The Food Lawyers® Respectfully Request That FDA Implements the Following

December 7, 2020

Dockets Management Staff (HFA-305) Filed Electronically Food and Drug Administration https://www.regulations.gov

Re: Sugars Metabolized Differently than Traditional Sugars (FDA-2020-N-1359)

Ladies and Gentlemen: One Page Executive Summary

FDA’s seeks information to “… promote the public health and help consumers make informed dietary decisions” regarding sugars that are metabolized differently than traditional sugars. Given the nation’s battles with diabetes and obesity, and the benefits that non-traditional sugars can offer in these battles, the Agency’s stated public policy goal goes to the very heart of American consumers’ health. This laudatory public policy’s realization is complicated by a lack of consumer awareness of how some sugars are metabolized differently than others.

In an effort to answer the questions posed by the Agency regarding the treatment of Sugars that Are Metabolized Differently Than Traditional Sugars, we suggest that the Agency adapt a mechanism that will seek to harmonize the public policy of promoting public health with consumers’ lack of awareness of sugars that are metabolized differently than sucrose. In particular, we suggest that FDA should consider the following:

1. Establish a new category of sugars called Rare Sugars that exhibit the following characteristics: a. Are naturally occurring b. Impart a sweet taste that is at least 50% the sweetness of sucrose c. 2.0 kcal/g or less. d. Resulting pH of 6.0 or greater of dental plaque after consumption. e. No or low glycemic response. f. No or low insulinemic response. 2. Exclude Rare Sugars from “Total Sugars” and “Added Sugars” declarations to stimulate their deployment by industry and consumption by the public. 3. Allow certain voluntarily disclosures for Rare Sugars on the Nutrition Facts Label. 4. Identify the initial Rare Sugars as Allulose, Allose, and Tagatose. 5. Accept Citizen Petitions for identification of additional Rare Sugars. 6. Exercise enforcement discretion regarding labeling of Rare Sugars, similar to the approach the Agency has applied to Allulose, until federal rule making can be completed.

We feel the above approach creates a “win-win” atmosphere wherein industry will be motivated to substitute Rare Sugars for traditional and familiar sugars, and the public will receive both the immediate benefit of an increased number of food product choices utilizing Rare Sugars as well as the longer term health benefits offered by Rare Sugars because they are metabolized differently than traditional sugars.

Detailed Analysis

A. 1. – Other Sugars That are Metabolized Differently:(1)

FDA Request: We are aware of three sugars that are metabolized differently in the body than traditional sugars: allulose, D-tagatose, and isomaltulose. What other sugars are metabolized differently in the body than traditional sugars? Please provide any studies that examine the chemical properties or physiological effects of these other sugars.

Response:

Isomaltulose belongs to a class of disaccharides known sucrose isomers which also includes the disaccharides Trehalulose, Leucrose and Turanose.(2) All four of the sucrose isomers have unique beneficial physiological effects and chemical properties. Although isomaltulose is metabolized differently in the body and the mouth microbiota than traditional sugars, it is completely hydrolyzed within the small intestine and provides a full 4 kcal/g to human metabolism, (3) rendering it less useful from a public health perspective regarding obesity than other members of its class. The caloric contributions of Trehalulose and Turanose are yet to be determined but the caloric contribution of Leucrose has been found to be 2 kcal/g (2).

Allulose and tagatose (4) are monosaccharides that belong to completely different class of compounds known as rare sugars.(5) This class of rare ketohexose and aldohexose compounds includes: allulose, tagatose, L-tagatose, D-sorbose, L-fructose, D-allose, L- glucose, D-gulose, L-talose, L-galactose, and L-fucose.(6) A wide range of beneficial physiological effects have been identified in these rare sugars, including antioxidant activity (free-radical scavenging), reducing blood lipids, reducing glycemic response, weight management, satiety and reduced caloric intake (6-10).

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1. Our Comment’s structure tracks that of FDA’s information request, e.g., FDA’s question A.2. regarding consumer awareness is discussed in our section A.2.

2. Tian Y, et al. (2019) Sucrose isomers as alternative sweeteners: properties, production, and applications. Appl Microbiol Biotechnol. 103(21‐22):8677‐8687. doi:10.1007/s00253‐019‐10132‐6, 10.1007/s00253‐019‐10132‐6

3. Maresch CC, et al. (2017) Low Glycemic Index Prototype Isomaltulose‐Update of Clinical Trials. Nutrients. 9(4) doi:10.3390/nu9040381, 10.3390/nu9040381

4. In this Comment, we refer to D‐tagatose as “tagatose,” because we believe this is a name that would be more acceptable to the general public. Since a leading purpose of FDA’s undertaking is to “promote public health,” we feel that public acceptability of the ingredient’s name is something worth careful consideration. We request that FDA adopt this protocol respecting D‐tagatose and tagatose. We are mindful of L‐tagatose’s existence, but since that ingredient has yet to garner any widespread use or support, we think continuing to call it L‐tagatose, at least for the time being, makes sense.

5. Gelski, J. (2020) Low‐caloric rare sugars enter sugar reduction. Food Business News July 14: https://www.foodbusinessnews.net/articles/16415‐low‐caloric‐rare‐sugars‐enter‐sugar‐reduction‐ category

6. Bilal M, et al. (2018) Metabolic engineering pathways for rare sugars biosynthesis, physiological functionalities, and applications‐a review. Crit Rev Food Sci Nutr. 58(16):2768‐2778. doi:10.1080/10408398.2017.1341385, 10.1080/10408398.2017.1341385

7. Mooradian AD, et al. (2019) In search for an alternative to sugar to reduce obesity. Int J Vitam Nutr Res. 89(3‐4):113‐117.

