The Hon. Dr. Marty Makary
Commissioner
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993

September 25, 2025

Dear Commissioner Makary,

The undersigned submits this petition under 21 C.F.R. § 10.30, the Administrative Procedure Act, 5 U.S.C. §§ 553(e), 505G, 21 C.F.R. Part 355, and 21 U.S.C. § 321, § 351, § 352, § 353, § 355, § 360 and § 371, as well as any other statutory provision for which authority has been delegated to the Commissioner of Food and Drugs to request the Commissioner of Food and Drugs to promulgate regulation to authorize the use of topical dental hygiene products containing xylitol for use in preventing and/or reducing the incidence rates of dental caries and other dental diseases (the or this “Petition”).

A. ACTION REQUESTED 

Specifically, this Petition requests that the FDA issue regulations designating xylitol as “active ingredients” for topical dental hygiene products under 21 C.F.R. Part B, § 355.10 (Anticaries active ingredients).

Such a listing is sought to apply broadly to xylitol as used in toothpastes, rinses, gels, mouthwashes, chewing gums, lozenges, and “candies”.

To the extent necessary to achieve the above, this Petition requests the FDA to issue an amendment to the Over-the-Counter Monograph M021: Anticaries Drug Products for Over-the-Counter Human Use, (posted May 2, 2023), such amendment to include the use of xylitol-based dental hygiene products within Part B (Active Ingredients).

Alternatively, and to the extent necessary, this Petition requests the FDA to issue a new monograph for the use of xylitol as an anticaries over-the-counter drug pursuant to section 505G of the FDCA.

Much like with toothpaste, mouthwash and other oral hygiene interventions, dosage (which implies ingestion) is the wrong regulatory benchmark. These interventions are not taken (e.g., ingested or consumed), but are topical. Rather, the benchmark should be concentration. For products, such as candies, lozenges, and gum, to be considered an anticaries OTC drug product, each product unit (e.g., piece of gum) should have 1 gram or more of xylitol per serving, with no other 6 carbon sugars or sugar alcohols or fermentable carbohydrates. For toothpastes and mouthwashes, the product should be at least 15 percent xylitol, with no 6 carbon sugars, sugar alcohols, or fermentable carbohydrates.

B. STATEMENT OF GROUNDS 

1. Safer and more effective approaches to combating caries are necessary:

The FDA has allowed the use and marketing of products containing fluoride as an anti-caries drug since the passage of the 1938 Food, Drug and Cosmetic Act (the FDCA), codified at 21 U.S.C. §§ 301 et seq.1  In the early 1900s, manufacturers began adding fluoride to toothpaste.  Pursuant to the FDCA, drugs in use prior to its passage were grandfathered in as approved and exempted from the requirement to file an Investigational New Drug Application (INDA).  At the time, the American Dental Association vehemently opposed the use of, and FDA approval for, fluoride.  See Council on Dental Therapeutics, Accepted Dental Remedies, J. Am. Dent. Ass. 24 (1937) 307-309, available at https://jada.ada.org/article/S0375-8451(37)42019-2/abstract (“The use of fluoride in dentifrices is unscientific and irrational, and therefore should not be permitted.”) Fluoride was grandfathered in without the required supporting research. 

Subsequently, in 1995, the FDA issued an over-the-counter (OTC) drug monograph for products, such as toothpaste, rinses and gels, that contain fluoride for the purpose of combatting dental caries.  To implement this monograph, on October 6, 1995, the FDA promulgated regulations providing that fluoride products that meet certain conditions could be marketed, sold and used as “anticaries drug product[s]”.  See FDA, Anticaries Drug Products for Over-the-Counter Human Use; Final Monograph, 60 Fed. Reg. 52507 (Oct. 6, 1995), codified at 21 C.F.R. Part 355. 

According to the CDC, in layman’s terms, “[c]avities (also called tooth decay or dental caries) are caused by the bacteria in your mouth that stick to your teeth. You feed the bacteria every time you eat or drink. The bacteria produce acid which starts to dissolve the outer enamel layer of your teeth. Your saliva clears away the acid and helps to repair the enamel. If the repair isn’t fast enough, bacteria get inside your tooth and make cavities. Cavities will get bigger unless the bacteria are stopped or removed.”  CDC, About Cavities (Tooth Decay), May 15, 2024, available at https://www.cdc.gov/oral-health/about/cavities-tooth-decay.html. 

