federal register /vol. 60, no. 139/thursday, july 20, … register/vol. 60, no. 139/thursday, july...

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

DEPARTMENT OF HEALTH ANDHUMAN SERVICES

Food and Drug Administration

21 CFR PART 101

[Docket No. 95P–0003]

Food Labeling: Health Claims; SugarAlcohols and Dental Caries

AGENCY: Food and Drug Administration,HHS.ACTION: Proposed rule.

SUMMARY: The Food and DrugAdministration (FDA) is proposing toauthorize the use, on food labels and infood labeling, of health claims on theassociation between sugar alcohols andthe nonpromotion of dental caries. Inaddition, FDA is proposing to exemptsugar alcohol-containing foods fromcertain provisions of the health claimsgeneral requirements regulation. FDA isproposing these actions in response to apetition filed by the NationalAssociation of Chewing GumManufacturers, Inc., and an ad hocworking group of sugar alcoholmanufacturers (hereinafter referred to asthe petitioners).DATES: Written comments by October 3,1995. The agency is proposing that anyfinal rule that may issue based upon thisproposal become effective 30 daysfollowing its publication.ADDRESSES: Written comments to theDockets Management Branch (HFA–305), Food and Drug Administration,rm. 1–23, 12420 Parklawn Dr.,Rockville, MD 20857.FOR FURTHER INFORMATION CONTACT:Joyce J. Saltsman, Center for Food Safetyand Applied Nutrition (HFS–165), Foodand Drug Administration, 200 C St. SW.,Washington, DC 20204, 202–205–5916.

SUPPLEMENTARY INFORMATION:

I. Background

A. The Nutrition Labeling andEducation Act of 1990

On November 8, 1990, the Presidentsigned into law the Nutrition Labelingand Education Act of 1990 (the 1990amendments) (Pub. L. 101–535). Thisnew law amended the Federal Food,Drug, and Cosmetic Act (the act) in anumber of important ways. One of themost notable aspects of the 1990amendments was that they confirmedFDA’s authority to regulate healthclaims on food labels and in foodlabeling. As amended by the 1990amendments, section 403(r)(1)(B) of theact (21 U.S.C. 343(r)(1)(B)) provides thata product is misbranded if it bears aclaim that characterizes the relationship

of a nutrient to a disease or health-related condition, unless the claim ismade in accordance with the proceduresand standards contained in regulationsadopted by FDA.

Under section 403(r)(3)(B)(i) of theact, the Secretary of Health and HumanServices (and, by delegation, FDA) shallpromulgate regulations authorizing suchclaims only if he or she determines,based on the totality of publiclyavailable scientific evidence (includingevidence from well-designed studiesconducted in a manner which isconsistent with generally recognizedscientific procedures and principles),that there is significant scientificagreement, among experts qualified byscientific training and experience toevaluate such claims, that the claim issupported by such evidence.

Section 403(r)(3)(B)(ii) and(r)(3)(B)(iii) of the act describes theinformation that must be included inany claim authorized under the act. Theact provides that the claim shall be anaccurate representation of thesignificance of the substance in affectingthe disease or health-related condition,and that it shall enable the public tocomprehend the information andunderstand its significance in thecontext of the total daily diet. Finally,section 403(r)(4)(A)(i) of the actprovides that any person may petitionFDA to issue a regulation authorizing ahealth claim.

The 1990 amendments, in addition toamending the act, directed FDA toconsider 10 substance-diseaserelationships as possible subjects ofhealth claims.

B. FDA’s ResponseIn the Federal Register of January 6,

1993 (58 FR 2478), FDA adopted a finalrule that implemented the health claimprovisions of the act. In that final rule,FDA adopted § 101.14 (21 CFR 101.14).The regulation sets out thecircumstances in which a substance iseligible to be the subject of a healthclaim (§ 101.14(b)), adopts the standardin section 403(r)(3)(B)(i) of the act as thestandard that the agency will apply indeciding whether to authorize a claimabout a substance-disease relationship(§ 101.14(c)), sets forth general rules onhow authorized claims are to be madein food labeling (§ 101.14(d)), andestablishes limitations on thecircumstances in which claims can bemade (§ 101.14(e)). The agency alsoadopted § 101.70 (21 CFR 101.70),which establishes a process forpetitioning the agency to authorizehealth claims about a substance-diseaserelationship (§ 101.70(a)) and sets outthe types of information that any such

petition must include (§ 101.70(d)).These regulations became effective onMay 8, 1993.

In addition, FDA conducted anextensive review of the evidence on the10 substance-disease relationships listedin the 1990 amendments. FDA hasauthorized claims that relate to 8 ofthese 10 relationships.

The present rulemaking on sugaralcohols and dental caries represents thefirst rulemaking that FDA hasconducted in response to a health claimpetition.

C. History of Sugar Alcohol LabelingIn a set of findings of fact and a

tentative order on label statements forspecial dietary foods that the agencyissued on July 19, 1977 (42 FR 37166),FDA addressed the issue of the use ofthe terms ‘‘sugar free,’’ ‘‘sugarless,’’ and‘‘no sugar.’’ The agency stated thatconsumers may associate the absence ofsugar in a product with weight controland with foods that are low calorie orthat have been altered to reduce caloriessignificantly. At that time, FDA viewedfoods intended to be useful inmaintaining or reducing calorie intakeor body weight as foods for specialdietary use, that is, as foods intended forsupplying particular dietary needs thatexist by reason of a physical,physiological, pathological, or othercondition.

Evidence had been introduced at apublic hearing in the 1977 rulemakingto show that the ‘‘sugarless’’ claim isuseful to identify foods like chewinggum, which is in sustained contact withthe teeth, in which the use of asweetener other than a fermentable orcariogenic carbohydrate may notpromote tooth decay. The secretary ofthe American Dental Association’sCouncil on Dental Therapeuticssupported the importance of advertisingand labeling sugarless chewing gum andmints as noncariogenic, in the sense thatthey did not contribute to thedevelopment of dental caries (Ref. 80).

In the final rule on label statementsfor special dietary foods published inthe Federal Register of September 22,1978 (43 FR 43248), FDA required astatement that a food is not low calorieor calorie reduced (unless it is in fact,a low or reduced calorie food) when a‘‘sugar free,’’ ‘‘sugarless,’’ or ‘‘no sugar’’claim is made for the food. The agencydecided to allow ‘‘useful only in notpromoting tooth decay’’ as analternative statement to accompanysuch claims. The agency stated that thestatements that the food is not lowcalorie or not useful for weight control,as well as ‘‘useful only in not promotingtooth decay,’’ were needed because the

37508 Federal Register / Vol. 60, No. 139 / Thursday, July 20, 1995 / Proposed Rules

term ‘‘sugar free’’ meant only that thefood was sucrose free. A ‘‘sugar free’’food could contain other fermentablecarbohydrates. Thus, the informationabout the effect of sugar alcohol-containing foods on the risk ofdeveloping dental caries was originallyplaced on the food label primarily toclarify that the product was notnecessarily useful in weight control, notto highlight the effect of sugar alcoholon dental caries production.

In the Federal Register of November27, 1991 (56 FR 60421), in response tothe 1990 amendments, FDA published aproposed rule entitled ‘‘Food Labeling:Nutrient Content Claims, GeneralPrinciples, Petitions, Definition ofTerms’’ (the nutrition labeling generalprinciples proposal). In that document,FDA recognized that developments innutrition science had established thatthe focus of nutrient content claims forproviding dietary guidance had shiftedfrom special populations with particularconditions to the general population(see 56 FR 60421). Therefore, in thenutrition labeling general principlesproposal, FDA proposed to treat severalclaims that had been subject toregulation in § 105.66 (21 CFR 105.66)as special dietary use claims as nutrientcontent claims for the generalpopulation. To eliminate redundancy inthe regulations and to conform § 105.66to the 1990 amendments, FDA proposedto define these claims in part 101 (21CFR part 101) and to remove them frompart 105 (21 CFR part 105). Specifically,FDA proposed to adopt definitions forterms such as ‘‘low calorie’’ and‘‘reduced calorie,’’ for other comparativecalorie claims, and for sugar claimsunder section 403(r)(2) of the act and tocodify them in § 101.60. It also proposedto delete these claims from § 105.66.

In the Federal Register of January 6,1993 (58 FR 2302), FDA published itsfinal rules on nutrient content claims.FDA adopted definitions for claims forthe calorie content of foods in § 101.60(58 FR 2302 at 2415). FDA definedclaims regarding the sugars content of afood, e.g., ‘‘sugar free,’’ ‘‘free of sugar,’’‘‘no sugar,’’ in § 101.60(c). In addition,FDA published a final rule that deletedthese claims from § 105.66 (58 FR 2427).

However, based on its considerationof comments on the use of the statement‘‘useful only in not promoting toothdecay’’ to qualify the ‘‘sugarless’’ claim,FDA concluded that the statement wasactually an unauthorized health claim(58 FR 2302 at 2326). The claim is ahealth claim because it characterizes therelationship of a substance (sugaralcohols) to a disease (dental caries).

In the nutrient content claim generalprinciples proposal (56 FR 60421 at

60437), the agency stated that itintended to reevaluate the usefulness ofchewing gums sweetened with sugaralcohols in not promoting tooth decay.The agency stated that the datasupporting the claim were over 20 yearsold and requested that new data besubmitted in accordance with the finalrule on health messages. In the nutrientcontent claim final rule, FDA stated thatit had received data on the validity ofa claim about this nutrient-diseaserelationship, and that it would make adetermination on whether to authorize aclaim in accordance with the final ruleon health claims (58 FR 2302 at 2326).

On February 5, 1993, under theprocedure established in section 701(e)of the act (21 U.S.C. 371(e)), a group ofsugar alcohol manufacturers submittedan objection to the revocation of§ 105.66(f) (Ref. 2) and asked for ahearing on their objection. At the sametime, the group petitioned forreconsideration of the agency’s decisionand for a stay of any administrativeaction by FDA pursuant to thedetermination announced in thepreamble of the nutrient content claimsrules that ‘‘useful only in not promotingtooth decay’’ is an unauthorized healthclaim.

Filing objections to the revocation of§ 105.66(f) stayed the effect of the finalrule as a matter of law. FDA’s responseto these objections and to the petitionsis set forth elsewhere in this issue of theFederal Register.

In the Federal Register of August 18,1993 (58 FR 44036), FDA publishedtechnical amendments to the healthclaim regulations in response tocomments that the agency received onthe implementation final rule that waspublished with the other final rules thatresponded to the 1990 amendments inJanuary of 1993 (see 58 FR 2066, August18, 1993). One of the comments statedthat if a petition were submitted for theclaim ‘‘Useful Only in Not PromotingTooth Decay,’’ virtually none of thesugar-free products on the market wouldbe eligible to bear the claim based onthe requirements of a subsection ofhealth claims general principlesregulation, § 101.14(e)(6). FDAacknowledged that certain foodproducts of limited nutritional valuethat have been specially formulatedrelative to a specific disease condition,such as dental caries, may bedetermined to be appropriate foods tobear a health claim (58 FR at 44036).The agency commented that it was itsintention to deal with such situationswithin the regulations authorizingspecific health claims. Therefore, FDAamended § 101.14(e)(6) to state that:

Except for dietary supplements or whereprovided for in other regulations in part 101,subpart E, the food contains 10 percent ormore of the Reference Daily Intake or theDaily Reference Value for vitamin A, vitaminC, iron, calcium, protein, or fiber perreference amount customarily consumedprior to any nutrient addition.

II. Petition for the Noncariogenicity ofSugarless Food Products SweetenedWith Sugar Alcohol

A. BackgroundOn August 31, 1994, the petitioners

submitted a health claim petition toFDA requesting that the agencyauthorize a health claim on therelationship of sugar alcohols (i.e.,xylitol, sorbitol, mannitol, maltitol,lactitol, isomalt, hydrogenated starchhydrolysates, and hydrogenated glucosesyrups) in sugarless foods to dentalcaries (Ref. 1). On September 15, 1994,FDA sent the petitioners a letter statingthat study reports that are needed tosupport the petition, and that arerequired for a health claim petitionunder § 101.70, were not included in thepetitioners’ submission. The agencystated that no further action would betaken until that information wasreceived (Ref. 3).

On September 27, 1994, thepetitioners filed an amendment to theirpetition submitting the requiredinformation. On October 7, 1994, theagency sent the petitioners a letteracknowledging receipt of the additionalinformation and stating that the agencyhad begun its scientific review of thepetition (Ref. 4).

In this document, the agency willconsider whether a health claim on therelationship between sugar alcohols anddental caries is justified under thestandard in section 403(r)(3)(B)(i) of theact and § 101.14(c) of FDA’s regulations.In addition, the agency will consider thepetitioners’ request that the agencyprovide in any regulation authorizing aclaim that foods sweetened with sugaralcohols be exempt from therequirement in § 101.14(e)(6). Thefollowing is a review of the health claimpetition.

B. Preliminary Requirements

1. The Substances That Are the Subjectsof the Petition

Sugar alcohols are a class of organiccompounds that contain chains ofcarbon atoms that bear two or morehydroxyl groups and have onlyhydroxyl functional groups (Ref. 1). Thehydroxyl groups replace ketone oraldehyde groups that are found insugars (§ 101.9(c)(6)(iii)). The specificsugar alcohols that are the subject of thispetition are xylitol, sorbitol, mannitol,


maltitol, maltitol syrup, maltitolsolution, isomalt, lactitol, and mixturesof sugar alcohol substances, i.e.,hydrogenated glucose syrup (HGS) andhydrogenated starch hydrolysate (HSH)products.

Xylitol is a monosaccharidepolyhydric alcohol with a 5-carbonbackbone. It occurs naturally in fruits(e.g., plums, strawberries, andraspberries) and vegetables (e.g.,cauliflower and endive) (Refs. 82 and83). Xylitol is made commercially by thehydrogenation of D-xylose.

Sorbitol is a monosaccharidepolyhydric alcohol with a 6-carbonbackbone. It is found naturally in manytypes of berries and fruits and inseaweeds and algae (Ref. 82). Sorbitol ismade by hydrogenation of glucose.

Mannitol is also a 6-carbon,monosaccharide polyhydric alcohol. Itoccurs widely in nature in plants (e.g.,pumpkins, mushrooms, onions, beets,celery, and olives), algae, and fungi.Like sorbitol, mannitol is madecommercially by the hydrogenation ofglucose.

Maltitol is a disaccharide alcohol (4–D-glucopyranosyl-D-sorbitol) with a 12-carbon backbone. It is producedcommercially by hydrogenation ofmaltose.

Lactitol is also a disaccharide alcohol(β-D-galactopyranosyl D-sorbitol) with a12-carbon backbone. It is produced byhydrogenation of lactose (Ref. 84).

HSH and HGS are mixtures of sugaralcohols manufactured byhydrogenation of corn starch or glucosesyrups. The composition of the sugaralcohols in the final product willdepend on the manufacturing process.Therefore, HSH and HGS products fromdifferent manufacturers may containdifferent proportions of the same sugaralcohols. One HSH product, under thetrade name ‘‘Lycasin,’’ was firstproduced in Sweden by hydrogenationof potato starch. The Swedish productcontained a mixture of sorbitol, maltitol,maltotrititol, and hydrogenateddextrines of various molecular weights.When the manufacturing process wasmoved to France in the 1970’s, theproduction process was also changed(Ref. 85). The French product, ‘‘Lycasin80/55,’’ was made from thehydrogenation of corn starch andcontained 6 to 8 percent sorbitol, 50 to55 percent hydrogenated disaccharides,20 to 25 percent trisaccharides, and 10to 20 percent hydrogenatedpolysaccharides (Ref. 75). Lycasin 80/55, or HSH 80/55, is less fermentableand produces less acid than theSwedish product (Ref. 85).

