Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37507

DEPARTMENT OF HEALTH AND of a nutrient to a disease or health- petition must include (§ 101.70(d)). HUMAN SERVICES related condition, unless the claim is These regulations became effective on made in accordance with the procedures May 8, 1993. Food and Drug Administration and standards contained in regulations In addition, FDA conducted an adopted by FDA. extensive review of the evidence on the 21 CFR PART 101 Under section 403(r)(3)(B)(i) of the 10 substance-disease relationships listed [Docket No. 95P±0003] act, the Secretary of Health and Human in the 1990 amendments. FDA has Services (and, by delegation, FDA) shall authorized claims that relate to 8 of Food Labeling: Health Claims; Sugar promulgate regulations authorizing such these 10 relationships. Alcohols and Dental Caries claims only if he or she determines, The present rulemaking on sugar based on the totality of publicly alcohols and dental caries represents the AGENCY: Food and Drug Administration, available scientific evidence (including first rulemaking that FDA has HHS. evidence from well-designed studies conducted in response to a health claim ACTION: Proposed rule. conducted in a manner which is petition. SUMMARY: The Food and Drug consistent with generally recognized C. History of Sugar Alcohol Labeling scientific procedures and principles), Administration (FDA) is proposing to In a set of findings of fact and a authorize the use, on food labels and in that there is significant scientific agreement, among experts qualified by tentative order on label statements for food labeling, of health claims on the special dietary foods that the agency association between sugar alcohols and scientific training and experience to evaluate such claims, that the claim is issued on July 19, 1977 (42 FR 37166), the nonpromotion of dental caries. In FDA addressed the issue of the use of addition, FDA is proposing to exempt supported by such evidence. Section 403(r)(3)(B)(ii) and the terms ‘‘sugar free,’’ ‘‘sugarless,’’ and sugar alcohol-containing foods from (r)(3)(B)(iii) of the act describes the ‘‘no sugar.’’ The agency stated that certain provisions of the health claims information that must be included in consumers may associate the absence of general requirements regulation. FDA is any claim authorized under the act. The sugar in a product with weight control proposing these actions in response to a act provides that the claim shall be an and with foods that are low calorie or petition filed by the National accurate representation of the that have been altered to reduce calories Association of Chewing Gum significance of the substance in affecting significantly. At that time, FDA viewed Manufacturers, Inc., and an ad hoc the disease or health-related condition, foods intended to be useful in working group of sugar alcohol and that it shall enable the public to maintaining or reducing calorie intake manufacturers (hereinafter referred to as comprehend the information and or body weight as foods for special the petitioners). understand its significance in the dietary use, that is, as foods intended for DATES: Written comments by October 3, context of the total daily diet. Finally, supplying particular dietary needs that 1995. The agency is proposing that any section 403(r)(4)(A)(i) of the act exist by reason of a physical, final rule that may issue based upon this provides that any person may petition physiological, pathological, or other proposal become effective 30 days FDA to issue a regulation authorizing a condition. following its publication. health claim. Evidence had been introduced at a ADDRESSES: Written comments to the The 1990 amendments, in addition to public hearing in the 1977 rulemaking Dockets Management Branch (HFA– amending the act, directed FDA to to show that the ‘‘sugarless’’ claim is 305), Food and Drug Administration, consider 10 substance-disease useful to identify foods like chewing rm. 1–23, 12420 Parklawn Dr., relationships as possible subjects of gum, which is in sustained contact with Rockville, MD 20857. health claims. the teeth, in which the use of a sweetener other than a fermentable or FOR FURTHER INFORMATION CONTACT: B. FDA’s Response Joyce J. Saltsman, Center for Food Safety cariogenic carbohydrate may not and Applied Nutrition (HFS–165), Food In the Federal Register of January 6, promote tooth decay. The secretary of and Drug Administration, 200 C St. SW., 1993 (58 FR 2478), FDA adopted a final the American Dental Association’s Washington, DC 20204, 202–205–5916. rule that implemented the health claim Council on Dental Therapeutics provisions of the act. In that final rule, supported the importance of advertising SUPPLEMENTARY INFORMATION: FDA adopted § 101.14 (21 CFR 101.14). and labeling sugarless chewing gum and I. Background The regulation sets out the mints as noncariogenic, in the sense that circumstances in which a substance is they did not contribute to the A. The Nutrition Labeling and eligible to be the subject of a health development of dental caries (Ref. 80). Education Act of 1990 claim (§ 101.14(b)), adopts the standard In the final rule on label statements On November 8, 1990, the President in section 403(r)(3)(B)(i) of the act as the for special dietary foods published in signed into law the Nutrition Labeling standard that the agency will apply in the Federal Register of September 22, and Education Act of 1990 (the 1990 deciding whether to authorize a claim 1978 (43 FR 43248), FDA required a amendments) (Pub. L. 101–535). This about a substance-disease relationship statement that a food is not low calorie new law amended the Federal Food, (§ 101.14(c)), sets forth general rules on or calorie reduced (unless it is in fact, Drug, and Cosmetic Act (the act) in a how authorized claims are to be made a low or reduced calorie food) when a number of important ways. One of the in food labeling (§ 101.14(d)), and ‘‘sugar free,’’ ‘‘sugarless,’’ or ‘‘no sugar’’ most notable aspects of the 1990 establishes limitations on the claim is made for the food. The agency amendments was that they confirmed circumstances in which claims can be decided to allow ‘‘useful only in not FDA’s authority to regulate health made (§ 101.14(e)). The agency also promoting tooth decay’’ as an claims on food labels and in food adopted § 101.70 (21 CFR 101.70), alternative statement to accompany labeling. As amended by the 1990 which establishes a process for such claims. The agency stated that the amendments, section 403(r)(1)(B) of the petitioning the agency to authorize statements that the food is not low act (21 U.S.C. 343(r)(1)(B)) provides that health claims about a substance-disease calorie or not useful for weight control, a product is misbranded if it bears a relationship (§ 101.70(a)) and sets out as well as ‘‘useful only in not promoting claim that characterizes the relationship the types of information that any such tooth decay,’’ were needed because the 37508 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules term ‘‘sugar free’’ meant only that the 60437), the agency stated that it Except for dietary supplements or where food was sucrose free. A ‘‘sugar free’’ intended to reevaluate the usefulness of provided for in other regulations in part 101, food could contain other fermentable chewing gums sweetened with sugar subpart E, the food contains 10 percent or carbohydrates. Thus, the information more of the Reference Daily Intake or the alcohols in not promoting tooth decay. Daily Reference Value for vitamin A, vitamin about the effect of sugar alcohol- The agency stated that the data C, iron, calcium, protein, or fiber per containing foods on the risk of supporting the claim were over 20 years reference amount customarily consumed developing dental caries was originally old and requested that new data be prior to any nutrient addition. placed on the food label primarily to submitted in accordance with the final II. Petition for the Noncariogenicity of clarify that the product was not rule on health messages. In the nutrient Sugarless Food Products Sweetened necessarily useful in weight control, not content claim final rule, FDA stated that With Sugar Alcohol to highlight the effect of sugar alcohol it had received data on the validity of on dental caries production. a claim about this nutrient-disease A. Background In the Federal Register of November relationship, and that it would make a On August 31, 1994, the petitioners 27, 1991 (56 FR 60421), in response to determination on whether to authorize a submitted a health claim petition to the 1990 amendments, FDA published a claim in accordance with the final rule FDA requesting that the agency proposed rule entitled ‘‘Food Labeling: on health claims (58 FR 2302 at 2326). authorize a health claim on the Nutrient Content Claims, General On February 5, 1993, under the relationship of sugar alcohols (i.e., Principles, Petitions, Definition of procedure established in section 701(e) xylitol, sorbitol, mannitol, maltitol, Terms’’ (the nutrition labeling general of the act (21 U.S.C. 371(e)), a group of lactitol, isomalt, hydrogenated starch principles proposal). In that document, sugar alcohol manufacturers submitted hydrolysates, and hydrogenated glucose FDA recognized that developments in an objection to the revocation of syrups) in sugarless foods to dental nutrition science had established that § 105.66(f) (Ref. 2) and asked for a caries (Ref. 1). On September 15, 1994, the focus of nutrient content claims for hearing on their objection. At the same FDA sent the petitioners a letter stating providing dietary guidance had shifted time, the group petitioned for that study reports that are needed to from special populations with particular reconsideration of the agency’s decision support the petition, and that are conditions to the general population and for a stay of any administrative required for a health claim petition (see 56 FR 60421). Therefore, in the action by FDA pursuant to the under § 101.70, were not included in the nutrition labeling general principles determination announced in the petitioners’ submission. The agency proposal, FDA proposed to treat several preamble of the nutrient content claims stated that no further action would be claims that had been subject to rules that ‘‘useful only in not promoting taken until that information was regulation in § 105.66 (21 CFR 105.66) tooth decay’’ is an unauthorized health received (Ref. 3). as special dietary use claims as nutrient claim. On September 27, 1994, the content claims for the general Filing objections to the revocation of petitioners filed an amendment to their population. To eliminate redundancy in § 105.66(f) stayed the effect of the final petition submitting the required the regulations and to conform § 105.66 information. On October 7, 1994, the to the 1990 amendments, FDA proposed rule as a matter of law. FDA’s response to these objections and to the petitions agency sent the petitioners a letter to define these claims in part 101 (21 acknowledging receipt of the additional CFR part 101) and to remove them from is set forth elsewhere in this issue of the Federal Register. information and stating that the agency part 105 (21 CFR part 105). Specifically, had begun its scientific review of the FDA proposed to adopt definitions for In the Federal Register of August 18, petition (Ref. 4). terms such as ‘‘low calorie’’ and 1993 (58 FR 44036), FDA published technical amendments to the health In this document, the agency will ‘‘reduced calorie,’’ for other comparative consider whether a health claim on the calorie claims, and for sugar claims claim regulations in response to comments that the agency received on relationship between sugar alcohols and under section 403(r)(2) of the act and to dental caries is justified under the codify them in § 101.60. It also proposed the implementation final rule that was published with the other final rules that standard in section 403(r)(3)(B)(i) of the to delete these claims from § 105.66. act and § 101.14(c) of FDA’s regulations. In the Federal Register of January 6, responded to the 1990 amendments in In addition, the agency will consider the 1993 (58 FR 2302), FDA published its January of 1993 (see 58 FR 2066, August petitioners’ request that the agency final rules on nutrient content claims. 18, 1993). One of the comments stated provide in any regulation authorizing a FDA adopted definitions for claims for that if a petition were submitted for the the calorie content of foods in § 101.60 claim ‘‘Useful Only in Not Promoting claim that foods sweetened with sugar (58 FR 2302 at 2415). FDA defined Tooth Decay,’’ virtually none of the alcohols be exempt from the claims regarding the sugars content of a sugar-free products on the market would requirement in § 101.14(e)(6). The food, e.g., ‘‘sugar free,’’ ‘‘free of sugar,’’ be eligible to bear the claim based on following is a review of the health claim ‘‘no sugar,’’ in § 101.60(c). In addition, the requirements of a subsection of petition. FDA published a final rule that deleted health claims general principles B. Preliminary Requirements these claims from § 105.66 (58 FR 2427). regulation, § 101.14(e)(6). FDA However, based on its consideration acknowledged that certain food 1. The Substances That Are the Subjects of comments on the use of the statement products of limited nutritional value of the Petition ‘‘useful only in not promoting tooth that have been specially formulated Sugar alcohols are a class of organic decay’’ to qualify the ‘‘sugarless’’ claim, relative to a specific disease condition, compounds that contain chains of FDA concluded that the statement was such as dental caries, may be carbon atoms that bear two or more actually an unauthorized health claim determined to be appropriate foods to hydroxyl groups and have only (58 FR 2302 at 2326). The claim is a bear a health claim (58 FR at 44036). hydroxyl functional groups (Ref. 1). The health claim because it characterizes the The agency commented that it was its hydroxyl groups replace ketone or relationship of a substance (sugar intention to deal with such situations aldehyde groups that are found in alcohols) to a disease (dental caries). within the regulations authorizing sugars (§ 101.9(c)(6)(iii)). The specific In the nutrient content claim general specific health claims. Therefore, FDA sugar alcohols that are the subject of this principles proposal (56 FR 60421 at amended § 101.14(e)(6) to state that: petition are xylitol, sorbitol, mannitol, Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37509 maltitol, maltitol syrup, maltitol equimolar mixture of the disaccharide The agency also points out, however, solution, isomalt, lactitol, and mixtures alcohols of ∝-D-glucopyranosyl-D- that some concerns about the safety of of sugar alcohol substances, i.e., sorbitol and ∝-D-glucopyranosyl-D- sugar alcohols do exist. For example, in hydrogenated glucose syrup (HGS) and mannitol. It is produced by treating a filing notice for the affirmation of the hydrogenated starch hydrolysate (HSH) sucrose with enzymes, followed by GRAS status of lactitol (58 FR 47746, products. hydrogenation of the resulting mixture. September 10, 1993), FDA stated that Xylitol is a monosaccharide ‘‘the agency’s notice of filing of GRASP 2. The Substances are Associated With polyhydric alcohol with a 5-carbon 2G0391 should not be interpreted either a Disease for Which the U.S. Population backbone. It occurs naturally in fruits as a determination, preliminary or is at Risk (e.g., plums, strawberries, and otherwise, that the issue of Leydig cell raspberries) and vegetables (e.g., Dental caries is recognized in The tumors has been resolved or that lactitol cauliflower and endive) (Refs. 82 and Surgeon General’s Report on Nutrition qualifies for GRAS affirmation.’’ Also, 83). Xylitol is made commercially by the and Health (Surgeon General’s report) by notice in the Federal Register of hydrogenation of D-xylose. as a disease or health-related condition December 13, 1994 (59 FR 64207), the Sorbitol is a monosaccharide for which the United States population agency announced the filing of a food polyhydric alcohol with a 6-carbon is at risk (Ref. 7). The overall prevalence additive petition (FAP 4A4412) to backbone. It is found naturally in many of dental caries imposes a substantial amend the interim food additive status types of berries and fruits and in burden on Americans. Of the 13 leading of mannitol to permit an alternate seaweeds and algae (Ref. 82). Sorbitol is health problems in the United States, method of manufacture. In this notice, made by hydrogenation of glucose. dental diseases rank second in direct the agency pointed out concerns about Mannitol is also a 6-carbon, costs (Ref. 7). data from studies on mannitol that monosaccharide polyhydric alcohol. It Based on this fact, FDA tentatively demonstrate a significant incidence of occurs widely in nature in plants (e.g., concludes that sugar alcohols meet the benign thymomas, and an abnormal pumpkins, mushrooms, onions, beets, requirement in § 101.14(b)(1). growth of thymus gland tissue, in celery, and olives), algae, and fungi. female rats fed mannitol. In addition, Like sorbitol, mannitol is made 3. The Substances Are Food the safety of sugar alcohols has been commercially by the hydrogenation of examined by the Federation of glucose. Sugar alcohols are used as Maltitol is a disaccharide alcohol (4– replacements for simple and complex American Societies for Experimental D-glucopyranosyl-D-sorbitol) with a 12- sugars as sweeteners and bulking agents Biology (FASEB) (Ref. 90), as well as carbon backbone. It is produced in foods (Ref. 1). Thus sugar alcohols are internationally by the Joint Expert commercially by hydrogenation of consumed for their taste and for their Committee on Food Additives (Ref. 91). maltose. effect as a stabilizer and thickener (21 The agency also notes that two of the Lactitol is also a disaccharide alcohol CFR 170.3(o)(28)). Therefore, FDA sugar alcohols that are listed in FDA’s (β-D-galactopyranosyl D-sorbitol) with a tentatively concludes that these food additive and GRAS regulations, 12-carbon backbone. It is produced by substances satisfy the preliminary i.e., mannitol (§ 180.25) and sorbitol hydrogenation of lactose (Ref. 84). requirements of § 101.14(b)(3)(i). (§ 184.1835), require a warning label regarding laxation if daily consumption HSH and HGS are mixtures of sugar 4. The Substances Are Safe and Lawful alcohols manufactured by of these sugar alcohols is expected to hydrogenation of corn starch or glucose Several of the sugar alcohols that are exceed 20 grams (g) per day for syrups. The composition of the sugar the subject of this proceeding are mannitol and 50 g per day for sorbitol. alcohols in the final product will currently listed in FDA’s food additive Nothing in this proposal alters these depend on the manufacturing process. and generally recognized as safe (GRAS) requirements. Therefore, HSH and HGS products from regulations, i.e., xylitol (21 CFR Based on the totality of the evidence, different manufacturers may contain 172.395), mannitol (§ 180.25 (21 CFR the agency is not challenging, at this different proportions of the same sugar 180.25)), and sorbitol (§ 184.1835 (21 time, the petitioner’s position that the alcohols. One HSH product, under the CFR 184.1835)). Moreover, GRAS use of sugar alcohols is safe and lawful. trade name ‘‘Lycasin,’’ was first affirmation petitions have been Although FDA tentatively concludes produced in Sweden by hydrogenation submitted for each of the remaining that the petitioner has satisfied the of potato starch. The Swedish product substances, i.e., maltitol (GRASP requirements of § 101.14(b)(3)(ii), the contained a mixture of sorbitol, maltitol, 6G0319), maltitol syrups (HGS syrups) agency requests comments on its maltotrititol, and hydrogenated (GRASP 3G0286), isomalt (GRASP tentative conclusion. dextrines of various molecular weights. 