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CFSAN/Office of Food Additive Safety
July 11, 2008
Mr. Daniel Dwyer
Kleinfeld, Kaplan and Becker, LLP
1140 Nineteenth Street, N.W.
Washington, D.C. 20036-6606
Re: GRAS Notice No. GRN 000232
Dear Mr. Dwyer:
The Food and Drug Administration (FDA) is responding to the notice, dated July 31, 2007, that you submitted on behalf of the firms Lipid Nutrition B.V. and Cognis GmbH (hereinafter referred to as "Lipid Nutrition and Cognis") 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 this notice on August 2, 2007, filed it on August 13, 2007, and designated it as GRAS Notice No. GRN 000232.
The subject of the notice is a glyceride mixture composed predominantly of a 1:1 mixture of cis-9, trans-11 and trans-10, cis-12 conjugated linoleic acids. For the purpose of this letter, FDA refers to the subject of the notice as "CLA-isomers." The notice informs FDA of the view of Lipid Nutrition and Cognis that CLA-isomers are GRAS, through scientific procedures, for use as an ingredient in certain specified foods within the general categories of soy milk, meal replacement beverages and bars, milk products and fruit juices at levels not to exceed 1.5 grams (g) per serving.
As part of their notice, Lipid Nutrition and Cognis include the report of a panel of individuals (Lipid Nutrition and Cognis' GRAS panel) who evaluated the data and information that are the basis for Lipid Nutrition and Cognis' GRAS determination. Lipid Nutrition and Cognis consider the members of their GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Lipid Nutrition and Cognis' GRAS panel reviewed and discusses CLA-isomers' composition, method of manufacture, specifications, and intended estimated dietary intake. Lipid Nutrition and Cognis' GRAS panel also discusses published and unpublished studies conducted with CLA-isomers. Based on this review, Lipid Nutrition and Cognis' GRAS panel concluded that CLA-isomers are GRAS when used as an ingredient in soy milk, meal replacement beverages and bars, milk products, and fruit juices at a level of 1.5 g per serving.
Lipid Nutrition and Cognis describe the method of manufacture and composition of CLA-isomers. CLA-isomers are manufactured through a series of chemical and physical processes. Safflower oil serves as the starting material for an alkali-catalyzed saponification, followed by conjugation of the released linoleic acid in situ. After conjugation, the reaction products are neutralized with acid, washed and dried, and then purified by short-path molecular distillation, yielding the free fatty acids, CLA-isomers. The CLA-isomers are esterified with glycerol in the presence of a lipase enzyme catalyst, and the resultant product is physically refined (i.e., bleaching and deodorization) to give the final CLA-isomers product. An antioxidant is added at the refining stage. Lipid Nutrition and Cognis note that the manufacturing process is consistent with other food industry practices.
Based on the 1994-1996, 1998 USDA Continuing Survey of Food Intakes by Individuals (CSFII) data on the foods to which CLA-isomers are intended for addition and the intended use levels, Lipid Nutrition and Cognis estimate the intake of their CLA-isomers would be 1.22 grams per person per day (g/p/day) at the mean and 2.33 g/p/d at the 90th percentile.
Lipid Nutrition and Cognis discuss generally available information about the presence of CLA in foods. Ruminant derived foods such as beef, milk, and cheese appear to have the highest CLA content. Naturally occurring CLA consists of a series of conjugated dienoic isomers of linoleic acid. The conjugated double bonds can be present in either the cis or trans configuration and are present predominately in positions 8 and 10, 9 and 11, 10 and 12, or 11 and 13. Lipid Nutrition and Cognis note that the cis-9, trans-11 isomer accounts for 90% of CLA intake in the diet. For the general United States population, Lipid Nutrition and Cognis note that the estimated mean intake of CLA from natural dietary sources is 0.21 and 0.15 g/p/day for men and women, respectively.
Lipid Nutrition and Cognis state that the metabolism of CLA has been extensively studied and reported in published literature and follows the standard pathway of dietary triglycerides. Lipid Nutrition and Cognis conclude that a review of the published clinical data demonstrates that consumption of CLA-isomers at levels of up to 6 g/p/day for up to 1 year and 3.4 g/p/day for up to 2 years is safe. In bioavailability studies, single oral intakes of up to approximately 15 g of CLA in oil (containing up to approximately 9 g of CLA-isomers) resulted in no reported adverse events.
Lipid Nutrition and Cognis conclude that published preclinical data demonstrate an absence of mutagenic, reproductive and developmental effects, or significant toxicological effects. Published studies report the absence of the mutagenic potential of CLA-isomers in two in vitro assays (reverse mutation and chromosomal aberration in human lymphocytes). Lipid Nutrition and Cognis state that an absence of mutagenicity and genotoxicity are further supported by published chronic studies that examined the effects of long term feeding of male rats with a diet containing 1% CLA-isomers (41.9% cis-9, trans-11 and 43.5% trans-10, cis-12) for a period of 18 months. Lipid Nutrition and Cognis further conclude that published clinical data confirm the absence of adverse effects on cardiovascular disease parameters, insulin sensitivity, and maternal milk fat deposition. These studies are discussed in the paragraphs below.