8. Nagata Y, et al. (2018) Rare sugars, d‐allulose, d‐tagatose and d‐sorbose, differently modulate lipid metabolism in rats. J Sci Food Agric. 98(5):2020‐2026.

9. Mooradian AD, et al. (2020) Naturally occurring rare sugars are free radical scavengers and can ameliorate endoplasmic reticulum stress. Int J Vitam Nutr Res. 90(3‐4): 210‐220.

10. Chen Z, et al. (2018) Recent research on the physiological functions, applications, and biotechnological production of D‐allose. Appl Microbiol Biotechnol. 102(10):4269‐4278. doi:10.1007/s00253‐018‐8916‐6, 10.1007/s00253‐018‐8916‐6

A. 2. -- Consumer Awareness:

FDA Request: What research on consumer awareness or understanding of the differences between sugars that are metabolized differently than traditional sugars and traditional sugars is available? Response:

We have been unable to find any peer reviewed research on consumer awareness of sugars that are metabolized differently than traditional sugars. The only research of which we are aware is a 2017 survey undertaken by Tate & Lyle to measure the public’s awareness of allulose. The publicly available information about it is reproduced below:(1)

We conducted extensive literature searches for “consumer awareness” and “consumer perception” respecting “rare sugars,” “allulose,” “tagatose,” and “isomaltose” -- -- and could only find the above reproduced chart.

Conclusion

There does not seem to be any evidence to suggest the general public is aware either of Rare Sugars(2) or that they are metabolized differently than traditional sugars.

Recommendations

We believe the fact that the public is apparently unaware of Rare Sugars or their metabolic characteristics. The public’s lack of such information should be an important factor in FDA’s decision process on how to approach the deployment of Rare Sugars to promote public health. We respectfully suggest that FDA should work within

consumers’ current perceptions to promote public health (a) in the short term by motivating industry to deploy Rare Sugars immediately, and (b) in the longer term, by establishing a framework that promotes public awareness regarding Rare Sugars.

FDA’s short-term strategy could be to exclude the gram quantities of and caloric content of Rare Sugars from total sugars and added sugars on the nutrition facts label. This would encourage purveyors to use these ingredients and encourage consumers to eat foods incorporating them. FDA is currently executing this strategy respecting allulose. We feel that the factors warranting this treatment respecting allulose are equally applicable to tagatose (discussed in greater depth below in this Comment).

FDA’s longer-term strategy could include adopting nomenclature that would be appealing to consumers as they learn about sugars that are metabolized differently than traditional sugars. We believe that “Rare Sugars” is a scientifically accurate and publicly appealing name for allulose, tagatose, and the similar sugars discussed in this Comment. We believe that referring to D-tagatose as “tagatose,” will also make it more appealing to the public when it is seen in ingredient declarations.

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1. Tate & Lyle, Allulose Applications In Ice Cream, page 21, https://foodsci.wisc.edu/frozendessertcenter/assets/Purohit_2019.pdf

2. This Comment refers to “sugars that are metabolized differently than traditional sugars,” as “Rare Sugars.”

B. 1. - Declaration of Total Sugars

FDA Request: We could take one of various approaches to account for sugars that are metabolized differently than traditional sugars in the declaration of “Total Sugars.” For example, we could require them to be declared within the “Total Sugars” declaration, we could exclude them from the “Total Sugars” declaration, or we could adjust the gram amount of the “Total Sugars” declaration based on their caloric contribution to the diet. What considerations could inform our approach?

Response:

We respectfully suggest that sugars which are not metabolized in the same manner as traditional and familiar sugars should be excluded from the “Total Sugars” category of the Nutrition Facts Label for the same reasons FDA employed for allulose (1). In concordance with allulose labeling, tagatose referred to above (and similar Rare Sugars in the future) should not be included in the “Total Sugars” of the Nutrition Facts Label. Sugars are traditionally accepted from a regulatory and public perspective as being the 4 kcal/g mono and disaccharides that result in a post prandial increase in blood glucose and insulin levels -- -- namely sucrose, fructose, glucose, maltose, lactose, and galactose. FDA has accepted 0.4 kcal/g as the caloric level for allulose, and although FDA has accepted 1.5 kcal/g for tagatose (2), tagatose actually offsets the absorption and circulatory impacts of the traditional sugars in the diet. Nygaard and Jensen (3) report that when 67% of sucrose in a balanced diet in pigs (pigs have digestion systems most similar to humans) is substituted with tagatose, 90.4% of the remaining sucrose is absorbed from the small intestine compared to 98.0% of the sucrose being absorbed without the tagatose present. Further, gross energy extracted from the diet drops from 80.7% to 74.4% with the tagatose substitution. The impact of tagatose upon the absorption and metabolism of other, more caloric sugars, is further demonstrated in a study in rats by Livesey and Brown (4) who concluded the net metabolizable energy of a diet supplemented with tagatose was actually reduced (-0.12 kcal/g of tagatose). Similarly, for fructose, Williams et al. (5) using isotopic C14 labeling showed that dosing fructose fed to rats with equal amounts of tagatose resulted in a 26% decrease in fructose reaching the blood plasma. Further, in a human study, Buemann et al. (6) concluded that tagatose provided no net energy during respiratory testing. Based on these characteristics, Rare Sugars such as allulose and tagatose should be excluded from the “Total Sugars” declaration, and no adjustment is needed to the gram amount of the “Total Sugars” declaration based on tagatose’s caloric contribution (or lack thereof) to the diet as well as its characteristic of blocking some of the absorption of traditional and familiar sugars.