As the CDC notes, “[c]avities will get bigger unless the bacteria are stopped or removed.”  Id. 

Unfortunately, fluoride, the only FDA approved OTC anticaries drug, does not meaningfully eliminate or stop the bacteria that produce the acid, which causes tooth decay.  Rather, fluoride anticaries OTC drug products primarily function by helping “remineralize” the dental enamel, in concept making it more resistant to acid. See Cate JM. Current Concepts on the Theories of the Mechanism of Action of Fluoride. Acta Odontol Scand 1999;57(06):325–329. 

As depicted in Insert A, individuals are at risk of cavities when three factors are present: 1) Fermentable carbohydrates from diet; 2) Cariogenic oral bacteria; and, 3) Susceptible teeth. However, dentistry’s approach to combatting caries does not focus on eliminating any of these three risk factors. Rather than addressing these known risk factors, dentistry’s singular focus has been on re-mineralizing teeth with the goal of making teeth more resistant to the disease.

While it is widely asserted that fluoride can also be antibacterial, recent data cast strong doubt on this assumption. A 2023 in vitro study published in the European Journal of General Dentistry, determined:

Pasiree Thongthai, et al., Fluoride Concentration, Antibacterial Effect, and Cytotoxicity in Children’s Toothpaste: In Vitro Study. 2023 Dec; 12:199–208, 206.  Interestingly, with respect to discerning what other ingredients may be behind the perceived antibacterial effect of fluoride, the study noted the presence of xylitol, which is known to have antibacterial effect, in the studied toothpastes.  Id. at 200 (citing Mäkinen KK. Sugar alcohol sweeteners as alternatives to sugar with special consideration of xylitol. Med Princ Pract 2011;20 (04):303–320 for the efficacy of xylitol in combating S Mutans bacteria).  Of the seven toothpastes included in that study, all seven included a sugar alcohol, including four that contained xylitol specifically.  

This result is not unique. A 2008 study, published in the Journal of Dental Research Dental Clinics Dental Prospects, concluded that “[f]luoride concentrations ranging from 500 to 1500 ppm did not affect bacterial growth.”  A. Klaophimai, et al. Antibacterial effects of children’s and adults’ toothpastes containing different amounts of fluoride: An in vitro study. J Dent Res Dent Clin Dent Prospects. 18(1):23-28. available at https://joddd.tbzmed.ac.ir/Article/joddd-40705.  It must be stressed, that under the FDA’s OTC rules, American toothpastes, in particular children’s toothpastes, fall within the study’s concentration range found to have no antibacterial effect. 

Which is to say, since 1938 and before, the FDA’s—and dentistry’s—singular response to the disease of dental caries has been fluoride, which does little to nothing to address the actual threat. Cf. Featherstone, J.D. Delivery Challenges for Fluoride, Chlorhexidine and Xylitol. BMC Oral Health 6 (Suppl 1), S8 (2006). https://doi.org/10.1186/1472-6831-6-S1-S8 (“Preventive dentistry has largely ignored the benefits of reducing the bacterial challenge, partially due to primitive and inadequate delivery systems.”) 

As noted by the CDC’s Fluoride Recommendations Work Group, the data that supports the efficacy of fluoride in dental hygiene products as an anticaries drug is deficient in several important respects: 

CDC, Fluoride Recommendations Work Group, Recommendations for Using Fluoride to Prevent and Control Dental Caries in the United States, Aug. 17, 2001, available at https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5014a1.htm (citations omitted). 

Importantly, the Work Group noted these deficiencies even though they were generally supportive of the continued use of these fluoride anticaries interventions.  Which is to say, while fluoride interventions may provide a benefit, the data indicates the need for better approaches to combatting dental caries. 

Real world evidence paints a similar picture.  According to the CDC’s Fluoride Work Group, “[b]y the 1990s, fluoride toothpaste accounted for >90% of the toothpaste market in the United States . . .”  Id.  The 2024 Delta Dental Oral Health and Well-Being Survey, concluded that “approximately 3 in 4” Americans meet the American Dental Association’s “criteria for brushing, rinsing, and flossing.”  Delta Dental, 2024 State of America’s Oral Health and Wellness Report, 2024, at 8, available at  https://www.deltadental.com/content/dam/ddpa/us/en/state-of-america%27s-oral-health-and-wellness-report/2024 State of America%27s Oral Health and Wellness Report.pdf.  Taken together, given that 3-4 Americans adequately brush, floss, and rinse, and 90 percent of the toothpastes, rinses and mouthwashes they use contain the FDA allowed amount of fluoride, if fluoride was truly effective, one should expect the rate of dental caries to be low.

