Agency Response Letter GRAS Notice No. GRN 000390
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CFSAN/Office of Food Additive Safety
January 9, 2012
Leslie Lake Curry
3300 Stelzer Road
Columbus, OH 43219
Re: GRAS Notice No. GRN 000390
Dear Ms. Curry:
The Food and Drug Administration (FDA) is responding to the notice, dated July 18, 2011, 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 July 20, 2011, filed it on July 26, 2011 and designated it as GRAS Notice No. GRN 000390.
The subject of the notice is suspended lutein. The notice informs FDA of the view of Abbott Nutrition (Abbott) that suspended lutein is GRAS, through scientific procedures, for use as an ingredient in formulas intended for premature infants at levels up to 210 micrograms lutein per liter (μg/L) of formula.
Our use of "suspended lutein" in this letter should not be considered an endorsement or recommendation of that term as an appropriate common or usual name for the purpose of declaring the substance in the ingredient statement of foods that contain that ingredient. Title 21 CFR 101.4 states that each ingredient must be declared by its common or usual name. In addition, 21 CFR 102.5 outlines general principles to use when establishing common or usual names for nonstandardized foods. Issues associated with labeling and the appropriate common or usual name of a food are the responsibility of the Office of Nutrition, Labeling and Dietary Supplements in the Center for Food Safety and Applied Nutrition.
As part of its notice, Abbott includes the report of a panel of individuals (Abbott's GRAS panel) who evaluated the data and information that are the basis for Abbott's GRAS determination. Abbott considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Abbott's GRAS panel discussed the method of manufacturing, specifications, and exposure, as well as genetic toxicity, animal, and human studies. Based on this review Abbott's GRAS panel concluded that suspended lutein is GRAS under the intended conditions of use.
Abbott discusses the identity, composition and method of manufacture of suspended lutein. Abbott prepares its suspended lutein from marigold (Tagetes erecta) flowers. It is a 20 percent suspension of lutein in safflower oil.
Abbott describes the manufacturing of the suspended lutein. First, marigold oleoresin is extracted from dried flower petals using hexane. The fatty acids are removed from the oleoresin using potassium hydroxide, propylene glycol, and water with heat and mixing. The resulting crystals are diluted with water, centrifuged, washed with water, and dried to form a cake base. This base is sifted to form the crystalline lutein product, which is then suspended in food-grade safflower oil at 20 percent lutein (CAS Reg. No. 127-40-2) and 1 percent zeaxanthin (CAS Reg. No. 144-68-3) by weight.
Abbott's suspended lutein is composed of lutein (≥ 20.0 percent), zeaxanthin (≥ 1.0 percent), waxes (14 – 16 percent), and moisture (≤ 1 percent). Abbott provides specifications for heavy metals, microbial contaminants, and solvent residues.
Abbott calculates that formulas supplemented with 210 μg lutein/L provide a lutein exposure of approximately 37 μg/kilogram body weight/day (μg/kg bw/d).
Abbott discusses a published reproductive study in which rats receiving up to 1000 milligrams/kg bw/d showed no adverse effects. Abbott also discusses published studies including in vitro bacterial or mammalian cell assays that showed no mutagenic or genotoxic activity, as well as repeat dose animal (mice, rat, dog, and monkey) studies that showed no adverse effects through diet or gavage exposure. Finally, Abbott discusses a number of published infant studies, including one in which premature infants received formula with a mean concentration of 211 μg/L of the suspended lutein; lutein was well tolerated and no adverse effects were reported.
Intended Use in Infant Formula
Under section 412 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Abbott should be aware that FDA's response to Abbott's GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains suspended lutein to make the submission required by section 412.
Potential Requirement for a Color Additive Petition
In its notice, Abbott describes the suspended lutein as an orange–red viscous oil. As such, the use of suspended lutein in food products may constitute the use of a color additive under section 201(t)(1) of the FD&C Act 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,  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 FD&C Act 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 suspended lutein constitutes use as a color additive within the meaning of section 201(t)(1) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the FD&C Act requires premarket review and approval of that use by FDA. Under section 402(c) of the FD&C Act, a food product that contains an unapproved color additive would be deemed adulterated. 
On September 28, 2011 FDA requested by e-mail that Abbott present its view on whether any of the intended uses of suspended lutein would be exempt from the definition of color additive. In an amendment dated September 30, 2011, Abbott confirms that suspended lutein as described in GRN 000390, is used for its nutritive value and not intended to impart color to the infant formula, therefore its use will be exempt from the definition of color additive under section 201(t) of the FD&C Act and FDA's implementing regulations in 21 CFR 70.3(f) and (g). Importantly, FDA's response to GRN 000390 does not include any comment by FDA about Abbott's view on this issue. If, after receipt of this letter, Abbott has any further questions about this issue, we recommend that Abbott contact the Division of Petition Review in the Office of Food Additive Safety.
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 Abbott's notice that suspended lutein is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing suspended lutein. Accordingly, this response should not be construed to be a statement that foods that contain suspended lutein, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Abbott, as well as other information available to FDA, the agency has no questions at this time regarding Abbott's conclusion that suspended lutein 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 suspended lutein. As always, it is the continuing responsibility of Abbott 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 000390, 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 http://www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition
The Secretary of the Department of Health and Human Services
 We note that section 721(b)(4) of the FD&C Act provides that a color additive shall be deemed to be safe and suitable for the purpose of listing under section 721(b) of the FD&C Act 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 FD&CA. Importantly, FDA's response to GRN 000390 does not constitute a "finding of the Secretary" within the meaning of section 721(b)(4) of the FD&C Act.