6G0321), lactitol (GRASP 2G0391), HSH III. Review of Scientific Evidence When the manufacturing process was (GRASP 5G0304) and HSH syrups moved to France in the 1970’s, the (GRASP 1G0375). A. Introduction production process was also changed The agency notes that these GRAS The development of dental caries is (Ref. 85). The French product, ‘‘Lycasin affirmation petitions are under the result of an interaction between 80/55,’’ was made from the consideration and that any positive sugars (and other fermentable hydrogenation of corn starch and action resulting from this proposed rule carbohydrates, such as refined flour) contained 6 to 8 percent sorbitol, 50 to should not be interpreted as an and oral bacteria in a suitable 55 percent hydrogenated disaccharides, indication that the agency has affirmed environment (Ref. 71). Microorganisms, 20 to 25 percent trisaccharides, and 10 those uses of the sugar alcohols as and Streptococcus mutans (S. mutans) to 20 percent hydrogenated GRAS. Such determinations can only be in particular, in dental plaque polysaccharides (Ref. 75). Lycasin 80/ made after the agency has completed its metabolize available dietary sugars, 55, or HSH 80/55, is less fermentable review of the GRAS petitions. A producing acid and sticky and produces less acid than the preliminary review of the GRAS polysaccharides that adhere to the tooth Swedish product (Ref. 85). affirmation petitions reveals that they as plaque. Acid produced from rapid Isomalt, also known by the contain significant evidence supporting and complete fermentation of sugars commercial name ‘‘Palatinit,’’ is an the safety of these substances. creates an acid environment within the 37510 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules plaque, characterized by a pH of usually fifth table provided a summary of foods containing no sugars, fermentable less than 5.0, that is capable of review articles. carbohydrates, or sugar alcohols. demineralizing tooth enamel and In addition to the information In the absence of studies that directly causing a carious lesion. submitted by the petitioner, the agency evaluate the nonpromotion of dental Studies designed to measure the considered other studies and reviews, caries by sugar alcohol-containing cariogenicity of a food assess the such as the reports on health aspects of foods, the agency gave the greatest potential to cause caries if it is sugar alcohols by the Life Sciences weight to those studies that evaluated in consumed in a standard way by a highly Research Office (LSRO) and the FASEB vivo the acidogenic potential of plaque susceptible subject (Ref. 8). The (Refs. 14 through 16). The agency also and plaque pH of sugar alcohols and methods used to measure cariogenic considered the results of additional sucrose in representative food systems potential include long-term controlled human epidemiological studies on (e.g., confectioneries and solutions). caries incidence and demineralization; human caries trials, in vivo and in vitro These in vivo measures can provide studies of animal caries; and in vitro plaque pH measurement, specific information about the effect of plaque pH studies. demineralization and remineralization sugar alcohols in the oral environment techniques, and rat caries models (Refs. 2. Criteria for Selection of Human and, more specifically, about the effect 8 through 11). Because long-term Studies of sugar alcohols on pH at the interface between dental plaque and tooth clinical caries trials are difficult to The criteria that the agency used to conduct, an integration of the plaque surfaces. The more acidic the select pertinent studies were that the environment on the tooth surface, the pH, animal caries, and demineralization studies: (1) Present data and adequate methodologies has been recommended greater the chance for enamel descriptions of study design and demineralization and caries formation. as the best measure for establishing the methods; (2) be available in English; (3) cariogenic potential of a food (Ref. 12). The agency also considered in vitro provide daily intakes of the sugar studies that measured plaque pH and Experts recommend, however, that these alcohol or enough information to methods be used with appropriate acid production of sugar alcohols in estimate their daily intakes; (4) include solution, and long-term caries trials that controls, such as sucrose, to assess in vivo or in vitro assessment of the experimental results (Ref. 13). evaluated caries development in a changes in plaque pH or plaque acid population using foods containing sugar Plaque acidity studies are useful in production; (5) for intervention studies alcohols and sucrose. Studies providing evidence on the effects of on caries development, be of no less investigating in situ the many microbial and physiological than 2 years (yr) in duration; and (6) be demineralization or remineralization of factors on the cariogenic potential of conducted in persons who generally enamel as a result of the action of sugar foods (Ref. 78). An acidic plaque represent the healthy United States’ alcohols on human dental plaque were environment at the tooth surface, population (adults or children). considered as supporting evidence by In selecting human studies for review, specifically a pH of less than 5.5, the agency. suggests microbial fermentation of a the agency decided that only those substrate resulting in microbial growth, studies investigating the use of sugar C. Human Studies alcohols in chewing gums and other plaque and acid production, and 1. Evaluation of Human Studies promotion of carious lesions from foods, including mouth rinses that enamel decalcification. Factors that can would be representative of beverages, FDA evaluated the results of studies modify these effects include the were appropriate for review. The agency against general criteria for good presence of promoters or inhibitors in excluded studies that were published in experimental design, execution, and food products that affect bacteria abstract form because they lacked analysis. The criteria that the agency growth, the nature of the acids produced sufficient detail on study design and used in evaluating these studies as a result of bacterial metabolism of methodologies, and because they lacked included appropriateness of subject food carbohydrates (Ref. 78), necessary primary data. In selecting selection criteria; adequacy of the intraplaque buffering, and the pH of animal and in vitro studies for review, description of the subject’s oral health mixed saliva (Ref. 74). the agency chose those studies that before intervention; extent of evaluation measured caries development, plaque of subject’s type of dental plaque (i.e., B. Review of Scientific Evidence pH, or acid production from plaque sticky or nonsticky, thick or thin); 1. Evidence Considered in Reaching the bacteria. methods of plaque collection; adequacy Decision of methods used to assess study 3. Criteria for Evaluating the endpoints (e.g., in vivo versus in vitro The petitioners submitted scientific Relationship Between Sugar Alcohols assessment of plaque pH); and other evidence on the various sugar alcohols and Human Dental Caries study design characteristics, including and their effects on plaque, plaque pH, The subject of the petitioned health randomization of subjects, and dental caries. This evidence claim is the nonpromotion of dental appropriateness of controls, report of included human (in vivo and caries by sugar alcohol-containing attrition rates (including reasons for epidemiological), animal, and in vitro foods, especially chewing gum and attrition), frequency of snack or studies regarding the association confectioneries. To support this claim, substance consumption, recognition and between consumption of sugar alcohols there needs to be significant scientific control of confounding factors (for from chewing gum and other foods and evidence to show that the sugar alcohol example, the subject’s use of fluoride plaque pH, acid production, plaque or sugar alcohol mixture, e.g., HSH, during the test period), and quantity and quality, bacteria levels, makes no contribution to the appropriateness of statistical tests and and the incidence of caries. The petition progression of dental carious lesions in comparisons. The agency also included four tables that summarized humans. It would be difficult, if not considered it desirable if information on the information for: (1) Human plaque impossible, to design and execute a treatment and control diets, the sugar and demineralization, (2) bacteriological study that would directly address this alcohol content of the test substance, studies, (3) animal experiments, and (4) issue because such a study would and daily sugar alcohol and nutrient human longitudinal and field studies. A require a control group that consumed intakes was available. Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37511

A review of the studies evaluating the sucrose. French HSH produced 20 to 40 production activity (APA) from dental effect of sugar alcohols on plaque pH percent and Swedish HSH 50 to 70 plaque suspended in glucose and each and acid production and of the in vitro percent of the acid produced by sucrose. of the four sugar alcohols was microbiological studies is provided in Birkhed et al. (Ref. 40) measured acid determined 1 wk before and 1 wk after Table 1. Table 2 provides a review of production in vitro and plaque pH the 3-mo consumption period. epidemiological studies evaluating the changes in vivo over a 30-min period The results with HSH showed that incidence of dental caries and studies following a 30-second(s) mouth rinse although plaque pH values differed on demineralization and with 10-percent glucose or sorbitol before and after the lozenge period, remineralization. solutions. To determine whether plaque differences were not statistically microorganisms can adapt to the significant, and that the lowest plaque 2. Summary of Evidence Relating Sugar presence of sorbitol, i.e., use it as a pH attained was above 6.0. In the Alcohol and Plaque pH or Acid source of energy like sucrose, with maltitol group, plaque pH before the Production repeated exposure to the sugar alcohol, lozenge period was higher than the pH Bibby and Fu (Ref. 38) measured investigators measured plaque pH and following the lozenge period. human plaque pH in vitro using 0.1-, acid production at the end of a 6-week Differences at 2, 10, and 30 min were 1.0-, or 10-percent solutions of the (wk) period. During the 6-wk period, statistically significant. However, there following sweeteners: Sucrose, HSH, each subject rinsed their mouth six were no significant differences in mannitol, isomalt, xylitol, isomaltulose, times per day for approximately 2 min plaque pH at any time compared to sorbose, saccharin, and aspartame. at a time with a 10-percent sorbitol baseline. The lowest plaque pH Results showed the lowest plaque pH solution. At the end of 6 wk, plaque pH recorded was about 6.9. Plaque pH in was attained with sucrose (1- and 10- was again measured for a 30-min period the xylitol group changed very slightly, percent solution: pH less than 5.0). following a mouth rinse with glucose remaining around pH 7. Plaque pH in Plaque pH decreased with increasing and sorbitol. The study results showed the sorbitol group was higher before concentrations of isomalt, sorbitol, acid production in the presence of than after the lozenge period. mannitol, and HSH. The lowest pH sorbitol, before adaptation, to be 11.3 Differences in pH at times 0 to 20 min attained for isomalt was about 5.6, for percent of that from glucose. After the and 0 to 30 min before compared with sorbitol 5.82, for mannitol 5.22, and for adaptation period, plaque acid after the test period were statistically HSH about 5.0. Negligible acid production from sorbitol increased to 30 significant (p<0.05). Final plaque pH production was measured from percent of the glucose rate. After the values after the 30-min test period were aspartame, saccharin, and xylitol. adaptation period to sorbitol, the between 6.7 and 7.0. There were no Solution mixtures of xylitol (5 to 20 glucose rinse produced mean plaque pH significant differences in plaque pH percent) and sucrose (10 percent) were values that were higher than before the between the test and control groups fermented to the same low pH as adaptation period. The differences in using any of the test rinses. sucrose alone. Thus, the presence of plaque pH, however, were only Comparing the APA results for each xylitol in a sucrose and xylitol mixture significant at 2 and 5 min following the sweetener with those for glucose did not affect acid production in plaque rinse. showed that HSH was 56 percent of that from sucrose. Overall results of this study suggest of glucose 1 wk before the lozenge The results of this study support the that sorbitol produces very little plaque period and 59 percent of that of glucose contention that xylitol does not promote acid. Mean plaque pH values after 1 wk after the lozenge period. The APA dental caries by lowering plaque pH sorbitol adaptation in the presence of for maltitol compared to glucose was 26 below 5.5. However, the results for the 10-percent sorbitol rinse showed percent (before) and 32 percent (after), sorbitol, mannitol, isomalt, and HSH do only a slight decrease from the baseline sorbitol was 15 percent (before) and 18 not support a ‘‘nonpromotion’’ claim. value. The differences in mean plaque percent (after), and xylitol was 0 percent The results suggest that when higher pH, compared to baseline, at 5, 10, 20, at both time periods. Differences before concentrations of these sweeteners are and 30 min following the rinse were and after each 3-mo lozenge period were present in food, the plaque pH may significant. The authors noted that the not statistically significant for any of the reach a level that will promote fermentability of sorbitol was more sugar alcohols. decalcification of dental enamel. pronounced after the adaptation period The results of this study suggest that Birkhed and Edwardsson (Ref. 39) than before. even though there is some acid measured plaque pH and acid Birkhed et al. (Ref. 41) studied the production from HSH, maltitol, and production of human plaque samples in effects on in vivo plaque pH and in vitro sorbitol, the effect on plaque pH in vivo solutions of mannitol, xylitol, maltitol, acid production from HSH (Swedish is not detrimental to tooth enamel. sorbitol, French HSH, Swedish HSH, HSH), maltitol, sorbitol, and xylitol. Frostell (Ref. 42) evaluated the effect fructose, and glucose syrups. Results Subjects in each group sucked on two on plaque pH of sugar solutions and showed that plaque pH in the presence lozenges a day, containing 0.5 g of one different types of candy and foods. of xylitol, maltitol, mannitol, and of the four sweeteners and 0.5 g of gum Although the focus of this study was not French HSH increased or slightly arabic, four times daily between meals sugar alcohols, the investigators used decreased from baseline (pH remaining (total of eight lozenges per day) for 3 sorbitol and HSH as a comparison to at 6.8 or above). Sorbitol showed a slight months (mo). Changes in plaque pH sucrose in some of the experiments. decrease in plaque pH, but the final pH over a 30-min period were measured in Plaque was collected prior to the test attained was about 6.0. The other each of the sugar alcohol groups after a period, and its pH was determined. sweeteners, including Swedish HSH, 30-s mouth rinse with a 50-percent Subjects then rinsed with a test solution depressed plaque pH below pH 6 over solution containing the same sweetener or ate a piece of candy or other food the 30-min (min) test period. The results as the lozenge. The rinse was used 1 wk being tested. Plaque was collected after of this study showed that mannitol and before and 1 wk after the lozenge 2, 5, 10, 20, and 30 min and its pH was xylitol produced no plaque acid period. A control group consumed no again measured. Sweeteners tested compared to sucrose. Maltitol and lozenges but rinsed with each of the included a sucrose rinse (concentrations sorbitol produced plaque acid at rates four sweeteners. At least 1 wk separated from 0.05 to 50 percent), sorbitol tablets that were 10 to 30 percent of that of each mouth rinse experiment. Acid (2 g sorbitol), sugar tablets (containing 37512 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules glucose and sucrose), HSH candy, sugar plaque pH of about 5.5, and a sucrose the influence of xylitol on glucose in candies (with sucrose, dextrose, and rinse with a plaque pH of about 4.5. growing cultures of S. mutans. Fresh maltose), marmalades (60-percent HSH The results of this study show that isolates of Streptococci and other strains or sucrose), and sugar-sweetened sponge food ingredients like soy flour can were obtained from caries free and cakes, ginger cakes, marshmallows, and contribute to the cariogenicity of a food caries active subjects. Acid production chocolates. Results with the sucrose regardless of the presence of a sugar in 1-percent solutions of glucose rinses showed that plaque pH decreased alcohol. (control), sorbose, sorbitol, xylitol, with increasing concentrations of Gallagher and Fussell (Ref. 44) lactitol, maltitol, and HSH was sucrose. compared the in vitro fermentability of determined by incubating the sweetener Comparing the effects on plaque pH xylitol and other sugar alcohols with in phenol red broth containing oral between the sorbitol and sucrose sucrose in dental plaque. Plaque bacteria. A color change indicated acid candies results showed that in the collected from adults and children of formation. Changes in pH was measured sorbitol group’s plaque pH increased different ages was incubated in broth after subculturing S. mutans in each of from about 6.5 (baseline) to 6.9 before culture. Acid production was measured the sweeteners, after frequent returning to baseline. Plaque pH as pH. The control media contained no subculturing in each sweetener to obtain decreased in the sucrose group from 6.5 added carbohydrates. adapted strains of S. mutans, and after The results of acid production (baseline) to about 6.0. After 10 min, the subculturing the adapted strains once in measurements showed that sucrose was pH in the sucrose group slowly glucose and resubculturing in the significantly more acidogenic compared increased to about 6.3. Differences in sweetener. Growth of S. mutans and pH to the control and xylitol. Differences plaque pH between the sorbitol candy measurements were also measured in a were significant. There was no and sucrose candy groups were glucose broth with and without added significant difference in acid production significant at all time periods. In the xylitol. between the control groups and the HSH candy group, plaque pH was The results showed no acid xylitol groups. significantly higher than that in the Gehring and Hufnagel (Ref. 45) production from xylitol or sorbose and group consuming sucrose candy. described intra- and extraoral pH acid production from sorbitol, lactitol, Differences were significant at all time measurements of dental plaque. Six and HSH. The authors stated that S. periods. The lowest plaque pH in the adult men and women rinsed for 2 min mutans slowly fermented maltitol. HSH group was above pH 6.3. The using one of seven test substances Results also showed no change in pH group consuming marmalade with HSH followed by intraoral plaque pH with xylitol and a moderate drop in pH experienced a drop in plaque pH to measurements after 3, 4, 5, 7, 9, 13, 17, to about 6 to 6.5 (actual values not about 6.0 (from 7.0) after 5 min, 21, 27, and 32 min. For the extraoral given) with maltitol, sorbitol, lactitol, followed by a gradual increase to a final test, visible plaque was removed, and HSH after 120 min. Adaptation by pH of about 6.5. The group consuming suspended in distilled water, and the S. mutans to the sweeteners resulted in sucrose marmalade experienced a pH measured at 3, 5, 7, 9, 11, 15, and a marked increase in fermentation, with plaque pH of about 5.3 after 5 min, 25 min after subjects rinsed with test final pH values dropping to about 4.5 to followed by a gradual increase in pH to substances. Test substances included 20 5.5. After one subculturing of the about 6.0. percent solutions of glucose, sucrose, adapted strain in glucose, S. mutans lost Toors and Herczog (Ref. 43) evaluated fructose, HSH, mannitol, isomalt, most of its ability to ferment the in vivo plaque pH and in vitro sorbitol, sorbose, or xylitol. sweeteners. The addition of small fermentability of an experimental The results of the intraoral plaque pH amounts of xylitol to glucose broth (nonsucrose) licorice in a pooled measurements showed only slight pH somewhat inhibited acid production plaque-saliva mixture. Fermentability decreases within 5 min after from S. mutans, but it had no effect on (i.e., acid production) of the test administration of xylitol and mannitol, final pH attained. substrates was expressed as a percentage with a return to baseline measures at the Jensen (Ref. 47) measured of the sucrose licorice. Plaque was end of the 32-min test period. Sorbitol, interproximal plaque pH in subjects collected from 12 volunteers on the day HSH, isomalt, and sorbose reached a using five different HSH’s and sorbitol after they consumed 10 pieces of the minimum pH just below 6.0 after 5 min and sucrose as controls. Four subjects candy. In vivo plaque pH was measured followed by a slight increase to about rinsed with a 5 milliliter (mL) portion during and after consumption of licorice pH 6.1 to 6.4 at the end of the test of the test solution for 60 min. Plaque by means of pH telemetry. Substrates period. Sucrose, glucose, and fructose pH was then monitored for 30 min. used in the above tests included sucrose showed a minimum pH value of about Following the pH measurements, the licorice, the experimental licorice, 4.6 to 4.7 (after 5 min) with an increase subject rinsed their mouth with distilled components of the experimental licorice to about pH 5.3 to 5.5 at the end of 32 water and chewed paraffin for about 5 (including sorbitol, potato starch min. Minimum plaque pH by extraoral min to bring oral pH back to resting derivative, soy flour, and others), measurements were higher than the pH levels. The test was repeated with each xylitol, hydrogenated potato starch according to intraoral measurements. subject using each of the four test (HPS) (a type of HSH), and a white Sucrose, glucose, and fructose minimum solutions. bread suspension. Results showed the pH values ranged from about 5.0 to 5.7 The results showed that plaque pH for fermentability of the test substrates to be after 5 min and increased to about 5.6 all test substances remained above pH as follows: Potato starch derivative (82 to 6.0 after 32 min. Other pH values 6.0 over the 30-min test period. Plaque percent), soy flour (75 percent), sorbitol were not given. The authors attribute pH using the sorbitol rinse was similar (12 percent), experimental licorice (68 the differences in intra- and extraoral to that using the test substances. Using percent), xylitol (5 percent), HPS (60 plaque pH measurements to methods in the sucrose rinse resulted in plaque pH percent), and white bread suspension handling plaque removal and the measurements of approximately 4.0 to (79 percent). In vivo plaque pH results influence of saliva substances. 