Unlike traditional and familiar sugars, neither allulose (7) nor tagatose induces dental caries and thus should not be included within the Total Sugars category of the Nutrition Facts label. Tagatose qualifies for a health claim (8) regarding not inducing dental caries due to lack of pH lowering in the mouth resulting from reduced fermentation compared with traditional sugars. Sugars such as allulose and tagatose which are metabolized differently than traditional and familiar sugars clearly differ regarding the impact they have on post prandial blood glucose. On the basis of a scale of 0 to 100 regarding post prandial blood glucose increase and

duration, tagatose (along with allulose) are considered ~0 compared to traditional and added sugars having blood glucose increase and duration ratings ranging from 23 for fructose to 100 for glucose (~105 for maltose) (9). Consequently, with ~0 post prandial blood glucose rise for D-tagatose and allulose, there is no post prandial rise in insulin following consumption (10). Further, tagatose has been shown to reduce hemoglobin A1c when utilized in diets over longer terms (11) (12). Thus, based on their glycemic and insulinemic behaviors, tagatose, allulose, and carbohydrates with similar behaviors should not be included with Total Sugars in the Nutrition Facts label, but rather, should have a unique category. Unlike the traditional and familiar sugars that are included in the Total Sugars category of the Nutrition Facts label, tagatose exhibits prebiotic effects when ingested. Tagatose has low small intestinal digestibility and high large intestinal fermentation, characteristics that constitute the prebiotic effect (3). Isotopic C14 labeling of tagatose fed to adapted rats 14 showed significant fermentation in the large intestine to isotopically labeled C O2 (13). The data gathered by Venema et al. indicate that daily consumption of 7.5 or 12.5 g tagatose may lead to increased production of gut healthy butyrate and to an increase of lactobacilli, without serious gastrointestinal complaints. In view of the health-promoting effects of butyrate and lactobacilli, tagatose may be considered a prebiotic substrate (14). Conclusions

Allulose, tagatose and similar carbohydrates are out of place in the category of “Total Sugars” in the Nutrition Facts Label by virtue of their metabolic fate upon consumption being so different from that of traditional and familiar sugars. Tagatose is not only a carbohydrate with low caloric content per se, it also blocks or reduces metabolization of traditional sugars when co-consumed. For example, assume that someone eats a jelly sandwich while drinking a soft drink sweetened with tagatose. The tagatose will offset the metabolization of some of the sugar that is in the jelly. To the extent that tagatose is blunting metabolization of the sugar in the jelly, it is helping to fight obesity. In addition, allulose, tagatose, and similar Rare Sugars demonstrate important health benefits such as zero or nearly zero post prandial glucose and insulin increases following consumption. Prebiotic action (low absorption in the small intestine, high fermentation in the large intestine) provides additional benefits.

Recommendation

Tagatose, allulose and other similar carbohydrates should be included in the ingredient declaration and voluntarily included in a category in the other carbohydrates section of the Nutrition Facts Label that better fits their metabolic characteristics, not in the sugars and added sugars sections.

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1. The Declaration of Allulose and Calories from Allulose on Nutrition and Supplement Facts Labels: Guidance for Industry (October 2020), Docket No. FDA‐2019‐D‐0725.

2. Lu, Y., Levin, GV., and Donner, TW., (2008) Tagatose, a new antidiabetic and obesity control drug, Diabetes, Obesity and Metabolism, 10: 109‐134. (See ref 10, Hoadley, JE. The FDA letter of October 25, 1999 to Ms. Marsha C. Wertzberger).

3. Nygaard, H., Jensen, B. (1999) D‐Tagatose Has Low Small Intestinal Digestibility but High Large Intestinal Fermentability in Pigs, Journal of Nutrition 129(5):1002‐9. DOI: 10.1093/jn/129.5.1002.

4. Livesey, G., Brown, JC. (1996) D‐tagatose is a bulk sweetener with zero energy determined in rats, J Nutr 126(6):1601‐9. DOI: 10.1093/jn/126.6.1601.

5. Williams, J., Spitnale, M., and Lodder, R. (2013) The Effect of D‐Tagatose on Fructose Absorption in a Rat Model, J Develop Drugs 2:3. DOI: 10.4172/2329‐6631.1000111

6. Buemann, B., Toubro, S., Astrup, A., (1998) D‐Tagatose, a Stereoisomer of D‐Fructose, Increases Hydrogen Production in Humans without Affecting 24‐Hour Energy Expenditure or Respiratory Exchange Ratio, The Journal of Nutrition, 128(9):1481‐1486. Doi.org/10.1093/jn/128.9.1481.

7. Anon (2020) The Declaration of Allulose and Calories from Allulose on Nutrition and Supplement Facts Labels: Guidance for Industry https://www.fda.gov/media/123342/download.

8. US Food and Drug Administration, Fed Regist. 2003 Jul 3;68(128):39831‐3. Food labeling: health claims; D‐ tagatose and dental caries. Final rule. Food and Drug Administration, HHS PMID: 12848171 https://pubmed.ncbi.nlm.nih.gov/12848171/

9. Lamothe, LM., Lê, KA., Samra, RA., Roger, O., Green, H., and Macé, K. (2019) The scientific basis for healthful carbohydrate profile, Critical Reviews in Food Science and Nutrition 59 (7):1058‐1070 https://doi.org/10.1080/10408398.2017.1392287

10. EFSA Panel on Dietary Products, Nutrition, and Allergies (NDA) (2011), Scientific Opinion on the substantiation of health claims related to the sugar replacers xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, D‐tagatose, isomaltulose, sucralose and polydextrose and maintenance of tooth mineralisation by decreasing tooth demineralisation (ID 463, 464, 563, 618, 647, 1182, 1591, 2907, 2921, 4300), and reduction of post‐prandial glycaemic responses (ID 617, 619, 669, 1590, 1762, 2903, 2908, 2920) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal 9(4) 2076:1‐25.