Unfortunately, this is not the case.  According to the National Institute of Dental and Craniofacial Research, “[n]early 90% of adults ages 20 to 64 years have had decay in their teeth, a percentage that has not changed significantly between the 1999–2004 and 2011–2016 [National Health and Nutrition Examination Survey] cycles.”  National Institute of Dental and Craniofacial Research, Dental Caries (Tooth Decay) in Adults (Ages 20 to 64 Years), Nov. 2022, available at https://www.nidcr.nih.gov/research/data-statistics/dental-caries/adults. 

While the NIDCR survey notes that overall caries rates in the US have declined since the 1960s, a “mid-1930s, a survey by the United States Public Health Service determined that 71 percent of 12- to 14-year-olds had one or more carious teeth.”  Frank Zelko, In the Teeth of History: Dental Decay in the Longue Durée, Rachel Carson Ctr Rev, Oct. 31, 2023, available at https://springs-rcc.org/in-the-teeth-of-history/.  It should be noted that the 1930s study was conducted before today’s ubiquity of fluoride in dental hygiene products (and drinking water).  Set aside data comparison issues, on a macro level, these data points taken together suggest that fluoride-based dental hygiene is having a rather limited—indeed inadequate—impact on American’s dental health. 

The need for more effective, alternative to fluoride countermeasures is growing.  In fact, this need has been growing for some time now.  See Featherstone, J.D. Delivery Challenges for Fluoride, Chlorhexidine and Xylitol. BMC Oral Health 6 (Suppl 1), S8 (2006). https://doi.org/10.1186/1472-6831-6-S1-S8.  In 2006, Featherstone summarized:  

Based on childhood health concerns, Health and Human Services (HHS) Secretary Robert Kennedy Jr. has called for the elimination of ingestible fluoride. Along these lines, this agency has begun to take steps to eliminate ingestible fluoride.  See FDA, FDA Begins Action to Remove Ingestible Fluoride Prescription Drug Products for Children from the Market, May 13, 2025, available at https://www.hhs.gov/press-room/fda-to-remove-ingestible-fluoride-drug-products-for-children.html (The U.S. Food and Drug Administration (FDA) today announced that it is initiating action to remove concentrated ingestible fluoride prescription drug products for children from the market.)

While concerns about the ingestion of fluoride have focused on drinking water, ingestion from fluoride-based dental hygiene product use also raise Secretary Kennedy’s concerns.  The CDC’s Fluoride Work Group discussed “[t]he propensity of young children to swallow toothpaste . . . .” CDC, Recommendations, supra.  The Recommendations calculated that, “[c]hildren aged <6 years swallow a mean of 0.3 g of toothpaste per brushing and can inadvertently swallow as much as 0.8 g (138,173–176). As a result, multiple brushings with fluoride toothpaste each day can result in ingestion of excess fluoride.”  Id. citations omitted.  The report also noted that, “[a] U.S. clinical trial of the efficacy of toothpaste with lower fluoride concentrations, required by FDA before approval for marketing and distribution, has not been conducted.”

In addition, the ongoing elimination of fluoride from drinking water only adds to the present need for such alternatives: 

• The Secretary has indicated that he intends to tell the CDC to stop recommending the use of fluoride in drinking water.  See PBS, RFK Jr. will tell CDC to stop recommending fluoride in drinking water, PBS News, Apr. 8, 2025, available at https://www.pbs.org/newshour/health/rfk-jr-will-tell-cdc-to-stop-recommending-fluoride-in-drinking-water;  

• In response, two states, namely Florida and Utah, have determined that the risks of fluoride in drinking water exceed the potential benefits and have mandated the removal of the compound from their drinking water systems.  See Natalie Neysa Alund, Two states have now passed fluoride bans. These other ones introduced bills, USA Today, May 16, 2025, available at https://www.usatoday.com/story/news/nation/2025/05/16/fluoride-bans-states-florida-utah/83667361007/ 

• There are indications that other states are considering similar action.  Id. (discussing Kentucky, Louisiana, Massachusetts, Nebraska and South Carolina pending legislation). 

