Agency Response Letter
GRAS Notice No. GRN 000119

Herbert D. Woolf, Ph.D.
Technical Manager
BASF Corporation
3000 Continental Drive North
Mount Olive, NJ 07828-1234

Re: GRAS Notice No. GRN 000119

Dear Dr. Woolf:

This letter corrects an inadvertent error in the letter issued to you on May 22, 2003, in response to GRAS Notice No. 000119. In that letter, at the end of the second paragraph (now the third paragraph in this letter), the levels of use were incorrectly expressed as "0.5 to 7.0 percent."

The Food and Drug Administration (FDA) is responding to the notice, dated November 13, 2002, that you submitted 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 20, 2003, filed it on November 27, 2003, and designated it as GRAS Notice No. GRN 000119.

The subject of the notice is synthetic lycopene. The notice informs FDA of the view of BASF Corporation (BASF) that synthetic lycopene is GRAS, through scientific procedures, for use as a direct food ingredient in breakfast cereals (ready-to-eat and cooked), drinks (juice drinks, energy drinks, and dairy fruit drinks), instant soup, low fat dressings, meal replacements, meatless meat products, nutrient bars, salty snacks, crackers and yogurt at levels ranging from 5 to 70 milligrams per kilogram of food.

For clarity, in this letter FDA uses the terms "lycopene," "synthetic lycopene," and "natural lycopene" as follows:

• We use the term "lycopene" to denote the chemical entity identified as Chemical Abstracts Service Registry Number 502-65-8. We use this term when describing the inherent properties of lycopene, regardless of the source of the lycopene.
• We use the term "synthetic lycopene" to denote the crystalline lycopene that is the subject of the notice and is produced by chemical synthesis.
• We use the term "natural lycopene" to denote the pigment that is produced during biosynthetic processes in developing plant tissue, such as that of tomato.

As part of its notice, BASF includes the report of a panel of individuals (BASF's GRAS panel) who evaluated the data and information that are the basis for BASF's GRAS determination. BASF considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. BASF's GRAS panel evaluated estimates of dietary exposure, method of production, and product specifications as well as published and unpublished studies. Based on this review, BASF's GRAS panel concluded that synthetic lycopene that meets its established food grade specifications is GRAS under the conditions of its intended use.

BASF describes generally available information about lycopene. Lycopene is an aliphatic hydrocarbon containing thirteen double bonds. Its molecular formula is C₄₀H₅₆. It is a member of the carotenoid class of compounds and is the most abundant carotenoid in ripe tomatoes. In tomatoes, as well as other fruits and vegetables, the all-trans isomer of lycopene predominates. However, storage, cooking, processing and exposure to light results in isomerization of the all-trans form to various cis forms.

BASF describes synthetic lycopene as a crystalline material derived from chemical synthesis and describes a three-stage process for this chemical synthesis.⁽¹⁾ Stage one produces an organic solution of C₁₅ phosphonium methanesulfonate in dichloromethane (DCM), and stage two produces an organic solution of C₁₀ dialdehyde in toluene. In stage three, the intermediates produced in stages one and two are gradually combined with sodium methoxide solution and undergo a condensation reaction to form crude lycopene. Glacial acetic acid and deionized water are added, the mixture is stirred vigorously, the aqueous and organic phases are allowed to separate, and the organic phase containing DCM and crude lycopene is extracted with water. Methanol is added to the organic phase, DCM is removed via distillation under reduced pressure, the crude methanolic lycopene solution is heated and then cooled to a crystalline slurry that is filtered and washed with methanol, and the lycopene crystals are then recrystalized and dried under heated nitrogen. BASF notes that synthetic lycopene is stored under nitrogen or suspended in an aqueous solution containing antioxidants to prevent oxidation and isomerization of lycopene.

BASF prepares three commercial products from synthetic lycopene: Lycopene 10 Percent (tablet grade), Lycopene 10 Cold Water Dispersion (CWD), and Lycopene Dispersion 20 Percent (lycopene in vegetable oil). Lycopene 10 Percent (tablet grade) is a powder consisting of spherical particles of synthetic lycopene in a food starch coated matrix of gelatin and sucrose. The powder is stabilized with sodium ascorbate and ascorbyl palmitate and contains tricalcium phosphate as a flow-aid. Lycopene 10 CWD is a powder consisting of pulverized synthetic lycopene imbedded in a matrix of gelatin and glucose and stabilized with dl-alpha-tocopherol, ascorbyl palmitate and ascorbic acid. Lycopene Dispersion 20 Percent is a liquid that contains pulverized synthetic lycopene dispersed in oil. BASF notes that the three commercial lycopene products may be used in any of the food products described in its notice, although each commercial lycopene product has a distinctive formulation characteristic that would be more suitable for certain food products. For example, BASF states that Lycopene Dispersion 20 Percent is more suitable for food products in which there is an oil/fat phase.

BASF provides product specifications for synthetic lycopene. These specifications include limits on total carotenoids, arsenic, lead, copper, zinc, and heavy metals, loss on drying and residue on ignition. BASF also provides specifications for the concentration of total carotenoids in the three commercial products. BASF provides typical values for percentages of cis and trans lycopene, but does not set specifications for these isomers. BASF reports that synthetic lycopene contains a minimum of 96 percent lycopene, although typical batches contain approximately 98 percent lycopene. BASF reports that the majority of lycopene in synthetic lycopene is in the form of trans isomers (70 to 84 percent) and notes that the trans isomer content reported for natural extracts of lycopene ranges from 67 to 98 percent. BASF also reports that some cis isomers of lycopene are also present in synthetic lycopene. BASF discusses lycopene-related substances and process residuals present in synthetic lycopene and identifies which substances are also present in extracts of tomatoes.