11. Ensor, M., Williams, J., Smith, R., Banfield, A. and Lodder, RA. (2014) Effects of Three Low‐Doses of D‐ Tagatose on Glycemic Control Over Six Months in Subjects with Mild Type 2 Diabetes Mellitus Under Control with Diet and Exercise, J Endocrinol Diabetes Obes. 2(4): 1057. PMCID: PMC4287278, NIHMSID: NIHMS643060, PMID: 5580449 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287278/

12. Ensor, M., Banfield, AB., Smith, RR., Williams, J. and Lodder, RA. (2015) Safety and Efficacy of D‐Tagatose in Glycemic Control in Subjects with Type 2 Diabetes, J Endocrinol Diabetes Obes. 3(1): 1065. PMCID: PMC4820068 NIHMSID: NIHMS712474 PMID: 27054147 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820068/

13. Saunders JP., Zehner LR. And Levin GV. (1999) Disposition of D‐[U‐14 C]Tagatose in the rat. Regul Toxicol Pharmacol, 29:S46 –S56. doi: 10.1006/rtph.1998.1251. PMID: 10341161 DOI: 10.1006/rtph.1998.1251

14. Venema, K., Vermunt, SHF. and Brink, EJ. (2005) D‐Tagatose increases butyrate production by the colonic microbiota in healthy men and women, Microbial Ecology in Health and Disease, 17(1): 47‐57. https://doi.org10.1080/08910600510035093.

2. - Declaration of Total Sugars

FDA Request: In the guidance regarding allulose, we discuss factors that we considered when determining whether a sugar should be excluded from the declaration of “Total Sugars,” including pH of dental plaque after consumption, caloric value, and glycemic and insulinemic response. What, if any, other factors impact whether a sugar should be excluded from the declaration of “Total Sugars?

Response:

In addition to the factors mentioned above, the prebiotic impact of sugars metabolized differently than traditional sugars should be taken into consideration as a reason for exclusion from the declaration of “Total Sugars.” For example, unlike the traditional and familiar sugars that are included in the Nutrition Facts Label, tagatose exhibits prebiotic effects when ingested. Tagatose has low small intestinal digestibility and high large intestinal fermentation -- -- characteristics that constitute the prebiotic effect (1). Feeding isotopic C14 labeled D-tagatose to adapted rats showed significant fermentation in the large intestine to 14 isotopically labeled C O2 (2). The data gathered by Venema et al. indicate that daily consumption of 7.5 or 12.5 g tagatose may lead to increased production of gut healthy butyrate and to an increase of lactobacilli, without serious gastrointestinal complaints. In view of the health-promoting effects of butyrate and lactobacilli, tagatose may be considered a prebiotic substrate (3) Allulose as well may demonstrate prebiotic properties (4)(5).

Conclusions

In addition to the factors enumerated by FDA in information request B. 2., the prebiotic effects of sugars not metabolized like traditional sugars should be taken into consideration.

Recommendation

The prebiotic effects of Rare Sugars (e.g. allulose and tagatose) is another factor militating in favor of not including them in the “Total Sugars,” category of the Nutrition Facts Label.

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1. Nygaard, H., Jensen, B. (1999) D‐Tagatose Has Low Small Intestinal Digestibility but High Large Intestinal Fermentability in Pigs, Journal of Nutrition 129(5):1002‐9. DOI: 10.1093/jn/129.5.1002.

2. Saunders JP., Zehner LR. And Levin GV. (1999) Disposition of D‐[U‐14 C]Tagatose in the rat. Regul Toxicol Pharmacol, 29:S46 –S56. doi: 10.1006/rtph.1998.1251. PMID: 10341161 DOI: 10.1006/rtph.1998.1251

3. Venema, K., Vermunt, SHF. and Brink, EJ. (2005) D‐Tagatose increases butyrate production by the colonic microbiota in healthy men and women, Microbial Ecology in Health and Disease, 17(1): 47‐57. https://doi.org10.1080/08910600510035093 4. Han, Y., Park, H., Choi, BR., Ji, Y., Eun‐Young Kwon, EY., and Choi, MS. (2020) Alteration of Microbiome Profile by D‐Allulose in Amelioration of High‐Fat‐Diet‐Induced Obesity in Mice, Nutrients 12(2):352. https://doi.org/10.3390/nu12020352

5. Choi, BR., Kwon, EY., Kim, HJ., Choi, MS. (2018) Role of Synbiotics Containing d‐Allulose in the Alteration of Body Fat and Hepatic Lipids in Diet‐Induced Obese Mice, Nutrients 10(11):1797. https://doi.org/10.3390/nu1011179

C.1. Declaration of Added Sugars

FDA Request: We could take one of various approaches to account for sugars that are metabolized differently than traditional sugars in the declaration of “Added Sugars.” For example, we could require them to be declared within the “Added Sugars” declaration, we could exclude them from the “Added Sugars” declaration, or we could adjust the gram amount of the “Added Sugars” or the %DV declaration based on their caloric contribution to the diet. What considerations could inform our approach?

Response:

We believe the guiding principle should be the approach that results in the best contribution to public health with the least amount of public confusion. We believe that FDA has already developed a superior and proven way to handle alternative sweetener caloric content through the way it regulates labeling of sugar alcohol sweeteners and soluble non-digestible carbohydrates (1). Sugar alcohols, like soluble non-digestible carbohydrates and soluble dietary fiber, contribute less than the 4 kcal/g attributed to digestible carbohydrates. However, the caloric content of these nutrients is not, in all cases, zero. FDA has decided not to have the sugar alcohols, soluble non-digestible carbohydrates and soluble dietary fiber which are greater than 0 kcal/g but less than 4 kcal/g included under the “Added Sugars” declaration or to adjust the gram amount of “Added Sugars” based on their caloric contribution to the diet even though both make a non-zero caloric contribution to the diet.