To the extent that fluoridated drinking water may have a benefit in reducing caries and dental decay, the elimination of such fluoridation raises the need for alternative interventions to address the dental caries health threat. 

The identification of safer and more effective, non-fluoride dental hygiene interventions is necessary.  Xylitol anticaries interventions offer a low-cost, safe, and effective tool to address this growing problem. 

2. Traditional uses of xylitol provide the basis for grandfathering xylitol in under 21 C.F.R. Part B: 

As discussed above, the FDA monograph and regulations thereunder grandfathered fluoride without the need for an INDA. 

Traditional use of xylitol for dental hygiene long pre-date the use of fluoride, both around the world and in the United States.  For thousands of years tooth cleaning was done with chewing sticks prepared from twigs, stems or roots of a variety of plant species. (many of which contained xylitol).  While naturally occurring, Xylitol, as a distinct compound, was identified in 1891, simultaneously by both German and French chemists.   

A 2002 analysis in the Journal of Periodontal Research explained: 

Wu, C.D., Darout, I.A. and Skaug, N. (2001), Chewing sticks: timeless natural toothbrushes for oral cleansing. Journal of Periodontal Research, 36: 275-284, available at https://doi.org/10.1034/j.1600-0765.2001.360502.x.  As noted in the Journal of Periodontal Research, clinical trial data indicates that the use of such chewing sticks is as safe and effective as toothbrushing.  See, e.g., Malik AS, Shaukat MS, Qureshi AA, Abdur R. Comparative effectiveness of chewing stick and toothbrush: a randomized clinical trial. N Am J Med Sci. 2014 Jul;6(7):333-7. doi: 10.4103/1947-2714.136916. PMID: 25077082; PMCID: PMC4114011; Almutairi, W., Duane, B. Can traditional oral hygiene methods compete with conventional toothbrushes in effectiveness?. Evid Based Dent 25, 154–155 (2024). https://doi.org/10.1038/s41432-024-01030-6. 

For example, paper birch, Betula papyrifera, chewsticks (and its resin) were used by Native Americans, particularly in the Great Lakes region and Northern New England, for dental hygiene purposes.  (In fact, the use of birch for dental hygiene is said to go back to the Neolithic age.) Paper birch contains xylitol.  See Flore Alpes, Xylitol: History, Composition, Extraction, undated, available at https://www.flore-alpes.com/magazine/post/16-xylitol-de-bouleau-histoire-composition-et-extraction?locale=en; Vehgro, Birch Sugar Xylitol, undated, available at https://www.vehgroshop.com/birch-sugar-xylitol.html  (“Our birch sugar is made exclusively from birch and beech wood from Scandinavia. The Xylitol is extracted from the wood sugar (xylose) in a very complex way.”) 

As a result, xylitol is commonly called “birch sugar” or “wood sugar.” 

In sum, Xylitol as a dental hygiene tool was delivered to the teeth through chew sticks, which dates back thousands of years, long pre-dating the FDCA 

Further, the outcome desired from using xylitol hasn’t changed: caries prevention through oral bacterial reduction.  Whether contained in a chew stick (one chews) or squeezed on to a toothbrush (one often chews), or contained in gum (that is chewed), all these uses—pre and post 1938—are functionally the same.  They all amount to the topical use of xylitol as a means of preventing caries and tooth decay. 

As such xylitol meets the legal standard for grandfathering.  See 21 U.S. Code § 321(p). 

3. Studies Support Listing Xylitol as an “active ingredient” under 21 C.F.R. Part B, § 355.10 (Anticaries active ingredients) and/or issuing a monograph authorizing it as an anticaries OTC drug

A. EFFICACY

Xylitol’s antibacterial/anticaries efficacy and mechanism of action is generally understood among researchers.  See, e.g., K Ly, et. al, Xylitol, Sweeteners, and Dental Caries, Am. Acad. Ped. Dentistry, Conf. Paper, Pediatr Dent 2006;28:154-163, at 155-58, available at https://www.aapd.org/globalassets/media/publications/archives/ly-28-2.pdf;2 Jihan Turkistani. The Modes of Dental Caries Prevention with Xylitol. On J Dent & Oral Health. 3(1): 2020. OJDOH. MS.ID.000555.3 

Nearly 20,000 international research publications confirm the safety and efficacy of xylitol.4  Xylitol inhibits Streptococcus mutans growth, metabolism and transmission. 