Using its proposed use levels and data from the United States Department of Agriculture 1994-1996 Continuing Surveys of Food Intakes by Individuals and 1998 Supplemental Children's Survey, BASF estimates that the intake of synthetic lycopene would be approximately 5 milligrams per person per day (mg/person/day) at the mean and approximately 11 mg/person/day at the 90th percentile. BASF notes that this estimate is comparable to the intake of lycopene from plant sources reported in the Third National Health and Nutrition Examination Survey and by the United States Department of Health and Human Services, National Center for Health Statistics, and Nutrition Coordinating Center.

BASF discusses published and unpublished studies regarding the potential toxicity of synthetic and natural lycopene. BASF describes results from a published 13-week oral toxicity study conducted in rats fed BASF's commercial synthetic lycopene products. BASF concludes that results of the study support a no-observed-adverse-effect-level (NOAEL) for synthetic lycopene of 324 milligrams per kilogram body weight per day (mg/kg bw/day). BASF notes that this amount is approximately 4000-fold higher on a body weight basis than the mean estimated dietary intake (EDI) of synthetic lycopene. BASF also states that no adverse effects were reported in an unpublished⁽²⁾ developmental toxicity study conducted in rats and rabbits fed BASF's commercial synthetic lycopene products, and that no mutagenic effects were observed in unpublished genotoxicity studies conducted with BASF's commercial synthetic lycopene products. In addition, BASF notes that no adverse effects were observed in several published clinical studies conducted with either BASF's commercial synthetic lycopene products or natural lycopene.

BASF discusses published human studies related to the bioavailability of natural lycopene and BASF's commercial synthetic lycopene products. BASF reports that results of these studies showed no adverse effects on the absorption of other carotenoids. BASF notes, however, that excessive intake of food or dietary supplements high in carotenoids or lycopene has been associated with carotenodermia⁽³⁾ and lycopenodermia⁽⁴⁾, respectively.

Potential requirement for a color additive petition

In its notice, BASF notes that synthetic lycopene imparts color to food. As such, the use of synthetic lycopene 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 synthetic lycopene 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.⁽⁶⁾

In its notice, BASF acknowledges that it intends to submit a color additive petition for uses of synthetic lycopene that would constitute use as a color additive, but is not explicit about its view on whether any of the uses already described in its GRAS notice would constitute use as a color additive. In a telephone conversation on February 25, 2003, between FDA and BASF, FDA requested that BASF present its view on this issue. In an amendment received by FDA on March 10, 2003, BASF presents its reasons for concluding that all of the intended uses of synthetic lycopene would be exempt from the definition of color additive under section 201(t) of the FFDCA and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000119 does not include any comment by FDA about BASF's view on this issue. If, after receipt of this letter, BASF has any specific questions about this issue, we recommend that you contact the Office of Food Additive Safety (OFAS), Division of Petition Review (HFS-265), 5100 Paint Branch Parkway, College Park, MD 20740. You can also reach this division by telephone at (202)418-3035.

Potential labeling issues

Under section 403(a) of the Federal Food, Drug, and Cosmetic Act (FFDCA), a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FFDCA lays out the statutory framework for a health claim. In describing the intended use of synthetic lycopene and in describing the information that BASF relies on to conclude that synthetic lycopene is GRAS under the conditions of its intended use, BASF raises potential labeling issues under these provisions of the FFDCA. These labeling issues consist of BASF's assertion that synthetic lycopene has physiological effects that BASF views as beneficial. If products that contain synthetic lycopene bear any claims about such benefits on the label or in labeling, such claims are the purview of the Office of Nutritional Products, Labeling, and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition (CFSAN). OFAS neither consulted with ONPLDS on these labeling issues nor evaluated the information in BASF's notice to determine whether it would support any claims made about synthetic lycopene on the label or in labeling.

Standards of Identity

In its notice, BASF states its intention to use synthetic lycopene in several food categories, including foods for which standards of identity exist, located in Title 21 of the Code of Federal Regulations. 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. If you have any questions about the use of synthetic lycopene in standardized foods that would be marketed in the United States, you should contact the staff in ONPLDS, Division of Food Labeling and Standards, 5100 Paint Branch Parkway, College Park, MD 20740. You can also reach this division by telephone at (301)436-2375.

Conclusions

Based on the information provided by BASF, as well as other information available to FDA, the agency has no questions at this time regarding BASF's conclusion that synthetic lycopene 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 synthetic lycopene. As always, it is the continuing responsibility of BASF to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements. In particular, we note that any use of synthetic lycopene that constitutes use as a color additive requires premarket review and approval by FDA.

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

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⁽¹⁾FDA notes that steps in the three stage process for the synthesis of synthetic lycopene have been described in U.S. patents (issued to BASF and other companies) and journal articles. FDA notes that the Wittig reaction scheme for carotenoid synthesis is generally known and has been described in many books.

⁽²⁾Although BASF does not describe this study as a published study, an article that describes this study is currently in press and available on the Internet.

⁽³⁾A reversible condition associated with a yellowish discoloration of the skin.

⁽⁴⁾A reversible condition associated with a deep orange discoloration of the skin.

⁽⁵⁾The Secretary of the Department of Health and Human Services (DHSS). The Secretary of DHSS has delegated the authority for this provision of the FFDCA to FDA.

⁽⁶⁾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 000119 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FFDCA.