Isomalt, also known by thecommercial name ‘‘Palatinit,’’ is an

equimolar mixture of the disaccharidealcohols of ∝-D-glucopyranosyl-D-sorbitol and ∝-D-glucopyranosyl-D-mannitol. It is produced by treatingsucrose with enzymes, followed byhydrogenation of the resulting mixture.

2. The Substances are Associated Witha Disease for Which the U.S. Populationis at Risk

Dental caries is recognized in TheSurgeon General’s Report on Nutritionand Health (Surgeon General’s report)as a disease or health-related conditionfor which the United States populationis at risk (Ref. 7). The overall prevalenceof dental caries imposes a substantialburden on Americans. Of the 13 leadinghealth problems in the United States,dental diseases rank second in directcosts (Ref. 7).

Based on this fact, FDA tentativelyconcludes that sugar alcohols meet therequirement in § 101.14(b)(1).

3. The Substances Are Food

Sugar alcohols are used asreplacements for simple and complexsugars as sweeteners and bulking agentsin foods (Ref. 1). Thus sugar alcohols areconsumed for their taste and for theireffect as a stabilizer and thickener (21CFR 170.3(o)(28)). Therefore, FDAtentatively concludes that thesesubstances satisfy the preliminaryrequirements of § 101.14(b)(3)(i).

4. The Substances Are Safe and Lawful

Several of the sugar alcohols that arethe subject of this proceeding arecurrently listed in FDA’s food additiveand generally recognized as safe (GRAS)regulations, i.e., xylitol (21 CFR172.395), mannitol (§ 180.25 (21 CFR180.25)), and sorbitol (§ 184.1835 (21CFR 184.1835)). Moreover, GRASaffirmation petitions have beensubmitted for each of the remainingsubstances, i.e., maltitol (GRASP6G0319), maltitol syrups (HGS syrups)(GRASP 3G0286), isomalt (GRASP6G0321), lactitol (GRASP 2G0391), HSH(GRASP 5G0304) and HSH syrups(GRASP 1G0375).

The agency notes that these GRASaffirmation petitions are underconsideration and that any positiveaction resulting from this proposed ruleshould not be interpreted as anindication that the agency has affirmedthose uses of the sugar alcohols asGRAS. Such determinations can only bemade after the agency has completed itsreview of the GRAS petitions. Apreliminary review of the GRASaffirmation petitions reveals that theycontain significant evidence supportingthe safety of these substances.

The agency also points out, however,that some concerns about the safety ofsugar alcohols do exist. For example, ina filing notice for the affirmation of theGRAS status of lactitol (58 FR 47746,September 10, 1993), FDA stated that‘‘the agency’s notice of filing of GRASP2G0391 should not be interpreted eitheras a determination, preliminary orotherwise, that the issue of Leydig celltumors has been resolved or that lactitolqualifies for GRAS affirmation.’’ Also,by notice in the Federal Register ofDecember 13, 1994 (59 FR 64207), theagency announced the filing of a foodadditive petition (FAP 4A4412) toamend the interim food additive statusof mannitol to permit an alternatemethod of manufacture. In this notice,the agency pointed out concerns aboutdata from studies on mannitol thatdemonstrate a significant incidence ofbenign thymomas, and an abnormalgrowth of thymus gland tissue, infemale rats fed mannitol. In addition,the safety of sugar alcohols has beenexamined by the Federation ofAmerican Societies for ExperimentalBiology (FASEB) (Ref. 90), as well asinternationally by the Joint ExpertCommittee on Food Additives (Ref. 91).The agency also notes that two of thesugar alcohols that are listed in FDA’sfood additive and GRAS regulations,i.e., mannitol (§ 180.25) and sorbitol(§ 184.1835), require a warning labelregarding laxation if daily consumptionof these sugar alcohols is expected toexceed 20 grams (g) per day formannitol and 50 g per day for sorbitol.Nothing in this proposal alters theserequirements.

Based on the totality of the evidence,the agency is not challenging, at thistime, the petitioner’s position that theuse of sugar alcohols is safe and lawful.Although FDA tentatively concludesthat the petitioner has satisfied therequirements of § 101.14(b)(3)(ii), theagency requests comments on itstentative conclusion.

III. Review of Scientific Evidence

A. IntroductionThe development of dental caries is

the result of an interaction betweensugars (and other fermentablecarbohydrates, such as refined flour)and oral bacteria in a suitableenvironment (Ref. 71). Microorganisms,and Streptococcus mutans (S. mutans)in particular, in dental plaquemetabolize available dietary sugars,producing acid and stickypolysaccharides that adhere to the toothas plaque. Acid produced from rapidand complete fermentation of sugarscreates an acid environment within the


plaque, characterized by a pH of usuallyless than 5.0, that is capable ofdemineralizing tooth enamel andcausing a carious lesion.

Studies designed to measure thecariogenicity of a food assess thepotential to cause caries if it isconsumed in a standard way by a highlysusceptible subject (Ref. 8). Themethods used to measure cariogenicpotential include long-term controlledhuman caries trials, in vivo and in vitroplaque pH measurement,demineralization and remineralizationtechniques, and rat caries models (Refs.8 through 11). Because long-termclinical caries trials are difficult toconduct, an integration of the plaquepH, animal caries, and demineralizationmethodologies has been recommendedas the best measure for establishing thecariogenic potential of a food (Ref. 12).Experts recommend, however, that thesemethods be used with appropriatecontrols, such as sucrose, to assessexperimental results (Ref. 13).

Plaque acidity studies are useful inproviding evidence on the effects ofmany microbial and physiologicalfactors on the cariogenic potential offoods (Ref. 78). An acidic plaqueenvironment at the tooth surface,specifically a pH of less than 5.5,suggests microbial fermentation of asubstrate resulting in microbial growth,plaque and acid production, andpromotion of carious lesions fromenamel decalcification. Factors that canmodify these effects include thepresence of promoters or inhibitors infood products that affect bacteriagrowth, the nature of the acids producedas a result of bacterial metabolism offood carbohydrates (Ref. 78),intraplaque buffering, and the pH ofmixed saliva (Ref. 74).

B. Review of Scientific Evidence

1. Evidence Considered in Reaching theDecision

The petitioners submitted scientificevidence on the various sugar alcoholsand their effects on plaque, plaque pH,and dental caries. This evidenceincluded human (in vivo andepidemiological), animal, and in vitrostudies regarding the associationbetween consumption of sugar alcoholsfrom chewing gum and other foods andplaque pH, acid production, plaquequantity and quality, bacteria levels,and the incidence of caries. The petitionincluded four tables that summarizedthe information for: (1) Human plaqueand demineralization, (2) bacteriologicalstudies, (3) animal experiments, and (4)human longitudinal and field studies. A

fifth table provided a summary ofreview articles.

In addition to the informationsubmitted by the petitioner, the agencyconsidered other studies and reviews,such as the reports on health aspects ofsugar alcohols by the Life SciencesResearch Office (LSRO) and the FASEB(Refs. 14 through 16). The agency alsoconsidered the results of additionalhuman epidemiological studies oncaries incidence and demineralization;studies of animal caries; and in vitroplaque pH studies.

2. Criteria for Selection of HumanStudies

The criteria that the agency used toselect pertinent studies were that thestudies: (1) Present data and adequatedescriptions of study design andmethods; (2) be available in English; (3)provide daily intakes of the sugaralcohol or enough information toestimate their daily intakes; (4) includein vivo or in vitro assessment of thechanges in plaque pH or plaque acidproduction; (5) for intervention studieson caries development, be of no lessthan 2 years (yr) in duration; and (6) beconducted in persons who generallyrepresent the healthy United States’population (adults or children).

In selecting human studies for review,the agency decided that only thosestudies investigating the use of sugaralcohols in chewing gums and otherfoods, including mouth rinses thatwould be representative of beverages,were appropriate for review. The agencyexcluded studies that were published inabstract form because they lackedsufficient detail on study design andmethodologies, and because they lackednecessary primary data. In selectinganimal and in vitro studies for review,the agency chose those studies thatmeasured caries development, plaquepH, or acid production from plaquebacteria.

3. Criteria for Evaluating theRelationship Between Sugar Alcoholsand Human Dental Caries

The subject of the petitioned healthclaim is the nonpromotion of dentalcaries by sugar alcohol-containingfoods, especially chewing gum andconfectioneries. To support this claim,there needs to be significant scientificevidence to show that the sugar alcoholor sugar alcohol mixture, e.g., HSH,makes no contribution to theprogression of dental carious lesions inhumans. It would be difficult, if notimpossible, to design and execute astudy that would directly address thisissue because such a study wouldrequire a control group that consumed

foods containing no sugars, fermentablecarbohydrates, or sugar alcohols.

In the absence of studies that directlyevaluate the nonpromotion of dentalcaries by sugar alcohol-containingfoods, the agency gave the greatestweight to those studies that evaluated invivo the acidogenic potential of plaqueand plaque pH of sugar alcohols andsucrose in representative food systems(e.g., confectioneries and solutions).These in vivo measures can providespecific information about the effect ofsugar alcohols in the oral environmentand, more specifically, about the effectof sugar alcohols on pH at the interfacebetween dental plaque and toothsurfaces. The more acidic theenvironment on the tooth surface, thegreater the chance for enameldemineralization and caries formation.

The agency also considered in vitrostudies that measured plaque pH andacid production of sugar alcohols insolution, and long-term caries trials thatevaluated caries development in apopulation using foods containing sugaralcohols and sucrose. Studiesinvestigating in situ thedemineralization or remineralization ofenamel as a result of the action of sugaralcohols on human dental plaque wereconsidered as supporting evidence bythe agency.

C. Human Studies

1. Evaluation of Human Studies

FDA evaluated the results of studiesagainst general criteria for goodexperimental design, execution, andanalysis. The criteria that the agencyused in evaluating these studiesincluded appropriateness of subjectselection criteria; adequacy of thedescription of the subject’s oral healthbefore intervention; extent of evaluationof subject’s type of dental plaque (i.e.,sticky or nonsticky, thick or thin);methods of plaque collection; adequacyof methods used to assess studyendpoints (e.g., in vivo versus in vitroassessment of plaque pH); and otherstudy design characteristics, includingrandomization of subjects,appropriateness of controls, report ofattrition rates (including reasons forattrition), frequency of snack orsubstance consumption, recognition andcontrol of confounding factors (forexample, the subject’s use of fluorideduring the test period), andappropriateness of statistical tests andcomparisons. The agency alsoconsidered it desirable if information ontreatment and control diets, the sugaralcohol content of the test substance,and daily sugar alcohol and nutrientintakes was available.


A review of the studies evaluating theeffect of sugar alcohols on plaque pHand acid production and of the in vitromicrobiological studies is provided inTable 1. Table 2 provides a review ofepidemiological studies evaluating theincidence of dental caries and studieson demineralization andremineralization.

2. Summary of Evidence Relating SugarAlcohol and Plaque pH or AcidProduction

Bibby and Fu (Ref. 38) measuredhuman plaque pH in vitro using 0.1-,1.0-, or 10-percent solutions of thefollowing sweeteners: Sucrose, HSH,mannitol, isomalt, xylitol, isomaltulose,sorbose, saccharin, and aspartame.Results showed the lowest plaque pHwas attained with sucrose (1- and 10-percent solution: pH less than 5.0).Plaque pH decreased with increasingconcentrations of isomalt, sorbitol,mannitol, and HSH. The lowest pHattained for isomalt was about 5.6, forsorbitol 5.82, for mannitol 5.22, and forHSH about 5.0. Negligible acidproduction was measured fromaspartame, saccharin, and xylitol.Solution mixtures of xylitol (5 to 20percent) and sucrose (10 percent) werefermented to the same low pH assucrose alone. Thus, the presence ofxylitol in a sucrose and xylitol mixturedid not affect acid production in plaquefrom sucrose.

The results of this study support thecontention that xylitol does not promotedental caries by lowering plaque pHbelow 5.5. However, the results forsorbitol, mannitol, isomalt, and HSH donot support a ‘‘nonpromotion’’ claim.The results suggest that when higherconcentrations of these sweeteners arepresent in food, the plaque pH mayreach a level that will promotedecalcification of dental enamel.

Birkhed and Edwardsson (Ref. 39)measured plaque pH and acidproduction of human plaque samples insolutions of mannitol, xylitol, maltitol,sorbitol, French HSH, Swedish HSH,fructose, and glucose syrups. Resultsshowed that plaque pH in the presenceof xylitol, maltitol, mannitol, andFrench HSH increased or slightlydecreased from baseline (pH remainingat 6.8 or above). Sorbitol showed a slightdecrease in plaque pH, but the final pHattained was about 6.0. The othersweeteners, including Swedish HSH,depressed plaque pH below pH 6 overthe 30-min (min) test period. The resultsof this study showed that mannitol andxylitol produced no plaque acidcompared to sucrose. Maltitol andsorbitol produced plaque acid at ratesthat were 10 to 30 percent of that of

sucrose. French HSH produced 20 to 40percent and Swedish HSH 50 to 70percent of the acid produced by sucrose.

Birkhed et al. (Ref. 40) measured acidproduction in vitro and plaque pHchanges in vivo over a 30-min periodfollowing a 30-second(s) mouth rinsewith 10-percent glucose or sorbitolsolutions. To determine whether plaquemicroorganisms can adapt to thepresence of sorbitol, i.e., use it as asource of energy like sucrose, withrepeated exposure to the sugar alcohol,investigators measured plaque pH andacid production at the end of a 6-week(wk) period. During the 6-wk period,each subject rinsed their mouth sixtimes per day for approximately 2 minat a time with a 10-percent sorbitolsolution. At the end of 6 wk, plaque pHwas again measured for a 30-min periodfollowing a mouth rinse with glucoseand sorbitol. The study results showedacid production in the presence ofsorbitol, before adaptation, to be 11.3percent of that from glucose. After theadaptation period, plaque acidproduction from sorbitol increased to 30percent of the glucose rate. After theadaptation period to sorbitol, theglucose rinse produced mean plaque pHvalues that were higher than before theadaptation period. The differences inplaque pH, however, were onlysignificant at 2 and 5 min following therinse.

Overall results of this study suggestthat sorbitol produces very little plaqueacid. Mean plaque pH values aftersorbitol adaptation in the presence ofthe 10-percent sorbitol rinse showedonly a slight decrease from the baselinevalue. The differences in mean plaquepH, compared to baseline, at 5, 10, 20,and 30 min following the rinse weresignificant. The authors noted that thefermentability of sorbitol was morepronounced after the adaptation periodthan before.