Xylitol’s anticaries efficacy is mode of administration agnostic; “The reduction of dental plaque and caries is achieved regardless of how the xylitol is administered.  The only prerequisite is to get the xylitol into contact with the teeth.” K. K. Mäkinen, E. Söderling, H. Hurttia, O.-P. Lehtonen, E. Luukkala,”Biochemical, microbiologic and clinical comparisons between two dentifices that contain different mixtures of sugar alcohols,” Journal of the American Dental Association, vol. 111, pp. 745-751, 1985; see also, P. Lif Holgerson, C. Stecksén-Blicks, I. Sjöström, M. Öberg, “Xylitol concentration in saliva and dental plaque after use of various xylitol-containing products,” Caries Research vol. 40, pp. 393-397, 2006 (“All xylitol-containing products resulted in significantly increased levels immediately after intake and remained elevated for 8–16 min in the different groups. The highest mean value in saliva was obtained immediately after use of chewing gums and the lowest was demonstrated after using toothpaste. No significant differences were demonstrated between chewing gums, sucking tablets, candy and rinses.”). 

Indeed a series of studies have shown that the use of xylitol decreases caries by upwards of 80 percent—a protective factor that is significantly greater than that of fluoride.  For example: 

• Mäkinen KK, Bennett CA, Hujoel PP, Isokangas PJ, Isotupa KP, Pape HR, Jr, et al. Xylitol chewing gums and caries rates: A 40-month cohort study. J Dent Res. 1995;74:1904–13. doi: 10.1177/00220345950740121501. 

• Hujoel PP, Mäkinen KK, Bennett CA, Isotupa KP, Isokangas PJ, Allen P, et al. The optimum time to initiate habitual xylitol gum-chewing for obtaining long-term caries prevention. J Dent Res. 1999;78:797–803. doi: 10.1177/00220345990780031301. 

• Söderling E, Isokangas P, Pienihäkkinen K, Tenovuo J. Influence of maternal xylitol consumption on acquisition of mutans streptococci by infants. J Dent Res. 2000;79:882–7. doi: 10.1177/00220345000790031601. 

A series of studies document the efficacy of xylitol when used as a dentifrice, to include: 

• L. Jannesson, S. Renvert, D. Birkhed, “Effect of xylitol in an enzyme-containing dentifrice without sodium lauryl sulfate on mutans streptococci in vivo,” Acta Odontologica Scandinavia  vol. 55, no. 4, pp. 212-216, August 1997 (“Thus, this study demonstrated 1) that addition of 10% xylitol to an enzyme-containing dentifrice without sodium lauryl sulfate has an inhibitory effect on MS counts in saliva and dental plaque, and 2) that the inhibitory effect seems to be dose-dependent.”) 

• E. Cutler, W. Bruce, J. Phillips, “Effect of high-xylitol-content dentifrice on periodontal markers,” (Unpublished results of 6-months trial), October 2000. (Toothpaste containing 36% xylitol (Squigle Enamel Saver®) was superior to regular, (non-xylitol) fluoride toothpaste with respect to bleeding index, gingival index and plaque index in a group of 78 periodontal patients.) 

• L. Jannesson, S. Renvert, P. Kjellsdotter, A. Gaffer, N. Nabi, “Effect of a triclosan-containing toothpaste supplemented with 10% xylitol on mutans streptococci in saliva and dental plaque. A 6-month clinical study,” Caries Research vol. 36, no.1, pp. 36-39, 2002. (“The addition of 10% xylitol to a triclosan-containing dentifrice reduces the number of MS in saliva and dental plaque.”) 

• A. Surdacka, J. Stopa, “The effect of xylitol toothpaste on the oral cavity environment,” The Journal of Preventive Medicine vol. 13, no. 1-2, pp. 98-107, 2005 (“Xylitol added to toothpastes has a positive influence on the quality of the oral environment and, as a result, it would be purposeful to introduce it into prophylactic programmes.”). 

• J. L. Sintes, A. Elías-Boneta, B. Stewart, A. R. Volpe, J. Lovett, “Anticaries efficacy of a sodium monofluorophosphate dentifrice containing xylitol in a dicalcium phosphate dihydrate base. A 30-month caries clinical study in Costa Rica,” American Journal of Dentistry, vol. 15, no. 4, pp. 215–219, 2002. 