The caloric contributions of Rare Sugars like allulose and tagatose and alternative sucrose isomers like leucrose, are similar to the caloric content of the sugar alcohols and soluble non- digestible carbohydrates (2). They additionally provide physiological benefits to the consumer consistent with those of dietary fibers. Equating the non-zero caloric contribution of these classes of sweeteners with undesirable physiological effects of “Added Sugars” would be inconsistent with the known physiological benefits these classes of sweeteners provide and it would be misleading to consumers (3-4). Labeling this class of beneficial sweetener differently than sugar alcohols or soluble non-digestible carbohydrates would result in additional confusion for the public regarding the need to limit consumption of “Added Sugars”.

We respectfully suggest that both Rare Sugars and sucrose isomers with caloric content less than 4 kcal/g be labeled in the same manner as sugar alcohols and soluble non-digestible carbohydrates with the following modifications shown in yellow highlight made to the existing 21CFR sections:

21CFR101.9(c)(1)(i)(C) (C) Using the general factors of 4, 4, and 9 calories per gram for protein, total carbohydrate (less the amount of non-digestible carbohydrates, sugar alcohols, Rare Sugars and sucrose isomers), and total fat, respectively, as described in USDA Handbook No. 74 (slightly revised, 1973) pp. 9-11. A general factor of 2 calories per gram for soluble non-digestible carbohydrates shall be used. The

general factors for caloric value of sugar alcohols, Rare Sugars and sucrose isomers provided in paragraph (c)(1)(i)(F) of this section shall be used;

21CFR101.9(c)(1)(i)(F) (F) Using the following general factors for caloric value of sugar alcohols: Isomalt--2.0 calories per gram, lactitol--2.0 calories per gram, xylitol--2.4 calories per gram, maltitol--2.1 calories per gram, sorbitol--2.6 calories per gram, hydrogenated starch hydrolysates--3.0 calories per gram, mannitol--1.6 calories per gram, and erythritol--0 calories per gram. Using the following general factors for caloric value of Rare Sugars: Allulose--0.4 calories per gram and Tagatose-- 1.5 calories per gram. Using the following general factors for caloric value of sucrose isomers: Leucrose--2.0 calories per gram.

We further respectfully suggest that voluntary labeling of Rare Sugars be allowed on the label similar to the allowance of for sugar alcohols under 21CFR101.9(c)(6)(iv) in order to provide further clarity to the public as to the difference of this class of sweeteners relative to traditional sugars.

The Current Section of the CFR Regarding Sugar Alcohols Is as Follows

21CFR101.9(c)(6)(iv) (iv) “Sugar alcohol” (VOLUNTARY): A statement of the number of grams of sugar alcohols in a serving may be declared voluntarily on the label, except that when a claim is made on the label or in labeling about sugar alcohol or total sugars, or added sugars when sugar alcohols are present in the food, sugar alcohol content shall be declared. For nutrition labeling purposes, sugar alcohols are defined as the sum of saccharide derivatives in which a hydroxyl group replaces a ketone or aldehyde group and whose use in the food is listed by FDA (e.g., mannitol or xylitol) or is generally recognized as safe (e.g., sorbitol). In lieu of the term “sugar alcohol,” the name of the specific sugar alcohol (e.g., “xylitol”) present in the food may be used in the nutrition label provided that only one sugar alcohol is present in the food. Sugar alcohol content shall be indented and expressed to the nearest gram, except that if a serving contains less than 1 gram, the statement “Contains less than 1 gram” or “less than 1 gram” may be used as an alternative, and if the serving contains less than 0.5 gram, the content may be expressed as zero.

FDA Could Provide For The Labeling Of Rare Sugars With the Following Proposed Addition To The CFR

21CFR101.9(c)(6)(v) (v) “Rare Sugars” (VOLUNTARY): A statement of the number of grams of Rare Sugars in a serving may be declared voluntarily on the label, except that when a claim is made on the label or in labeling about Rare Sugars or total sugars, or added sugars when Rare Sugars are present in the food, Rare Sugars content shall

be declared. For nutrition labeling purposes, Rare Sugars are defined as the sum of saccharides that are metabolized differently than the traditional sugars (fructose, glucose, sucrose, maltose, lactose and galactose), whose use is generally recognized as safe, and has been approved by rule making as a Rare Sugar (e.g. allulose and tagatose). In lieu of the term “Rare Sugars,” the name of the specific rare sugar (e.g., “allulose”, tagatose”, “allose”) present in the food may be used in the nutrition label provided that only one Rare Sugar is present in the food. Rare Sugar content shall be indented and expressed to the nearest gram, except that if a serving contains less than 1 gram, the statement “Contains less than 1 gram” or “less than 1 gram” may be used as an alternative, and if the serving contains less than 0.5 gram, the content may be expressed as zero.

In addition to the above reasons why Rare Sugars should not be included in Added Sugars in the Nutrition Facts Label, we take note of the Agency’s discussion at 81 FR 33742 at 33835 regarding whether Added Sugars is consistent with the concept of “empty calories.” We respectfully suggest that this discussion regarding “empty calories,” provides another reason why Rare Sugars should not be included in Added Sugars. Traditional and familiar sugars that are included in Added Sugars provide caloric intake but no nutritive benefit. Rare Sugars provide physiological benefits while resulting in reduced caloric intake. Rare Sugars are therefore not “empty calories,” and, we respectfully submit, they should not be included in Added Sugars also for this reason.

Conclusions

Rare Sugars are fundamentally different than traditional and familiar sugars in the way the Rare Sugars are metabolized and in the physiological benefits they provide. Including them with Added Sugars in the Nutrition Facts Label will deter people from consuming the Rare Sugars in the mistaken belief they are traditional and familiar sugars.

Recommendations

Rare Sugars should not be included in Added Sugars in the Nutrition Facts Label.