Birkhed et al. (Ref. 41) studied theeffects on in vivo plaque pH and in vitroacid production from HSH (SwedishHSH), maltitol, sorbitol, and xylitol.Subjects in each group sucked on twolozenges a day, containing 0.5 g of oneof the four sweeteners and 0.5 g of gumarabic, four times daily between meals(total of eight lozenges per day) for 3months (mo). Changes in plaque pHover a 30-min period were measured ineach of the sugar alcohol groups after a30-s mouth rinse with a 50-percentsolution containing the same sweeteneras the lozenge. The rinse was used 1 wkbefore and 1 wk after the lozengeperiod. A control group consumed nolozenges but rinsed with each of thefour sweeteners. At least 1 wk separatedeach mouth rinse experiment. Acid

production activity (APA) from dentalplaque suspended in glucose and eachof the four sugar alcohols wasdetermined 1 wk before and 1 wk afterthe 3-mo consumption period.

The results with HSH showed thatalthough plaque pH values differedbefore and after the lozenge period,differences were not statisticallysignificant, and that the lowest plaquepH attained was above 6.0. In themaltitol group, plaque pH before thelozenge period was higher than the pHfollowing the lozenge period.Differences at 2, 10, and 30 min werestatistically significant. However, therewere no significant differences inplaque pH at any time compared tobaseline. The lowest plaque pHrecorded was about 6.9. Plaque pH inthe xylitol group changed very slightly,remaining around pH 7. Plaque pH inthe sorbitol group was higher beforethan after the lozenge period.Differences in pH at times 0 to 20 minand 0 to 30 min before compared withafter the test period were statisticallysignificant (p<0.05). Final plaque pHvalues after the 30-min test period werebetween 6.7 and 7.0. There were nosignificant differences in plaque pHbetween the test and control groupsusing any of the test rinses.

Comparing the APA results for eachsweetener with those for glucoseshowed that HSH was 56 percent of thatof glucose 1 wk before the lozengeperiod and 59 percent of that of glucose1 wk after the lozenge period. The APAfor maltitol compared to glucose was 26percent (before) and 32 percent (after),sorbitol was 15 percent (before) and 18percent (after), and xylitol was 0 percentat both time periods. Differences beforeand after each 3-mo lozenge period werenot statistically significant for any of thesugar alcohols.

The results of this study suggest thateven though there is some acidproduction from HSH, maltitol, andsorbitol, the effect on plaque pH in vivois not detrimental to tooth enamel.

Frostell (Ref. 42) evaluated the effecton plaque pH of sugar solutions anddifferent types of candy and foods.Although the focus of this study was notsugar alcohols, the investigators usedsorbitol and HSH as a comparison tosucrose in some of the experiments.Plaque was collected prior to the testperiod, and its pH was determined.Subjects then rinsed with a test solutionor ate a piece of candy or other foodbeing tested. Plaque was collected after2, 5, 10, 20, and 30 min and its pH wasagain measured. Sweeteners testedincluded a sucrose rinse (concentrationsfrom 0.05 to 50 percent), sorbitol tablets(2 g sorbitol), sugar tablets (containing


glucose and sucrose), HSH candy, sugarcandies (with sucrose, dextrose, andmaltose), marmalades (60-percent HSHor sucrose), and sugar-sweetened spongecakes, ginger cakes, marshmallows, andchocolates. Results with the sucroserinses showed that plaque pH decreasedwith increasing concentrations ofsucrose.

Comparing the effects on plaque pHbetween the sorbitol and sucrosecandies results showed that in thesorbitol group’s plaque pH increasedfrom about 6.5 (baseline) to 6.9 beforereturning to baseline. Plaque pHdecreased in the sucrose group from 6.5(baseline) to about 6.0. After 10 min, thepH in the sucrose group slowlyincreased to about 6.3. Differences inplaque pH between the sorbitol candyand sucrose candy groups weresignificant at all time periods. In theHSH candy group, plaque pH wassignificantly higher than that in thegroup consuming sucrose candy.Differences were significant at all timeperiods. The lowest plaque pH in theHSH group was above pH 6.3. Thegroup consuming marmalade with HSHexperienced a drop in plaque pH toabout 6.0 (from 7.0) after 5 min,followed by a gradual increase to a finalpH of about 6.5. The group consumingsucrose marmalade experienced aplaque pH of about 5.3 after 5 min,followed by a gradual increase in pH toabout 6.0.

Toors and Herczog (Ref. 43) evaluatedin vivo plaque pH and in vitrofermentability of an experimental(nonsucrose) licorice in a pooledplaque-saliva mixture. Fermentability(i.e., acid production) of the testsubstrates was expressed as a percentageof the sucrose licorice. Plaque wascollected from 12 volunteers on the dayafter they consumed 10 pieces of thecandy. In vivo plaque pH was measuredduring and after consumption of licoriceby means of pH telemetry. Substratesused in the above tests included sucroselicorice, the experimental licorice,components of the experimental licorice(including sorbitol, potato starchderivative, soy flour, and others),xylitol, hydrogenated potato starch(HPS) (a type of HSH), and a whitebread suspension. Results showed thefermentability of the test substrates to beas follows: Potato starch derivative (82percent), soy flour (75 percent), sorbitol(12 percent), experimental licorice (68percent), xylitol (5 percent), HPS (60percent), and white bread suspension(79 percent). In vivo plaque pH resultsshowed sucrose licorice with aminimum plaque pH of about 5.0,experimental licorice with a minimum

plaque pH of about 5.5, and a sucroserinse with a plaque pH of about 4.5.

The results of this study show thatfood ingredients like soy flour cancontribute to the cariogenicity of a foodregardless of the presence of a sugaralcohol.

Gallagher and Fussell (Ref. 44)compared the in vitro fermentability ofxylitol and other sugar alcohols withsucrose in dental plaque. Plaquecollected from adults and children ofdifferent ages was incubated in brothculture. Acid production was measuredas pH. The control media contained noadded carbohydrates.

The results of acid productionmeasurements showed that sucrose wassignificantly more acidogenic comparedto the control and xylitol. Differenceswere significant. There was nosignificant difference in acid productionbetween the control groups and thexylitol groups.

Gehring and Hufnagel (Ref. 45)described intra- and extraoral pHmeasurements of dental plaque. Sixadult men and women rinsed for 2 minusing one of seven test substancesfollowed by intraoral plaque pHmeasurements after 3, 4, 5, 7, 9, 13, 17,21, 27, and 32 min. For the extraoraltest, visible plaque was removed,suspended in distilled water, and thepH measured at 3, 5, 7, 9, 11, 15, and25 min after subjects rinsed with testsubstances. Test substances included 20percent solutions of glucose, sucrose,fructose, HSH, mannitol, isomalt,sorbitol, sorbose, or xylitol.

The results of the intraoral plaque pHmeasurements showed only slight pHdecreases within 5 min afteradministration of xylitol and mannitol,with a return to baseline measures at theend of the 32-min test period. Sorbitol,HSH, isomalt, and sorbose reached aminimum pH just below 6.0 after 5 minfollowed by a slight increase to aboutpH 6.1 to 6.4 at the end of the testperiod. Sucrose, glucose, and fructoseshowed a minimum pH value of about4.6 to 4.7 (after 5 min) with an increaseto about pH 5.3 to 5.5 at the end of 32min. Minimum plaque pH by extraoralmeasurements were higher than the pHaccording to intraoral measurements.Sucrose, glucose, and fructose minimumpH values ranged from about 5.0 to 5.7after 5 min and increased to about 5.6to 6.0 after 32 min. Other pH valueswere not given. The authors attributethe differences in intra- and extraoralplaque pH measurements to methods inhandling plaque removal and theinfluence of saliva substances.

Havenaar et al. (Ref. 46) evaluated invitro acid formation from oral bacteriain the presence of sugar substitutes and

the influence of xylitol on glucose ingrowing cultures of S. mutans. Freshisolates of Streptococci and other strainswere obtained from caries free andcaries active subjects. Acid productionin 1-percent solutions of glucose(control), sorbose, sorbitol, xylitol,lactitol, maltitol, and HSH wasdetermined by incubating the sweetenerin phenol red broth containing oralbacteria. A color change indicated acidformation. Changes in pH was measuredafter subculturing S. mutans in each ofthe sweeteners, after frequentsubculturing in each sweetener to obtainadapted strains of S. mutans, and aftersubculturing the adapted strains once inglucose and resubculturing in thesweetener. Growth of S. mutans and pHmeasurements were also measured in aglucose broth with and without addedxylitol.

The results showed no acidproduction from xylitol or sorbose andacid production from sorbitol, lactitol,and HSH. The authors stated that S.mutans slowly fermented maltitol.Results also showed no change in pHwith xylitol and a moderate drop in pHto about 6 to 6.5 (actual values notgiven) with maltitol, sorbitol, lactitol,and HSH after 120 min. Adaptation byS. mutans to the sweeteners resulted ina marked increase in fermentation, withfinal pH values dropping to about 4.5 to5.5. After one subculturing of theadapted strain in glucose, S. mutans lostmost of its ability to ferment thesweeteners. The addition of smallamounts of xylitol to glucose brothsomewhat inhibited acid productionfrom S. mutans, but it had no effect onfinal pH attained.

Jensen (Ref. 47) measuredinterproximal plaque pH in subjectsusing five different HSH’s and sorbitoland sucrose as controls. Four subjectsrinsed with a 5 milliliter (mL) portionof the test solution for 60 min. PlaquepH was then monitored for 30 min.Following the pH measurements, thesubject rinsed their mouth with distilledwater and chewed paraffin for about 5min to bring oral pH back to restinglevels. The test was repeated with eachsubject using each of the four testsolutions.

The results showed that plaque pH forall test substances remained above pH6.0 over the 30-min test period. PlaquepH using the sorbitol rinse was similarto that using the test substances. Usingthe sucrose rinse resulted in plaque pHmeasurements of approximately 4.0 to4.1. The identity of the test substanceswas not provided in this unpublishedstudy. Results indicate that the HSHsolutions used in this study were


significantly less acidogenic thansucrose and no different than sorbitol.

Maki et al. (Ref. 48) compared acidproduction in vivo from isomaltulose,sorbitol, xylitol, and sucrose (control) inhuman dental plaque. Dental plaquewas collected from 12 individuals andincubated with phosphate buffer. Afterendogenous acid production wasmeasured, a 1-percent solution of thetest substance in the same buffer wasadded, and acid production measuredagain.

The results showed no acidproduction in the presence of xylitol.Compared to sucrose (100-percent acidproduction), acid production fromsorbitol was 1 percent. The authorsnoted that the percent acid productionfrom sorbitol may vary considerablyamong individuals and with the amountof exposure to sorbitol.

Park et al. (Ref. 49) measuredinterproximal plaque pH in five subjectsafter consuming one of three snacksalone or one of three snacks followed bya single mint containing sorbitol (94percent) or a sorbitol and xylitol blend(79 percent and 15 percent,respectively). When mints were used,they were consumed 3 min followingingestion of the sweet snack. Snackstested included a sandwich cookie,cupcake, and granola bar. A randomizedblock design was used to administer thetest products and mints (see Table 2 forfurther details). The lowest plaque pHattained after consuming the three testproducts without mints ranged from4.02 to 4.16. When the sorbitol mint wasconsumed following the test product,mean plaque pH values increased andranged from 4.68 to 5.04. When thesorbitol and xylitol mint was consumedfollowing consumption of the testproducts, mean plaque pH increased toa range of 5.32 to 5.60. Differences inmean plaque pH values between themint products differed significantlywhen the mints were used after thegranola bar and cupcake challenges.There was no significant difference inmean plaque pH between the sorbitol(5.04) and the sorbitol and xylitol mint(5.60) products when these productswere used after the sandwich cookiechallenge.

The results show that consumption ofa sugarless mint reduced theacidogenicity of the test snacks,although final pH values remainedbelow pH 5.5 in all but one test. Theauthors attributed the results of thisstudy to the stimulatory effects onsalivary flow by sugar alcohols.Increasing salivary flow increases thebuffering capacity of saliva, thusreducing the acidogenic potential of avariety of snack foods. The authors also

attributed the additional bufferingeffects of the sorbitol and xylitol mint tothe presence of xylitol and its potentialbenefits in reducing plaque microbialactivity. Without a sucrose-containingmint as a comparison, however, theinfluence of sugar alcohols on salivaproduction cannot be adequatelyassessed.

Soderling and coworkers (Ref. 50)investigated the effect on dental plaqueof chewing gums that contained eitherxylitol, sorbitol, or a mixture of xylitoland sorbitol and compared the resultswith those obtained with subjects whoused sucrose gums. Twenty-one subjects(adults, ages 19 to 35 yr) who were nothabitual gum chewers were randomlyassigned to chew gum containing eitherxylitol, sorbitol, or a blend of the twosugar alcohols for 2 wk. Subjectschewed 10 pieces of gum per day for anintake of either 10.9 g xylitol, 10.9 gsorbitol, or 10.9 g xylitol and sorbitol(8.5 g xylitol and 2.4 g sorbitol). Thecontrol group was made up of sevenhabitual sucrose gum users. Subjectsmaintained their usual diets and oralhygiene except just before to clinicvisits. Interdental plaque pH wascollected, and the resting plaque pHdetermined. Plaque pH was measured at2, 5, 10, 15, and 20 min after an oralrinse containing the same sugar alcoholsas used in the gum. Afterward, subjectsrinsed with water and chewed a pieceof paraffin for 1 min to expedite removalof sugar alcohols from the mouth.Baseline pH was again measured,followed by a mouth rinse with 10 mLof 10-percent sucrose. Plaque pH wasagain determined.

The results from using gum for 2 wkshowed no significant changes in restingplaque pH in the xylitol and xylitol andsorbitol groups, whereas the use ofsorbitol gum was associated with alower pH. Final plaque pH values afteruse of sorbitol gum were significantlylower than baseline values, but all finalvalues remained above pH 6.0.

Birkhed and Skude (Ref. 51)evaluated, among other tests, the APAfrom glucose, soluble starch, andSwedish HSH in dental plaque. Elevenadults were instructed to avoid oralhygienic procedures for 2 days. Nodietary changes were required. At theend of 2 days, plaque was collected. TheAPA was determined from 3-percentsolutions of glucose, boiled solublestarch, and HSH. The APA was alsodetermined in increasing concentrations(0.003 to 12 percent weight per volume(w/v)) of starch and HSH.

The results showed significantlylower (p<0.001) APA from solublestarch (75.7 percent) and HSH (61.5percent) compared to glucose (99.7

percent). The APA from HSH was alsosignificantly lower (p<0.01) than thatfrom soluble starch. The range ofoptimum acid production for bothsubstrates was 0.03 to 6 percent. Theauthors noted that Swedish HSH ismore fermentable than French HSH,which contains less high molecularweight hydrogenated saccharides thanSwedish HSH.

Grenby et al. (Ref. 76) evaluated thedental properties of lactitol compared tofive other bulk sweeteners, i.e., sucrose,glucose, sorbitol, mannitol, and xylitol,in vitro using a standardized mixedculture of dental plaquemicroorganisms. Sweeteners wereincubated for 24 hours (h) in mediacontaining a 1-percent solution of one ofthe six sweeteners. Plaquemicroorganisms were also incubated inmedia containing the sweeteners withsegments of intact surfaces or withsegments of pulverized dental enamel.The demineralization action of the acidproduced by microbial fermentation wasassayed by calcium and phosphorousanalyses.