• H. Sano, S. Nakashima, Y. Songpaisan, P. Phantumvanit, “Effect of a xylitol and fluoride containing toothpaste on the remineralization of human enamel in vitro,” Journal of Oral Science, vol. 49, no. 1, pp. 67–73, 2007. 

Moreover, a number of these studies reflect that the addition of xylitiol to fluoride toothpaste increases the efficacy of the fluoride toothpaste, to include the remineralizing effect, for example: 

• H. Sano, S. Nakashima, Y. Songpaisan, P. Phantumvanit, “Effect of a xylitol and fluoride containing toothpaste on the remineralization of human enamel in vitro,” Journal of Oral Science, vol. 49, no. 1, pp. 67–73, 2007 (Adding xylitol to fluoride toothpaste enhanced the remineralizing effect). 

• L. G. Petersson, D. Birkhed, A. Gleerup, M. Johansson, G. Jönsson, “Caries-preventive effect of dentifrices containing various types and concentrations of fluorides and sugar alcohols,” Caries Research, vol. 25, no. 1, pp. 74–79, 1991 (“Children with no detectable approximal caries at baseline, who used the MFP toothpaste with the xylitol-sorbitol mixture, showed a lower (p < 0.05) caries increment as compared with children who used the MFP toothpaste with sorbitol alone.”). 

A series of studies also document the efficacy of xylitol when used as a mouthwash or rinse, for example: 

• S. E. Calamari, A. I. Azcurra, E. R. Luna Maldonado, L. J. Battellino, S. T. Cattoni, R. G. Colantonio, “Effects of xylitol, sorbitol and fluoride mouthrinses on glucose clearance in adolescents,” Acta  Odontológica Latinoamericana vol. 10, no. 1, pp. 25-36, 1997 (Xylitol treatment (14 days) provoked an increase in oral glucose clearance, which was proportional to its concentration in the mouthrinse formula, up to 40% with 1% xylitol concentration. 

• P. Lingström, F. Lundgren, D. Birkhed, I. Takazoe, G. Frostell, “Effects of frequent mouthrinses with palatinose and xylitol on dental plaque,” European Journal of Oral Science  vol. 105, no. 2, pp. 162-169, April 1997 (The most pronounced pH drop for the sugar substitutes was found when rinsing with palatinose, and the least with xylitol.  MS counts and plaque index scores decreased after xylitol). 

Additionally, other studies document the efficacy of xylitol, with prevention factors reaching upwards of 60 percent, when administered via chewing gum/and or candies, for example: 

• ALHumaid J, Bamashmous M. Meta-analysis on the Effectiveness of Xylitol in Caries Prevention, J Int Soc Prev Community Dent. 2022 Apr 8;12(2):133-138. doi: 10.4103/jispcd.JISPCD_164_21. PMID: 35462747; PMCID: PMC9022379 (“a 3-year randomized clinical trial, children 10–12 years of age were randomized into three groups consuming either candies or chewing gum or a control group with no xylitol product. Both xylitol candies and chewing gum showed a significant reduction in caries from 35% to 60%.; “Deshpande and Jaded have also supported the preventive effect of sugar alcohol in dental caries prevention with an overall preventive fraction of 58% with the use of xylitol chewing gum.” 

• Hujoel PP, Mäkinen KK, Bennett CA, et al. The optimum time to initiate habitual xylitol gum-chewing for obtaining long-term caries prevention. J Dent Res 1999;78(3): 797-803. 

• Mäkinen KK, Bennett CA, Hujoel PP, et al. Xylitol chewing gums and caries rates: A 40-month cohort study. J Dent Res 1995;74(12):1904-13. 

• Isokangas, P., et al. (1989). Long-term effect of xylitol chewing gum on dental caries. Community Dentistry and Oral Epidemiology, 17(4), 200–203. https://doi.org/10.1111/j.1600-0528.1989.tb00611.x  PubMed ID: 2758793 (Demonstrated greater frequency of xylitol gum on school days resulted in greater dental benefits.  Also showed long-term protection against tooth decay). 