4.1. The identity of the test substances showed sucrose licorice with a Havenaar et al. (Ref. 46) evaluated in was not provided in this unpublished minimum plaque pH of about 5.0, vitro acid formation from oral bacteria study. Results indicate that the HSH experimental licorice with a minimum in the presence of sugar substitutes and solutions used in this study were Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37513 significantly less acidogenic than attributed the additional buffering percent). The APA from HSH was also sucrose and no different than sorbitol. effects of the sorbitol and xylitol mint to significantly lower (p<0.01) than that Maki et al. (Ref. 48) compared acid the presence of xylitol and its potential from soluble starch. The range of production in vivo from isomaltulose, benefits in reducing plaque microbial optimum acid production for both sorbitol, xylitol, and sucrose (control) in activity. Without a sucrose-containing substrates was 0.03 to 6 percent. The human dental plaque. Dental plaque mint as a comparison, however, the authors noted that Swedish HSH is was collected from 12 individuals and influence of sugar alcohols on saliva more fermentable than French HSH, incubated with phosphate buffer. After production cannot be adequately which contains less high molecular endogenous acid production was assessed. weight hydrogenated saccharides than measured, a 1-percent solution of the So¨derling and coworkers (Ref. 50) Swedish HSH. test substance in the same buffer was investigated the effect on dental plaque Grenby et al. (Ref. 76) evaluated the added, and acid production measured of chewing gums that contained either dental properties of lactitol compared to again. xylitol, sorbitol, or a mixture of xylitol five other bulk sweeteners, i.e., sucrose, The results showed no acid and sorbitol and compared the results glucose, sorbitol, mannitol, and xylitol, production in the presence of xylitol. with those obtained with subjects who in vitro using a standardized mixed Compared to sucrose (100-percent acid used sucrose gums. Twenty-one subjects culture of dental plaque production), acid production from (adults, ages 19 to 35 yr) who were not microorganisms. Sweeteners were sorbitol was 1 percent. The authors habitual gum chewers were randomly incubated for 24 hours (h) in media noted that the percent acid production assigned to chew gum containing either containing a 1-percent solution of one of from sorbitol may vary considerably xylitol, sorbitol, or a blend of the two the six sweeteners. Plaque among individuals and with the amount sugar alcohols for 2 wk. Subjects microorganisms were also incubated in of exposure to sorbitol. chewed 10 pieces of gum per day for an media containing the sweeteners with Park et al. (Ref. 49) measured intake of either 10.9 g xylitol, 10.9 g segments of intact surfaces or with interproximal plaque pH in five subjects sorbitol, or 10.9 g xylitol and sorbitol segments of pulverized dental enamel. after consuming one of three snacks (8.5 g xylitol and 2.4 g sorbitol). The The demineralization action of the acid alone or one of three snacks followed by control group was made up of seven produced by microbial fermentation was a single mint containing sorbitol (94 habitual sucrose gum users. Subjects assayed by calcium and phosphorous percent) or a sorbitol and xylitol blend maintained their usual diets and oral analyses. (79 percent and 15 percent, hygiene except just before to clinic The greatest amount of acid respectively). When mints were used, visits. Interdental plaque pH was production and lowest pH (significantly they were consumed 3 min following collected, and the resting plaque pH different than the sugar alcohols) were ingestion of the sweet snack. Snacks determined. Plaque pH was measured at reported with sucrose and glucose (pH tested included a sandwich cookie, 2, 5, 10, 15, and 20 min after an oral of 4.0 to 4.3). Lactitol and xylitol cupcake, and granola bar. A randomized rinse containing the same sugar alcohols showed only slight changes in pH and block design was used to administer the as used in the gum. Afterward, subjects acid production over the 24 h (final pH test products and mints (see Table 2 for rinsed with water and chewed a piece of 6.1 to 6.3); whereas sorbitol and further details). The lowest plaque pH of paraffin for 1 min to expedite removal mannitol showed slight changes in pH attained after consuming the three test of sugar alcohols from the mouth. during the first 12 h (pH≥6), then products without mints ranged from Baseline pH was again measured, gradually decreased to a final pH of 4.6 4.02 to 4.16. When the sorbitol mint was followed by a mouth rinse with 10 mL to 5.1 after 24 h. consumed following the test product, of 10-percent sucrose. Plaque pH was The results of the demineralization mean plaque pH values increased and again determined. test showed highly significant ranged from 4.68 to 5.04. When the The results from using gum for 2 wk differences (p<0.001) between sucrose sorbitol and xylitol mint was consumed showed no significant changes in resting and glucose and the sugar alcohols. The following consumption of the test plaque pH in the xylitol and xylitol and reductions in calcium and phosphorous products, mean plaque pH increased to sorbitol groups, whereas the use of dissolving in sorbitol was a range of 5.32 to 5.60. Differences in sorbitol gum was associated with a approximately 80 to 85 percent, mean plaque pH values between the lower pH. Final plaque pH values after mannitol 63 to 69 percent, and lactitol mint products differed significantly use of sorbitol gum were significantly and xylitol 94 to 98 percent compared when the mints were used after the lower than baseline values, but all final to mineral loss in the presence of granola bar and cupcake challenges. values remained above pH 6.0. glucose. There was no significant difference in Birkhed and Skude (Ref. 51) mean plaque pH between the sorbitol evaluated, among other tests, the APA 3. Summary of Evidence Relating Sugar (5.04) and the sorbitol and xylitol mint from glucose, soluble starch, and Alcohol and Dental Caries: Long-Term (5.60) products when these products Swedish HSH in dental plaque. Eleven Studies were used after the sandwich cookie adults were instructed to avoid oral Mo¨ller and Poulsen (Ref. 20) challenge. hygienic procedures for 2 days. No determined the effect of long-term The results show that consumption of dietary changes were required. At the chewing of sorbitol chewing gum on the a sugarless mint reduced the end of 2 days, plaque was collected. The incidence of dental caries, plaque, and acidogenicity of the test snacks, APA was determined from 3-percent gingivitis. The sorbitol chewing gum although final pH values remained solutions of glucose, boiled soluble contained calcium phosphate which below pH 5.5 in all but one test. The starch, and HSH. The APA was also acts as a buffer in saliva to help authors attributed the results of this determined in increasing concentrations maintain pH and aid remineralization. study to the stimulatory effects on (0.003 to 12 percent weight per volume Two groups of children, ages 8 to 12 yr salivary flow by sugar alcohols. (w/v)) of starch and HSH. of age, from two different schools in Increasing salivary flow increases the The results showed significantly Denmark took part in this 2-yr study. buffering capacity of saliva, thus lower (p<0.001) APA from soluble Group 1 chewed one piece of sorbitol- reducing the acidogenic potential of a starch (75.7 percent) and HSH (61.5 containing gum three times a day, after variety of snack foods. The authors also percent) compared to glucose (99.7 meals. Group 2 chewed no gum and 37514 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules served as the control. At the start of the Rather, an entire class was assigned to second premolars in the xylitol group. study, subjects in group 1 had more one of the three groups. The XYL65 This trend was not observed in the decayed and filled toothsurfaces than group consumed 3.4 g xylitol per day, sucrose group. Results of these studies the control group; however, the and the XYL15 group consumed 0.8 g support the observation that xylitol is differences were not statistically per day. less cariogenic than sucrose. significant. The results showed significantly In a World Health Organization The results showed that the sorbitol lower net progression of decay (NPD) (WHO) field trial in Hungary (Ref. 26), group had a significantly lower (i.e., the difference in the number of the effects of a partial substitution of incidence of dental caries compared to reversals from the progressions of decay sucrose for xylitol in the diets of 689 the control after 2 yr. The control group, for each child) in the XYL65 group institutionalized children, ages 6 to 11 which did not chew gum, did not (1.25) than in XYL15 group (1.87) (p< yr, were examined. The xylitol group experience the same salivary 0.05), and each xylitol group had used fluoride dentifrice and consumed stimulation from the chewing of gum, significantly (p<0.001) lower NPD than no more than 20 g of xylitol per day in nor did they have an equivalent source the control. The decayed, missing, filled chewing gum, chocolate, hard candy, of calcium phosphate. These are large surfaces (DMFS) increment was also and wafers. The fluoride group received confounders in this study. The authors significantly lower in the xylitol groups fluoride in dentifrice, water, and milk, noted a number of factors that could compared to the control. There was no but consumed no xylitol products. The contribute to the observed results, such significant difference in DMFS between control group received no fluoride as the sorbitol content of the chewing the gum groups. Results of this study treatment and consumed no xylitol- gum, reduced consumption of sugar- suggest that chewing gum containing containing products. After 3 yr, the containing sweets, intra-examiner xylitol or a blend of xylitol and sorbitol xylitol group had a statistically variability, and other unknown provided more benefits for teeth than significant (p<0.001) lower incidence of conditions. not chewing gum at all. caries compared to the control and Ba´no´zcy et al. (Ref. 21) evaluated the Rekola (Ref. 23) compared the fluoride groups. The authors noted that effect of sorbitol-containing sweets on progression of incipient carious lesions results from this study were obtained the caries increment of children aged 3 on buccal smooth surfaces in subjects under conditions where caries to 12 yr, in a clinical longitudinal study participating in the 2-yr Turku sugar prevalence and incidence were still planned for 3 yr. The test group study (Ref. 24). Subjects consumed high. Results of this study support the consumed 8 g of sorbitol per day either a diet containing sucrose or one observation that xylitol-containing between meals, while the control group with almost complete replacement of products are less cariogenic than consumed a similar amount of sucrose- sucrose products with xylitol-containing sucrose-containing products. containing sweets. products. The progression of carious In a 2-yr substudy (Ref. 28) of the The results showed that mean lesions were assessed by use of color WHO xylitol field studies in Hungary decayed, missing, or filled (DMF) values dental photographs of the right and left (Ref. 26), Scheinin and coworkers for teeth in the sorbitol group were 1.09, sides and of the front of maxillary and assessed the caries increment with 0.90, and 1.18 in the first, second, and mandibular teeth. systemic fluoride (fluoride group) and third yr, respectively. The sucrose group The results showed that the sucrose restorative treatment only (control had mean DMF values of 2.61, 1.86, and group had a significant tendency for group). This study differed from the 3- 1.13 for the first, second, and third yr, increased size of carious lesions over yr study primarily in baseline respectively. The differences in caries the 2-yr period compared to the group differences. Children entering the increments were significant (p<0.001) in consuming xylitol (p<0.01). The white institutions during the first yr of the 3- the first and second yr but not in the spot lesions in the xylitol group were yr study were included in this substudy. third yr. The authors noted that the lack significantly smaller than those in the The substudy showed similar of significance in the third yr may be sucrose group. favorable results with xylitol compared attributed somewhat to a lack of subject Rekola (Ref. 25) quantified changes in to the control. The caries increment was compliance since the children in the the size of approximal carious lesions in 3.8 in the xylitol group, 4.8 in the sorbitol group traded sweets with the subjects after 2 yr of almost complete fluoride group, and 6.0 in the control sucrose group, in addition to other substitution of dietary sucrose with group. The differences in caries factors. Results of this study indicate xylitol (Ref. 23). Bitewing radiographs increment between the xylitol group that sorbitol is less cariogenic than were taken during the 2-yr study. In this and the other two groups were sucrose. study, the radiographs were projected significant (p<0.001). Results again Kandelman and Gagnon (Ref. 22) onto a planimetry plate so that the area supported a lower incidence of caries reported on the incidence and of the lesions could be determined. The when xylitol is substituted for sucrose progression of dental caries in school sizes of the lesions at the different time in the diet. children after 12 mo of a 2-yr study periods were compared, and the rate of In a WHO field trial in Thailand and using xylitol in chewing gum. The caries progression was also compared. French Polynesia (Ref. 29), the subjects were 433 children, ages 8 to 9 At the beginning of the study, there was usefulness of a fluoride rinse, yr old, from 13 elementary schools, and no difference in the mean size of carious fluoridated sucrose chewing gum, and were from low socioeconomic areas lesions between groups. The size of the fluoridated xylitol (51 percent) and with a high caries rate. The children approximal lesions, i.e., lesions that sorbitol gum in controlling dental caries were assigned to one of three groups: A were neither filler nor overlapping at 0 was evaluated in children over a 3-yr control group that received no chewing and 24 mo, in the sucrose group period. In French Polynesia, a fourth gum and chewed no gum while at increased significantly (p<0.001) over 2 group used nonfluoridated chewing school, a test group that received gum yr compared to the lesions in the xylitol gum sweetened with xylitol (51 percent) containing 15-percent xylitol and 50- group. The lesion size in the xylitol and sorbitol. Approximately 250 percent sorbitol (XYL15), and a second group remained virtually unchanged. children at each of the ages 6 to 7 yr, test group that received gum containing The authors reported a trend towards 9 to 10 yr, and 12 to 13 yr were 65-percent xylitol (XYL65). Students decreasing lesion size in canines and examined. The 12- to 13-yr age group were not randomly assigned to groups. first molars compared to molars and was intended to provide data for Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37515 comparison with the 9- to 10-yr old in addition to HSH candy. The score of 2.70 for sucrose. These group, who would be ages 12 to 13 yr consumption of HSH candy was differences were significant. In the at the end of the study. reported from 50 to 75 percent of the animal study, one group was provided The results from the Thailand study total candy consumption. a feed with 26-percent maltitol and 30- showed that the fluoridated xylitol and The results showed no significant percent starch, a second group was sorbitol gum group had lower decayed, differences in caries scores after 11⁄2 to provided a feed with sucrose instead of missing, and filled teeth (DMFT) and 21⁄2 yr with HSH candy consumption maltitol, and a third group consumed a DMFS scores than either the fluoride compared to sucrose candy diet without sucrose. Results showed a rinse group or the fluoridated sucrose consumption. When investigators caries score of 45.8 for the sucrose gum group. Results from the French analyzed the data of those children group, 3.2 for the maltitol group, and 5.2 Polynesia study showed that the whose parents consumed the correct for the no-sucrose group. Differences subjects started with much higher candy for their group, the differences in between the sucrose group and the other DMFT and DMFS mean scores initially caries increment between the groups groups were statistically significant. than the subjects in Thailand. Although were still not significant but showed a Yagi (Ref. 34) evaluated the effects of the results with the fluoride gum trend towards a lower incidence of maltitol on changes in enamel hardness. sweetened with the sugar alcohols were caries in the HSH group. The results of Enamel decalcification was measured better than any of the other treatments, this study were confounded by poor using an ICT with a denture containing the overall caries incidence in this compliance, inter-examiner variability, two bovine enamel slabs. Four subjects population is very high. The presence of lack of blinding, and inconsistent wore the dentures for 7 days. Each day, fluoride in the chewing gums confounds results and do not support significant one enamel slab was exposed to a 3- the results of the sugar alcohols. The dental benefits from the use of HSH. percent maltitol solution and the other authors describe this study population Glass (Ref. 32) evaluated the to a 3-percent sucrose solution. Enamel as a community experiencing an cariogenicity of sorbitol chewing gum hardness was measured at the end of the increase in the prevalence of the with regular use by children, ages 7 to wk. disease. This study group does not 11 yr old, living in a nonfluoride area. The results showed that the average reflect the general population of the In this 2-yr study subjects were change in hardness compared to United States. randomly assigned to either a no- pretreatment levels for the enamel in In another WHO field trial, chewing group (control) or to the one maltitol was 1.47 micrometers Kandelman and coworkers (Ref. 30) which chewed gum twice daily. compared to 3.35 micrometers for the evaluated the effects of xylitol Subjects in the gum group were enamel in sucrose. Differences between intervention on dental caries in French provided two sticks of gum daily for use the two measurements were significant. Polynesian children, ages 7 to 12 yr. Of at school and four sticks of gum for use The authors noted that there were 746 subjects enrolled in this 32-mo at home when school was not in considerable differences in individual study, 468 completed the study. session. responses to sucrose and maltitol. They Subjects in the xylitol groups consumed The results showed that over the 2-yr attributed these differences to the oral 20 g of xylitol daily in various food study period, mean caries increments environment (e.g., plaque bacteria and products, such as chewing gum, hard were 4.6 new decayed and filled (DF) quality and quantity of saliva). candy, chocolate, and gumdrops. The surfaces for the sorbitol gum group However, general observations were that control group received no xylitol- (n=269) and 4.7 new DF surfaces for the sucrose causes significant loss of containing products. no-gum group (n=271). The difference enamel, as evidenced by changes in The results showed significantly between the groups was not statistically enamel hardness, compared to the effect reduced caries increment rate by 37 significant. Although the results of this of maltitol on tooth enamel. percent to 39 percent in the xylitol study suggest that adding sorbitol- Leach et al. (Ref. 35) evaluated in situ groups compared to the controls. This containing gum to the diet did not result the effect on remineralization of study was neither randomized nor in any additional dental caries, the artificial caries-like lesions in human blinded. Results support the observation effect of chewing gum per se on the enamel with sorbitol. Ten adult subjects that xylitol-containing products are less incidence of dental caries was not wore cast bands containing enamel on cariogenic than the sucrose-containing considered. one lower first molar tooth for two 3-wk products. periods during which they continued to Frostell and coworkers (Ref. 31) 4. Summary of Evidence Relating Sugar use normal oral hygiene procedures. determined the effect on caries Alcohol and Dental Caries: Short-Term Artificial caries lesions were made in increment in children, ages from 21⁄2 to Studies each enamel slab and covered with 4 yr, of substituting HSH for sucrose in Ikeda et al. (Ref. 33) evaluated the gauze to encourage the formation and candy. During this 11⁄2- to 21⁄2-yr study, cariogenicity of maltitol and a accumulation of plaque on the enamel subjects in the test group consumed polysaccharide alcohol using an surface. Subjects were given snack foods candies made with HSH and chewing intraoral cariogenicity test (ICT) and rat (chocolate bar, raisins, cream-filled gum made with sorbitol. The control tests. Most of the details of the methods wafers, and cream-filled, iced cupcake) group consumed sucrose candies and used in the ICT were not provided, and instructed to consume one each gum. Investigators monitored the intake making the results difficult to interpret. morning and afternoon between meals. of candies by use of coupons which the Bovine enamel fragments were During the first experimental period, parents used at local stores to buy the extraorally dipped in 3-percent subjects chewed, for 20 min each, five candy. An analysis of the coupons used solutions of sucrose (control), maltitol, sticks per day of commercial sugarless showed that parents of the children in or the polysaccharide alcohol for 1 min gum after meals and snacks. The gum the test group used a smaller number of every day. After 1 wk, hardness was was sweetened primarily with sorbitol coupons than the parents of the children measured. The higher the value for and small amounts of mannitol, HGS, in the control group. Based on inquiries, hardness means a softer enamel and a and aspartame. During the second the investigators discovered that the greater loss of enamel. experimental period, snacks were parents of the subjects in the HSH group The results showed a decalcification consumed but without chewing gum had also given the children other candy score for maltitol of 1.66 compared to a (control). 37516 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules

The results showed statistically Artificial enamel lesions were created in attrition, and inability to blind the significant (p<0.001) remineralization vitro in sound human enamel and study. The majority of these trials during both experimental periods mounted for wearing just opposite the compared sucrose consumers to compared to the original lesion. The lower first and second molars. Baseline individuals who had partial or complete difference between the remineralization mineral contents were measured. substitution of sugar alcohols for with and without gum was also Subjects used a fluoridated dentifrice sucrose. The results consistently significantly different (p<0.01), twice daily and maintained their regular demonstrated significantly fewer caries indicating overall promotion of diets. Six subjects chewed five sticks of in the group consuming sugar alcohols remineralization by gum chewing. The chewing gum containing sorbitol and than in the group consuming sucrose. authors attributed the remineralization some HGS and aspartame after each Although the relationship between during the nongum period to the meal and snack. The gum was chewed some of the sugar alcohols and presence of gauze used with the for 20 min in order to minimize any promotion of dental caries has not been intraoral device to collect plaque. The deleterious effects of sucrose. Six other well studied in humans, it is becoming gauze could have concentrated calcium subjects received no gum and served as increasingly evident that sugar alcohols, and phosphates from the diet in plaque the control. At the end of 7 wk, the test when substituted for sucrose and other and fluoride from dentifrice. It is not subjects became the control group, and fermentable carbohydrates, may provide known what effects the duration and the control subjects became the new test important dental health benefits for the timing of the gum chewing had on the group. The new test group then chewed consumers of those products. results. Without a comparison to sucrose-containing gum for 7 wk. D. Animal Studies sucrose-containing gum and a The results showed that after using nonsweetened gum, it is not possible to sugar-free gum for 7 wk, the degree of FDA reviewed over 20 animal studies evaluate the effect of chewing gum for mineral loss for the enamel investigating the effects of sugar alcohol 20 min. corresponded to a remineralization consumption on the incidence of dental Rundegren et al. (Ref. 36) evaluated in value of 18.2 percent. After 7 wk of caries or on the acidogenic potential of situ the effect on demineralization of chewing sucrose gum, the percent dental, S. mutans, or mixed oral sucrose substitutes in a 4-wk test. remineralization was calculated to be microorganisms. Most of the animal Intraoral devices containing bovine 18.3 percent. The difference between studies that have been done to test the enamel mounted on acrylic blocks were the sorbitol and sucrose gum groups was effect of sugar alcohols on the incidence used with group 1. Partial dentures with not significant. Results of this study of caries were programmed feeding enamel slabs were used with group 2. suggest that chewing gum for 20 min, studies using weanling rats. The Sweeteners tested included 10 percent regardless of the sweetener, can be animals were usually divided into solutions of sucrose, maltitol, and HSH. beneficial to dental health. groups and fed diets containing Sucrose was used as the positive A common problem in studies different test sweeteners. The control control, and 0.9-percent solution of evaluating the dental health benefits of diets were either a basal diet with no sodium chloride was used as a negative sugar alcohol-containing chewing gum carbohydrate sweeteners or sugar control. Subjects immersed the test sites is the absence of an appropriate control substitutes or a basal diet with added of their appliances in the test sweetener group. Most of the studies that have sucrose. The test diets were four times a day for a 10-min period. been done use a control group that does administered over a period of weeks, Plaque was collected at the end of 4 wk not chew gum. Ideally, to evaluate the increasing the sugar substitute and plated to determine the content of relationship of sugar alcohol-sweetened concentration slowly to allow the S. mutans. The degree of chewing gum in not promoting dental animals time to adapt to the specific demineralization was measured by caries, the control group would chew an sweetener and to minimize the severity evaluating changes in microhardness of unsweetened gum product. Such a of diarrhea, a side effect of sugar alcohol the enamel. The buffering capacity of group is needed to take into consumption that increases with whole saliva was evaluated weekly by consideration the effects of chewing increasing concentration of the sugar measuring final pH in a mixture of 1 mL gum itself on the endpoint measure, e.g., alcohol. of saliva and 3 mL of sodium chloride. plaque pH or plaque acid production. Investigators also evaluated the The results showed a higher degree of Chewing gum is known to stimulate general health and growth of the demineralization overall in the adults saliva, which can help neutralize oral animals during the experimental period. (ages 56 to 59 yr) using the partial acids, raise plaque pH, and help to Many animals, and rats in particular, do dentures compared to students (age 19 promote enamel remineralization in not like the taste of sugar alcohols and, yr) using an intraoral device. Results some circumstances. It would be therefore, will eat less of the test diet from the test (n=4) of enamel considered unethical by standards in and increase their intake of water. Most microhardness in HSH versus sodium the United States to use a control group investigators monitored the animals’ chloride suggest that HSH does not that chews sucrose-containing gum and, total dietary intake to ensure that contribute to demineralization, and that as a consequence, puts the subjects at consumption patterns were similar measured changes in microhardness risk of dental disease, in order to between the control and test animals. reflected the background of fermentable compare the incidence of dental caries A potential confounding factor in carbohydrates in the diet. Comparing to that from a sugar alcohol-containing these studies is the effect of total food the differences in microhardness of gum. and water intake on caries development. enamel slabs between the sucrose and The few long-term caries field trials If animals consume less of a sugar HSH diets and the sucrose and maltitol that were submitted with this petition alcohol diet compared to the control diets showed that sucrose results in show how multiple problems in the animals consuming a sucrose diet, any significant demineralization compared execution of clinical studies can easily significant differences in caries to the sugar alcohols. confound the results. Problems often incidence may actually be attributable Creanor et al. (Ref. 37) evaluated the include subject compliance, reporting to the differences in food and water effect of chewing gum for 20 min on in and control of dietary intake, selection consumption and not to an effect of the situ enamel lesion remineralization of appropriate control foods, inter- and sugar substitute. Some studies reported compared to a fluoridated dentifrice. intraexaminer variability, subject a lower survival rate in animals on the Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37517 sugar alcohol diets. This finding made Havenaar and coworkers (Ref. 55) fed Mu¨ hlemann and coworkers (Ref. 58) interpretation of the results more one group of rats a basal diet containing compared the cariogenicity of diet 2000 difficult because of uneven group sizes. 20-percent sucrose, 5-percent glucose, (containing 64-percent wheat flour) to In order to promote the cariogenic and 25-percent starch. The test group the same diet containing xylitol or process, the animals were inoculated received the basal diet with 20-percent sorbitol (15 percent and 25 percent of with either mixed strains of plaque starch and 5-percent xylitol and the flour replaced) or sucrose (15 bacteria or purified strains of S. mutans fluoride. After 54, 75, or 96 days, rats percent and 25 percent of the flour and other microorganisms found in were crossed over to the other diet for replaced). Sweetener mixtures dental plaque. Experimental periods an additional 21 to 42 days. Results containing 15-percent sucrose and 15- lasted, on the whole, for 60 to 70 days. showed that the xylitol group had percent xylitol or sorbitol and 25- These periods included the time given significantly fewer fissure caries than percent sucrose and 25-percent xylitol for the animals to adapt to the test diets. the sucrose group. The authors also or sorbitol were also substituted for the Havenaar et al. (Ref. 52) fed S. mutans reported that the longer the flour ingredient of the basal diet. The inoculated rats one of six diets 18 times experimental period, the more severe rats consuming diets with 15- and 25- a day: The basal diet plus 50-percent the caries, irrespective of the presence percent sucrose experienced 17.3 and starch, or the basal diet plus 30-percent of xylitol. After crossover, total numbers 17.8 smooth surface caries, respectively. starch and 20 percent of either sucrose, of caries did not change, but the xylitol Rats consuming animal chow with 15- HSH’s, xylitol, sorbitol, or L-sorbose. In group showed significantly fewer initial percent xylitol or sorbitol experienced a second experiment, the rats were fed lesions compared with the mean caries 0.0 and 1.9 smooth surface caries, the same diets 14 times a day and incidence in the sucrose group on day respectively. The caries score for the alternated with the basal diet containing 54. control group was 4.9. The highest 20-percent sucrose and 10-percent Grenby and Colley (Ref. 56) fed a number of fissure caries (11.3) occurred glucose (four times a day). In both control group of rats a cariogenic diet in the 25-percent sucrose group. The experiments, the starch, HSH, xylitol, containing 46-percent sucrose and fed control group had 5.1 lesions. and L-sorbose groups showed two test groups the same cariogenic diet Substituting xylitol (25 percent) in the significantly less fissure lesions than the either with 20 percent of the sucrose diet resulted in fewer caries (0.2) sorbitol and sucrose groups. The replaced with xylitol, sorbitol, mannitol, compared to the control, but differences sorbitol group showed significantly less or wheat starch (experiment A). The were not significant. Twenty-five animals consuming sorbitol and fissure caries in the mandibular molars percent sorbitol in the diet produced a mannitol did not remain healthy during with respect to the severity of the caries score of 2.8. the experiment, so this part of the Shyu and Hsu (Ref. 59) evaluated the lesions compared to the sucrose group. experiment was terminated. The cariogenicity of 10-percent xylitol, Havenaar et al. (Ref. 53) in five animals consuming xylitol also mannitol, sorbitol, and sucrose in rats successive experiments, fed rats ad experienced difficult health effects at fed a plain basal diet. A control group libitum on diets containing sucrose or first but later improved and were was fed the basal diet without HSH 80/55. In each experiment, the rats returned to the 20-percent xylitol diet. sweetener. Caries evaluations were were inoculated with plaque from rats In experiment B there were only two made on the 45th and 90th days of in the previous experiment (Ref. 52). diets: A cariogenic diet with 46-percent feeding. The xylitol group had 86 Results showed that compared to sucrose and an experimental diet with percent fewer caries (significant) sucrose, HSH was relatively 10 percent of the sucrose in the diet compared to the sucrose group and 76 noncariogenic. The incidence of fissure replaced with xylitol. percent fewer caries than the control. caries in the mandibular molars for rats In experiment A, significantly fewer The mannitol group experienced 70 and consuming 20-percent sucrose was 13.1, caries were experienced only in the 51 percent fewer caries than the sucrose whereas the fissure caries incidence in group consuming the sucrose and and control groups, respectively. The rats consuming 20-percent HSH was 1.5 xylitol diet compared to the control sorbitol group experienced 48 and 14 to 2.5 (p<0.001). group. In experiment B, the level of percent fewer caries than the sucrose Havenaar et al. (Ref. 54) evaluated the caries was high for both the sucrose and control groups, respectively. usefulness of diets for testing the caries group and the sucrose and xylitol group. Bramstedt et al. (Ref. 60) evaluated promoting or inhibiting properties of The overall caries scores were not the cariogenicity of isomalt, xylitol, and sugar substitutes. The investigators fed significantly different. sucrose in 60 rats divided into five two groups of rats experimental diet Karle and Gehring (Ref. 57) evaluated groups. The control diet was a basic diet 2000 containing 50-percent sucrose and the effect of sugar alcohols and sucrose containing half synthetic feed. Another 14-percent starch or 50-percent sucrose, on both xerostomized (salivary glands control group received a special basic 9-percent starch, and 5-percent xylitol removed) and nonxerostomized rats. diet containing no low molecular weight for a period of 42 days. Results showed The control group consumed a basal carbohydrates. The test groups received no significant differences in caries diet without sweetener. Test groups the basic diet with increasing doses of incidence between the sucrose starch, received the basal diet plus sucrose, sweetener up to 30 percent of the diet. the xylitol group and the sucrose and xylitol, isomalt, or other sweeteners. The sucrose group had a significantly starch group. In another experiment Sweetener concentrations were higher number of caries than either of animals were fed diet SSP 20/5 increased over a 3-wk period to a level the sugar alcohol groups. The group containing 20-percent sucrose, 5-percent of 30 percent of the diet. The consuming the special basic diet had the glucose, and 25-percent starch or 20- xerostomized rats had more caries with lowest incidence of caries. There were percent sucrose, 5-percent glucose, 20- all substances than the nonxerostomized no significant differences in the number percent starch, and 5-percent xylitol for rats. Sucrose was shown to be the most of caries between the basic diet, xylitol, a period of 66 days. Results showed the cariogenic sweetener, and xylitol the and isomalt groups, although the xylitol, sucrose, and starch group to least cariogenic, in the nonxerostomized isomalt group showed a slightly higher have significantly fewer caries (12.3 rats. Both the xylitol and isomalt groups incidence of caries. caries versus 14.8) compared to the had significantly fewer caries than the Izumiya et al. (Ref. 61) fed rats 10 or sucrose, starch, and glucose group. sucrose group. 20 percent by weight of sweeteners in 37518 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules feed. Rats consuming a dietary feed containing 56 percent sucrose, was used The results of experiment 3 showed containing 10-percent maltitol had as a control ration. Sucrose substitutes significantly (p<0.001) fewer smooth significantly fewer caries than the used in at least one of the experiments surface caries in groups receiving potato sucrose group. Details of this study and included glucose, fructose, mannitol, starch, fructose, sorbitol plus starch, the results were not given in this sorbitol, potato starch, starch/sucrose dextrose plus fructose, dextrose, and reference. mixtures, or HPS (contains sorbitol and hydrogenated starch compared to the Gehring and Karle (Ref. 62) evaluated hydrogenated dextrins). In the first sucrose group. The overall results the cariogenic properties of isomalt, in experiment each group was fed diet showed that reducing the exposure to comparison to those of sucrose and 2000 for a few days, then they were sucrose results in fewer carious lesions. xylitol in the basal diet of conventional changed to one of the diets containing Mu¨ hlemann (Ref. 65) tested the effects and gnotobiotic (i.e., specially reared a sucrose substitute. Each test diet was of topical applications of sugar laboratory animals in which the fed for 7 out of every 14 days followed substitutes on caries incidence and microflora are specifically known) rats. by rotation back to the control diet. The bacterial agglomerate formation in rats The final concentration of sweetener in diets were changed every 2 or 3 days receiving a cariogenic diet containing the feed was 30 percent. A second according to a predetermined schedule. 20-percent sucrose. Sweeteners tested experiment was performed using A second experiment was designed to (50 percent w/v) included the following: isomalt, xylitol, sorbitol, and sucrose in determine the effect of feeding the Sucrose, mannitol, GPS, GPM, isomalt, chocolate. The basal diet constituted 40 sucrose diet after the period of bacterial sorbitol, maltitol, and French HSH. percent of the total diet, and the implantation on diets containing Three control groups were used: (1) One chocolate constituted 60 percent. The sucrose substitutes. The animals group received the cariogenic diet (20- isomalt group had significantly fewer consumed one of the test diets the first percent sucrose) and no topical caries than the sucrose group, and the week while being inoculated with S. applications, (2) the second group xylitol group had significantly fewer mutans, followed in the final 7 wk by received a topical application of water caries than the isomalt group. The the control diet containing sucrose. A with the cariogenic diet, and (3) the second experiment showed significant third experiment was designed to third group was treated topically with differences in caries experience after the determine the effect of feeding sucrose chlorhexidin digluconate (0.5 percent) T (initial caries lesions) and B and sucrose-substitute diets as a positive control. Topical solutions (advanced caries) stages between the intermittently after the period of were applied five times a day for 23 sucrose and sorbitol chocolate groups, bacterial implantation on the sucrose days. the sorbitol and isomalt chocolate diet. The animals consumed diet 2000 Among the carbohydrates treatments, groups, and also between the isomalt the first wk, followed in the final 7 wk the isomalt, GPS, and GPM groups had and xylitol chocolate group. The order by diets containing the sugar the lowest incidence of fissure and of cariogenicity of the test substances substitutes. smooth surface caries. The differences, was sucrose greater than (>) sorbitol > The results of the first experiment however, between the caries incidence isomalt > xylitol > control. An in vitro showed significantly (p<0.001) fewer in these three groups and the other test microbiological experiment was smooth surface caries with all sugar groups were not statistically significant. performed to test acid production alcohols, potato starch, dextrose, and The incidence of caries in the capacity of plaque microorganisms in 10 hydrogenated starch compared to the chlorhexidine control group was percent solutions of isomalt, sucrose group. Significantly (p<0.05) statistically significantly lower than all glucopyranosido mannitol (GPM), fewer sulcal caries were experienced in treatment groups. The control groups glucopyranosido sorbitol (GPS), sorbitol, the groups receiving mannitol, sorbitol receiving no application and water both mannitol, sucrose, and fructose. GPS plus starch, potato starch, and HPS experienced slightly more caries than and GPM are the two components that compared to the sucrose group. The the sugar alcohol groups. Results of make up isomalt. Sucrose produced acid authors observed that in all of the these studies suggest that in the rapidly and had the greatest acid experiments, every group in which presence of a cariogenic diet, topical formation. Sorbitol and mannitol sucrose was restricted, whether by application of mannitol, isomalt, produced acid slowly, and isomalt and dietary substitution or by shortened sorbitol, maltitol, or HSH does not affect its two components had practically no feeding periods, developed significantly the promotion by sucrose of dental acid production in vitro. fewer caries on smooth surfaces caries in rats. Karle and Gehring (Ref. 63) evaluated compared to the sucrose control Ooshima et al. (Ref. 66) evaluated the the cariogenicity of isomalt in rats. Six animals. The animals in the mannitol, cariogenicity of maltitol in rats infected groups of rats received the basic diet sorbitol plus starch, and sorbitol groups with S. mutans. Animals were divided without low molecular weight consumed less food during the test into 12 groups. Group A received a carbohydrates in addition to xylitol, period compared to the sucrose control diet containing 56-percent sorbose, isomalt, lactose, and sucrose. controls. The authors stated that food wheat flour. Groups B through L The control group received only the consumption and weight gains were received the same diet as the control basic diet. Sweetener concentrations directly related to the incidence of group but had portions of the wheat were increased slowly up to 30 percent caries. flour replaced with one of the test by weight of the basic feed. The highest The results of experiment 2 showed substances. The sweeteners tested were number of fissure caries were caused by significantly (p<0.001) fewer smooth as follows: 10-percent maltitol plus 46- sucrose (about 33) followed by lactose surface caries in groups fed percent wheat flour (group B), 20- (25), isomalt (about 13), sorbose (about hydrogenated starch, potato starch, percent maltitol plus 36-percent wheat 12), xylitol (about 7) and the control (5). dextrose, fructose, sorbitol plus starch, flour (group C), 10-percent sucrose plus Differences in caries incidence between dextrose plus fructose compared to the 46-percent wheat flour (group D), 10- the sucrose and the other groups were sucrose group. Groups receiving HPS, percent sucrose plus 10-percent maltitol significant. fructose, and sorbitol plus starch plus 36-percent wheat flour (group E), Larje and Larson (Ref. 64) fed rats a experienced significantly (p<0.001) 20-percent sucrose plus 36-percent caries diet, diet 2000, to which various fewer sulcal caries compared to the wheat flour (group F), 20-percent sweeteners were added. The caries diet, sucrose group. sucrose plus 20-percent maltitol plus Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37519