The greatest amount of acidproduction and lowest pH (significantlydifferent than the sugar alcohols) werereported with sucrose and glucose (pHof 4.0 to 4.3). Lactitol and xylitolshowed only slight changes in pH andacid production over the 24 h (final pHof 6.1 to 6.3); whereas sorbitol andmannitol showed slight changes in pHduring the first 12 h (pH≥6), thengradually decreased to a final pH of 4.6to 5.1 after 24 h.

The results of the demineralizationtest showed highly significantdifferences (p<0.001) between sucroseand glucose and the sugar alcohols. Thereductions in calcium and phosphorousdissolving in sorbitol wasapproximately 80 to 85 percent,mannitol 63 to 69 percent, and lactitoland xylitol 94 to 98 percent comparedto mineral loss in the presence ofglucose.

3. Summary of Evidence Relating SugarAlcohol and Dental Caries: Long-TermStudies

Moller and Poulsen (Ref. 20)determined the effect of long-termchewing of sorbitol chewing gum on theincidence of dental caries, plaque, andgingivitis. The sorbitol chewing gumcontained calcium phosphate whichacts as a buffer in saliva to helpmaintain pH and aid remineralization.Two groups of children, ages 8 to 12 yrof age, from two different schools inDenmark took part in this 2-yr study.Group 1 chewed one piece of sorbitol-containing gum three times a day, aftermeals. Group 2 chewed no gum and


served as the control. At the start of thestudy, subjects in group 1 had moredecayed and filled toothsurfaces thanthe control group; however, thedifferences were not statisticallysignificant.

The results showed that the sorbitolgroup had a significantly lowerincidence of dental caries compared tothe control after 2 yr. The control group,which did not chew gum, did notexperience the same salivarystimulation from the chewing of gum,nor did they have an equivalent sourceof calcium phosphate. These are largeconfounders in this study. The authorsnoted a number of factors that couldcontribute to the observed results, suchas the sorbitol content of the chewinggum, reduced consumption of sugar-containing sweets, intra-examinervariability, and other unknownconditions.

Banozcy et al. (Ref. 21) evaluated theeffect of sorbitol-containing sweets onthe caries increment of children aged 3to 12 yr, in a clinical longitudinal studyplanned for 3 yr. The test groupconsumed 8 g of sorbitol per daybetween meals, while the control groupconsumed a similar amount of sucrose-containing sweets.

The results showed that meandecayed, missing, or filled (DMF) valuesfor teeth in the sorbitol group were 1.09,0.90, and 1.18 in the first, second, andthird yr, respectively. The sucrose grouphad mean DMF values of 2.61, 1.86, and1.13 for the first, second, and third yr,respectively. The differences in cariesincrements were significant (p<0.001) inthe first and second yr but not in thethird yr. The authors noted that the lackof significance in the third yr may beattributed somewhat to a lack of subjectcompliance since the children in thesorbitol group traded sweets with thesucrose group, in addition to otherfactors. Results of this study indicatethat sorbitol is less cariogenic thansucrose.

Kandelman and Gagnon (Ref. 22)reported on the incidence andprogression of dental caries in schoolchildren after 12 mo of a 2-yr studyusing xylitol in chewing gum. Thesubjects were 433 children, ages 8 to 9yr old, from 13 elementary schools, andwere from low socioeconomic areaswith a high caries rate. The childrenwere assigned to one of three groups: Acontrol group that received no chewinggum and chewed no gum while atschool, a test group that received gumcontaining 15-percent xylitol and 50-percent sorbitol (XYL15), and a secondtest group that received gum containing65-percent xylitol (XYL65). Studentswere not randomly assigned to groups.

Rather, an entire class was assigned toone of the three groups. The XYL65group consumed 3.4 g xylitol per day,and the XYL15 group consumed 0.8 gper day.

The results showed significantlylower net progression of decay (NPD)(i.e., the difference in the number ofreversals from the progressions of decayfor each child) in the XYL65 group(1.25) than in XYL15 group (1.87) (p<0.05), and each xylitol group hadsignificantly (p<0.001) lower NPD thanthe control. The decayed, missing, filledsurfaces (DMFS) increment was alsosignificantly lower in the xylitol groupscompared to the control. There was nosignificant difference in DMFS betweenthe gum groups. Results of this studysuggest that chewing gum containingxylitol or a blend of xylitol and sorbitolprovided more benefits for teeth thannot chewing gum at all.

Rekola (Ref. 23) compared theprogression of incipient carious lesionson buccal smooth surfaces in subjectsparticipating in the 2-yr Turku sugarstudy (Ref. 24). Subjects consumedeither a diet containing sucrose or onewith almost complete replacement ofsucrose products with xylitol-containingproducts. The progression of cariouslesions were assessed by use of colordental photographs of the right and leftsides and of the front of maxillary andmandibular teeth.

The results showed that the sucrosegroup had a significant tendency forincreased size of carious lesions overthe 2-yr period compared to the groupconsuming xylitol (p<0.01). The whitespot lesions in the xylitol group weresignificantly smaller than those in thesucrose group.

Rekola (Ref. 25) quantified changes inthe size of approximal carious lesions insubjects after 2 yr of almost completesubstitution of dietary sucrose withxylitol (Ref. 23). Bitewing radiographswere taken during the 2-yr study. In thisstudy, the radiographs were projectedonto a planimetry plate so that the areaof the lesions could be determined. Thesizes of the lesions at the different timeperiods were compared, and the rate ofcaries progression was also compared.At the beginning of the study, there wasno difference in the mean size of cariouslesions between groups. The size of theapproximal lesions, i.e., lesions thatwere neither filler nor overlapping at 0and 24 mo, in the sucrose groupincreased significantly (p<0.001) over 2yr compared to the lesions in the xylitolgroup. The lesion size in the xylitolgroup remained virtually unchanged.

The authors reported a trend towardsdecreasing lesion size in canines andfirst molars compared to molars and

second premolars in the xylitol group.This trend was not observed in thesucrose group. Results of these studiessupport the observation that xylitol isless cariogenic than sucrose.

In a World Health Organization(WHO) field trial in Hungary (Ref. 26),the effects of a partial substitution ofsucrose for xylitol in the diets of 689institutionalized children, ages 6 to 11yr, were examined. The xylitol groupused fluoride dentifrice and consumedno more than 20 g of xylitol per day inchewing gum, chocolate, hard candy,and wafers. The fluoride group receivedfluoride in dentifrice, water, and milk,but consumed no xylitol products. Thecontrol group received no fluoridetreatment and consumed no xylitol-containing products. After 3 yr, thexylitol group had a statisticallysignificant (p<0.001) lower incidence ofcaries compared to the control andfluoride groups. The authors noted thatresults from this study were obtainedunder conditions where cariesprevalence and incidence were stillhigh. Results of this study support theobservation that xylitol-containingproducts are less cariogenic thansucrose-containing products.

In a 2-yr substudy (Ref. 28) of theWHO xylitol field studies in Hungary(Ref. 26), Scheinin and coworkersassessed the caries increment withsystemic fluoride (fluoride group) andrestorative treatment only (controlgroup). This study differed from the 3-yr study primarily in baselinedifferences. Children entering theinstitutions during the first yr of the 3-yr study were included in this substudy.

The substudy showed similarfavorable results with xylitol comparedto the control. The caries increment was3.8 in the xylitol group, 4.8 in thefluoride group, and 6.0 in the controlgroup. The differences in cariesincrement between the xylitol groupand the other two groups weresignificant (p<0.001). Results againsupported a lower incidence of carieswhen xylitol is substituted for sucrosein the diet.

In a WHO field trial in Thailand andFrench Polynesia (Ref. 29), theusefulness of a fluoride rinse,fluoridated sucrose chewing gum, andfluoridated xylitol (51 percent) andsorbitol gum in controlling dental carieswas evaluated in children over a 3-yrperiod. In French Polynesia, a fourthgroup used nonfluoridated chewinggum sweetened with xylitol (51 percent)and sorbitol. Approximately 250children at each of the ages 6 to 7 yr,9 to 10 yr, and 12 to 13 yr wereexamined. The 12- to 13-yr age groupwas intended to provide data for


comparison with the 9- to 10-yr oldgroup, who would be ages 12 to 13 yrat the end of the study.

The results from the Thailand studyshowed that the fluoridated xylitol andsorbitol gum group had lower decayed,missing, and filled teeth (DMFT) andDMFS scores than either the fluoriderinse group or the fluoridated sucrosegum group. Results from the FrenchPolynesia study showed that thesubjects started with much higherDMFT and DMFS mean scores initiallythan the subjects in Thailand. Althoughthe results with the fluoride gumsweetened with the sugar alcohols werebetter than any of the other treatments,the overall caries incidence in thispopulation is very high. The presence offluoride in the chewing gums confoundsthe results of the sugar alcohols. Theauthors describe this study populationas a community experiencing anincrease in the prevalence of thedisease. This study group does notreflect the general population of theUnited States.

In another WHO field trial,Kandelman and coworkers (Ref. 30)evaluated the effects of xylitolintervention on dental caries in FrenchPolynesian children, ages 7 to 12 yr. Of746 subjects enrolled in this 32-mostudy, 468 completed the study.Subjects in the xylitol groups consumed20 g of xylitol daily in various foodproducts, such as chewing gum, hardcandy, chocolate, and gumdrops. Thecontrol group received no xylitol-containing products.

The results showed significantlyreduced caries increment rate by 37percent to 39 percent in the xylitolgroups compared to the controls. Thisstudy was neither randomized norblinded. Results support the observationthat xylitol-containing products are lesscariogenic than the sucrose-containingproducts.

Frostell and coworkers (Ref. 31)determined the effect on cariesincrement in children, ages from 21⁄2 to4 yr, of substituting HSH for sucrose incandy. During this 11⁄2- to 21⁄2-yr study,subjects in the test group consumedcandies made with HSH and chewinggum made with sorbitol. The controlgroup consumed sucrose candies andgum. Investigators monitored the intakeof candies by use of coupons which theparents used at local stores to buy thecandy. An analysis of the coupons usedshowed that parents of the children inthe test group used a smaller number ofcoupons than the parents of the childrenin the control group. Based on inquiries,the investigators discovered that theparents of the subjects in the HSH grouphad also given the children other candy

in addition to HSH candy. Theconsumption of HSH candy wasreported from 50 to 75 percent of thetotal candy consumption.

The results showed no significantdifferences in caries scores after 11⁄2 to21⁄2 yr with HSH candy consumptioncompared to sucrose candyconsumption. When investigatorsanalyzed the data of those childrenwhose parents consumed the correctcandy for their group, the differences incaries increment between the groupswere still not significant but showed atrend towards a lower incidence ofcaries in the HSH group. The results ofthis study were confounded by poorcompliance, inter-examiner variability,lack of blinding, and inconsistentresults and do not support significantdental benefits from the use of HSH.

Glass (Ref. 32) evaluated thecariogenicity of sorbitol chewing gumwith regular use by children, ages 7 to11 yr old, living in a nonfluoride area.In this 2-yr study subjects wererandomly assigned to either a no-chewing group (control) or to the onewhich chewed gum twice daily.Subjects in the gum group wereprovided two sticks of gum daily for useat school and four sticks of gum for useat home when school was not insession.

The results showed that over the 2-yrstudy period, mean caries incrementswere 4.6 new decayed and filled (DF)surfaces for the sorbitol gum group(n=269) and 4.7 new DF surfaces for theno-gum group (n=271). The differencebetween the groups was not statisticallysignificant. Although the results of thisstudy suggest that adding sorbitol-containing gum to the diet did not resultin any additional dental caries, theeffect of chewing gum per se on theincidence of dental caries was notconsidered.

4. Summary of Evidence Relating SugarAlcohol and Dental Caries: Short-TermStudies

Ikeda et al. (Ref. 33) evaluated thecariogenicity of maltitol and apolysaccharide alcohol using anintraoral cariogenicity test (ICT) and rattests. Most of the details of the methodsused in the ICT were not provided,making the results difficult to interpret.Bovine enamel fragments wereextraorally dipped in 3-percentsolutions of sucrose (control), maltitol,or the polysaccharide alcohol for 1 minevery day. After 1 wk, hardness wasmeasured. The higher the value forhardness means a softer enamel and agreater loss of enamel.

The results showed a decalcificationscore for maltitol of 1.66 compared to a

score of 2.70 for sucrose. Thesedifferences were significant. In theanimal study, one group was provideda feed with 26-percent maltitol and 30-percent starch, a second group wasprovided a feed with sucrose instead ofmaltitol, and a third group consumed adiet without sucrose. Results showed acaries score of 45.8 for the sucrosegroup, 3.2 for the maltitol group, and 5.2for the no-sucrose group. Differencesbetween the sucrose group and the othergroups were statistically significant.

Yagi (Ref. 34) evaluated the effects ofmaltitol on changes in enamel hardness.Enamel decalcification was measuredusing an ICT with a denture containingtwo bovine enamel slabs. Four subjectswore the dentures for 7 days. Each day,one enamel slab was exposed to a 3-percent maltitol solution and the otherto a 3-percent sucrose solution. Enamelhardness was measured at the end of thewk.

The results showed that the averagechange in hardness compared topretreatment levels for the enamel inmaltitol was 1.47 micrometerscompared to 3.35 micrometers for theenamel in sucrose. Differences betweenthe two measurements were significant.The authors noted that there wereconsiderable differences in individualresponses to sucrose and maltitol. Theyattributed these differences to the oralenvironment (e.g., plaque bacteria andquality and quantity of saliva).However, general observations were thatsucrose causes significant loss ofenamel, as evidenced by changes inenamel hardness, compared to the effectof maltitol on tooth enamel.

Leach et al. (Ref. 35) evaluated in situthe effect on remineralization ofartificial caries-like lesions in humanenamel with sorbitol. Ten adult subjectswore cast bands containing enamel onone lower first molar tooth for two 3-wkperiods during which they continued touse normal oral hygiene procedures.Artificial caries lesions were made ineach enamel slab and covered withgauze to encourage the formation andaccumulation of plaque on the enamelsurface. Subjects were given snack foods(chocolate bar, raisins, cream-filledwafers, and cream-filled, iced cupcake)and instructed to consume one eachmorning and afternoon between meals.During the first experimental period,subjects chewed, for 20 min each, fivesticks per day of commercial sugarlessgum after meals and snacks. The gumwas sweetened primarily with sorbitoland small amounts of mannitol, HGS,and aspartame. During the secondexperimental period, snacks wereconsumed but without chewing gum(control).


The results showed statisticallysignificant (p<0.001) remineralizationduring both experimental periodscompared to the original lesion. Thedifference between the remineralizationwith and without gum was alsosignificantly different (p<0.01),indicating overall promotion ofremineralization by gum chewing. Theauthors attributed the remineralizationduring the nongum period to thepresence of gauze used with theintraoral device to collect plaque. Thegauze could have concentrated calciumand phosphates from the diet in plaqueand fluoride from dentifrice. It is notknown what effects the duration andtiming of the gum chewing had on theresults. Without a comparison tosucrose-containing gum and anonsweetened gum, it is not possible toevaluate the effect of chewing gum for20 min.