• Campus G, Cagetti MG, Sale S, Petruzzi M, Solinas G, Strohmenger L, Lingström P. Six months of high-dose xylitol in high-risk caries subjects – a 2-year randomised, clinical trial. Clin Oral Invest. 2013;17:785–91. https://doi.org/10.1007/s00784-012-0774-5 (A school-based preventive programme based on 6 months’ administration of a high dose of xylitol via chewing gum proved to be efficacious in controlling caries increment in high-risk children). 

• Alanen P, Isokangas P, Gutmann K. Xylitol candies in caries prevention: results of a field study in Estonian children. Community Dent Oral Epidemiol. 2000;28:218–224. doi: 10.1034/j.1600-0528.2000.280308.x. 

• Söderling E, Isokangas P, Pienihäkkinen K, Tenovuo J., Influence of maternal xylitol consumption on acquisition of mutans streptococci by infants. J Dent Res 2000;79 (3):882-7. 

In addition, studies show that the maternal use of xylitol has an anticaries benefit for their infants post-partum.  Additionally, these studies show that the anticaries benefits of maternal xylitol use are long-lasting.  For example: 

• Nakai, Y., et al. (2010). Xylitol gum and maternal transmission of mutans streptococci. Journal of Dental Research, 89(3), 306–310.   https://doi.org/10.1177/002203451036324. 

• Milgrom P, Ly KA, Tut OK, Mancl L, Roberts MC, Briand K, et al. Xylitol pediatric topical oral syrup to prevent dental caries: A double-blind randomized clinical trial of efficacy. Arch Pediatr Adolesc Med. 2009;163:601–7. doi: 10.1001/archpediatrics.2009.77 (Xylitol oral syrup administered topically 2 or 3 times daily at a total daily dose of 8 g was effective in preventing early childhood caries). 

• Mäkinen KK, Järvinen KL, Anttila CH, Luntamo LM, Vahlberg T., Topical xylitol administration by parents for the promotion of oral health in infants: a caries prevention experiment at a Finnish Public Health Centre. Int Dent J. 2013 Aug;63(4):210-24. doi: 10.1111/idj.12038. Epub 2013 Apr 15. PMID: 23879257; PMCID: PMC9375031 (previously demonstrated xylitol–associated reduction in the probability of mother–child transmission of MS was still found in the children’s MS counts at the age of 3 and 6 years). 

• E. Söderling, P. Isokangas, K. Pienihäkkinen, J. Tenovuo, P. Alanen; Influence of Maternal Xylitol Consumption on Mother–Child Transmission of Mutans Streptococci: 6–Year Follow–Up. Caries Res 1 June 2001; 35 (3): 173–177. 

In sharp contrast, there is no evidence that the use of fluoride in any form by mothers provides an anti-caries, or other dental health benefit, to their children post birth.

On the whole the anticaries, dental health benefits efficacy of xylitol meets or exceeds the prevention factor for fluoride dentifrice. 

As noted above, a series of studies have shown that the use of xylitol decreases caries by upwards of 80 percent depending on the mode of the intervention and the introduction coinciding with tooth eruption. 

In comparison, a meta-analysis of studies examining fluoride toothpaste use by children concluded that the prevention factor of fluoride was just 24 percent, “[t]his means that 1.6 children need to brush with a fluoride rather than nonfluoride toothpaste over 3 years to prevent 1 [DMFS] in populations with a caries increment of 2.6 [DMFS] per year (or 3.7 children in populations with a caries increment of 1.1 [DMFS] per year).”  Hausen, H., Fluoride toothpaste prevents caries. Evid Based Dent 4, 28 (2003). https://doi.org/10.1038/sj.ebd.6400176, available at https://www.nature.com/articles/6400176.  Most notably this analysis demonstrated that there was significant heterogeneity in the data between and among the studies included, and that the efficacy of fluoride toothpaste was highly variable and nor fully replicable. 

Most notably another study that examined the efficacy of fluoride toothpaste among children with average caries risk determined that low-concentration fluoride toothpastes provided no additional benefit over the control. Davies, GM, et al., 

A randomised controlled trial of the effectiveness of providing free fluoride toothpaste from the age of 12 months on reducing caries in 5-6 year old children, 

Community Dent Health. 2002; 19:131-136; see also Wright, J. T. et al., Fluoride toothpaste efficacy and safety in children younger than 6 years 

The Journal of the American Dental Association, Volume 145, Issue 2, 182 – 189 , available at https://jada.ada.org/article/S0002-8177(14)60225-7/fulltext. 