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1. 21CFR101.9(c)(1)(i)(C)

2. 21CFR101.9(c)(1)(i)(F)

3. Bilal M, et al. (2018) Metabolic engineering pathways for rare sugars biosynthesis, physiological functionalities, and applications‐a review. Crit Rev Food Sci Nutr. 58(16):2768‐2778. doi:10.1080/10408398.2017.1341385, 10.1080/10408398.2017.1341385

4. Tian Y, et al. (2019) Sucrose isomers as alternative sweeteners: properties, production, and applications. Appl Microbiol Biotechnol. 103(21‐22):8677‐8687. doi:10.1007/s00253‐019‐10132‐6, 10.1007/s00253‐019‐10132‐6

C. 2. Declaration of Added Sugars

FDA Request: In the guidance regarding allulose, we discuss factors that we considered when determining whether a sugar should be excluded from the declaration of “Added Sugars,” including caloric value and glycemic and insulinemic response. What other factors, if any, impact whether a sugar should be excluded from the declaration of “Added Sugars”? Please provide any data or other information that supports your response.

Response:

In addition to the factors mentioned in the guidance regarding allulose, the prebiotic impact of sugars metabolized differently than traditional sugars should be taken into consideration as a reason for exclusion from the declaration of “Added Sugars”. For example, unlike the traditional and familiar sugars that are included in the Nutrition Facts Label, tagatose exhibits prebiotic effects when ingested. Tagatose has low small intestinal digestibility and high large intestinal fermentation -- -- characteristics that constitute the prebiotic effect (1). Isotopic C14 labeled tagatose fed to adapted rats showed significant fermentation in the large intestine to isotopically labeled 14 C O2 (2). The data gathered by Venema et al. indicate that daily consumption of 7.5 or 12.5 g tagatose may lead to increased production of gut healthy butyrate and to an increase of lactobacilli, without serious gastrointestinal complaints. In view of the health-promoting effects of butyrate and lactobacilli, tagatose may be considered a prebiotic substrate (3). Allulose as well may demonstrate prebiotic properties (4)(5).

Conclusions

In addition to the factors named in the allulose guidance to be considered when determining whether a sugar should be excluded from the declaration of “Added Sugars” -- -- i.e. the pH of dental plaque after consumption, caloric value, and glycemic and insulinemic response -- -- the prebiotic effects of sugars not metabolized like traditional sugars such as tagatose should also be taken into consideration.

Recommendations

For all of the reasons discussed above, Rare Sugars not metabolized like traditional sugars (e.g. allulose and tagatose) should not be included in the “Added Sugars,” category of the Nutrition Facts label.

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4. Han, Y., Park, H., Choi, BR., Ji, Y., Eun‐Young Kwon, EY., and Choi, MS. (2020) Alteration of Microbiome Profile by D‐Allulose in Amelioration of High‐Fat‐Diet‐Induced Obesity in Mice, Nutrients 12(2):352. https://doi.org/10.3390/nu12020352

C. 3. Declaration of Added Sugars

FDA Request: [Regarding whether the sugar should be excluded from “Added Sugars.”] We might adjust the %DV for “Added Sugars” for the U.S. population 4 years of age and older based on the caloric contribution of the sugar. For example:

Assume a product contains 5 g of sucrose and 10 g of another sugar with a caloric value of 2 kcal/g per serving.

Step 1. Calculate the Total Caloric Contribution of Sugars (amount of sucrose (g/serving) × caloric value (kcal/g)) + (amount of other sugar (g/serving) × caloric value (kcal/g))

a. Sucrose: 5 g/serving × 4 kcal/g (caloric value of sucrose) = 20 kcal/serving

b. Other sugar: 10 g/serving × 2 kcal/g (caloric value of other sugar) = 20 kcal/serving

c. Total Caloric Contribution = 20 kcal/serving (sucrose) + 20 kcal/serving (other sugar) = 40 kcal/serving

Step 2. Calculate Total Amount of Sugars Adjusted for the Total Caloric Contribution (Total Caloric Contribution of Sugars (kcal/serving) ÷ 4 kcal/g))

Amount of Sugars Adjusted for Caloric Contribution = 40 kcal/serving ÷ 4 kcal/g = 10 g- equivalent/serving

Step 3. Calculate %DV for Added Sugars (Amount of Sugars Adjusted for Caloric Contribution (g-equivalent) ÷ 50 g/day (DV for Added Sugars for the general U.S. population 4 years of age and older) × 100))

%DV = (10 g-equivalent ÷ 50 g/day) × 100 = 20%

What considerations are there with respect to adjusting the %DV declaration based on the caloric contribution of the sugar?

Response:

Please see our response to C.1, above. We respectfully suggest that both Rare Sugars (e.g. allulose and tagatose) and sucrose isomers (e.g. leucrose) which have

known caloric content less than 4 kcal/g and beneficial physiological effects be labeled in the same manner as sugar alcohols and soluble non-digestible carbohydrates as prescribed in 21CFR101.9(c)(1)(i)(C), 21CFR101.9(c)(1)(i)(F). We respectfully suggest that Rare Sugars and sucrose isomers be subject to voluntary labeling as prescribed for sugar alcohols in 21CFR101.9(c)(6)(iv). We believe proceeding in this manner will be less confusing for the public, consistent with existing regulations, and consistent with the documented physiological benefits these sweeteners provide.

We also do not believe any adjustment to the sugars and added sugars caloric considerations is necessary, since tagatose does not raise blood glucose and insulin levels and basically is zero net calories when consumed with other sugars. We do believe that tagatose should be included in the ingredients statement and should be included in other carbohydrates. The caloric value of 1.5 kcal/g for tagatose should be included in the Total Calories of the food quantity since tagatose might well be consumed as a sweetener in the absence of the other sugars generally consumed in the diet.