Rundegren et al. (Ref. 36) evaluated insitu the effect on demineralization ofsucrose substitutes in a 4-wk test.Intraoral devices containing bovineenamel mounted on acrylic blocks wereused with group 1. Partial dentures withenamel slabs were used with group 2.Sweeteners tested included 10 percentsolutions of sucrose, maltitol, and HSH.Sucrose was used as the positivecontrol, and 0.9-percent solution ofsodium chloride was used as a negativecontrol. Subjects immersed the test sitesof their appliances in the test sweetenerfour times a day for a 10-min period.Plaque was collected at the end of 4 wkand plated to determine the content ofS. mutans. The degree ofdemineralization was measured byevaluating changes in microhardness ofthe enamel. The buffering capacity ofwhole saliva was evaluated weekly bymeasuring final pH in a mixture of 1 mLof saliva and 3 mL of sodium chloride.

The results showed a higher degree ofdemineralization overall in the adults(ages 56 to 59 yr) using the partialdentures compared to students (age 19yr) using an intraoral device. Resultsfrom the test (n=4) of enamelmicrohardness in HSH versus sodiumchloride suggest that HSH does notcontribute to demineralization, and thatmeasured changes in microhardnessreflected the background of fermentablecarbohydrates in the diet. Comparingthe differences in microhardness ofenamel slabs between the sucrose andHSH diets and the sucrose and maltitoldiets showed that sucrose results insignificant demineralization comparedto the sugar alcohols.

Creanor et al. (Ref. 37) evaluated theeffect of chewing gum for 20 min on insitu enamel lesion remineralizationcompared to a fluoridated dentifrice.

Artificial enamel lesions were created invitro in sound human enamel andmounted for wearing just opposite thelower first and second molars. Baselinemineral contents were measured.Subjects used a fluoridated dentifricetwice daily and maintained their regulardiets. Six subjects chewed five sticks ofchewing gum containing sorbitol andsome HGS and aspartame after eachmeal and snack. The gum was chewedfor 20 min in order to minimize anydeleterious effects of sucrose. Six othersubjects received no gum and served asthe control. At the end of 7 wk, the testsubjects became the control group, andthe control subjects became the new testgroup. The new test group then chewedsucrose-containing gum for 7 wk.

The results showed that after usingsugar-free gum for 7 wk, the degree ofmineral loss for the enamelcorresponded to a remineralizationvalue of 18.2 percent. After 7 wk ofchewing sucrose gum, the percentremineralization was calculated to be18.3 percent. The difference betweenthe sorbitol and sucrose gum groups wasnot significant. Results of this studysuggest that chewing gum for 20 min,regardless of the sweetener, can bebeneficial to dental health.

A common problem in studiesevaluating the dental health benefits ofsugar alcohol-containing chewing gumis the absence of an appropriate controlgroup. Most of the studies that havebeen done use a control group that doesnot chew gum. Ideally, to evaluate therelationship of sugar alcohol-sweetenedchewing gum in not promoting dentalcaries, the control group would chew anunsweetened gum product. Such agroup is needed to take intoconsideration the effects of chewinggum itself on the endpoint measure, e.g.,plaque pH or plaque acid production.Chewing gum is known to stimulatesaliva, which can help neutralize oralacids, raise plaque pH, and help topromote enamel remineralization insome circumstances. It would beconsidered unethical by standards inthe United States to use a control groupthat chews sucrose-containing gum and,as a consequence, puts the subjects atrisk of dental disease, in order tocompare the incidence of dental cariesto that from a sugar alcohol-containinggum.

The few long-term caries field trialsthat were submitted with this petitionshow how multiple problems in theexecution of clinical studies can easilyconfound the results. Problems ofteninclude subject compliance, reportingand control of dietary intake, selectionof appropriate control foods, inter- andintraexaminer variability, subject

attrition, and inability to blind thestudy. The majority of these trialscompared sucrose consumers toindividuals who had partial or completesubstitution of sugar alcohols forsucrose. The results consistentlydemonstrated significantly fewer cariesin the group consuming sugar alcoholsthan in the group consuming sucrose.

Although the relationship betweensome of the sugar alcohols andpromotion of dental caries has not beenwell studied in humans, it is becomingincreasingly evident that sugar alcohols,when substituted for sucrose and otherfermentable carbohydrates, may provideimportant dental health benefits for theconsumers of those products.

D. Animal StudiesFDA reviewed over 20 animal studies

investigating the effects of sugar alcoholconsumption on the incidence of dentalcaries or on the acidogenic potential ofdental, S. mutans, or mixed oralmicroorganisms. Most of the animalstudies that have been done to test theeffect of sugar alcohols on the incidenceof caries were programmed feedingstudies using weanling rats. Theanimals were usually divided intogroups and fed diets containingdifferent test sweeteners. The controldiets were either a basal diet with nocarbohydrate sweeteners or sugarsubstitutes or a basal diet with addedsucrose. The test diets wereadministered over a period of weeks,increasing the sugar substituteconcentration slowly to allow theanimals time to adapt to the specificsweetener and to minimize the severityof diarrhea, a side effect of sugar alcoholconsumption that increases withincreasing concentration of the sugaralcohol.

Investigators also evaluated thegeneral health and growth of theanimals during the experimental period.Many animals, and rats in particular, donot like the taste of sugar alcohols and,therefore, will eat less of the test dietand increase their intake of water. Mostinvestigators monitored the animals’total dietary intake to ensure thatconsumption patterns were similarbetween the control and test animals.

A potential confounding factor inthese studies is the effect of total foodand water intake on caries development.If animals consume less of a sugaralcohol diet compared to the controlanimals consuming a sucrose diet, anysignificant differences in cariesincidence may actually be attributableto the differences in food and waterconsumption and not to an effect of thesugar substitute. Some studies reporteda lower survival rate in animals on the


sugar alcohol diets. This finding madeinterpretation of the results moredifficult because of uneven group sizes.

In order to promote the cariogenicprocess, the animals were inoculatedwith either mixed strains of plaquebacteria or purified strains of S. mutansand other microorganisms found indental plaque. Experimental periodslasted, on the whole, for 60 to 70 days.These periods included the time givenfor the animals to adapt to the test diets.

Havenaar et al. (Ref. 52) fed S. mutansinoculated rats one of six diets 18 timesa day: The basal diet plus 50-percentstarch, or the basal diet plus 30-percentstarch and 20 percent of either sucrose,HSH’s, xylitol, sorbitol, or L-sorbose. Ina second experiment, the rats were fedthe same diets 14 times a day andalternated with the basal diet containing20-percent sucrose and 10-percentglucose (four times a day). In bothexperiments, the starch, HSH, xylitol,and L-sorbose groups showedsignificantly less fissure lesions than thesorbitol and sucrose groups. Thesorbitol group showed significantly lessfissure caries in the mandibular molarswith respect to the severity of thelesions compared to the sucrose group.

Havenaar et al. (Ref. 53) in fivesuccessive experiments, fed rats adlibitum on diets containing sucrose orHSH 80/55. In each experiment, the ratswere inoculated with plaque from ratsin the previous experiment (Ref. 52).Results showed that compared tosucrose, HSH was relativelynoncariogenic. The incidence of fissurecaries in the mandibular molars for ratsconsuming 20-percent sucrose was 13.1,whereas the fissure caries incidence inrats consuming 20-percent HSH was 1.5to 2.5 (p<0.001).

Havenaar et al. (Ref. 54) evaluated theusefulness of diets for testing the cariespromoting or inhibiting properties ofsugar substitutes. The investigators fedtwo groups of rats experimental diet2000 containing 50-percent sucrose and14-percent starch or 50-percent sucrose,9-percent starch, and 5-percent xylitolfor a period of 42 days. Results showedno significant differences in cariesincidence between the sucrose starch,the xylitol group and the sucrose andstarch group. In another experimentanimals were fed diet SSP 20/5containing 20-percent sucrose, 5-percentglucose, and 25-percent starch or 20-percent sucrose, 5-percent glucose, 20-percent starch, and 5-percent xylitol fora period of 66 days. Results showed thexylitol, sucrose, and starch group tohave significantly fewer caries (12.3caries versus 14.8) compared to thesucrose, starch, and glucose group.

Havenaar and coworkers (Ref. 55) fedone group of rats a basal diet containing20-percent sucrose, 5-percent glucose,and 25-percent starch. The test groupreceived the basal diet with 20-percentstarch and 5-percent xylitol andfluoride. After 54, 75, or 96 days, ratswere crossed over to the other diet foran additional 21 to 42 days. Resultsshowed that the xylitol group hadsignificantly fewer fissure caries thanthe sucrose group. The authors alsoreported that the longer theexperimental period, the more severethe caries, irrespective of the presenceof xylitol. After crossover, total numbersof caries did not change, but the xylitolgroup showed significantly fewer initiallesions compared with the mean cariesincidence in the sucrose group on day54.

Grenby and Colley (Ref. 56) fed acontrol group of rats a cariogenic dietcontaining 46-percent sucrose and fedtwo test groups the same cariogenic dieteither with 20 percent of the sucrosereplaced with xylitol, sorbitol, mannitol,or wheat starch (experiment A). Theanimals consuming sorbitol andmannitol did not remain healthy duringthe experiment, so this part of theexperiment was terminated. Theanimals consuming xylitol alsoexperienced difficult health effects atfirst but later improved and werereturned to the 20-percent xylitol diet.In experiment B there were only twodiets: A cariogenic diet with 46-percentsucrose and an experimental diet with10 percent of the sucrose in the dietreplaced with xylitol.

In experiment A, significantly fewercaries were experienced only in thegroup consuming the sucrose andxylitol diet compared to the controlgroup. In experiment B, the level ofcaries was high for both the sucrosegroup and the sucrose and xylitol group.The overall caries scores were notsignificantly different.

Karle and Gehring (Ref. 57) evaluatedthe effect of sugar alcohols and sucroseon both xerostomized (salivary glandsremoved) and nonxerostomized rats.The control group consumed a basaldiet without sweetener. Test groupsreceived the basal diet plus sucrose,xylitol, isomalt, or other sweeteners.Sweetener concentrations wereincreased over a 3-wk period to a levelof 30 percent of the diet. Thexerostomized rats had more caries withall substances than the nonxerostomizedrats. Sucrose was shown to be the mostcariogenic sweetener, and xylitol theleast cariogenic, in the nonxerostomizedrats. Both the xylitol and isomalt groupshad significantly fewer caries than thesucrose group.

Muhlemann and coworkers (Ref. 58)compared the cariogenicity of diet 2000(containing 64-percent wheat flour) tothe same diet containing xylitol orsorbitol (15 percent and 25 percent ofthe flour replaced) or sucrose (15percent and 25 percent of the flourreplaced). Sweetener mixturescontaining 15-percent sucrose and 15-percent xylitol or sorbitol and 25-percent sucrose and 25-percent xylitolor sorbitol were also substituted for theflour ingredient of the basal diet. Therats consuming diets with 15- and 25-percent sucrose experienced 17.3 and17.8 smooth surface caries, respectively.Rats consuming animal chow with 15-percent xylitol or sorbitol experienced0.0 and 1.9 smooth surface caries,respectively. The caries score for thecontrol group was 4.9. The highestnumber of fissure caries (11.3) occurredin the 25-percent sucrose group. Thecontrol group had 5.1 lesions.Substituting xylitol (25 percent) in thediet resulted in fewer caries (0.2)compared to the control, but differenceswere not significant. Twenty-fivepercent sorbitol in the diet produced acaries score of 2.8.

Shyu and Hsu (Ref. 59) evaluated thecariogenicity of 10-percent xylitol,mannitol, sorbitol, and sucrose in ratsfed a plain basal diet. A control groupwas fed the basal diet withoutsweetener. Caries evaluations weremade on the 45th and 90th days offeeding. The xylitol group had 86percent fewer caries (significant)compared to the sucrose group and 76percent fewer caries than the control.The mannitol group experienced 70 and51 percent fewer caries than the sucroseand control groups, respectively. Thesorbitol group experienced 48 and 14percent fewer caries than the sucroseand control groups, respectively.

Bramstedt et al. (Ref. 60) evaluatedthe cariogenicity of isomalt, xylitol, andsucrose in 60 rats divided into fivegroups. The control diet was a basic dietcontaining half synthetic feed. Anothercontrol group received a special basicdiet containing no low molecular weightcarbohydrates. The test groups receivedthe basic diet with increasing doses ofsweetener up to 30 percent of the diet.The sucrose group had a significantlyhigher number of caries than either ofthe sugar alcohol groups. The groupconsuming the special basic diet had thelowest incidence of caries. There wereno significant differences in the numberof caries between the basic diet, xylitol,and isomalt groups, although theisomalt group showed a slightly higherincidence of caries.

Izumiya et al. (Ref. 61) fed rats 10 or20 percent by weight of sweeteners in


feed. Rats consuming a dietary feedcontaining 10-percent maltitol hadsignificantly fewer caries than thesucrose group. Details of this study andthe results were not given in thisreference.

Gehring and Karle (Ref. 62) evaluatedthe cariogenic properties of isomalt, incomparison to those of sucrose andxylitol in the basal diet of conventionaland gnotobiotic (i.e., specially rearedlaboratory animals in which themicroflora are specifically known) rats.The final concentration of sweetener inthe feed was 30 percent. A secondexperiment was performed usingisomalt, xylitol, sorbitol, and sucrose inchocolate. The basal diet constituted 40percent of the total diet, and thechocolate constituted 60 percent. Theisomalt group had significantly fewercaries than the sucrose group, and thexylitol group had significantly fewercaries than the isomalt group. Thesecond experiment showed significantdifferences in caries experience after theT (initial caries lesions) and B(advanced caries) stages between thesucrose and sorbitol chocolate groups,the sorbitol and isomalt chocolategroups, and also between the isomaltand xylitol chocolate group. The orderof cariogenicity of the test substanceswas sucrose greater than (>) sorbitol >isomalt > xylitol > control. An in vitromicrobiological experiment wasperformed to test acid productioncapacity of plaque microorganisms in 10percent solutions of isomalt,glucopyranosido mannitol (GPM),glucopyranosido sorbitol (GPS), sorbitol,mannitol, sucrose, and fructose. GPSand GPM are the two components thatmake up isomalt. Sucrose produced acidrapidly and had the greatest acidformation. Sorbitol and mannitolproduced acid slowly, and isomalt andits two components had practically noacid production in vitro.

Karle and Gehring (Ref. 63) evaluatedthe cariogenicity of isomalt in rats. Sixgroups of rats received the basic dietwithout low molecular weightcarbohydrates in addition to xylitol,sorbose, isomalt, lactose, and sucrose.The control group received only thebasic diet. Sweetener concentrationswere increased slowly up to 30 percentby weight of the basic feed. The highestnumber of fissure caries were caused bysucrose (about 33) followed by lactose(25), isomalt (about 13), sorbose (about12), xylitol (about 7) and the control (5).Differences in caries incidence betweenthe sucrose and the other groups weresignificant.

