Agency Response Letter GRAS Notice No. GRN 000381
CFSAN/Office of Food Additive Safety
June 6, 2012
Ms. Fumi Tsuno
Tsuno Food Industrial Co., Ltd.
94, Shinden, Katsuragi
Ito-gun, Wakayama, 649-7194
Re: GRAS Notice No. GRN 000381
Dear Ms. Tsuno:
The Food and Drug Administration (FDA) is responding to the notice, dated May 19, 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 May 23, 2011, filed it on June 1, 2011, and designated it as GRAS Notice No. GRN 000381.
The subject of the notice is phytic acid (also known as inositol hexakisphosphate). The notice informs FDA of the view of Tsuno Food Industrial Co., Ltd. (Tsuno) that phytic acid is GRAS, through scientific procedures, for use as an antioxidant, chelating agent, and antimicrobial agent in beverages and beverage bases, milk products, processed vegetables, and vegetable juices at a level of 0.2%. The notice also informs FDA of Tsuno’s view that phytic acid is GRAS for use in limiting solubility reduction and providing strength to dietary supplement capsules at a level of 8.0%.
As part of its notice, Tsuno includes the report of a panel of individuals (Tsuno’s GRAS panel) who evaluated the data and information that are the basis for Tsuno’s GRAS determination. Tsuno considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Tsuno’s GRAS panel evaluated the method of manufacture and product specifications for phytic acid, estimates of dietary exposure, and published safety studies. Based on this review, Tsuno’s GRAS panel concluded that phytic acid that meets its established food grade specifications is GRAS under the conditions of its intended use.
Tsuno presents information about the identity and method of manufacture of phytic acid. Phytic acid is freely soluble in water. It has a molecular weight of 660.03 grams per mole, an empirical formula of C6H16O24P, and is identified by the CAS Registry Number 83-86-3. Phytate is the salt of phytic acid. The method of manufacture for phytic acid includes treating defatted food-grade rice bran with diluted sulfuric acid to dissociate phytate from iron and protein complexes. The resulting solution is then centrifuged, filtered to remove impurities, neutralized with base, and further diluted. Phytic acid is released from bound minerals by the addition of sulfuric acid. The phytic acid-containing solution is then adjusted for pH, decolorized, and vacuum concentrated to obtain the final product, which is a 50% phytic acid solution in water. Tsuno states that phytic acid is produced according to current good manufacturing practices and that all the materials used during manufacturing meet appropriate food-grade specifications. Tsuno provides data from three non-consecutive lots of phytic acid to confirm that the product is consistent with the set specifications.
Phytate is the primary storage form for phosphorus and comprises up to 9% of dry matter in plants that are commonly consumed as food. Tsuno discusses published data describing the phytic acid/phytate1 content of commonly consumed foods. Tsuno cites published studies on the dietary intake of phytic acid/phytate. One published study states that humans consume phytic acid/phytate through the intake of cereals, legumes, oilseeds, and nuts. Another published study reports that the daily dietary intake of phytic acid/phytate depends on the type of diet consumed. According to the authors of the study, male lacto-ovo-vegetarians are the highest level consumers of phytic acid/phytate in the United States, consuming up to 5577 milligrams per day (mg/d).
Tsuno uses the National Center for Health Statistics’ 2003-2004 and 2005-2006 National Health and Nutrition Examination Surveys to calculate the potential dietary exposure to its phytic acid ingredient under the intended conditions of use. Tsuno estimates the daily intake of phytic acid from the intended food uses on an all-user basis to be 223 mg/d and 610 mg/d at the mean and 90th percentile, respectively. Tsuno states that the estimated intakes of phytic acid from the new intended use levels are a fraction of the background dietary intakes.2
Tsuno states that the published results of in vitro tests, as well as in vivo studies, show that phytic acid is not mutagenic or genotoxic. In repeat-dose studies conducted using rodents, the authors reported indirect adverse effects. The authors linked these adverse effects to high phosphorus levels in drinking water from added phytic acid, which causes an imbalance in the calcium:phosphorus ratio and can then lead to nephrocalcinosis, a common disorder in rodents. Tsuno states that humans are less susceptible to calcium:phosphorus imbalances than rodents. Tsuno states that the dietary intake of phosphorus in the U.S. is about 1000 to 2200 mg/d, as compared to the Tolerable Upper Limit of 4000 mg/d set by the Institute of Medicine. Tsuno notes that the intended uses of phytic acid could provide a total of 172 mg/d phosphorus, leaving an adequate safety margin for exposure to phosphorus. Based on information about the lower susceptibility of humans to calcium:phosphorus imbalances and dietary intake data for phosphorus, and that human systemic exposure to phytic acid from the intended food uses will be far lower than exposure in the rodent studies, Tsuno concludes that the adverse effects observed in the rodent studies are not relevant to human safety.
Tsuno discusses data demonstrating that phytic acid can be safely consumed by humans, including data showing differences in absorption of phytic acid in rodents and humans. Published studies show that humans can only absorb about 0.01% of orally administered phytic acid, whereas rats can absorb 79% of orally administered phytic acid. Tsuno states that the difference in phytic acid absorption between rodents and humans may be attributed to a difference in phytase activity. In a published study, the authors observed that the human small intestine had 30 times less phytase activity than the rat small intestine.
Tsuno discusses published human studies on the potential effects of phytic acid on mineral bioavailability.3 Phytic acid is consumed in the human diet as phytate. Published human studies show that daily consumption of 1000 to 2000 mg/d phytate along with balanced diets do not affect mineral status. Other published studies show that adverse effects on mineral absorption have been observed in humans only when phytate is consumed in large quantities in combination with mineral-poor diets. In clinical studies, 14 young women and 14 elderly women consumed up to 1723 mg/d phytate for 10 days which resulted in no observed adverse events, nor were any adverse events reported when healthy subjects received a single dose of 3200 mg phytate.
Based on the long history of consumption and current background consumption of phytic acid by humans as well as published data showing (1) that phytic acid is not readily absorbed by humans; (2) that phytic acid (reported as phytate) affects mineral bioavailability only in combination with mineral-poor diets, and (3) that phytic acid can be safely consumed by humans, Tsuno concludes that phytic acid is GRAS for the intended uses.
Standards of Identity
In the notice, Tsuno states its intention to use phytic acid 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.
Section 301(ll) of the Federal Food, Drug, and Cosmetic Act (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 Tsuno’s notice that phytic acid is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing phytic acid. Accordingly, this response should not be construed to be a statement that foods that contain phytic acid, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Tsuno, as well as other information available to FDA, the agency has no questions at this time regarding Tsuno’s conclusion that phytic acid 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 phytic acid. As always, it is the continuing responsibility of Tsuno 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 000381, 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 www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
1The term “phytic acid/phytate” is used in the published literature that Tsuno cites. Tsuno uses the term “phytic acid/phytate” in its discussion of the published dietary intake data.
2Based on the intended use levels, the mean intake level of phytic acid would be 4% of the highest observed background dietary intake reported in the literature (5577 mg/d, reported as phytic acid/phytate). The mean intake level of phytic acid would be 17% of the average background dietary intake reported in the published literature (1300 mg of phytic acid/phytate, reported as phytate).
3Phytic acid is an antinutrient in certain animal diets.