Conclusions and Recommendations

Increased use of Rare Sugars such as allulose (.4 kcal/g) and tagatose (1.5 kcal/g) will decrease the overall caloric intake of a nation engaged in a war on obesity. Rare Sugars also provide additional physiological benefits. Tagatose also blunts the metabolization of traditional and familiar sugars when they are co-consumed. Amending existing regulations to increase sugars and added sugars to reflect the presence of Rare Sugars will deter their consumption and would be misleading because such an adjustment does not reflect the physiological benefits of Rare Sugars aside from their reduced caloric contribution. We therefore feel that such a change does not advance the value of improving public health and is not something that should be done.

D. 1. -- Label Declarations

FDA Request: We currently require the disclosure of sugar alcohols and sugars that are metabolized differently than traditional sugars in the ingredient statement in accordance with §101.4(a), but also allow for the voluntary declaration of sugar alcohols on the Nutrition Facts label (§ 101.9(c)(6)(iv)). Please provide any data or other information that we could consider when determining whether we should allow for the voluntary declaration on the Nutrition Facts label of sugars that are metabolized differently than traditional sugars.

Response:

Please see our response to C.1 above. We respectfully suggest that both Rare Sugars (e.g. allulose and tagatose) and sucrose isomers (e.g. leucrose) which have known caloric content less than 4 kcal/g and beneficial physiological effects be labeled in the same manner as sugar alcohols and soluble non-digestible carbohydrates as prescribed in 21CFR101.9(c)(1)(i)(C) and 21CFR101.9(c)(1)(i)(F). We respectfully suggest that Rare Sugars and sucrose isomers be subject to voluntary labeling as prescribed for sugar alcohols in 21CFR101.9(c)(6)(iv). We believe proceeding in this manner will be less confusing for the public, consistent with existing regulations, and consistent with the documented physiological benefits these sweeteners provide.

The voluntary declaration of sugar alcohols in the Nutrition Facts label is a positive labeling attribute that serves consumers seeking information above and beyond the caloric and glycemic sugars information related to traditional and familiar sugars. This provides consumers access to the content of the food product regarding the attributes they are actively seeking. Similarly, voluntary labeling of sugars that are metabolized differently than traditional sugars on the Nutrition Facts Label will be desirable for individuals seeking to adjust their diets based on heath needs, e.g. individuals with prediabetes, diabetes, carrying excess weight, or at high risk of developing dental caries. Food purveyors will know their customer/audience and will make the voluntary disclosures that are consistent with the needs and interests of their target market.

Sugars that are metabolized differently that traditional sugars, such as allulose and tagatose, differ from traditional and familiar sugars with respect to the impact they have on post prandial blood glucose. On the basis of a scale of 0 to 100 regarding post prandial blood glucose increase and duration, tagatose (along with allulose) are considered ~0 compared to traditional and added sugars having blood glucose increase ratings ranging from 23 for fructose to 100 for glucose (~105 for maltose) (1). Consequently, with ~0 post prandial blood glucose rise for allulose and tagatose, there is no post prandial rise in insulin following consumption (2). Further, tagatose has been shown to reduce hemoglobin A1c when utilized in diets over longer terms (3)(4). Tagatose has been affirmed with a caloric value of 1.5 kcal/g (5) and approved for reducing the risk of dental caries (6). Tagatose does not contribute to dental caries and qualifies for a health claim regarding the same (7).

Conclusion

The caloric content, glycemic and insulinemic behavior, and dental caries risk reduction of tagatose, allulose and other carbohydrates with similar behaviors, indicate that sugars that are metabolized differently than traditional sugars should not be required to be included with Sugars and Added Sugars in the Nutrition Facts Label. Instead, they should be voluntarily declared in a unique category to provide information to consumers seeking data with regard to their diet relative to their individual health status.

Recommendation

Provide for voluntary labeling of a separate category for sugars that are metabolized differently than traditional sugars.

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1. Lamothe, LM., Lê, KA., Samra, RA., Roger, O., Green, H., and Macé, K. (2019) The scientific basis for healthful carbohydrate profile, Critical Reviews in Food Science and Nutrition 59 (7):1058‐1070 https://doi.org/10.1080/10408398.2017.1392287

2. EFSA Panel on Dietary Products, Nutrition, and Allergies (NDA) (2011), Scientific Opinion on the substantiation of health claims related to the sugar replacers xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt, erythritol, D‐tagatose, isomaltulose, sucralose and polydextrose and maintenance of tooth mineralisation by decreasing tooth demineralisation (ID 463, 464, 563, 618, 647, 1182, 1591, 2907, 2921, 4300), and reduction of post‐ prandial glycaemic responses (ID 617, 619, 669, 1590, 1762, 2903, 2908, 2920) pursuant to Article 13(1) of Regulation (EC) No 1924/2006, EFSA Journal 9(4) 2076:1‐25.

3. Ensor, M., Williams, J., Smith, R., Banfield, A. and Lodder, RA. (2014) Effects of Three Low‐Doses of D‐Tagatose on Glycemic Control Over Six Months in Subjects with Mild Type 2 Diabetes Mellitus Under Control with Diet and Exercise, J Endocrinol Diabetes Obes. 2(4): 1057. PMCID: PMC4287278, NIHMSID: NIHMS643060, PMID: 5580449 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287278/

4. Ensor, M., Banfield, AB., Smith, RR., Williams, J. and Lodder, RA. (2015) Safety and Efficacy of D‐Tagatose in Glycemic Control in Subjects with Type 2 Diabetes, J Endocrinol Diabetes Obes. 3(1): 1065. PMCID: PMC4820068 NIHMSID: NIHMS712474 PMID: 27054147

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820068/

6. Lu, Y., Levin, GV., and Donner, TW., (2008) Tagatose, a new antidiabetic and obesity control drug, Diabetes, Obesity and Metabolism, 10: 109‐134. (See ref 10, Hoadley, JE. The FDA letter of October 25, 1999 to Ms. Marsha C. Wertzberger).