Larje and Larson (Ref. 64) fed rats acaries diet, diet 2000, to which varioussweeteners were added. The caries diet,

containing 56 percent sucrose, was usedas a control ration. Sucrose substitutesused in at least one of the experimentsincluded glucose, fructose, mannitol,sorbitol, potato starch, starch/sucrosemixtures, or HPS (contains sorbitol andhydrogenated dextrins). In the firstexperiment each group was fed diet2000 for a few days, then they werechanged to one of the diets containinga sucrose substitute. Each test diet wasfed for 7 out of every 14 days followedby rotation back to the control diet. Thediets were changed every 2 or 3 daysaccording to a predetermined schedule.A second experiment was designed todetermine the effect of feeding thesucrose diet after the period of bacterialimplantation on diets containingsucrose substitutes. The animalsconsumed one of the test diets the firstweek while being inoculated with S.mutans, followed in the final 7 wk bythe control diet containing sucrose. Athird experiment was designed todetermine the effect of feeding sucroseand sucrose-substitute dietsintermittently after the period ofbacterial implantation on the sucrosediet. The animals consumed diet 2000the first wk, followed in the final 7 wkby diets containing the sugarsubstitutes.

The results of the first experimentshowed significantly (p<0.001) fewersmooth surface caries with all sugaralcohols, potato starch, dextrose, andhydrogenated starch compared to thesucrose group. Significantly (p<0.05)fewer sulcal caries were experienced inthe groups receiving mannitol, sorbitolplus starch, potato starch, and HPScompared to the sucrose group. Theauthors observed that in all of theexperiments, every group in whichsucrose was restricted, whether bydietary substitution or by shortenedfeeding periods, developed significantlyfewer caries on smooth surfacescompared to the sucrose controlanimals. The animals in the mannitol,sorbitol plus starch, and sorbitol groupsconsumed less food during the testperiod compared to the sucrosecontrols. The authors stated that foodconsumption and weight gains weredirectly related to the incidence ofcaries.

The results of experiment 2 showedsignificantly (p<0.001) fewer smoothsurface caries in groups fedhydrogenated starch, potato starch,dextrose, fructose, sorbitol plus starch,dextrose plus fructose compared to thesucrose group. Groups receiving HPS,fructose, and sorbitol plus starchexperienced significantly (p<0.001)fewer sulcal caries compared to thesucrose group.

The results of experiment 3 showedsignificantly (p<0.001) fewer smoothsurface caries in groups receiving potatostarch, fructose, sorbitol plus starch,dextrose plus fructose, dextrose, andhydrogenated starch compared to thesucrose group. The overall resultsshowed that reducing the exposure tosucrose results in fewer carious lesions.

Muhlemann (Ref. 65) tested the effectsof topical applications of sugarsubstitutes on caries incidence andbacterial agglomerate formation in ratsreceiving a cariogenic diet containing20-percent sucrose. Sweeteners tested(50 percent w/v) included the following:Sucrose, mannitol, GPS, GPM, isomalt,sorbitol, maltitol, and French HSH.Three control groups were used: (1) Onegroup received the cariogenic diet (20-percent sucrose) and no topicalapplications, (2) the second groupreceived a topical application of waterwith the cariogenic diet, and (3) thethird group was treated topically withchlorhexidin digluconate (0.5 percent)as a positive control. Topical solutionswere applied five times a day for 23days.

Among the carbohydrates treatments,the isomalt, GPS, and GPM groups hadthe lowest incidence of fissure andsmooth surface caries. The differences,however, between the caries incidencein these three groups and the other testgroups were not statistically significant.The incidence of caries in thechlorhexidine control group wasstatistically significantly lower than alltreatment groups. The control groupsreceiving no application and water bothexperienced slightly more caries thanthe sugar alcohol groups. Results ofthese studies suggest that in thepresence of a cariogenic diet, topicalapplication of mannitol, isomalt,sorbitol, maltitol, or HSH does not affectthe promotion by sucrose of dentalcaries in rats.

Ooshima et al. (Ref. 66) evaluated thecariogenicity of maltitol in rats infectedwith S. mutans. Animals were dividedinto 12 groups. Group A received acontrol diet containing 56-percentwheat flour. Groups B through Lreceived the same diet as the controlgroup but had portions of the wheatflour replaced with one of the testsubstances. The sweeteners tested wereas follows: 10-percent maltitol plus 46-percent wheat flour (group B), 20-percent maltitol plus 36-percent wheatflour (group C), 10-percent sucrose plus46-percent wheat flour (group D), 10-percent sucrose plus 10-percent maltitolplus 36-percent wheat flour (group E),20-percent sucrose plus 36-percentwheat flour (group F), 20-percentsucrose plus 20-percent maltitol plus


16-percent wheat flour (group G), 24-percent sucrose plus 32-percent wheatflour (group H), 24-percent sucrose plus16-percent maltitol plus 16-percentwheat flour (group I), 28-percent sucroseplus 28-percent wheat flour (group J),28-percent sucrose plus 12-percentmaltitol plus 16-percent wheat flour(group K), or 40-percent sucrose plus12-percent wheat flour (group L).

The results of this study showed thatthe maltitol did not induce dental cariesin groups B and C compared to thewheat flour alone (group A). Groups A,B, and C experienced significantly(p<0.001) fewer caries than the sucrosegroup (group L). Groups D through I andK reported significantly (p<0.001 andp<0.01, respectively) fewer caries thangroup L. There was no significantdifference in caries score between groupJ (equal parts sucrose and wheat flour)and group L. Thus, this study suggeststhat replacing sucrose with lesscariogenic sweeteners or wheat flourresults in fewer dental caries in rats.

Tate et. al. (Ref. 67) reported on thecorrelations between progressive cariesand sugar intake in hamsters inoculatedwith S. mutans. Animals were fed a dietwith 10-percent sucrose (group 1), 20-percent sucrose (group 2), 10-percentsucrose plus 10-percent maltitol (group3), 10-percent sucrose plus 10-percentcoupling sugar (group 4), 10-percentmaltitol (group 5), or 10-percentcoupling sugar (group 6). Group 2experienced the most caries. There wasno significant difference in caries scorebetween group 1 and groups 3 and 4.Groups 5 and 6 had significantly(p<0.01) fewer caries than groups 1 or2. This reference did not providesufficient details regarding themethodology and analysis of results forpurposes of evaluating the weight of theresults.

Leach and Green (Ref. 68) fed twogroups of rats a basal diet supplementedwith sucrose plus 3-percent xylitol or 6-percent xylitol. The control groupconsumed the basal diet with sucrose.In experiment 1, rats were continuouslyfed the same diet during theexperimental period. In experiment 2,rats were fed diets alternating betweenthe control diet one day and the test dietthe next day. In experiment 1, rats fedthe sucrose and 6-percent xylitolmixture had significantly (p<0.02) fewerfissure caries than the control. Therewere no significant differences in thexylitol mixture groups. In experiment 2,both xylitol mixture diet groups hadsignificantly (p<0.001) fewer fissurecaries than the control. There were nosignificant differences among the xylitolmixture groups.

Mukasa (Ref. 69) evaluated thecariogenicity of maltitol and SE58 inrats. Product SE58 is a highly purifiedcorn starch treated with enzyme andhydrogenated. It contains 20- to 25-percent sorbitol, 20- to 30-percentmaltitol, 15- to 25-percent maltotrititol,and 30- to 40-percent maltopentaitol. Inexperiment one, three groups of ratswere fed diet 2000 containing either 56-percent sucrose, maltitol, or SE58,among other ingredients. Because therats consuming the maltitol and SE58diets experienced serious growthproblems, experiment one wasdiscontinued. In experiment two, thelevel of all sweeteners in diet 2000 wasreduced to 26 percent, with theremaining 30 percent as added cornstarch. The sucrose group had a meanfissure caries score of 31.5 and a smoothsurface caries score of 14.1. The maltitolgroup had 3.1 fissure caries and nosmooth surface caries. The SE58 grouphad 4.6 fissure caries and 0.5 smoothsurface caries. Differences between thesucrose group and each sugar alcoholgroup were significant.

Van der Hoeven (Ref. 70) evaluatedthe cariogenicity of isomalt in rats. Testdiets consisted of a base diet containing16-percent sucrose and 44-percentwheat flour and a base diet with 16-percent isomalt and 44-percent wheatflour. The control diet consisted of 60-percent wheat flour and no addedsweetener. Diets were offered ad libitumover a period of 14 wk. Results showedincreasing incidence of dentinal fissurelesions in the sucrose group (wk 2 = 4;wk 14 = 14 lesions) and almost no cariesin the isomalt group (wk 2 = 0; wk 8 =4; wk 14 = 1 lesion). There was nodifference in the incidence of cariesbetween the isomalt and the controlgroups.

Van der Hoeven (Ref. 73) evaluatedthe cariogenicity of lactitol in program-fed rats. The sweetener wasincorporated into a powdered diet,described by Havenaar et al. (Ref. 54),consisting of a basic part (50 percent),wheat flour (25-percent), and testsubstance (25-percent). Lactitol wascompared with sorbitol, xylitol, sucrose,and a control with wheat flour inaddition to the basic part. The animalsreceived 9 g of diet divided into 18portions of 0.5 g each per day. Theanimals on the xylitol and sorbitol dietswere reported to experience reducedweight gains and a reduced appearanceof the fur. None of the animals sufferedfrom diarrhea.

There were significantly fewer cariesin the xylitol, lactitol, sorbitol, andwheat flour groups compared to thesucrose group. The incidence of cariesin the lactitol and sorbitol groups was

slightly, but not significantly, higherthan in the wheat flour group. Theincidence of caries was lowest in thexylitol group.

In a twofold experiment using caries-active rats, Grenby and Phillips (Ref. 77)evaluated: (1) The cariogenicity oflactitol, sucrose, and xylitol at a level of160 g per (/) kilogram (kg), a level statedto approximate the average sucrosecontent of the diet in developedcountries, and (2) the cariogenicity oflactitol in a sweet biscuit compared toa sucrose-sweetened biscuit. In the firstexperiment, the sweetener wasincorporated into a laboratory chowcontaining white flour, skim milkpowder, liver powder, and a vitamin-mineral supplement. In the second partof the experiment, biscuits, containing166 g of lactitol/kg, were incorporatedinto the animal chow for a finalconcentration of lactitol of 110 g/kg.Animals were fed the diets for a periodof 8 wk. Experiment 1 showed highlysignificant differences in caries score,total number of lesions, and severity oflesions in the sugar alcohol groupscompared to the sucrose controls. Thesugar alcohol groups had very fewcaries, and differences between groupswere not significant. The animals inboth the xylitol and lactitol groupsrequired several weeks to adapt to thediets, showing increased water intakeand decreased food intake. Because ofpoor physical condition, only 11 of the22 rats in the xylitol group completedthe full 8-wk test. Animals on thesucrose diet were significantly heavierthan the sugar alcohol animals.

Results of the second test showedhighly significant differences betweenthe lactitol- and sucrose-biscuits groupsin all caries parameters. The averagecaries score for the lactitol group wasless than one per animal. Weight gains,however, were consistently lower, andwater intake increased in the lactitolgroup.

The results of the above animalstudies show that animals fed sugaralcohols in animal chow had fewer andless extensive caries than animals fedsucrose. The studies also show that, ingeneral, rats do not eat as much of asugar alcohol-containing diet as asucrose-containing diet and, therefore,tend to gain less weight and have morephysiological problems.

E. Summary of Human and AnimalStudies

1. Xylitol

In its 1978 review of the studies onxylitol, FASEB concluded that xylitolappeared to be noncariogenic in studiesevaluating the effect of sucrose


replacement with xylitol and in studiesevaluating the effect of partialreplacement of sucrose with xylitol inchewing gum (Ref. 14). However,FASEB concluded that it was essentialthat these studies be replicated by otherworkers in order to confirm theobservations and conclusions.

Rekola (Refs. 23 and 25) conducted afollowup assessment of results from the2-yr Turku sugar study evaluating theprogression of incipient carious lesionsand lesion sizes on buccal smoothsurfaces with dietary substitution ofxylitol for sucrose. In the 2-yr Turkusugar study, dietary xylitol was almostcompletely substituted for sucrose.Subjects were assigned to groups basedon individual preference. Rekolaexamined color dental photographs,taken during the 2-yr study, of 33subjects in the sucrose group and 47subjects in the xylitol group. The xylitolgroup showed significantly smallerwhite spot lesions and had asignificantly lower caries scorecompared to the sucrose group.

Results of several more recent humancaries studies (Refs. 22, 26, and 28through 30) reported significantly fewercaries in the xylitol group compared tothe sucrose group. Kandelman andGagnon (Ref. 22) reported significantlyless NPD and incidence of DMFT inschool children chewing three sticks perday of xylitol gum (3.4 g) or xylitol andsorbitol gum (0.9 g xylitol and 2.4 gsorbitol) compared to the nongumcontrol group. Results of xylitol fieldstudies in Hungary (Refs. 26 and 28),French Polynesia (Refs. 29 and 30), andThailand (Ref. 29) conducted by WHOshowed lower caries incidence andcaries increment rate in childrenconsuming xylitol and sorbitol inchewing gum (Ref. 29) and xylitol inother snack foods (Ref. 30) compared toa nonsugar alcohol group. However,results of the gum study in FrenchPolynesia and Thailand (Ref. 29) wereconfounded by the presence of fluoridein the gums tested. In addition, theprevalence and incidence of dentalcaries in these population groups werehigh and increasing and do not reflectthe general healthy population of theUnited States.

The effect of xylitol on acidproduction or plaque pH was studied inten studies (Refs. 38, 39, 41, 43 through46, 48, 50, and 76). In nine of these(Refs. 38, 39, 41, 43 through 46, 48, and50), xylitol was found to result innegligible to no acid production withlittle to no change in plaque pH.Similarly, results showed no significanteffect of xylitol on resting plaque pH.Plaque pH from exposure to xylitol was

always significantly higher than that ofsucrose or glucose.

Twelve animal studies (Refs. 52, 54,56 through 60, 62, 63, 68, 73, and 77)evaluated the effects of xylitol on dentalcaries in rats or hamsters. Eight of these(Refs. 52, 57 through 60, 62, 63, and 77)used a test diet that contained only onesweetener, either sucrose or xylitol. Inall of these studies, there weresignificantly fewer caries reported inanimals consuming the basal diet withxylitol compared to sucrose controls.The incidence of caries was alsosignificantly less in the xylitol groupcompared to animals consuming isomalt(Ref. 63) and sorbitol (Ref. 52). Theconcentrations of xylitol in the test dietsranged from 10 percent up to 30 percentby weight.

Results of the animal studiesevaluating the effect of xylitol in dietscontaining sucrose (Refs. 54, 56, 68, and73) showed mixed results depending onthe concentrations of sucrose and xylitolin the test diets. Havenaar et al. (Ref 54)showed no significant difference incaries in animals consuming a diet withsucrose and 5-percent xylitol, but asignificant difference in caries when thesucrose was lowered to 20-percent ofthe diet and xylitol 5-percent. Grenbyand Colley (Ref. 56) reported a highcaries level in animals consuming eithera diet containing 46-percent sucrose or36-percent sucrose and 10-percentxylitol. The caries score wassignificantly lower in rats consuming adiet with 26-percent sucrose and 20-percent xylitol compared to the 46-percent sucrose diet. An in vitromicrobiological test showed no acidproduction by S. mutans from xylitol.Van der Hoeven (Ref. 73) reportedsignificantly fewer caries in ratsconsuming a diet with 25-percentxylitol compared to the rats consuminga basic diet with 25-percent sucrose.The xylitol group also had fewer cariesthan the wheat flour control group.