16-percent wheat flour (group G), 24- Mukasa (Ref. 69) evaluated the slightly, but not significantly, higher percent sucrose plus 32-percent wheat cariogenicity of maltitol and SE58 in than in the wheat flour group. The flour (group H), 24-percent sucrose plus rats. Product SE58 is a highly purified incidence of caries was lowest in the 16-percent maltitol plus 16-percent corn starch treated with enzyme and xylitol group. wheat flour (group I), 28-percent sucrose hydrogenated. It contains 20- to 25- In a twofold experiment using caries- plus 28-percent wheat flour (group J), percent sorbitol, 20- to 30-percent active rats, Grenby and Phillips (Ref. 77) 28-percent sucrose plus 12-percent maltitol, 15- to 25-percent maltotrititol, evaluated: (1) The cariogenicity of maltitol plus 16-percent wheat flour and 30- to 40-percent maltopentaitol. In lactitol, sucrose, and xylitol at a level of (group K), or 40-percent sucrose plus experiment one, three groups of rats 160 g per (/) kilogram (kg), a level stated 12-percent wheat flour (group L). were fed diet 2000 containing either 56- to approximate the average sucrose The results of this study showed that percent sucrose, maltitol, or SE58, content of the diet in developed the maltitol did not induce dental caries among other ingredients. Because the countries, and (2) the cariogenicity of in groups B and C compared to the rats consuming the maltitol and SE58 lactitol in a sweet biscuit compared to wheat flour alone (group A). Groups A, diets experienced serious growth a sucrose-sweetened biscuit. In the first B, and C experienced significantly problems, experiment one was experiment, the sweetener was (p<0.001) fewer caries than the sucrose discontinued. In experiment two, the incorporated into a laboratory chow group (group L). Groups D through I and level of all sweeteners in diet 2000 was containing white flour, skim milk K reported significantly (p<0.001 and reduced to 26 percent, with the powder, liver powder, and a vitamin- p<0.01, respectively) fewer caries than remaining 30 percent as added corn mineral supplement. In the second part group L. There was no significant starch. The sucrose group had a mean of the experiment, biscuits, containing difference in caries score between group fissure caries score of 31.5 and a smooth 166 g of lactitol/kg, were incorporated J (equal parts sucrose and wheat flour) surface caries score of 14.1. The maltitol into the animal chow for a final and group L. Thus, this study suggests group had 3.1 fissure caries and no concentration of lactitol of 110 g/kg. that replacing sucrose with less smooth surface caries. The SE58 group Animals were fed the diets for a period cariogenic sweeteners or wheat flour had 4.6 fissure caries and 0.5 smooth of 8 wk. Experiment 1 showed highly results in fewer dental caries in rats. surface caries. Differences between the significant differences in caries score, Tate et. al. (Ref. 67) reported on the sucrose group and each sugar alcohol total number of lesions, and severity of correlations between progressive caries group were significant. lesions in the sugar alcohol groups Van der Hoeven (Ref. 70) evaluated and sugar intake in hamsters inoculated compared to the sucrose controls. The the cariogenicity of isomalt in rats. Test with S. mutans. Animals were fed a diet sugar alcohol groups had very few diets consisted of a base diet containing with 10-percent sucrose (group 1), 20- caries, and differences between groups 16-percent sucrose and 44-percent percent sucrose (group 2), 10-percent were not significant. The animals in wheat flour and a base diet with 16- sucrose plus 10-percent maltitol (group both the xylitol and lactitol groups percent isomalt and 44-percent wheat required several weeks to adapt to the 3), 10-percent sucrose plus 10-percent flour. The control diet consisted of 60- coupling sugar (group 4), 10-percent diets, showing increased water intake percent wheat flour and no added and decreased food intake. Because of maltitol (group 5), or 10-percent sweetener. Diets were offered ad libitum coupling sugar (group 6). Group 2 poor physical condition, only 11 of the over a period of 14 wk. Results showed 22 rats in the xylitol group completed experienced the most caries. There was increasing incidence of dentinal fissure no significant difference in caries score the full 8-wk test. Animals on the lesions in the sucrose group (wk 2 = 4; sucrose diet were significantly heavier between group 1 and groups 3 and 4. wk 14 = 14 lesions) and almost no caries Groups 5 and 6 had significantly than the sugar alcohol animals. in the isomalt group (wk 2 = 0; wk 8 = Results of the second test showed (p<0.01) fewer caries than groups 1 or 4; wk 14 = 1 lesion). There was no 2. This reference did not provide highly significant differences between difference in the incidence of caries the lactitol- and sucrose-biscuits groups sufficient details regarding the between the isomalt and the control methodology and analysis of results for in all caries parameters. The average groups. caries score for the lactitol group was purposes of evaluating the weight of the Van der Hoeven (Ref. 73) evaluated less than one per animal. Weight gains, results. the cariogenicity of lactitol in program- however, were consistently lower, and Leach and Green (Ref. 68) fed two fed rats. The sweetener was water intake increased in the lactitol groups of rats a basal diet supplemented incorporated into a powdered diet, group. with sucrose plus 3-percent xylitol or 6- described by Havenaar et al. (Ref. 54), The results of the above animal percent xylitol. The control group consisting of a basic part (50 percent), studies show that animals fed sugar consumed the basal diet with sucrose. wheat flour (25-percent), and test alcohols in animal chow had fewer and In experiment 1, rats were continuously substance (25-percent). Lactitol was less extensive caries than animals fed fed the same diet during the compared with sorbitol, xylitol, sucrose, sucrose. The studies also show that, in experimental period. In experiment 2, and a control with wheat flour in general, rats do not eat as much of a rats were fed diets alternating between addition to the basic part. The animals the control diet one day and the test diet received 9 g of diet divided into 18 sugar alcohol-containing diet as a the next day. In experiment 1, rats fed portions of 0.5 g each per day. The sucrose-containing diet and, therefore, the sucrose and 6-percent xylitol animals on the xylitol and sorbitol diets tend to gain less weight and have more mixture had significantly (p<0.02) fewer were reported to experience reduced physiological problems. fissure caries than the control. There weight gains and a reduced appearance E. Summary of Human and Animal were no significant differences in the of the fur. None of the animals suffered Studies xylitol mixture groups. In experiment 2, from diarrhea. both xylitol mixture diet groups had There were significantly fewer caries 1. Xylitol significantly (p<0.001) fewer fissure in the xylitol, lactitol, sorbitol, and In its 1978 review of the studies on caries than the control. There were no wheat flour groups compared to the xylitol, FASEB concluded that xylitol significant differences among the xylitol sucrose group. The incidence of caries appeared to be noncariogenic in studies mixture groups. in the lactitol and sorbitol groups was evaluating the effect of sucrose 37520 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules replacement with xylitol and in studies always significantly higher than that of evidence of adaptation of oral flora after evaluating the effect of partial sucrose or glucose. long-term use of sorbitol-containing replacement of sucrose with xylitol in Twelve animal studies (Refs. 52, 54, products. FASEB noted that a human chewing gum (Ref. 14). However, 56 through 60, 62, 63, 68, 73, and 77) population that regularly consumes FASEB concluded that it was essential evaluated the effects of xylitol on dental sorbitol-containing foods, such as jams that these studies be replicated by other caries in rats or hamsters. Eight of these and jellies, baked goods, or other food workers in order to confirm the (Refs. 52, 57 through 60, 62, 63, and 77) products, has not been identified and observations and conclusions. used a test diet that contained only one studied to establish whether sorbitol Rekola (Refs. 23 and 25) conducted a sweetener, either sucrose or xylitol. In significantly alters the carious process. followup assessment of results from the all of these studies, there were Two studies submitted with the 2-yr Turku sugar study evaluating the significantly fewer caries reported in petition evaluated the cariogenicity of progression of incipient carious lesions animals consuming the basal diet with sorbitol in chewing gum (Refs. 20 and and lesion sizes on buccal smooth xylitol compared to sucrose controls. 32), and one study (Ref. 35) evaluated surfaces with dietary substitution of The incidence of caries was also the effect of sorbitol in chewing gum on xylitol for sucrose. In the 2-yr Turku significantly less in the xylitol group demineralization of enamel. Mo¨ller and sugar study, dietary xylitol was almost compared to animals consuming isomalt Poulsen (Ref. 20) reported an increased completely substituted for sucrose. (Ref. 63) and sorbitol (Ref. 52). The number of sound tooth surfaces and a Subjects were assigned to groups based concentrations of xylitol in the test diets smaller caries increment rate in children on individual preference. Rekola ranged from 10 percent up to 30 percent consuming sorbitol gum containing examined color dental photographs, by weight. calcium phosphate compared to the taken during the 2-yr study, of 33 Results of the animal studies control group that did not consume subjects in the sucrose group and 47 evaluating the effect of xylitol in diets chewing gum. However, the presence of subjects in the xylitol group. The xylitol containing sucrose (Refs. 54, 56, 68, and calcium phosphate, which acts as a group showed significantly smaller 73) showed mixed results depending on buffer in saliva to help reduce its the concentrations of sucrose and xylitol white spot lesions and had a acidity, and the absence of gum chewing in the test diets. Havenaar et al. (Ref 54) significantly lower caries score in the control group, confound these showed no significant difference in compared to the sucrose group. observations. caries in animals consuming a diet with Glass (Ref. 32) reported no significant Results of several more recent human sucrose and 5-percent xylitol, but a differences in the number of DF surfaces caries studies (Refs. 22, 26, and 28 significant difference in caries when the or teeth in children using sorbitol through 30) reported significantly fewer sucrose was lowered to 20-percent of chewing gum for 2 yr compared to a no- caries in the xylitol group compared to the diet and xylitol 5-percent. Grenby the sucrose group. Kandelman and and Colley (Ref. 56) reported a high gum group. This study, however, did Gagnon (Ref. 22) reported significantly caries level in animals consuming either not consider the effect of chewing gum less NPD and incidence of DMFT in a diet containing 46-percent sucrose or per se on dental caries. school children chewing three sticks per 36-percent sucrose and 10-percent Leach et al. (Ref. 35) conducted an day of xylitol gum (3.4 g) or xylitol and xylitol. The caries score was intraoral test in subjects fitted with sorbitol gum (0.9 g xylitol and 2.4 g significantly lower in rats consuming a bands containing human enamel with sorbitol) compared to the nongum diet with 26-percent sucrose and 20- artificial white spot lesions. The control group. Results of xylitol field percent xylitol compared to the 46- subjects consumed sucrose-containing studies in Hungary (Refs. 26 and 28), percent sucrose diet. An in vitro snacks. During one of the test periods, French Polynesia (Refs. 29 and 30), and microbiological test showed no acid the subjects chewed gum containing Thailand (Ref. 29) conducted by WHO production by S. mutans from xylitol. sorbitol with small amounts of showed lower caries incidence and Van der Hoeven (Ref. 73) reported mannitol, HGS, and aspartame, for 20 caries increment rate in children significantly fewer caries in rats min at a time after each meal and snack. consuming xylitol and sorbitol in consuming a diet with 25-percent The study showed significantly more chewing gum (Ref. 29) and xylitol in xylitol compared to the rats consuming remineralization during the sorbitol other snack foods (Ref. 30) compared to a basic diet with 25-percent sucrose. gum period compared to baseline and a nonsugar alcohol group. However, The xylitol group also had fewer caries the no-gum (sucrose) period. Results of results of the gum study in French than the wheat flour control group. this study are confounded, however, Polynesia and Thailand (Ref. 29) were because of the duration (i.e., 20 min) confounded by the presence of fluoride 2. Sorbitol and timing (i.e., immediately after meals in the gums tested. In addition, the In its March 1979, review of sorbitol and snacks) of the gum chewing. In prevalence and incidence of dental in health and disease (Ref. 15), FASEB addition, the effect of sorbitol alone caries in these population groups were reviewed available animal and human cannot be determined because of the high and increasing and do not reflect studies regarding the cariogenicity of presence of other sugar alcohols and the general healthy population of the sorbitol. FASEB concluded that the aspartame in the test gum. United States. weight of evidence from animal studies Ba´no´czy et al. (Ref. 21) reported a The effect of xylitol on acid suggests that sorbitol is less cariogenic significantly lower caries increment in production or plaque pH was studied in than sucrose, fructose, glucose, and children consuming sorbitol-containing ten studies (Refs. 38, 39, 41, 43 through dextrin. Based on the human studies sweets between meals compared to 46, 48, 50, and 76). In nine of these published in the early to mid-1970’s, children consuming sucrose-containing (Refs. 38, 39, 41, 43 through 46, 48, and FASEB noted that the results do not sweets between meals over a 2-yr 50), xylitol was found to result in provide definitive data on the effect of period. Differences between groups negligible to no acid production with sorbitol on the caries process. It noted were not significant during the third yr little to no change in plaque pH. that the results of studies on plaque pH of this study, however, the authors Similarly, results showed no significant suggest that sorbitol is slowly fermented attributed the lack of significance during effect of xylitol on resting plaque pH. to plaque pH levels of about 6. It also the third yr to the trading of sweets Plaque pH from exposure to xylitol was said that some studies have provided between groups. Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37521

Twelve studies evaluated changes in other sugar alcohols was lost after Results of plaque exposed to a 20- plaque pH after exposure to sorbitol- subculturing once in glucose. percent mannitol solution showed the sweetened mouth rinses (Refs. 39 Results of animal studies evaluating minimum pH obtained was slightly through 41, 45, and 47), solutions (Refs. sorbitol (Refs. 35, 52, 58, 59, 62, 64, and above 6.0. The plaque samples in these 38, 46, and 76), tablets (Ref. 42), mints 73) showed significantly fewer caries in two studies were not concentrated as (Ref. 49), chewing gum (Ref. 50), and the sorbitol group than in the sucrose they were in the study by Bibby and Fu licorice (Ref. 43). Plaque pH changes in group. However, use of sorbitol resulted (Ref. 38) or by Grenby et al. (Ref. 76), the presence of sorbitol decreased from in more caries compared to animals which may account for the differences baseline pH but remained consuming other sugar alcohols, such as in plaque pH values reported for approximately at or above a pH of 6.0 xylitol and HSH (Refs. 52, 64, and 73). mannitol solutions. The results of one (Refs. 39 through 42, 45 through 47, and The concentration of sorbitol in these other in vitro microbiological study, 50). Bibby and Fu (Ref. 38) reported studies ranged from 10 percent up to 56 with 10-percent mannitol and an progressively decreasing plaque pH percent. incubation time of 48 h (Ref. 62), values in vitro with increasing 3. Mannitol support the observation that mannitol is concentrations of sorbitol in a fermented very slowly, resulting in little concentrated plaque suspension. Only In its August 1979, review of mannitol acid production and small pH changes. slight decreases in pH were reported in in health and disease, FASEB (Ref. 16) Animals fed mannitol (Refs. 59 and 0.1- to 1.0-percent solutions. In the reviewed available animal and human 64) or maltitol (Refs. 66, 67, and 69) presence of a 10-percent sorbitol studies regarding the effect of mannitol showed significantly fewer caries solution, plaque pH dropped to about on acid production, plaque pH changes, compared to animals fed sucrose diets. 