7. US Food and Drug Administration, Fed Regist. 2003 Jul 3;68(128):39831‐3. Food labeling: health claims; D‐ tagatose and dental caries. Final rule. Food and Drug Administration, HHS PMID: 12848171 https://pubmed.ncbi.nlm.nih.gov/12848171/

D. 2. -- Label Declarations

FDA Request: Sugar alcohols fall into a separate category of labeling and are excluded from the “Total Sugars” and “Added Sugars” declarations. Please provide any data or other information that we could consider when determining whether sugars that are metabolized differently than traditional sugars should be combined with sugar alcohols into one declaration within the Nutrition Facts label.

Response:

Clearly, sugars that are metabolized differently that the historically common sugars in the diet (fructose, glucose, sucrose, maltose, lactose and galactose) and that provide additional physiological benefits do not belong in the Total Sugars or Added Sugars category. Consumers understand that total sugars and added sugars provide ~4kcal/g consumed, increase the risk of dental caries, and elevate blood glucose as well as blood insulin in normal healthy subjects. Although sugars that are metabolized differently than traditional sugars share many of the same metabolic effects of sugar alcohols -- -- i.e. lower caloric value, prebiotic behavior in the alimentary canal, low glycemic response, low insulinemic response, and reduced risk of dental caries -- -- ketoses and aldoses with these characteristics are not considered alcohols or sugar alcohols from a chemical nomenclature standpoint. Labeling a ketose or an aldose as an alcohol would lead to consumer confusion and not promote better understanding among consumers interested in practicing methods that will impact their diets.

Conclusion

Since labeling a ketose or an aldose as an alcohol will lead to further consumer confusion and is technically incorrect, ketoses and aldoses that are metabolized differently than the historically commonly consumed sugars belong in a separate voluntarily labeled category of their own which acknowledges the properties of the differentiated metabolism. Optionally, a voluntarily labeled category of atypical carbohydrates under the “other carbohydrates” category with subcategories of sugar alcohols and Rare Sugars.

Recommendation

Sugars that are metabolized differently than traditional sugars should not be included in the voluntarily labeled sugar alcohols category. Rather, a provision should be made for separate voluntary labeling of Rare Sugars for said ketoses and aldoses as a subcategory along with a voluntarily labeled subcategory of sugar alcohols under the “other carbohydrates” category.

D. 3. -- Label Declarations

FDA Request: If sugars that are metabolized differently than traditional sugars are excluded from the “Total Sugars” and “Added Sugars” declarations and are combined with sugar alcohols in a separate labeling category within the Nutrition Facts label, what names would be scientifically appropriate for such a category? Please provide any data or other information that supports your recommendation.

Response:

Please see our responses to A.1 and C.1 above. We believe that the categories “Rare Sugars” for allulose and tagatose-type compounds, and “sucrose isomers” for isomaltulose and leucrose-type compounds, captures all of the alternative sugars that are metabolized differently than traditional sugars that have accepted caloric values. This proposed category provides an umbrella in the regulations for accurate placement when future research indicates a sugar that is not digested in the manner of traditional sugars is accepted into the food ingredient supply. Further, these are the currently accepted scientific classifications in the peer-reviewed literature for these distinct physiologically beneficial sweetener classes.

One Page Summary and Conclusions

We feel that FDA’s exploration of how to label Rare Sugars gives the Agency and the American People a unique opportunity to attack the two-headed monster of diabetes and obesity head on. Rare Sugars offer reduced caloric intake, in some cases reduce the metabolization of traditional and familiar sugars and offer other physiological benefits. We believe that to the extent FDA embraces and advances the deployment of Rare Sugars, it will make substantial progress in the fight against diabetes and obesity without real cost to the public either financially or in their enjoyment of food.

To facilitate the widespread use of Rare Sugars, they should be incorporated into food products in a mechanism that is embraced by both consumers as well as food producers. With this in mind, The Food Lawyers® respectfully request that FDA implements the following:

1. Establish a new category of sugars called Rare Sugars that exhibit the following characteristics: a. Are naturally occurring b. Impart a sweet taste that is at least 50% the sweetness of sucrose c. 2.0 kcal/g or less. d. Resulting pH of 6.0 or greater of dental plaque after consumption. e. No or low glycemic response. f. No or low insulinemic response. 2. Exclude Rare Sugars from “Total Sugars” and “Added Sugars” declarations in order to stimulate their deployment by industry and consumption by the public. 3. Allow certain voluntarily disclosures for Rare Sugars on the Nutrition Facts Label. 4. Identify the initial Rare Sugars as Allulose, Allose, and Tagatose. 5. Accept Citizen Petitions for identification of additional Rare Sugars. 6. Exercise enforcement discretion regarding labeling of Rare Sugars, similar to the approach the Agency has applied to Allulose, until federal rule making can be completed.

We feel the above approach creates an atmosphere wherein industry will be motivated to substitute Rare Sugars for traditional and familiar sugars, the public will receive the immediate benefit of Rare Sugars as an ingredient in food products and in the longer term the public will be able to focus on, and learn about, Rare Sugars that are metabolized differently than traditional sugars. “Rare Sugars” is a simple, attractive terminology that the public can easily assimilate.

We want to thank FDA for letting us participate in this process. Opportunities to make a real difference in public health are too infrequent and we feel fortunate for the regulatory attention granted to us to submit our thoughts.

Sincerely,

® The Food Lawyers George C. Salmas By: ______George C. Salmas Managing Principal E-mail: [email protected]