effectiveness of the ingredient in performing the intended purpose of use and the assurance that the conditions of use will not result in an adulterated product, or one that misleads consumers.

FSIS requested that FDA advise LycoRed to seek regulatory guidance from FSIS, Labeling and Consumer Protection Staff, about the use of these ingredients in meat products. LycoRed should direct such an inquiry to Dr. Robert Post, Director, Labeling and Consumer Protection Staff, Office of Policy, Program, and Employee Development, Food Safety and Inspection Service, 1400 Independence Ave., S.W., Suite 602, Annex, Washington, DC 20250-3700. The telephone number for that office is (202) 205-0279 and the telefax number is (202) 205-3625.

Conclusions

Based on the information provided by LycoRed, as well as other information available to FDA, the agency has no questions at this time regarding LycoRed's conclusion that their tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract 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 tomato lycopene extracts (1.5 percent and 6 percent) and crystallized tomato lycopene extract. As always, it is the continuing responsibility of LycoRed 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,    /s/ Laura M. Tarantino, Ph.D. Director Office of Food Additive Safety Center for Food Safety      and Applied Nutrition

cc: Dr. Robert Post, Director
Labeling and Consumer Protection Staff
Office of Policy, Program, and Employee Development
Food Safety and Inspection Service
1400 Independence Ave., SW, Suite 602, Annex
Washington, DC 20250-3700

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⁽¹⁾The specified value for "total fatty acids" includes free fatty acids and mono-, di- and tri-glycerides.

⁽²⁾Cis isomers of lycopene include; 5-, 9-, 13-, and 15-cis-lycopene. FDA notes that isomerization of trans to cis lycopene is limited when the food matrix (e.g., raw tomato) is intact but occurs more readily during processing and exposure to light and oxygen.

⁽³⁾LycoRed notes that the petitioned use level of the tomato lycopene extract as a color additive is not to exceed 50 mg/kg, resulting in a mean intake of 5.3 mg/p/d lycopene and a 90th percentile intake of 9.2 mg/p/d lycopene.

⁽⁴⁾LycoRed notes that tomato lycopene extract (1.5 percent) and crystallized tomato lycopene extract are prepared from tomato lycopene extract 6 percent.

⁽⁵⁾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.