5.8. Grenby et al. (Ref. 76) reported a pH and changes in microhardness of bovine The concentrations of the sugar alcohols of about 6.0 after 12 h and a final pH enamel in an ICT. It noted that human in these studies ranged from 10 to 56 in vitro of about 4.6 after 24 h of plaque studies in vivo or in vitro found percent. An in vitro microbiological incubating concentrated plaque with 10- that plaque pH decreases from 0 up to study (Ref. 62) showed that a 10-percent percent sorbitol. The results of these 1.0 units over a 30-min test period. solution of mannitol was fermented very studies suggest that higher FASEB concluded that the results were slowly. consistent with the results of animal concentrations of sorbitol may lead to 4. Maltitol further decreases in plaque pH to a level experiments showing that mannitol, in that may become detrimental to tooth the absence of adaptation of the oral Three studies (Refs. 33, 34, and 36) enamel (i.e., at or below pH 5.5). microflora, is less cariogenic than measured the effects on enamel Park et al. (Ref. 49) found that use of sucrose. decalcification of maltitol and sucrose sorbitol mints or mints with a blend of Bibby and Fu (Ref. 38) measured in solutions using an ICT with bovine sorbitol and xylitol helped reduce the vitro plaque pH changes, over a 20-min enamel fragments adhered to a partial acidogenic potential of certain snack incubation period, in the presence of denture. Ikeda and coworkers (Ref. 33) foods, although final pH values increasing concentrations of mannitol showed significantly more remained low. Toors and Herczog (Ref. (0.1-, 1.0-, and 10-percent decalcification in the presence of 43) showed that plaque pH is affected concentrations) in a concentrated sucrose as compared to maltitol. by more than the sweetener component plaque suspension. Results showed that Additional rat caries tests were in of a food. Results of plaque pH in vivo plaque pH decreased with increasing agreement with the results of the ICT. with an experimental licorice, concentrations of mannitol. Final Rats fed a diet with maltitol had containing sorbitol, soy flour, and plaque pH values were 5.67, 5.54, and significantly fewer caries than the potato starch derivative among other 5.22, respectively. Similar plaque pH sucrose group. In this study maltitol was ingredients, showed a minimum pH of values were reported by Grenby et. al. almost noncariogenic. Yagi (Ref. 34) about 5.5. A sucrose-containing licorice (Ref. 76). Results of the Grenby study reported significantly harder enamel used in this study lowered plaque pH to showed that a 1-percent solution of after exposure to maltitol than after about 5.0. The fermentability of both the mannitol, when incubated for 24 h with exposure to sucrose. Lack of details in potato starch derivative (82 percent) and concentrated plaque and pieces of a this study, however, make it difficult to soy flour (75 percent) contributed to the human molar tooth, resulted in slight completely interpret the results. observed changes in plaque pH in the acid production and pH decrease over a Rundegren (Ref. 36) reported experimental licorice. The 12-h period, but that after 24 h, the final significantly less enamel fermentability of sorbitol in the pH was about 5.1. However, results from demineralization with maltitol experimental licorice was 12 percent. an in vitro demineralization test showed compared to sucrose. The authors Five studies (Refs. 39 through 41, 43, very little loss of calcium and associated the changes that they and 48) measured the APA of plaque phosphorus, significantly less than the observed in enamel hardness in the with sorbitol. In all cases, sorbitol was loss of minerals with glucose. maltitol group with the effects of other fermented slowly with a reported range Results of other studies, however, dietary carbohydrates and not maltitol. of acid production of 10 to 30 percent show that mannitol results in little Sucrose was found to exert an effect on compared to sucrose or glucose. The change to plaque pH. Birkhed and enamel hardness that is not related to higher acid production rate (i.e., 30 Edwardsson (Ref. 39) reported only the effects of other dietary percent) was attributed to adaptation to slight changes in plaque pH following carbohydrates. sorbitol by S. mutans and other plaque use of a mouth rinse with a Three studies (Refs. 39, 41, and 46) microorganisms capable of fermenting concentrated solution of mannitol. In evaluated plaque pH or acid production carbohydrates. Havenaar et al. (Ref. 46) addition, they reported an acid in maltitol. Birkhed and Edwardsson also reported a marked increase in production rate from mannitol in dental (Ref. 39) measured in vitro acid fermentation of sorbitol and other sugar plaque suspension of 0 percent production and pH changes in human alcohols after multiple subculturing of compared to sucrose (100 percent). dental plaque following the use of plaque microorganisms with the sugar Gehring and Hufnagel (Ref. 45) used various sweeteners in a mouth rinse. alcohol. However, the investigators intraoral measurements to evaluate the The results with maltitol showed an reported that adaptation to sorbitol and effect of sugar alcohols on plaque pH. acid production rate of 10 to 30 percent 37522 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules of that of sucrose. Changes in plaque pH xylitol group and the wheat flour Eight studies measured plaque pH in the presence of maltitol showed only control group and fewer caries than the changes from exposure to HSH in a slight decrease from baseline pH sorbitol group. There was no significant solutions (Refs. 38 and 46), rinses (Refs. (about pH 6.9). difference between the caries score in 39, 41, 45, and 47), and candy (Refs. 42 Birkhed et al. (Ref. 41) measured in animals fed lactitol-containing or and 43). Bibby and Fu (Ref. 38) showed vivo pH changes in human dental xylitol-containing chow (Ref. 77). There that as the concentration of HSH plaque after subjects consumed lozenges were significantly fewer caries in increased, plaque pH decreased. The sweetened with various sweeteners for 3 animals fed lactitol-containing biscuits lowest plaque pH value (10-percent mo and then rinsed with a mouth rinse compared to the sucrose biscuit group solution of HSH) obtained was about sweetened with the same sweetener as (Ref. 77). The average caries score in the 5.0. Havenaar et al. (Ref. 46) showed in the lozenge. A sucrose mouth rinse lactitol biscuit group was less than one that a 1-percent solution of HSH was was also used by each sweetener group. per animal. fermented by S. mutans and Results with maltitol showed small, but Actinomyces. Cell suspensions of S. 6. Isomalt some significant, changes in plaque pH mutans in HSH showed a pH decrease compared to baseline pH (about pH 7.0) Two studies investigated the effects from a baseline of about pH 7.0 to about over the 30-min test period. The lowest on plaque pH with isomalt (Refs. 38 and pH 6.5. Adaptation of S. mutans by plaque pH recorded, however, was 45). Bibby and Fu (Ref. 38) measured pH frequent subculturing in HSH showed a about pH 6.8. In vitro acid production changes in fresh plaque from adult marked increase in fermentation by S. with maltitol was found to be about 26 volunteers with increasing mutans to give a plaque pH of slightly to 32 percent of glucose. concentrations of isomalt. Results below 6.0. However, the ability to Havenaar et al. (Ref. 46) measured showed that as the concentration of the ferment the sugar alcohol was lost after changes in pH and acid production in sugar alcohol increased, the pH of the one subculturing of the adapted strain vitro in growing cultures of oral bacteria plaque decreased. The range of plaque in glucose. obtained from caries active and caries pH values reported for isomalt was from Birkhed and Edwardsson (Ref. 39) free subjects. Results showed that a 1 6.6 (0.1 percent solution) to measured plaque pH in vitro following percent solution of maltitol was slowly approximately 5.7 (10-percent solution). the use of a mouth rinse containing fermented to acid by plaque bacteria. Gehring and Hufnagel (Ref. 45) reported Swedish or French HSH. French HSH Cell suspensions of S. mutans in a minimum plaque pH of about 6.0 after appeared to have little effect on plaque maltitol showed pH decreased from a 5 min with isomalt. This value pH. Plaque pH values remained slightly baseline of about pH 7.0 to about pH increased gradually over the next 27 below or at 7.0. Swedish HSH showed 6.5. Adaptation of S. mutans by frequent min to about pH 6.3. As discussed a decrease in plaque pH within 5 to 10 subculturing in maltitol showed a above, the methods and type of dental min to just less than pH 6.0. Over the marked increase in fermentation by S. plaque must be considered when remaining 20 min, the pH increased to mutans. However, the ability to ferment comparing the results of these studies. just over 6.0. Birkhed et al. (Ref. 41) the sugar alcohol was lost after one Results of animal studies with measured pH changes in human dental subculturing of the adapted strain in concentrations of isomalt from 16 to 30 plaque after subjects consumed lozenges glucose. percent of the rat diet showed sweetened with Swedish HSH for 3 mo significantly fewer caries compared to 5. Lactitol and then rinsed with a mouth rinse sucrose diets (Refs. 57, 60, 62, 63, 65, sweetened with Swedish HSH. Plaque Havenaar et al. (Ref. 46) showed that and 70). The caries incidence was high pH was also measured after a sucrose a 1 percent solution of lactitol was in xerostomized rats consuming either mouth rinse. The results of the study fermented by S. mutans and sucrose or isomalt (Ref. 57). The isomalt showed that HSH resulted in a drop in Actinomyces. Cell suspensions of S. group of nonxerostomized rats, plaque pH in all tests; however, the mutans in lactitol showed pH decreased however, had significantly fewer caries minimum pH values reached were from a baseline of about pH 7.0 to about than the sucrose group. above 6.0. Gehring and Hufnagel (Ref. pH 6.5 or above after a 2-h incubation 45) reported an intraoral plaque pH 7. HGS and HSH period. Adaptation of S. mutans by change with a HSH rinse (20 percent frequent subculturing in lactitol showed Frostell et al. (Ref. 31) studied the solution) from about pH 6.6 to about 5.6. a marked increase in fermentation by S. effect on caries increment in children of Jensen (Ref. 47) showed interproximal mutans to give a plaque pH of about 5.0. substitution of HSH for sucrose in plaque pH values from five different However, the ability to ferment the candy. The results of this study are HGS rinses were statistically sugar alcohol was lost after one confounded for a number of reasons (see significantly different compared to the subculturing of the adapted strain in Table 2) and do not support a significant sucrose control. Differences between the glucose. Grenby et al. (Ref. 76) showed dental benefit from the use of HSH HGS test solutions and a sorbitol control that a 1-percent solution of lactitol, candies in place of sucrose-containing were not significantly different. The when incubated for 24 h with human candies. minimum pH values obtained with the plaque and pieces of a human molar Rundegren et al. (Ref. 36) measured HGS solutions were above pH 6.0. tooth, resulted in slight acid production enamel hardness in the presence of Composition of the HGS test substances and a final pH of about 6.3 and almost sucrose, sodium chloride, or HSH using was not provided. no loss of calcium and phosphorus from an ICT. The investigators reported Frostell (Ref. 42) reported a slight tooth enamel. significantly less enamel decrease in vitro plaque pH (from about Results of two animal studies (Refs. demineralization with HSH. The results 6.7 to about 6.5) after subjects consumed 73 and 77) showed that substitution of of the study were that only sucrose HSH candy. After consuming a sucrose lactitol for sucrose in laboratory chow promoted demineralization over and lozenge, plaque pH decreased to about resulted in significantly fewer caries in above the effect of dietary 5.8. A sucrose solution resulted in a the lactitol group compared to the carbohydrates. The authors attributed minimum plaque pH of about 5.3. Toors sucrose group. The lactitol group (Ref. the demineralization measured in the and Herczog (Ref. 43) showed that 73) experienced slightly, but not presence of HSH to the effect of dietary plaque pH is affected by more than the significantly, more caries than the carbohydrates. sweetener component of a food. Results Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37523 of plaque pH in vivo with an A. Xylitol plaque acid did not decrease pH to experimental licorice, containing soy In its 1978 review of the xylitol levels associated with incipient enamel flour, HPS, and potato starch derivative studies, FASEB concluded that xylitol decalcification (i.e., approximately at among other ingredients, showed a appeared to be noncariogenic in studies pH 5.5 or below). There is some minimum pH of about 5.5. The evaluating the effect of sucrose evidence that suggests that long-term, fermentability of the HPS (60 percent), replacement with xylitol and in studies uninterrupted use of sorbitol results in potato starch derivative (82 percent) and evaluating the effect of partial adaptation by S. mutans and other soy flour (75 percent) contributed to the replacement of sucrose with xylitol in plaque microorganisms and, therefore, in more acid production. However, observed changes in plaque pH in the chewing gum (Ref. 14). experimental licorice. The agency reviewed over 15 studies there are no human caries trials to show Acid production in vitro was reported published since the FASEB report that whether such adaptation results in a in two studies (Refs. 39 and 51). Birkhed change in the incidence of dental caries. evaluated the relationship between and Edwardsson (Ref. 39) reported an There is some evidence to show that xylitol and dental caries, plaque pH, acid production rate from French HSH adaptation may be lost in the presence and acid production. Overall results of 20 to 40 percent and from Swedish of other sugars. HSH of 50 to 70 percent compared to from the human caries field trials (Refs. The results of six animal studies glucose syrups. Birkhed and Skude (Ref. 26 and 28) suggest that substitution of confirmed the observations from human 51) reported significantly lower acid xylitol-containing foods and chewing studies. The incidence of caries in production rates (i.e., slower rate of gums for sucrose-containing foods and animals consuming diets containing fermentation) from a 3 percent solution chewing gums is associated with a sorbitol was significantly less than the of Swedish HSH (61.5 percent) lower incidence of dental caries. Plaque caries incidence in animals consuming compared to glucose (99.7 percent). The pH and acid production studies further diets containing sucrose. FDA investigators also reported that HSH was support this result. In both in vivo and tentatively concludes that the overall metabolized significantly more slowly in vitro studies, xylitol had negligible to results from human and animal studies than soluble starch. no effect on plaque pH or plaque acid show that oral bacteria cannot be Results of animal studies evaluating production. In some instances, xylitol sustained in the presence of sorbitol, the effect of HSH showed the sweetener increased plaque pH above the mean and that changes in acidity are within to be relatively noncariogenic compared baseline value, suggesting that xylitol a range that is safe for tooth enamel. to sucrose (Refs. 52, 53, 64, and 69). may truly be nonpromotional of dental Differences in the incidence of caries caries. The results of over 10 animal C. Mannitol between the sucrose and HSH groups studies confirm the observations from In its 1979 report on mannitol, FASEB were significant. clinical and in vitro studies. concluded that results of acid Substituting xylitol (from 10 to 30 production, plaque pH changes, and IV. Decision To Propose a Health Claim percent) for sucrose in a basic laboratory changes in microhardness of bovine Relating Sugar Alcohols To the chow resulted in significantly fewer enamel were consistent with the results Nonpromotion of Dental Caries dental caries. FDA tentatively concludes of animal experiments indicating that FDA limited its review of the that the overall results from human and mannitol, in the absence of adaptation scientific evidence relating sugar animal studies strongly support the of the oral microflora, is less cariogenic alcohols and dental caries to those observation that xylitol does not than sucrose (Ref. 16). One study studies evaluating changes in plaque promote acid production in plaque and, evaluated plaque pH with mannitol in a pH, plaque acid production, therefore, does not promote dental concentrated plaque suspension in vitro decalcification or remineralization of caries. (Ref. 38). One and ten percent solutions tooth enamel, and the incidence of B. Sorbitol of mannitol resulted in a plaque pH of dental caries with sugar alcohols. FDA 5.5 or below. Contrary to these results, considered these limitations to be In its 1979 report on sorbitol, FASEB however, three studies showed only appropriate because previous Federal concluded that the weight of evidence slight acid production and small government and other authoritative from animal studies suggests that changes in plaque pH to a value not reviews had focused on these areas sorbitol is less cariogenic than sucrose below pH 6.0 from mannitol (Refs. 39, (Refs. 14 through 16), and the majority and other fermentable sugars (Ref. 15). 45, and 76). Likewise, there was little of research efforts to date have focused The report noted that the results of evidence of demineralization from on these areas. human plaque studies show that mannitol in vitro (Ref. 76). Two rat FDA tentatively concludes that, based sorbitol does not lower plaque pH below studies, in which mannitol was on the totality of publicly available 5.5, the pH of plaque where substituted for sucrose in animal chow, scientific evidence regarding the decalcification may begin. FASEB showed significantly fewer caries with relationship among sugar alcohols, concluded that it could be assumed that the mannitol diet (Refs. 59 and 64). FDA plaque pH, and dental caries, there is sorbitol may have similar relative tentatively concludes that the overall significant scientific agreement to cariogenic properties in humans as results from both human and animal support the relationship between the observed in animals. studies support the claim that mannitol use of xylitol, sorbitol, mannitol, The agency reviewed over 10 clinical does not promote dental caries. maltitol, isomalt, lactitol, HSH, HGS, or studies with sorbitol published since a combination of these sugar alcohols the FASEB report. Subjects consuming D. Maltitol and the nonpromotion of dental caries. sorbitol-containing sweets between Results of three ICT’s showed Thus, it appears that use of a health meals experienced fewer dental caries significantly less decalcification with claim relating the use of sugar-alcohol than those consuming sucrose- maltitol than sucrose. Additional plaque containing products to dental caries will containing sweets. Plaque pH and acid pH studies showed that maltitol is be useful in helping consumers identify production studies consistently show fermented very slowly (acid production food products consumption of which that sorbitol is slowly fermented by of 10 to 30 percent) compared to sucrose will not promote the development of plaque microflora and by S. mutans in and is associated with small plaque pH dental caries. particular. However, results show that changes from resting baseline values. 37524 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules

Four animal studies confirmed that and the other in France) used in the of which are a significant source of any maltitol was significantly less cariogenic studies reviewed gave dramatically nutrients. The petition states that the than sucrose. FDA tentatively concludes different results in plaque pH and acid use of these products in lieu of that the overall results from both human production tests. The Swedish version, traditional sugar-based confectionery and animal studies support the claim which has a higher percentage of higher would be consistent with public health that maltitol does not promote dental molecular weight, fermentable recommendations, and that the health caries. polysaccharides than the French claim statement, ‘‘useful only in not version, produced plaque pH values of promoting tooth decay,’’ is an important E. Isomalt 5.5 to 6.0 and an acid production of 50 and useful message for consumers in The agency reviewed two plaque pH to 70 percent compared to sucrose. The making decisions on which foods to studies evaluating the acidogenic French version produced final plaque purchase. potential of isomalt. Results with 10 pH values above 6.0 and an acid FDA has tentatively determined that percent isomalt showed a minimum in production rate of 20 to 40 percent of there is significant public health vitro plaque pH of 5.7. An intraoral test sucrose. Results with HGS of evidence to support providing an with a 20 percent solution of isomalt unidentified composition showed exemption to § 101.14(e)(6) for sugar reported a minimum pH of about 6.0. minimum plaque pH values all above alcohol-containing foods, e.g., chewing Results of five animal studies 6.0. Results of 4 rat studies support the gums, hard candies, and mints. In the consistently showed that isomalt was observations that HSH (source not Surgeon General’s Report (Ref. 7), dental significantly less cariogenic than identified) is significantly less caries is recognized as an important and sucrose. FDA tentatively concludes that cariogenic than sucrose. FDA tentatively widespread public health problem in the overall results show that isomalt concludes that the overall results the United States. Although dental does not lower plaque pH below 5.5 and support the claim that HSH and HGS do caries among children are declining, the does not promote dental caries. not promote dental caries. overall prevalence of the condition Based on its review of the scientific imposes a substantial economic burden F. Lactitol evidence, the agency noted that the HSH on American health care costs. The Two in vitro plaque pH studies and HGS sugar alcohol mixtures may Surgeon General’s report states that of showed that lactitol produced little acid vary in their acidogenic response in the 13 leading health problems in the and only slight changes in plaque pH dental plaque. For example, HSH United States, dental disorders rank from resting baseline values. Results of manufactured in Sweden usually gave a second in direct costs (Ref. 7). two animal studies are consistent with lower plaque pH response than the The role of sugars, and of sucrose in these results and showed lactitol to be French version of HSH. This variation particular, in the etiology of dental significantly less cariogenic than in acidogenic response has been caries is well established. Caries- sucrose. The cariogenicity of lactitol attributed to the differences in the producing bacteria can readily was not significantly different than chemical composition of these metabolize a range of simple sugars xylitol. FDA tentatively concludes that substances. HSH and HGS are not well (e.g., sucrose, glucose, fructose) to acids the overall results support the claim that defined chemical substances as are that can demineralize teeth. The unique