2. SorbitolIn its March 1979, review of sorbitol

in health and disease (Ref. 15), FASEBreviewed available animal and humanstudies regarding the cariogenicity ofsorbitol. FASEB concluded that theweight of evidence from animal studiessuggests that sorbitol is less cariogenicthan sucrose, fructose, glucose, anddextrin. Based on the human studiespublished in the early to mid-1970’s,FASEB noted that the results do notprovide definitive data on the effect ofsorbitol on the caries process. It notedthat the results of studies on plaque pHsuggest that sorbitol is slowly fermentedto plaque pH levels of about 6. It alsosaid that some studies have provided

evidence of adaptation of oral flora afterlong-term use of sorbitol-containingproducts. FASEB noted that a humanpopulation that regularly consumessorbitol-containing foods, such as jamsand jellies, baked goods, or other foodproducts, has not been identified andstudied to establish whether sorbitolsignificantly alters the carious process.

Two studies submitted with thepetition evaluated the cariogenicity ofsorbitol in chewing gum (Refs. 20 and32), and one study (Ref. 35) evaluatedthe effect of sorbitol in chewing gum ondemineralization of enamel. Moller andPoulsen (Ref. 20) reported an increasednumber of sound tooth surfaces and asmaller caries increment rate in childrenconsuming sorbitol gum containingcalcium phosphate compared to thecontrol group that did not consumechewing gum. However, the presence ofcalcium phosphate, which acts as abuffer in saliva to help reduce itsacidity, and the absence of gum chewingin the control group, confound theseobservations.

Glass (Ref. 32) reported no significantdifferences in the number of DF surfacesor teeth in children using sorbitolchewing gum for 2 yr compared to a no-gum group. This study, however, didnot consider the effect of chewing gumper se on dental caries.

Leach et al. (Ref. 35) conducted anintraoral test in subjects fitted withbands containing human enamel withartificial white spot lesions. Thesubjects consumed sucrose-containingsnacks. During one of the test periods,the subjects chewed gum containingsorbitol with small amounts ofmannitol, HGS, and aspartame, for 20min at a time after each meal and snack.The study showed significantly moreremineralization during the sorbitolgum period compared to baseline andthe no-gum (sucrose) period. Results ofthis study are confounded, however,because of the duration (i.e., 20 min)and timing (i.e., immediately after mealsand snacks) of the gum chewing. Inaddition, the effect of sorbitol alonecannot be determined because of thepresence of other sugar alcohols andaspartame in the test gum.

Banoczy et al. (Ref. 21) reported asignificantly lower caries increment inchildren consuming sorbitol-containingsweets between meals compared tochildren consuming sucrose-containingsweets between meals over a 2-yrperiod. Differences between groupswere not significant during the third yrof this study, however, the authorsattributed the lack of significance duringthe third yr to the trading of sweetsbetween groups.


Twelve studies evaluated changes inplaque pH after exposure to sorbitol-sweetened mouth rinses (Refs. 39through 41, 45, and 47), solutions (Refs.38, 46, and 76), tablets (Ref. 42), mints(Ref. 49), chewing gum (Ref. 50), andlicorice (Ref. 43). Plaque pH changes inthe presence of sorbitol decreased frombaseline pH but remainedapproximately at or above a pH of 6.0(Refs. 39 through 42, 45 through 47, and50). Bibby and Fu (Ref. 38) reportedprogressively decreasing plaque pHvalues in vitro with increasingconcentrations of sorbitol in aconcentrated plaque suspension. Onlyslight decreases in pH were reported in0.1- to 1.0-percent solutions. In thepresence of a 10-percent sorbitolsolution, plaque pH dropped to about5.8. Grenby et al. (Ref. 76) reported a pHof about 6.0 after 12 h and a final pHin vitro of about 4.6 after 24 h ofincubating concentrated plaque with 10-percent sorbitol. The results of thesestudies suggest that higherconcentrations of sorbitol may lead tofurther decreases in plaque pH to a levelthat may become detrimental to toothenamel (i.e., at or below pH 5.5).

Park et al. (Ref. 49) found that use ofsorbitol mints or mints with a blend ofsorbitol and xylitol helped reduce theacidogenic potential of certain snackfoods, although final pH valuesremained low. Toors and Herczog (Ref.43) showed that plaque pH is affectedby more than the sweetener componentof a food. Results of plaque pH in vivowith an experimental licorice,containing sorbitol, soy flour, andpotato starch derivative among otheringredients, showed a minimum pH ofabout 5.5. A sucrose-containing licoriceused in this study lowered plaque pH toabout 5.0. The fermentability of both thepotato starch derivative (82 percent) andsoy flour (75 percent) contributed to theobserved changes in plaque pH in theexperimental licorice. Thefermentability of sorbitol in theexperimental licorice was 12 percent.

Five studies (Refs. 39 through 41, 43,and 48) measured the APA of plaquewith sorbitol. In all cases, sorbitol wasfermented slowly with a reported rangeof acid production of 10 to 30 percentcompared to sucrose or glucose. Thehigher acid production rate (i.e., 30percent) was attributed to adaptation tosorbitol by S. mutans and other plaquemicroorganisms capable of fermentingcarbohydrates. Havenaar et al. (Ref. 46)also reported a marked increase infermentation of sorbitol and other sugaralcohols after multiple subculturing ofplaque microorganisms with the sugaralcohol. However, the investigatorsreported that adaptation to sorbitol and

other sugar alcohols was lost aftersubculturing once in glucose.

Results of animal studies evaluatingsorbitol (Refs. 35, 52, 58, 59, 62, 64, and73) showed significantly fewer caries inthe sorbitol group than in the sucrosegroup. However, use of sorbitol resultedin more caries compared to animalsconsuming other sugar alcohols, such asxylitol and HSH (Refs. 52, 64, and 73).The concentration of sorbitol in thesestudies ranged from 10 percent up to 56percent.

3. MannitolIn its August 1979, review of mannitol

in health and disease, FASEB (Ref. 16)reviewed available animal and humanstudies regarding the effect of mannitolon acid production, plaque pH changes,and changes in microhardness of bovineenamel in an ICT. It noted that humanplaque studies in vivo or in vitro foundthat plaque pH decreases from 0 up to1.0 units over a 30-min test period.FASEB concluded that the results wereconsistent with the results of animalexperiments showing that mannitol, inthe absence of adaptation of the oralmicroflora, is less cariogenic thansucrose.

Bibby and Fu (Ref. 38) measured invitro plaque pH changes, over a 20-minincubation period, in the presence ofincreasing concentrations of mannitol(0.1-, 1.0-, and 10-percentconcentrations) in a concentratedplaque suspension. Results showed thatplaque pH decreased with increasingconcentrations of mannitol. Finalplaque pH values were 5.67, 5.54, and5.22, respectively. Similar plaque pHvalues were reported by Grenby et. al.(Ref. 76). Results of the Grenby studyshowed that a 1-percent solution ofmannitol, when incubated for 24 h withconcentrated plaque and pieces of ahuman molar tooth, resulted in slightacid production and pH decrease over a12-h period, but that after 24 h, the finalpH was about 5.1. However, results froman in vitro demineralization test showedvery little loss of calcium andphosphorus, significantly less than theloss of minerals with glucose.

Results of other studies, however,show that mannitol results in littlechange to plaque pH. Birkhed andEdwardsson (Ref. 39) reported onlyslight changes in plaque pH followinguse of a mouth rinse with aconcentrated solution of mannitol. Inaddition, they reported an acidproduction rate from mannitol in dentalplaque suspension of 0 percentcompared to sucrose (100 percent).Gehring and Hufnagel (Ref. 45) usedintraoral measurements to evaluate theeffect of sugar alcohols on plaque pH.

Results of plaque exposed to a 20-percent mannitol solution showed theminimum pH obtained was slightlyabove 6.0. The plaque samples in thesetwo studies were not concentrated asthey were in the study by Bibby and Fu(Ref. 38) or by Grenby et al. (Ref. 76),which may account for the differencesin plaque pH values reported formannitol solutions. The results of oneother in vitro microbiological study,with 10-percent mannitol and anincubation time of 48 h (Ref. 62),support the observation that mannitol isfermented very slowly, resulting in littleacid production and small pH changes.

Animals fed mannitol (Refs. 59 and64) or maltitol (Refs. 66, 67, and 69)showed significantly fewer cariescompared to animals fed sucrose diets.The concentrations of the sugar alcoholsin these studies ranged from 10 to 56percent. An in vitro microbiologicalstudy (Ref. 62) showed that a 10-percentsolution of mannitol was fermented veryslowly.

4. MaltitolThree studies (Refs. 33, 34, and 36)

measured the effects on enameldecalcification of maltitol and sucrosesolutions using an ICT with bovineenamel fragments adhered to a partialdenture. Ikeda and coworkers (Ref. 33)showed significantly moredecalcification in the presence ofsucrose as compared to maltitol.Additional rat caries tests were inagreement with the results of the ICT.Rats fed a diet with maltitol hadsignificantly fewer caries than thesucrose group. In this study maltitol wasalmost noncariogenic. Yagi (Ref. 34)reported significantly harder enamelafter exposure to maltitol than afterexposure to sucrose. Lack of details inthis study, however, make it difficult tocompletely interpret the results.Rundegren (Ref. 36) reportedsignificantly less enameldemineralization with maltitolcompared to sucrose. The authorsassociated the changes that theyobserved in enamel hardness in themaltitol group with the effects of otherdietary carbohydrates and not maltitol.Sucrose was found to exert an effect onenamel hardness that is not related tothe effects of other dietarycarbohydrates.

Three studies (Refs. 39, 41, and 46)evaluated plaque pH or acid productionin maltitol. Birkhed and Edwardsson(Ref. 39) measured in vitro acidproduction and pH changes in humandental plaque following the use ofvarious sweeteners in a mouth rinse.The results with maltitol showed anacid production rate of 10 to 30 percent


of that of sucrose. Changes in plaque pHin the presence of maltitol showed onlya slight decrease from baseline pH(about pH 6.9).

Birkhed et al. (Ref. 41) measured invivo pH changes in human dentalplaque after subjects consumed lozengessweetened with various sweeteners for 3mo and then rinsed with a mouth rinsesweetened with the same sweetener asin the lozenge. A sucrose mouth rinsewas also used by each sweetener group.Results with maltitol showed small, butsome significant, changes in plaque pHcompared to baseline pH (about pH 7.0)over the 30-min test period. The lowestplaque pH recorded, however, wasabout pH 6.8. In vitro acid productionwith maltitol was found to be about 26to 32 percent of glucose.

Havenaar et al. (Ref. 46) measuredchanges in pH and acid production invitro in growing cultures of oral bacteriaobtained from caries active and cariesfree subjects. Results showed that a 1percent solution of maltitol was slowlyfermented to acid by plaque bacteria.Cell suspensions of S. mutans inmaltitol showed pH decreased from abaseline of about pH 7.0 to about pH6.5. Adaptation of S. mutans by frequentsubculturing in maltitol showed amarked increase in fermentation by S.mutans. However, the ability to fermentthe sugar alcohol was lost after onesubculturing of the adapted strain inglucose.

5. LactitolHavenaar et al. (Ref. 46) showed that

a 1 percent solution of lactitol wasfermented by S. mutans andActinomyces. Cell suspensions of S.mutans in lactitol showed pH decreasedfrom a baseline of about pH 7.0 to aboutpH 6.5 or above after a 2-h incubationperiod. Adaptation of S. mutans byfrequent subculturing in lactitol showeda marked increase in fermentation by S.mutans to give a plaque pH of about 5.0.However, the ability to ferment thesugar alcohol was lost after onesubculturing of the adapted strain inglucose. Grenby et al. (Ref. 76) showedthat a 1-percent solution of lactitol,when incubated for 24 h with humanplaque and pieces of a human molartooth, resulted in slight acid productionand a final pH of about 6.3 and almostno loss of calcium and phosphorus fromtooth enamel.

Results of two animal studies (Refs.73 and 77) showed that substitution oflactitol for sucrose in laboratory chowresulted in significantly fewer caries inthe lactitol group compared to thesucrose group. The lactitol group (Ref.73) experienced slightly, but notsignificantly, more caries than the

xylitol group and the wheat flourcontrol group and fewer caries than thesorbitol group. There was no significantdifference between the caries score inanimals fed lactitol-containing orxylitol-containing chow (Ref. 77). Therewere significantly fewer caries inanimals fed lactitol-containing biscuitscompared to the sucrose biscuit group(Ref. 77). The average caries score in thelactitol biscuit group was less than oneper animal.

6. IsomaltTwo studies investigated the effects

on plaque pH with isomalt (Refs. 38 and45). Bibby and Fu (Ref. 38) measured pHchanges in fresh plaque from adultvolunteers with increasingconcentrations of isomalt. Resultsshowed that as the concentration of thesugar alcohol increased, the pH of theplaque decreased. The range of plaquepH values reported for isomalt was from6.6 (0.1 percent solution) toapproximately 5.7 (10-percent solution).Gehring and Hufnagel (Ref. 45) reporteda minimum plaque pH of about 6.0 after5 min with isomalt. This valueincreased gradually over the next 27min to about pH 6.3. As discussedabove, the methods and type of dentalplaque must be considered whencomparing the results of these studies.

Results of animal studies withconcentrations of isomalt from 16 to 30percent of the rat diet showedsignificantly fewer caries compared tosucrose diets (Refs. 57, 60, 62, 63, 65,and 70). The caries incidence was highin xerostomized rats consuming eithersucrose or isomalt (Ref. 57). The isomaltgroup of nonxerostomized rats,however, had significantly fewer cariesthan the sucrose group.

7. HGS and HSHFrostell et al. (Ref. 31) studied the

effect on caries increment in children ofsubstitution of HSH for sucrose incandy. The results of this study areconfounded for a number of reasons (seeTable 2) and do not support a significantdental benefit from the use of HSHcandies in place of sucrose-containingcandies.

Rundegren et al. (Ref. 36) measuredenamel hardness in the presence ofsucrose, sodium chloride, or HSH usingan ICT. The investigators reportedsignificantly less enameldemineralization with HSH. The resultsof the study were that only sucrosepromoted demineralization over andabove the effect of dietarycarbohydrates. The authors attributedthe demineralization measured in thepresence of HSH to the effect of dietarycarbohydrates.

Eight studies measured plaque pHchanges from exposure to HSH insolutions (Refs. 38 and 46), rinses (Refs.39, 41, 45, and 47), and candy (Refs. 42and 43). Bibby and Fu (Ref. 38) showedthat as the concentration of HSHincreased, plaque pH decreased. Thelowest plaque pH value (10-percentsolution of HSH) obtained was about5.0. Havenaar et al. (Ref. 46) showedthat a 1-percent solution of HSH wasfermented by S. mutans andActinomyces. Cell suspensions of S.mutans in HSH showed a pH decreasefrom a baseline of about pH 7.0 to aboutpH 6.5. Adaptation of S. mutans byfrequent subculturing in HSH showed amarked increase in fermentation by S.mutans to give a plaque pH of slightlybelow 6.0. However, the ability toferment the sugar alcohol was lost afterone subculturing of the adapted strainin glucose.