Because of concerns over the safety of fluoride ingestion (fluorosis), the FDA’s approval for OTC fluoride in dentifrices limits the concentration of fluoride to relatively low concentrations.  FDA, Anticaries Drug Products for Over-the-Counter Human Use; Final Monograph, 60 Fed. Reg. 52507 (Oct. 6, 1995), codified at 21 C.F.R. Subpart B, § 355.10(a)-(b) (Anticaries active ingredients)(limiting concentrations to 850 to 1,150 ppm).  This allowable concentration range includes concentrations below which studies have shown no prevention factor efficacy. In sum, taken together, studies indicate that many of the lower concentration toothpastes authorized as OTC drugs by FDA have little to no efficacy in preventing caries. 

Additionally, as discussed above, studies have found that the combination of xylitol and fluoride in dental intervention increases the efficacy of the fluoride’s benefits. 

B. SAFETY

The FDA has determined that xylitol is GRAS (generally recognized as safe) for ingestion/use as sweetener/food additive. See 21 CFR §172.395. As such the lesser, topical use of xylitol in dental hygiene is GRAS. 

In contrast, there is increasing concern about the safety of fluoride, especially among children. 

As a result, low-concentration fluoride toothpaste is considered safe, higher concentration toothpastes are not.  Similarly, ingestible fluoride supplements (tablets, lozenges, or drops) are not considered GRAS—in sharp contrast to similar xylitol modes of administration (e.g., lozenges and gums), which are GRAS. 

C. ENVIRONMENTAL IMPACT

Pursuant to 212 CFR § 25.31(c) (Human drugs and biologics), the FDA’s regulation of xylitol under 21 C.F.R. Part B, § 355.10 is exempted from the requirement of an environmental impact statement.  This request seeks, in effect a monograph for xylitol. Xylitol is a naturally occurring sugar alcohol.  The result of this action would not “alter significantly the concentration or distribution of the substance, its metabolites, or degradation products in the environment.” 

D. ECONOMIC IMPACT

As required by the relevant rules, upon request of the Commissioner, the requisite information will be provided.  Generally speaking, the FDA action requested here would have a net positive economic benefit upon the United States, its industries and the American workforce. 

Most notably, in 2024, the CDC estimated that oral disease costs the United States $136 billion per year.  CDC, Health and Economic Benefits of Oral Disease Interventions, Oct. 21, 2024, available at https://www.cdc.gov/nccdphp/priorities/oral-disease.html – :~:text=The high cost of oral,8.  To include: 

• On average, over 34 million school hours are lost each year because of unplanned (emergency) dental care. 

• Almost $46 billion is lost in productivity in the United States each year because of untreated oral disease. 

• In 2017, there were 2.1 million emergency room visits for dental emergencies. Medicaid pays for about 69% of these visits for children and about 40% for adults. 

• During 1996–2013, $26.5 billion was spent on dental care for children and adolescents. About 70% of this total was used for preventive services, such as general exams and cleanings, X-rays, and orthodontic treatment (such as braces). 

• Nearly 18% of working-age adults report that the appearance of their mouth and teeth affects their ability to interview for a job. For people with low incomes, the percentage increases to 29%. 

Id. (citations omitted). 

The expanded use of xylitol to reduce dental caries is expected to significantly reduce these economic burdens. 

E. SIGNATORIES STATEMENT OF EXPERTISE

This petition is hereby submitted on behalf of the lead sponsors, the American Dental Hygienists’ Association (ADHA) and Xlear.   

ADHA represents the 220,000 registered dental hygienists (RDHs) nationwide.   

Xlear is one of the nation’s leaders in effective xylitol hygiene products, available in pharmacies, big box stores, natural retailers and online.

CONCLUSION

For the reasons set out above, the undersigned hereby respectfully request the Commissioner of Food and Drugs to promulgate regulation to authorize the use of topical dental hygiene products containing xylitol as an OTC drug for use in preventing and/or reducing the incidence rates of dental caries. 

CERTIFICATION:

We the undersigned certify, that, to our best knowledge and belief, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioners, including any known information unfavorable to the petition. 

Respectfully Submitted, 

Petitioners: 

ADHA: Lancette VanGuilder, BS, RDH, PHEDH, CEAS, FADHA 

Xlear: Nathan Jones, CEO 

Counsel to the Petitioners: 

Rob Housman 

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