lactitol does not promote dental caries. xylitol and sorbitol. Instead, the sugar role of sucrose, however, is related to its ability to be used by S. mutans, the G. Hydrogenated Starch Hydrolysates alcohol compositions of these primary etiologic agent in coronal and Hydrogenated Glucose Syrups substances will vary depending on the manufacturing process. Therefore, the caries, and other oral bacteria to form In an ICT, a solution of HSH resulted agency is asking for comments on how extracellular polymers of glucose or in significantly less demineralization to determine whether sugar alcohol fructose that adhere firmly to tooth than sucrose. The investigators mixtures, such as HSH, when used in a surfaces (Ref. 7). attributed the observed food whose label bears a dental caries The Surgeon General’s report demineralization with HSH to an effect health claim, are in compliance with recommends several types of of other dietary components. The effects any final rule resulting from this intervention to help reduce the risk of of sucrose on enamel demineralization, proposal. dental caries. The diet-related factors however, were noted to be over and include the use of fluoridated drinking above the effect of other dietary V. Decision To Propose An Exemption water and control of sugars components. From § 101.14(E)(6) For Chewing Gum consumption. In this regard, the Seven studies evaluating the effect of and Confectioneries Surgeon General’s report recommends HSH on plaque pH showed inconsistent Section 101.14(e)(6) provides, as that those who are particularly results in final pH values reported. The stated above, that except for dietary vulnerable to dental caries, especially differences in results are attributed to supplements or where provided for in children, should limit their the source of the HSH. HSH is other regulations in part 101, subpart E, consumption and frequency of use of manufactured by hydrolyzing a source to be eligible to bear a health claim, a foods containing relatively high levels of food grade starch (usually potato or food must contain 10 percent or more of of sugars. corn starch) with acid or an enzyme to the reference daily intake or the daily FDA agrees that limiting the amount a mixture of sugars and dextrins of reference value for vitamin A, vitamin of sugars in the diet is one important various glucose lengths (i.e., glucose C, iron, calcium, protein, or fiber per approach to help reduce the risk of syrups). The hydrogenated mixture reference amount customarily dental caries. Sugar alcohols can be contains sorbitol, maltitol, maltitriol, consumed before there is any nutrient used to replace dietary sugars in food by maltotrititol, and hydrogenated dextrins addition. providing sweetness and usefulness as of various molecular weights (Ref. 79). The petition states that products bulking agents. Sugar alcohol- The percentage of each component containing sugar alcohols often will not containing chewing gum and sugar alcohol in the final substance be able to satisfy the requirement of confectioneries, such as hard candies depends on the manufacturing process § 101.14(e)(6) because the products and mints, are specifically formulated and controls. The two major forms of utilizing sugar alcohols are largely without dietary sugars. Although these HSH (i.e., one manufactured in Sweden chewing gum and confectioneries, none foods have little or no nutritional value, Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37525 they are an important alternative to Diets in the United States tend to be the relationship between sugar alcohols sucrose-containing snacks. Therefore, high in sugars. Although there has been and the nonpromotion of dental caries. FDA tentatively finds that the use of a decline in the prevalence of dental This action is consistent with the health claims on the label of sugar caries in the United States, there has agency’s review of the scientific alcohol-containing products will been no decline in the consumption of evidence, which showed that, although facilitate compliance with dietary sugars. Furthermore, the incidence of sugar alcohols are slowly fermented by guidelines that recommend a reduced dental caries is still widespread (Ref. 7). S. mutans and can form some acid, they intake of dietary sugars to reduce the Sugar alcohols are used as sweeteners do not contribute to the promotion of risk of dental caries. Moreover, the sugar and bulking agents to replace dietary dental caries. alcohol and dental caries health claim, sugars in foods. Because of their In new § 101.80(c)(2)(i)(A), the agency if authorized, will apply in large composition, sugar alcohols are not as is proposing to require that in measure, although not entirely, to snack fermentable by plaque bacteria as describing the relationship between foods that do not play a fundamental sucrose and are, therefore, less sugar alcohols and dental caries, the role in structuring a healthy diet. cariogenic than dietary sugars. claim states ‘‘does not promote,’’ Section 101.14(e)(6) was included in Replacing dietary sugars with sugar ‘‘useful in not promoting,’’ or ‘‘expressly FDA’s regulations to ensure that those alcohols helps to maintain dental for not promoting’’ dental caries. FDA foods that bear a health claim are useful health. finds that these terms accurately in structuring a healthy diet. Usually describe the relationship between sugar B. Significance of Sugar Alcohols in the alcohol consumption and dental caries. usefulness in structuring a healthy diet Caries Process derives from the vitamin, mineral, In new § 101.80(c)(2)(i)(B), the agency protein, or fiber content of the food. In As explained in section IV of this is proposing to require that the terms this case, however, FDA tentatively document, based on the totality of the ‘‘dental caries’’ or ‘‘tooth decay’’ be used finds that the replacement of dietary publicly available evidence, FDA has in specifying the disease. These terms sugars with sugar alcohols will help tentatively concluded that there is are commonly used in dental and reduce the risk of dental caries and thus significant scientific agreement among dietary guidance materials and are will help to facilitate compliance with experts qualified by training and familiar to consumers. the dietary guidelines. In recognition of experience to evaluate such claims that Under § 101.14(d), a health claim the special character of the foods there is adequate scientific evidence to must be complete, truthful, and not involved, FDA tentatively concludes conclude that the sugar alcohols xylitol, misleading. It must enable the public to that it is appropriate to exempt these sorbitol, mannitol, maltitol, isomalt, comprehend the information provided food products from § 101.14(e)(6). lactitol, HSH, and HGS are less and to understand the relative Therefore, in new § 101.80(c)(1), FDA is cariogenic than sucrose and do not significance of such information in the context of a total daily diet. In addition, proposing to exempt sugar alcohol- promote dental caries. In proposed a health claim may not attribute any containing food products from the § 101.80(b), FDA discusses the specific degree of reduction in risk of provisions of paragraph 101.14(e)(6). significance of the relationship between sugar alcohols and dental caries. disease from consumption of the VI. Description And Rationale For Sugar alcohols have been shown in product. Components Of Health Claim human and animal studies to be In recognition of these general nonfermentable (i.e., xylitol) or slowly requirements, and in light of the fact A. Relationship Between Sugar Alcohols that both environmental and genetic and Dental Caries fermentable (i.e., sorbitol, maltitol, mannitol, isomalt, lactitol, HSH, and factors, as well as eating behaviors, all In proposed § 101.80(a), FDA HGS) by S. mutans and other acid- affect a person’s risk of developing describes the relationship between sugar forming microorganisms in dental dental caries (see proposed alcohols and dental caries. Dental caries plaque. Human studies have shown a § 101.80(a)(1)), FDA is proposing in is a multifactorial disease, characterized reduced rate of acid production in § 101.80(c)(2)(i)(C) that for packages that by the demineralization of the surface of plaque and, in some studies, a reduced have a total surface area available for tooth enamel by acid-forming organisms incidence of dental caries from the use labeling of 15 or more square inches, the in dental plaque. It is well established of sugar alcohol-containing products. claim must state that dental caries that the relationship between sugars depends on many factors. consumption and dental caries is one of C. Nature of the Claim FDA is aware that many sugar cause and effect within the In new § 101.80(c)(1), FDA is alcohol-containing chewing gum and multifactorial context (Refs. 71 and 72). proposing that all requirements of confectionery products have a total The role of sucrose in the etiology of § 101.14 be met except, as explained surface area available for labeling of less dental caries is related to its ability to above, that sugar alcohol-containing than 15 square inches, however. Such a be metabolized by oral bacteria into foods are exempt from § 101.14(e)(6). small area would preclude the use of a extracellular polymers that adhere Under § 101.14(d)(3), nutrition health claim that included all of the firmly to the tooth surfaces, at the same labeling in accordance with § 101.9 required elements. Many of these time forming acids that can must be provided on the label or products, packaged in small packages, demineralize tooth enamel (Ref. 7). The labeling of any food for which a health have used the claim ‘‘useful only in not extracellular polymers that adhere to claim is made. Therefore, if FDA adopts promoting dental caries’’ on their labels tooth surfaces (i.e., plaque) facilitate the this proposed regulation, the labeling of for more than 15 years. Because of the further attachment of additional plaque the amount of sugar alcohol in a serving potential dental health benefits to to teeth and the proliferation of bacteria. will have to be declared on the nutrition consumers resulting from a positive Although saliva can help neutralize label in accordance with action on this proposal and given the plaque acids and influence the § 101.9(c)(6)(iii) when a claim is made unique history of this claim, the agency attachment of oral bacteria to the tooth on the label or in labeling about sugar tentatively finds that continued use of surface (Ref. 7), it has limited access to alcohols and dental caries. an abbreviated claim on packages with the acids generated at the tooth surface In new § 101.80(c)(2)(i), FDA is less than 15 square inches of surface beneath the plaque. proposing to authorize a health claim on area will not be misleading or confusing 37526 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules to consumers of these products. The agency is not specifying a level of assurance that, consistent with the However, the agency continues to sugar alcohols in the food product health claim, the food will not promote believe that the fact that dental caries because these ingredients are being used dental caries. are multifactorial in their etiology is as a substitute for sugars. Therefore, the The methods that have been described fundamental to an understanding of the amount of the substance required is that as the most suitable for assessing plaque claim. Therefore, the agency tentatively needed to achieve a desired level of acidity of dietary constituents in concludes that this fact is a material sweetness. humans are indwelling electrode fact, and that it must be disclosed on In new § 101.80(c)(2)(ii)(C), the systems, such as the intraoral plaque pH packages with space available for agency is proposing that to qualify to telemetric test used in the Swiss labeling of 15 or more square inches. In bear a claim, the sugar alcohol- program (Refs. 8 and 75). ICT’s (Ref. 88), § 101.80(c)(2)(i)(D), given the unique containing food, when tested for its which incorporate enamel blocks into circumstances surrounding this claim, effects on plaque pH using in vivo dental appliances for the production of FDA is proposing to exempt packages methods, must not lower plaque pH carious lesions when used in with a total surface area available for below 5.7. Based on the agency’s review combination with intraoral plaque pH labeling of less than 15 square inches of the scientific evidence, foods that telemetry, are also good methods for from the provisions of lowered plaque pH below 5.5 were assessing changes in plaque pH in § 101.80(c)(2)(i)(C). contributing to an acidic environment in response to food. The agency is asking In proposed § 101.80(c)(2)(i)(E), FDA the mouth that is detrimental to tooth for comments on whether establishing a states that the claim must not attribute enamel. Although a ‘‘critical’’ plaque pH minimum plaque pH that is measured in any degree of nonpromotion of dental has not been defined, changes in pH to vivo during consumption and up to 30 caries to the use of the sugar alcohol- a minimum that is above 5.5 are min following consumption is a containing food. Based on the agency’s generally considered above the level reasonable approach to use to determine review of human and animal studies in where enamel decalcification would be whether a sugar alcohol-containing this document, none of the studies promoted (Refs. 8, 75, 86, and 87). food, other than sugar alcohol- In its review of the scientific provide a basis for determining the containing chewing gum and evidence, the agency noted that sugar percent reduction in risk of dental caries confectioneries, that contains other alcohol-containing chewing gum and from consuming sugar alcohol- carbohydrate ingredients is in confectioneries, such as mints, that do containing foods. This requirement is compliance with any final rule resulting not contain fermentable carbohydrates, also consistent with the general from this proposal. did not lower plaque pH below 5.5. requirements for health claims in However, in one study that evaluated E. Optional Information § 101.14(d), and those health claims the cariogenic potential of an authorized under part 101, subpart E. FDA is proposing in new experimental licorice that contained soy § 101.80(d)(1), consistent with the D. Nature of the Food flour, the soy flour was shown to be regulations that have authorized other highly fermentable and dropped plaque health claims, that health claims about In § 101.80(c)(2)(ii)(A), FDA is pH to below 5.5 (Ref. 43). The agency proposing to require that the food is concerned that use of sugar alcohols the relationship between sugar alcohols bearing this health claim meet the in a food product that contains an and dental caries may provide requirement in § 101.60(c)(1)(i) with ingredient, such as refined flour, that additional information that is drawn respect to sugars content, that is, qualify would cause plaque pH to drop below from proposed § 101.80 (a) and (b). to bear the claim ‘‘sugar free.’’ This 5.5 would thus cause the food to be In new § 101.80(d)(2), the agency is requirement is consistent with the cariogenic. proposing that when referring to scientific evidence showing that foods In the Swiss ‘‘zahnschonend’’ sucrose, the claim may use the term with a mixture of sugar alcohols and program, if a food does not promote a ‘‘sucrose’’ or ‘‘sugar.’’ The use of either sugars are still acidogenic (Ref. 38) and drop in plaque pH, using intraoral of these terms is consistent with FDA’s cariogenic (Refs. 52, 55, and 56, for plaque pH telemetric tests, below 5.7 by regulation that affirms that use of this examples). bacterial fermentation either during substance is GRAS (§ 184.1854). In new § 101.80(c)(2)(ii)(B), the consumption or up to 30 min later, the FDA is proposing in § 101.80(d)(3), agency is proposing that the sugar food is considered ‘‘safe for teeth’’ and consistent with the health claims that it alcohols be limited to xylitol, sorbitol, may be labeled as such (Ref. 75). The has already authorized under part 101, mannitol, maltitol, isomalt, lactitol, intraoral plaque pH telemetric test is an subpart E, to allow manufacturers to HSH, HGS, or a combination of these. in vivo method that measures the provide additional information about This requirement reflects the available acidogenicity of foods and dietary risk factors associated with the scientific evidence on the sugar alcohols patterns. Based on experience and development of dental caries. Although and their effects on the promotion of experimentation, foods judged by the sugars consumption and infection with dental caries. Swiss program to be safe for teeth are S. mutans are often identified as the Sugar alcohols in combination with those that have been shown not to cause of dental caries, there are several high intensity sugar substitutes, such as promote dental decay in animal or risk factors that play significant roles in aspartame and saccharin, are also used human model systems (Ref. 75). the etiology of this disease (Ref. 71). to replace sucrose. The agency notes In this proposed rule, FDA is These factors include frequent that under proposed § 101.80(c)(2)(ii)(A) proposing to require in consumption of sucrose or other and (c)(2)(ii)(B), a sugar alcohol and § 101.80(c)(2)(ii)(C) that to be eligible to fermentable carbohydrates, presence of dental caries claim could appear on a bear the claim, the food product not oral bacteria capable of fermenting food that contains a combination of lower plaque pH below 5.7, based on in sugars, length of time sugars are in sugar alcohols and high intensity vivo measurements, during the time contact with the teeth, lack of exposure sweeteners but no sugars. The agency food is consumed and for up to 30 min to fluoride, individual susceptibility, notes that high intensity sweeteners are after the food is consumed. The agency socioeconomic and cultural factors, and not considered fermentable by oral is proposing a more conservative value characteristics of tooth enamel, saliva, bacteria (Ref. 75). than pH 5.5 because such a value gives and plaque (Refs. 7, 71, and 89). Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37527

F. Model Health Claims and Drug Administration, rm. 1–23, 12. Working Group Consensus Report, In proposed § 101.80(e), FDA is 12420 Parklawn Dr., Rockville, MD ‘‘Integration of methods,’’ Journal of providing model health claims to 20857, written comments regarding this Dental Research, 65(Special illustrate the requirements of new proposal. Two copies of any comments Issue):1537–1539, 1986. § 101.80. FDA emphasizes that these are to be submitted, except that 13. DePaola, D. P., ‘‘Executive model health claims are illustrative individuals may submit one copy. summary,’’ Scientific Consensus only. If the agency authorizes claims Comments are to be identified with the Conference on Methods for Assessment about the relationship between sugar docket number found in brackets in the of the Cariogenic Potential of Foods, alcohols and dental caries, heading of this document. Received Journal of Dental Research, 65(Special manufacturers will be free to design comments may be seen in the office Issue)1540–1543, 1986. their own claim so long as it is above between 9 a.m. and 4 p.m., 14. LSRO, FASEB, ‘‘Dietary Sugars in consistent with § 101.80(c). Monday through Friday. Health and Disease, II. Xylitol,’’ Bethesda, MD, July, 1978. VII. Environmental Impact XI. References 15. LSRO, FASEB, ‘‘Dietary Sugars in The agency has determined under 21 The following references have been Health and Disease, III. Sorbitol,’’ CFR 25.24 (a)(11) that this action is of placed on display in the Dockets Bethesda, MD, July, 1978. a type that does not individually or Management Branch (address above) 16. LSRO, FASEB, ‘‘Dietary Sugars in cumulatively have a significant effect on and may be seen by interested persons Health and Disease, IV. Mannitol,’’ the human environment. Therefore, between 9 a. m. and 4 p. m., Monday Bethesda, MD, July, 1978. neither an environmental assessment through Friday. 17. Working Group Consensus Report, nor an environmental impact statement 1. Drozen, Melvin S., ‘‘Health claim ‘‘Animal caries,’’ Journal of Dental is required. petition regarding the noncariogenicity Research, 65:1528–1529, 1986. of sugar alcohols,’’ August 31, 1994. 18. Working Group Consensus Report, VIII. Analysis of Impacts 2. Drozen, Melvin S., ‘‘Objections and ‘‘Human plaque acidity,’’ Journal of FDA has examined the impacts of the request for a hearing by Working Group Dental Research, 65:1530–1531, 1986. proposed rule under Executive Order of sugar alcohol manufacturers to the 19. Working Group Consensus Report, 12866 and the Regulatory Flexibility Act revocation of 21 C.F.R. section ‘‘Demineralization/remineralization,’’ (Pub. L. 96–354). Executive Order 12866 105.66(f),’’ Docket No. 91N–384L, Journal of Dental Research, 65:1532– directs agencies to assess all costs and Dockets Management Branch, FDA, 1536, 1986. 