Lipid Nutrition and Cognis discuss three aspects of the safety of CLA-isomers with regard to cardiovascular disease. The first aspect is the effect of CLA-isomers on biomarkers of inflammation. Included in this discussion are human intervention studies that report no effect on lipid parameters and trials which show statistically significant changes in lipid parameters, but remain within population range. Literature reports state that consumption of the single trans-10, cis-12 CLA isomer resulted in increased C-reactive protein (CRP) levels, while consumption of the 1:1 CLA-isomer mixture did not. Another study in healthy men showed no adverse effects of consumption of either isomer on CRP levels. Lipid Nutrition and Cognis also discuss a study of men and women without cardiovascular disease that assessed traditional risk factors and CRP. The study reports that for those with elevated traditional risk factors, higher CRP levels indicate cardiovascular disease risk, whereas elevated CRP levels alone provided no further prognostic information beyond traditional office examination risk factor assessment to predict future cardiovascular disease events. Lipid Nutrition and Cognis conclude that human studies conducted with CLA-isomers demonstrate no effect on biomarkers of inflammation related to cardiovascular disease risk.
The second aspect of cardiovascular disease discussed by Lipid Nutrition and Cognis addresses the results of human studies that demonstrate increased levels of isoprostanes with consumption of CLA-isomers. Lipid Nutrition and Cognis note that increased levels of isoprostanes are detected in diseases involving inflammation and oxidative stress above normal levels of isoprostanes found in animal and human biological fluids. Lipid Nutrition and Cognis state that a certain level of ongoing lipid peroxidation takes place and is incompletely suppressed by antioxidant defenses, even in the normal state. Lipid Nutrition and Cognis conclude that no association between isoprostanes and cardiovascular disease risk has been determined.
The third aspect of cardiovascular disease discussed by Lipid Nutrition and Cognis addresses a study that reports impaired endothelial function in healthy overweight men who consumed CLA-isomers. The notifier concludes that this study was marked by variability in samples, thus preventing a reliable conclusion. In contrast, additional studies conducted with CLA-isomers report no significant effects on arterial elasticity and that soluble vascular cell adhesion molecule (a plasma biomarker of endothelial dysfunction) decreased in comparison with a placebo group.
Lipid Nutrition and Cognis address the safety of CLA-isomers with respect to insulin sensitivity. They state that studies that rely on fasting serum glucose and insulin measures as markers of metabolic change were not considered to be pivotal to their GRAS determination since these methods are inherently variable. Instead, Lipid Nutrition and Cognis discuss studies which report oral glucose tolerance and clamp techniques to demonstrate that CLA-isomers present no adverse effects on glucose and insulin.
Lipid Nutrition and Cognis address the effects of CLA-isomers on milk fat deposition. They state that naturally occurring dietary and biological phenomena can alter milk fat production in humans, and only one published study reported significant effects on milk fat deposition. The negative results from the majority of human milk studies contradict animal studies which demonstrate milk fat deposition after CLA administration. The notifier states the effects of CLA on milk fat production seen in cows and rodents cannot be relied on as evidence of the effects of CLA on lipogenesis in humans due to differences in the physiology and biochemistry between ruminants or rodents, and humans. The notifier reports that one human study shows a reduction of milk fat associated with CLA consumption, whereas a more recent study from the same authors using the same protocol showed no effect. Lipid Nutrition and Cognis conclude that the consumption of CLA-isomers by lactating women would not affect milk fat levels beyond the range of normal biological variation, and published reproductive and developmental toxicity studies with CLA-isomers in rats and pigs demonstrate a lack of adverse effects on maternal food consumption and body weight, litter size, and offspring growth and development.
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 the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. In describing the intended use of CLA-isomers and in describing the information that Lipid Nutrition and Cognis rely on to conclude that CLA-isomers are GRAS under the intended conditions of use, Lipid Nutrition and Cognis raise a potential issue under these labeling provisions of the FFDCA. This issue consists of physiological effects of CLA-isomers that Lipid Nutrition and Cognis view as beneficial. If products that contain CLA-isomers bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS). The Office of Food Additive Safety (OFAS) neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about CLA-isomers on the label or in labeling.
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FFDCA, 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 Lipid Nutrition and Cognis' notice that CLA-isomers are GRAS for use as an ingredient in certain specified foods within the general categories of soy milk, meal replacement beverages and bars, milk products and fruit juices, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing CLA-isomers. Accordingly, this response should not be construed to be a statement that foods that contain CLA-isomers, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
In the notice, Lipid Nutrition and Cognis state their intention to use CLA-isomers 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.
Based on the information provided by Lipid Nutrition and Cognis, as well as other information available to FDA, the agency has no questions at this time regarding Lipid Nutrition and Cognis' conclusion that CLA-isomers, meeting the specifications listed in GRN 000232, 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 CLA-isomers. As always, it is the continuing responsibility of Lipid Nutrition and Cognis to ensure that food ingredients these firms market 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 000232, 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 OFAS (on the Internet at http://www.cfsan.fda.gov/~lrd/foodadd.html).
Laura M. Tarantino, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
cc: Ms. Diane McEnroe
Sidley Austin, LLP
787 Seventh Avenue
New York, New York 10019