20. Mo¨ller, I. J., and S. Poulsen, ‘‘The benefits of available regulatory Rockville, MD. effect of sorbitol-containing chewing alternatives and, when regulation is 3. Saltsman, Joyce J., CFSAN, FDA, gum on the incidence of dental caries, necessary, to select regulatory Letter to Melvin S. Drozen, September plaque and gingivitis,’’ Community approaches that maximize net benefits 15, 1994. Dental and Oral Epidemiology, 1:58–67, (including potential economic, 4. Saltsman, Joyce J., CFSAN, FDA, 1973. environmental, public health and safety, Letter to Melvin S. Drozen, October 7, and other advantages; distributive 21. Ba´no´zcy, J., E. Hadas, I. Eszta´ry, I. 1994. Marosi, and J. Nemes, ‘‘Three-year impacts; and equity). The agency 5. Drozen, Melvin S., Letter to FDA, believes that this proposed rule is results with sorbitol in clinical November 15, 1994. longitudinal experiments,’’ Journal of consistent with the regulatory 6. Saltsman, Joyce J., CFSAN, FDA, philosophy and principles identified in the International Association of Memorandum of telephone Dentistry in Children, 12:59–63, 1981. the Executive Order. In addition, the conversation, December 8, 1994. proposed rule is not a significant 22. Kandelman, D., and G. Gagnon, 7. DHHS, Public Health Service ‘‘Clinical results after 12 months from a regulatory action as defined by the (PHS), ‘‘The Surgeon General’s Report Executive Order and so is not subject to study of the incidence and progression on Nutrition and Health,’’ U.S. of dental caries in relation to review under the Executive Order. Government Printing Office, The Regulatory Flexibility Act consumption of chewing-gum Washington, DC, 1988. requires agencies to analyze regulatory containing xylitol in school preventive 8. Harper, D. S., D. C. Abelson, and M. options that would minimize any programs,’’ Journal of Dental Research, E. Jensen, ‘‘Human plaque acidity significant impact of a rule on small 66:1407–1411, 1987. models,’’ Journal of Dental Research, 65 entities. Because it enables firms to 23. Rekola, M., ‘‘Changes in buccal (Special Issue):1503–1510, 1986. make claims that they would otherwise white spots during two-year total be prohibited from making, the agency 9. Ten Cate, J. M., ‘‘Demineralization substitution of dietary sucrose with certifies that the proposed rule will not models: Mechanistic aspects of the xylitol,’’ Acta Odontologica have a significant economic impact on caries process with special emphasis on Scandinavica, 44:285–290, 1986. a substantial number of small entities. the possible role of foods,’’ Journal of 24. Ma¨kinen, K. K., and A. Scheinin, Therefore, under the Regulatory Dental Research, 65 (Special ‘‘Turku sugar studies. VI. The Flexibility Act, no further analysis is Issue):1511–1515, 1986. administration of the trial and the required. 10. Curzon, M. E. J., ‘‘Integration of control of the dietary regimen,’’ Acta methods for determining the cariogenic Odontologica Scandanavia, 33:105–127, IX. Effective Date potential of foods: Is this possible with 1975. FDA is proposing to make these present technologies?,’’ Journal of 25. Rekola, M., ‘‘Approximal caries regulations effective 30 days after the Dental Research, 65 (Special development during 2-year total publication of a final rule based on this Issue):1520–1524, 1986. substitution of dietary sucrose with proposal. 11. Stookey, G. K., ‘‘Considerations in xylitol,’’ Caries Research, 21:87–94, determining the cariogenic potential of 1987. X. Comments foods: How should existing knowledge 26. Scheinin, A., J. Ba´no´czy, J. Szo¨ke, Interested persons may, on or before be combined?,’’ Journal of Dental I. Eszta´ri, K. Pieniha¨kkinen, U. October 3, 1995, submit to the Dockets Research, 65(Special Issue):1525–1527, Scheinin, J. Tiekso, P. Zimmerman, and Management Branch (HFA–305), Food 1986. E. Hadas, ‘‘Collaborative WHO xylitol 37528 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules field studies in Hungary. I. Three-year 38. Bibby, B. G., and J. Fu, ‘‘Changes 51. Birkhed, D., and G. Skude, caries activity in institutionalized in plaque pH in vitro by sweeteners,’’ ‘‘Relation of amylase to starch and children,’’ Acta Odontologica Journal of Dental Research, 64:1130– Lycasin metabolism in human dental Scandinavica, 43:327–347, 1985. 1133, 1985. plaque in vitro,’’ Scandinavian Journal 27. Ba´no´czy, J., A. Scheinin, R. Pados, 39. Birkhed, D., and S. Edwardsson, of Dental Research, 86:248–258, 1978. G. Ember, P. Kerte´sz, and K. ‘‘Acid production from sucrose 52. Havenaar, R., J. S. Drost, J. D. de Pieniha¨kkinen, ‘‘Collaborative WHO substitutes in human dental plaque,’’ Stoppelaar, J. H. J. Huis in’t Veld, and xylitol field studies in Hungary. II. Proceedings of ERGOB Conference, pp. O. Backer Dirks, ‘‘Potential cariogenicity General background and control of the 211–217, 1978. of Lycasin 80/55 in comparison to dietary regimen,’’ Acta Odontologica 40. Birkhed, D., S. Edwardsson, B. starch, sucrose, xylitol, sorbitol and L- Scandinavica, 43:349–357, 1985. Svensson, F. Moskovitz, and G. Frostell, sorbose in rats,’’ Caries Research, 28. Scheinin, A., K. Pieniha¨kkinen, J. ‘‘Acid production from sorbitol in 18:375–384, 1984. Tiekso, J. Ba´no´czy, J. Szo¨ke, I. Eszta´ri, human dental plaque,’’ Archives of Oral 53. Havenaar, R., J. S. Drost, J. H. J. P. Zimmerman, and E. Hadas, Biology, 23:971–975, 1978. Huis in’t Veld, O. Backer Dirks, and J. ‘‘Collaborative WHO xylitol field 41. Birkhed, D., S. Edwardsson, M. L. D. de Stoppelaar,, ‘‘Potential studies in Hungary. VII. Two-year caries Ahlden, and G. Frostell, ‘‘Effects of 3 mo cariogenicity of Lycasin 80/55 before incidence in 976 institutionalized frequent consumption of hydrogenated and after repeated transmissions of the children,’’ Acta Odontologica starch hydrolysate (Lycasin), maltitol, dental plaque flora in rats,’’ Archives of Scandinavica, 43:381–387, 1985. sorbitol and xylitol on human dental Oral Biology, 29:993–999, 1984. 29. Barmes, D., J. Barnaud, S. plaque,’’ Acta Odontologica 54. Havenaar, R., J. H. J. Huis In’t Khambonanda, and J. Sardo Infirri, Scandinavica, 37:103–115, 1979. Veld, J. D. de Stoppelaar, and O. Backer ‘‘Field trials of preventive regimes in 42. Frostell, G., ‘‘Dental plaque pH in Dirks, ‘‘A purified cariogenic diet for Thailand and French Polynesia,’’ relation to intake of carbohydrate rats to test sugar substitutes with special International Dental Journal, 35:66–72, products,’’ Acta Odontologica emphasis on general health,’’ Caries 1985. Scandanavia, 27:3–29, 1969. Research, 17:340–352, 1983. 30. Kandelman, D., A. Ba¨r, and A. 43. Toors, F. A., and J. I. B. Herczog, 55. Havenaar, R., J. D. Huis in’t Veld, Hefti, ‘‘Collaborative WHO xylitol field ‘‘Acid production from a nonsugar J. D. J. de Stoppelaar, and O. B. Dirks, study in French Polynesia. I. Baseline licorice and different sugar substitutes ‘‘Anti-cariogenic and remineralizing Prevalence and 32-month caries in Streptococcus mutans monoculture properties of xylitol in combination increment,’’ Caries Research, 22:1–10, and pooled plaque-saliva mixtures,’’ with sucrose in rats inoculated with 1988. Caries Research, 12:60–68, 1978. Streptococcus mutans,’’ Caries 31. Frostell, G., L. Blo¨mlof, I. 44. Gallagher, I. H., and S. J. Fussell, Research, 18:269–277, 1984. Blomqvist, G. M. Dahl, S. Edward, A. ‘‘Acidogenic fermentation of pentose 56. Grenby, T. H., and J. Colley, Fjellstrom, C. O. Henrikson, O. Larje, C. alcohols by human dental plaque ‘‘Dental effects of xylitol compared with E. Nord, and K. J. Nordenvall, microorganisms,’’ Archives of Oral other carbohydrates and polyols in the ‘‘Substitution of sucrose by Lycasin in Biology, 24:673–679, 1979. diet of laboratory rats,’’ Archives of Oral candy. ‘The Roslagen study’,’’ Acta 45. Gehring, F., and H. D. Hufnagel, Biology, 28:745–758, 1983. Odontologica Scandinavica, 32:235– ‘‘Intra- and extraoral pH measurements 57. Karle, E. J., and F. Gehring, 253, 1974. on human dental plaque after rinsing ‘‘Kariogenita¨tsuntersuchungen von 32. Glass, R. L., ‘‘A two year clinical with some sugar and sucrose substitute zuckeraustauschstoffen an trial of sorbitol gum,’’ Caries Research, solutions,’’ Oralprophylaxe, 5:13–19, xerostomierlen ratten. (Studies on the 17:365–368, 1983. 1983. cariogenesis of sugar substitutes in 33. Ikeda, T., K. Ochiai, Y. Doi, T. 46. Havenaar, R., J. H. J. Huis In’t xerostomized rats),’’ Deutsche Mukasa, and S. Yagi, ‘‘Maltitol and Veld, O. Backer Dirks, and J. D. de Zahnarztliche Zeitschrift, 34:551–554, SE58 in rats and decalcification as Stoppelaar, ‘‘Some bacteriological 1979. human intraoral substrate, Nihon aspects of sugar substitutes,’’ 58. Mu¨ hlemann, H. R., R. Schmid, T. University Journal of Oral Science, Proceedings from ERGOB Conference, Noguchi, T. Imfeld, and R. S. Hirsch, 25:1–5, 1975. pp. 192–196, 1978. ‘‘Some dental effects of xylitol under 34. Yagi, S., ‘‘Effects of maltitol on 47. Jensen, M. E., ‘‘Human plaque laboratory and in vivo conditions,’’ insoluble glucan synthesis by S. mutans acidogenicity studies with hydrogenated Caries Research, 11:263–276, 1977. and change of enamel hardness,’’ Nihon starch hydrolysates,’’ unpublished. 59. Shyu, K.-W., and M.-Y Hsu, ‘‘The University Journal of Oral Science, 48. Maki, Y., K. Ohta, I. Takazoe, Y. cariogenicity of xylitol, mannitol, 4:136–144, 1978. Matsukubo, Y. Takaesu, V. Topitsoglou, sorbitol and sucrose,’’ Proceedings of 35. Leach, S. A., G. T. R. Lee, and W. and G. Frostell, ‘‘Acid production from the National Science Council ROC, M. Edgar, ‘‘Remineralization of artificial isomaltulose, sucrose, sorbitol, xylitol in 4:21–26, 1980. caries-like lesions in human enamel in suspensions of human dental plaque,’’ 60. Bramstedt, F., F. Gehring, and E. situ by chewing sorbitol gum,’’ Journal Caries Research, 17:335–339, 1983. J. Karle, ‘‘Comparative study of the of Dental Research, 68:1064–1068, 1989. 49. Park, K. K., B. R. Schemehorn, J. cariogenic effects of Palatinit, xylitol 36. Rundegren, J., T. Koulourides, and W. Bolton, and G. K. Stookey, and saccharose in animals,’’ T. Ericson, ‘‘Contribution of maltitol ‘‘Comparative effect of sorbitol and unpublished, 1976. and Lycasin to experimental enamel xylitol mints on plaque acidogenicity,’’ 61. Izumiya, A., T. Ohshima, and S. demineralized in the human mouth,’’ presented at the International Sofue, ‘‘Caries inducibility of various Caries Research, 14:67–74, 1980. Association for Dental Research, April sweeteners,’’ Academy of Pedodontia, p. 37. Creanor, S. L., R. Strang, W. H. 17–21, 1991. 65, May 1984. Gilmour, R. H. Foye, J. Brown, D. A. M. 50. So¨derling, E., K. K. Ma¨kinen, C.- 62. Gehring, F., and E. J. Karle, ‘‘The Geddes, and A. F. Hall, ‘‘The effect of Y. Chen, H. R. Pape, and P.-L. Ma¨kinen, sugar substitute Palatinit with special chewing gum use on in situ enamel ‘‘Effect of sorbitol, xylitol and xylitol/ emphasis on microbiological and caries- lesion remineralization,’’ Journal of sorbitol gums on dental plaque,’’ Caries preventing aspects,’’ Zeitschrift Dental Research, 71:1895–1900, 1992. Research, 23:378–384, 1989. Ernahrungswiss, 20:96–106, 1981. Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37529

63. Karle, E. J., and F. Gehring, 77. Grenby, T. H., and A. Phillips, Therefore, under the Federal Food, ‘‘Palatinit-A New Sugar Substitute and ‘‘Dental and metabolic effects of lactitol Drug, and Cosmetic Act and under its Carioprophylactic Assessment,’’ in the diet of laboratory rats,’’ British authority delegated to the Commissioner Deutsche Zalnarztliche Zeitschrift Journal of Nutrition, 61:17–24, 1989. of Food and Drugs, it is proposed that 33:189–191, 1978. 78. Edgar, W. M., and D. A. M. 21 CFR part 101 be amended as follows: 64. Larje, O., and R. H. Larson, Geddes, ‘‘Plaque acidity models for ‘‘Reduction of dental caries in rats by cariogenicity testing—some theoretical PART 101ÐFOOD LABELING and practical observations,’’ Journal of intermittent feeding with sucrose 1. The authority citation for 21 CFR Dental Research, 65 (Special Issue): substitutes, Archives of Oral Biology, part 101 is revised to read as follows: 15:805–816, 1970. 1498–1502, 1986. 65. Mu¨ hlemann, H. R., ‘‘Effect of 79. Birkhed, D., S. Kalfas, G. Authority: Secs. 4, 5, 6 of the Fair topical application of sugar substitutes Svensa¨ter, and S. Edwardsson, Packaging and Labeling Act (15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, on bacterial agglomerate formation, ‘‘Microbiological aspects of some caloric sugar substitutes,’’ International Dental 701 of the Federal Food, Drug, and Cosmetic caries incidence and solution rates of Act (21 U.S.C. 321, 331, 342, 343, 348, 371). molars in the rat,’’ unpublished, 1978. Journal, 35:9–17, 1985. 66. Ooshima, T., A. Izumitani, T. 80. Schrotenboer, G. H., ‘‘In the 2. New § 101.80 is added to subpart E Minami, T. Yoshida, S. Sobue, T. Matter of Revising the Regulation for to read as follows: Fujiwari, and S. Hamada, ‘‘Non- Foods for Special Dietary Uses,’’ Docket No. FDC–78, March 4, 1970 at 6–7. § 101.80 Health claims: dietary sugar cariogenicity of maltitol in SPF rats 81. Saltsman, Joyce J., CFSAN, FDA, alcohols and dental caries. infected with mutans streptococci,’’ Memorandum to file—Environmental (a) Relationship between dietary sugar submitted for publication. Assessment of Health Claim Petition, alcohols and dental caries. (1) Dental 67. Tate, N., S. Wada, H. Tani, and K. December 23, 1994. caries, or tooth decay, is a disease Oikawa, ‘‘Experimental studies on 82. Ayers, C. S., and R. A. Abrams, caused by many factors. Both correlations between progressive caries ‘‘Noncariogenic sweeteners, sugar environmental and genetic factors can and sugar intake,’’ unpublished. substitutes for caries control,’’ Dental affect the development of dental caries. 68. Leach, S. A., and R. M. Green, Hygiene, April, 162–167:1987. Risk factors include tooth enamel ‘‘Effect of xylitol-supplemented diets on 83. Rugg-Gunn, A. J., and W. M. crystal structure and mineral content, the progression and regression of fissure Edgar, ‘‘Sweeteners and dental health,’’ plaque quantity and quality, saliva caries in the albino rat,’’ Caries Community Dental Health, 2:213–223, quantity and quality, individual Research, 14:16–23, 1980. 1985. immune response, types and physical 69. Mukasa, T., ‘‘The possibility of 84. Grenby, T. H., ‘‘Nutritive sucrose characteristics of foods consumed, maltitol and SE 58 as non-cariogenic substitutes and dental health,’’ In: eating behaviors, presence of acid sweeteners: their utilization by Developments in Sweeteners, editors: producing oral bacteria, and cultural Streptococcus mutans for insoluble T. H. Grenby, K. J. Parker, and M. G. influences. glucan synthesis and experimental Lindley, Elsevier Science, Inc., 2:51–88, (2) The relationship between dietary dental caries in rats,’’ Nihon University 1983. sugars consumption and tooth decay is  Journal of Oral Science, 3:266–275, 85. Rugg-Gunn, A. J., ‘‘Lycasin and well established. Sucrose is one of the 1977. the prevention of dental caries,’’ In: most, but not the only, cariogenic sugar 70. Hoeven, J. S. van der, Progress in Sweeteners, editor: T. H. in the diet. Bacteria found in the mouth ‘‘Cariogenicity of disaccharide alcohols Grenby, Elsevier Science, Inc., pp. 311– are able to metabolize sugars producing in rats,’’ Caries Research, 14:61–66, 328, 1989. acid and forming dental plaque. 1980. 86. Loesche, W. J., ‘‘The rationale for Prolonged exposure of the tooth enamel 71. Burt, B. A., and A. I. Ismail, ‘‘Diet, caries prevention through use of sugar to acids from dental plaque causes tooth nutrition, and food cariogenicity,’’ substitutes,’’ International Dental enamel to demineralize, or decay. Journal of Dental Research, 65 (Special Journal, 35:1–8, 1985. Frequent between-meal consumption of Issue): 1475–1484, 1986. 87. Mandel, I. D., ‘‘Dental caries,’’ sugary foods, particularly foods that 72. National Research Council, American Scientist, 67:680–688, 1979. easily stick to the teeth, can cause tooth 88. Koulourides, T., R. Bodden, S. National Academy of Sciences, ‘‘Diet decay. Keller, L. Manson-Hing, J. Lastra, and T. and Health,’’ National Academy Press, (3) U.S. diets tend to be high in sugars Housch, ‘‘Cariogenicity of nine sugars Washington, DC, 1989. consumption. Although there has been tested with an intraoral device in man,’’ 73. Hoeven, J.S. van der, ‘‘Carigenicity a decline in the prevalence of dental Caries Research 10:427–441, 1976. of lactitol in program-fed rats,’’ Caries 89. Baer, A., ‘‘Significance and caries in the United States, per capita Research, 20:441–443, 1986. promotion of sugar substitution for the consumption of sugars has not declined, 74. Imfeld, T., and H. R. Mu¨ hlemann, prevention of dental caries,’’ Lben.-Wiss and the disease remains widespread ‘‘Cariogenicity and acidogenicity of U. Technology, Academic Press, 22:46– throughout the population. Federal food, confectionery and beverages,’’ 53, 1989. government agencies and nationally Pharmacology and Therapeutic 90. LSRO, FASEB ‘‘Health Aspect of recognized health professional Dentistry, 3:53–68, 1978. Sugar Alcohols and Lactose,’’ Bethesda, organizations recommend decreased 75. Imfeld, T., ‘‘Identification of Low MD, December 1986. consumption of sugars. Caries Risk Dietary Components,’’ 91. Joint FAO/WHO Expert (4) Dietary sugar alcohols can be used Monographs in Oral Science, vol. 11, Committee on Food Additives, to replace dietary sugars in food. Sugar Karger, Basel, Switzerland, pp. 1–8 and ‘‘Evaluation of Certain Food Additives alcohols are significantly less cariogenic 117–144, 1983. and Contaminants,’’ Geneva, than dietary sugars. Thus, replacing 76. Grenby, T. H., A. Phillips, and M. Switzerland, pp. 16–17, 1993. dietary sugars with sugar alcohols helps Mistry, ‘‘Studies of the dental properties to maintain dental health. of lactitol compared with five other bulk List of Subjects in 21 CFR Part 101 (b) Significance of the relationship sweeteners in vitro,’’ Caries Research, Food labeling, Nutrition, Reporting between sugar alcohols and dental 23:315–319, 1989. and recordkeeping requirements. caries. Sugar alcohols do not promote 37530 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules dental caries because they are slowly (E) The claim shall not attribute any lack of exposure to fluoride; individual metabolized by bacteria to form some degree of nonpromotion of dental caries susceptibility; socioeconomic and acid. The rate and amount of acid to the use of the sugar alcohol- cultural factors; and characteristics of production is significantly less than that containing food. tooth enamel, saliva, and plaque. from sucrose and does not cause the loss (ii) Nature of the food. (A) The food (e) Model health claim. The following of important minerals from tooth shall meet the requirement in model health claims may be used in enamel. § 101.60(c)(1)(i) with respect to sugars food labeling to describe the (c) Requirements. (1) All requirements content. relationship between sugar alcohol and set forth in § 101.14 shall be met, except (B) The sugar alcohol in the food shall dental caries. that sugar alcohol-containing foods are be xylitol, sorbitol, mannitol, maltitol, (1) For packages with total surface exempt from section § 101.14(e)(6). isomalt, lactitol, hydrogenated starch area available for labeling of less than 15 (2) Specific requirements. (i) Nature hydrolysates, hydrogenated glucose square inches: of the claim. A health claim relating syrups, or a combination of these. (i) Useful only in not promoting tooth (C) The sugar alcohol-containing food sugar alcohols and the nonpromotion of decay; shall not lower plaque pH below 5.7 by dental caries may be made on the label (ii) Does not promote tooth decay; and bacterial fermentation either during or labeling of a food described in consumption or up to 30 minutes after (iii) [This product] does not promote (c)(2)(ii) of this section, provided that: consumption, as measured by in vivo tooth decay. (A) The claim shall state ‘‘does not tests. (2) For packages with total surface promote,’’ ‘‘useful in not promoting,’’ or (d) Optional information. (1) The area available for labeling of 15 or more ‘‘expressly for not promoting’’ dental claim may include information from square inches: caries. paragraphs (a) and (b) of this section, (i) Tooth decay is a disease caused by (B) In specifying the disease, the which describe the relationship between many factors including frequent claim uses the following terms: ‘‘dental diets containing sugar alcohols and between meal consumption of sugary caries’’ or ‘‘tooth decay.’’ dental caries. foods. [Name of sugar alcohol] does not (C) For packages with a total surface (2) In referring to sucrose, the claim promote tooth decay. area available for labeling of 15 or more may use the term ‘‘sucrose’’ or ‘‘sugar.’’ (ii) [Reserved]. square inches, the claim shall indicate (3) The claim may identify one or Dated: July 7, 1995. that dental caries depends on many more of the following risk factors for William B. Schultz, factors. dental caries: Frequent consumption of Deputy Commissioner for Policy. (D) Packages with a total surface area sucrose or other fermentable available for labeling of less than 15 carbohydrates; presence of oral bacteria Note: The following tables will not appear square inches are exempt from capable of fermenting sugars; length of in the annual Code of Federal Regulations. paragraph (C) of this section. time sugars are in contact with the teeth; BILLING CODE 4160±01±P Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37531 37532 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37533 37534 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37535 37536 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37537 37538 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37539 37540 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37541 37542 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37543 37544 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37545 37546 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37547 37548 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules 37549

[FR Doc. 95–17505 Filed 7–19–95; 8:45 am] BILLING CODE 4160±01±C