Birkhed and Edwardsson (Ref. 39)measured plaque pH in vitro followingthe use of a mouth rinse containingSwedish or French HSH. French HSHappeared to have little effect on plaquepH. Plaque pH values remained slightlybelow or at 7.0. Swedish HSH showeda decrease in plaque pH within 5 to 10min to just less than pH 6.0. Over theremaining 20 min, the pH increased tojust over 6.0. Birkhed et al. (Ref. 41)measured pH changes in human dentalplaque after subjects consumed lozengessweetened with Swedish HSH for 3 moand then rinsed with a mouth rinsesweetened with Swedish HSH. PlaquepH was also measured after a sucrosemouth rinse. The results of the studyshowed that HSH resulted in a drop inplaque pH in all tests; however, theminimum pH values reached wereabove 6.0. Gehring and Hufnagel (Ref.45) reported an intraoral plaque pHchange with a HSH rinse (20 percentsolution) from about pH 6.6 to about 5.6.

Jensen (Ref. 47) showed interproximalplaque pH values from five differentHGS rinses were statisticallysignificantly different compared to thesucrose control. Differences between theHGS test solutions and a sorbitol controlwere not significantly different. Theminimum pH values obtained with theHGS solutions were above pH 6.0.Composition of the HGS test substanceswas not provided.

Frostell (Ref. 42) reported a slightdecrease in vitro plaque pH (from about6.7 to about 6.5) after subjects consumedHSH candy. After consuming a sucroselozenge, plaque pH decreased to about5.8. A sucrose solution resulted in aminimum plaque pH of about 5.3. Toorsand Herczog (Ref. 43) showed thatplaque pH is affected by more than thesweetener component of a food. Results


of plaque pH in vivo with anexperimental licorice, containing soyflour, HPS, and potato starch derivativeamong other ingredients, showed aminimum pH of about 5.5. Thefermentability of the HPS (60 percent),potato starch derivative (82 percent) andsoy flour (75 percent) contributed to theobserved changes in plaque pH in theexperimental licorice.

Acid production in vitro was reportedin two studies (Refs. 39 and 51). Birkhedand Edwardsson (Ref. 39) reported anacid production rate from French HSHof 20 to 40 percent and from SwedishHSH of 50 to 70 percent compared toglucose syrups. Birkhed and Skude (Ref.51) reported significantly lower acidproduction rates (i.e., slower rate offermentation) from a 3 percent solutionof Swedish HSH (61.5 percent)compared to glucose (99.7 percent). Theinvestigators also reported that HSH wasmetabolized significantly more slowlythan soluble starch.

Results of animal studies evaluatingthe effect of HSH showed the sweetenerto be relatively noncariogenic comparedto sucrose (Refs. 52, 53, 64, and 69).Differences in the incidence of cariesbetween the sucrose and HSH groupswere significant.

IV. Decision To Propose a Health ClaimRelating Sugar Alcohols To theNonpromotion of Dental Caries

FDA limited its review of thescientific evidence relating sugaralcohols and dental caries to thosestudies evaluating changes in plaquepH, plaque acid production,decalcification or remineralization oftooth enamel, and the incidence ofdental caries with sugar alcohols. FDAconsidered these limitations to beappropriate because previous Federalgovernment and other authoritativereviews had focused on these areas(Refs. 14 through 16), and the majorityof research efforts to date have focusedon these areas.

FDA tentatively concludes that, basedon the totality of publicly availablescientific evidence regarding therelationship among sugar alcohols,plaque pH, and dental caries, there issignificant scientific agreement tosupport the relationship between theuse of xylitol, sorbitol, mannitol,maltitol, isomalt, lactitol, HSH, HGS, ora combination of these sugar alcoholsand the nonpromotion of dental caries.Thus, it appears that use of a healthclaim relating the use of sugar-alcoholcontaining products to dental caries willbe useful in helping consumers identifyfood products consumption of whichwill not promote the development ofdental caries.

A. Xylitol

In its 1978 review of the xylitolstudies, FASEB concluded that xylitolappeared to be noncariogenic in studiesevaluating the effect of sucrosereplacement with xylitol and in studiesevaluating the effect of partialreplacement of sucrose with xylitol inchewing gum (Ref. 14).

The agency reviewed over 15 studiespublished since the FASEB report thatevaluated the relationship betweenxylitol and dental caries, plaque pH,and acid production. Overall resultsfrom the human caries field trials (Refs.26 and 28) suggest that substitution ofxylitol-containing foods and chewinggums for sucrose-containing foods andchewing gums is associated with alower incidence of dental caries. PlaquepH and acid production studies furthersupport this result. In both in vivo andin vitro studies, xylitol had negligible tono effect on plaque pH or plaque acidproduction. In some instances, xylitolincreased plaque pH above the meanbaseline value, suggesting that xylitolmay truly be nonpromotional of dentalcaries. The results of over 10 animalstudies confirm the observations fromclinical and in vitro studies.Substituting xylitol (from 10 to 30percent) for sucrose in a basic laboratorychow resulted in significantly fewerdental caries. FDA tentatively concludesthat the overall results from human andanimal studies strongly support theobservation that xylitol does notpromote acid production in plaque and,therefore, does not promote dentalcaries.

B. Sorbitol

In its 1979 report on sorbitol, FASEBconcluded that the weight of evidencefrom animal studies suggests thatsorbitol is less cariogenic than sucroseand other fermentable sugars (Ref. 15).The report noted that the results ofhuman plaque studies show thatsorbitol does not lower plaque pH below5.5, the pH of plaque wheredecalcification may begin. FASEBconcluded that it could be assumed thatsorbitol may have similar relativecariogenic properties in humans asobserved in animals.

The agency reviewed over 10 clinicalstudies with sorbitol published sincethe FASEB report. Subjects consumingsorbitol-containing sweets betweenmeals experienced fewer dental cariesthan those consuming sucrose-containing sweets. Plaque pH and acidproduction studies consistently showthat sorbitol is slowly fermented byplaque microflora and by S. mutans inparticular. However, results show that

plaque acid did not decrease pH tolevels associated with incipient enameldecalcification (i.e., approximately atpH 5.5 or below). There is someevidence that suggests that long-term,uninterrupted use of sorbitol results inadaptation by S. mutans and otherplaque microorganisms and, therefore,in more acid production. However,there are no human caries trials to showwhether such adaptation results in achange in the incidence of dental caries.There is some evidence to show thatadaptation may be lost in the presenceof other sugars.

The results of six animal studiesconfirmed the observations from humanstudies. The incidence of caries inanimals consuming diets containingsorbitol was significantly less than thecaries incidence in animals consumingdiets containing sucrose. FDAtentatively concludes that the overallresults from human and animal studiesshow that oral bacteria cannot besustained in the presence of sorbitol,and that changes in acidity are withina range that is safe for tooth enamel.

C. MannitolIn its 1979 report on mannitol, FASEB

concluded that results of acidproduction, plaque pH changes, andchanges in microhardness of bovineenamel were consistent with the resultsof animal experiments indicating thatmannitol, in the absence of adaptationof the oral microflora, is less cariogenicthan sucrose (Ref. 16). One studyevaluated plaque pH with mannitol in aconcentrated plaque suspension in vitro(Ref. 38). One and ten percent solutionsof mannitol resulted in a plaque pH of5.5 or below. Contrary to these results,however, three studies showed onlyslight acid production and smallchanges in plaque pH to a value notbelow pH 6.0 from mannitol (Refs. 39,45, and 76). Likewise, there was littleevidence of demineralization frommannitol in vitro (Ref. 76). Two ratstudies, in which mannitol wassubstituted for sucrose in animal chow,showed significantly fewer caries withthe mannitol diet (Refs. 59 and 64). FDAtentatively concludes that the overallresults from both human and animalstudies support the claim that mannitoldoes not promote dental caries.

D. MaltitolResults of three ICT’s showed

significantly less decalcification withmaltitol than sucrose. Additional plaquepH studies showed that maltitol isfermented very slowly (acid productionof 10 to 30 percent) compared to sucroseand is associated with small plaque pHchanges from resting baseline values.


Four animal studies confirmed thatmaltitol was significantly less cariogenicthan sucrose. FDA tentatively concludesthat the overall results from both humanand animal studies support the claimthat maltitol does not promote dentalcaries.

E. IsomaltThe agency reviewed two plaque pH

studies evaluating the acidogenicpotential of isomalt. Results with 10percent isomalt showed a minimum invitro plaque pH of 5.7. An intraoral testwith a 20 percent solution of isomaltreported a minimum pH of about 6.0.Results of five animal studiesconsistently showed that isomalt wassignificantly less cariogenic thansucrose. FDA tentatively concludes thatthe overall results show that isomaltdoes not lower plaque pH below 5.5 anddoes not promote dental caries.

F. LactitolTwo in vitro plaque pH studies

showed that lactitol produced little acidand only slight changes in plaque pHfrom resting baseline values. Results oftwo animal studies are consistent withthese results and showed lactitol to besignificantly less cariogenic thansucrose. The cariogenicity of lactitolwas not significantly different thanxylitol. FDA tentatively concludes thatthe overall results support the claim thatlactitol does not promote dental caries.

G. Hydrogenated Starch Hydrolysatesand Hydrogenated Glucose Syrups

In an ICT, a solution of HSH resultedin significantly less demineralizationthan sucrose. The investigatorsattributed the observeddemineralization with HSH to an effectof other dietary components. The effectsof sucrose on enamel demineralization,however, were noted to be over andabove the effect of other dietarycomponents.

Seven studies evaluating the effect ofHSH on plaque pH showed inconsistentresults in final pH values reported. Thedifferences in results are attributed tothe source of the HSH. HSH ismanufactured by hydrolyzing a sourceof food grade starch (usually potato orcorn starch) with acid or an enzyme toa mixture of sugars and dextrins ofvarious glucose lengths (i.e., glucosesyrups). The hydrogenated mixturecontains sorbitol, maltitol, maltitriol,maltotrititol, and hydrogenated dextrinsof various molecular weights (Ref. 79).The percentage of each componentsugar alcohol in the final substancedepends on the manufacturing processand controls. The two major forms ofHSH (i.e., one manufactured in Sweden

and the other in France) used in thestudies reviewed gave dramaticallydifferent results in plaque pH and acidproduction tests. The Swedish version,which has a higher percentage of highermolecular weight, fermentablepolysaccharides than the Frenchversion, produced plaque pH values of5.5 to 6.0 and an acid production of 50to 70 percent compared to sucrose. TheFrench version produced final plaquepH values above 6.0 and an acidproduction rate of 20 to 40 percent ofsucrose. Results with HGS ofunidentified composition showedminimum plaque pH values all above6.0. Results of 4 rat studies support theobservations that HSH (source notidentified) is significantly lesscariogenic than sucrose. FDA tentativelyconcludes that the overall resultssupport the claim that HSH and HGS donot promote dental caries.

Based on its review of the scientificevidence, the agency noted that the HSHand HGS sugar alcohol mixtures mayvary in their acidogenic response indental plaque. For example, HSHmanufactured in Sweden usually gave alower plaque pH response than theFrench version of HSH. This variationin acidogenic response has beenattributed to the differences in thechemical composition of thesesubstances. HSH and HGS are not welldefined chemical substances as arexylitol and sorbitol. Instead, the sugaralcohol compositions of thesesubstances will vary depending on themanufacturing process. Therefore, theagency is asking for comments on howto determine whether sugar alcoholmixtures, such as HSH, when used in afood whose label bears a dental carieshealth claim, are in compliance withany final rule resulting from thisproposal.

V. Decision To Propose An ExemptionFrom § 101.14(E)(6) For Chewing Gumand Confectioneries

Section 101.14(e)(6) provides, asstated above, that except for dietarysupplements or where provided for inother regulations in part 101, subpart E,to be eligible to bear a health claim, afood must contain 10 percent or more ofthe reference daily intake or the dailyreference value for vitamin A, vitaminC, iron, calcium, protein, or fiber perreference amount customarilyconsumed before there is any nutrientaddition.

The petition states that productscontaining sugar alcohols often will notbe able to satisfy the requirement of§ 101.14(e)(6) because the productsutilizing sugar alcohols are largelychewing gum and confectioneries, none

of which are a significant source of anynutrients. The petition states that theuse of these products in lieu oftraditional sugar-based confectionerywould be consistent with public healthrecommendations, and that the healthclaim statement, ‘‘useful only in notpromoting tooth decay,’’ is an importantand useful message for consumers inmaking decisions on which foods topurchase.

FDA has tentatively determined thatthere is significant public healthevidence to support providing anexemption to § 101.14(e)(6) for sugaralcohol-containing foods, e.g., chewinggums, hard candies, and mints. In theSurgeon General’s Report (Ref. 7), dentalcaries is recognized as an important andwidespread public health problem inthe United States. Although dentalcaries among children are declining, theoverall prevalence of the conditionimposes a substantial economic burdenon American health care costs. TheSurgeon General’s report states that ofthe 13 leading health problems in theUnited States, dental disorders ranksecond in direct costs (Ref. 7).

The role of sugars, and of sucrose inparticular, in the etiology of dentalcaries is well established. Caries-producing bacteria can readilymetabolize a range of simple sugars(e.g., sucrose, glucose, fructose) to acidsthat can demineralize teeth. The uniquerole of sucrose, however, is related to itsability to be used by S. mutans, theprimary etiologic agent in coronalcaries, and other oral bacteria to formextracellular polymers of glucose orfructose that adhere firmly to toothsurfaces (Ref. 7).

The Surgeon General’s reportrecommends several types ofintervention to help reduce the risk ofdental caries. The diet-related factorsinclude the use of fluoridated drinkingwater and control of sugarsconsumption. In this regard, theSurgeon General’s report recommendsthat those who are particularlyvulnerable to dental caries, especiallychildren, should limit theirconsumption and frequency of use offoods containing relatively high levelsof sugars.

FDA agrees that limiting the amountof sugars in the diet is one importantapproach to help reduce the risk ofdental caries. Sugar alcohols can beused to replace dietary sugars in food byproviding sweetness and usefulness asbulking agents. Sugar alcohol-containing chewing gum andconfectioneries, such as hard candiesand mints, are specifically formulatedwithout dietary sugars. Although thesefoods have little or no nutritional value,


they are an important alternative tosucrose-containing snacks. Therefore,FDA tentatively finds that the use ofhealth claims on the label of sugaralcohol-containing products willfacilitate compliance with dietaryguidelines that recommend a reducedintake of dietary sugars to reduce therisk of dental caries. Moreover, the sugaralcohol and dental caries health claim,if authorized, will apply in largemeasure, although not entirely, to snackfoods that do not play a fundamentalrole in structuring a healthy diet.

Section 101.14(e)(6) was included inFDA’s regulations to ensure that thosefoods that bear a health claim are usefulin structuring a healthy diet. Usuallyusefulness in structuring a healthy dietderives from the vitamin, mineral,protein, or fiber content of the food. Inthis case, however, FDA tentativelyfinds that the replacement of dietarysugars with sugar alcohols will helpreduce the risk of dental caries and thuswill help to facilitate compliance withthe dietary guidelines. In recognition ofthe special character of the foodsinvolved, FDA tentatively concludesthat it is appropriate to exempt thesefood products from § 101.14(e)(6).Therefore, in new § 101.80(c)(1), FDA isproposing to exempt sugar alcohol-containing food products from theprovisions of paragraph 101.14(e)(6).

VI. Description And Rationale ForComponents Of Health Claim

A. Relationship Between Sugar Alcoholsand Dental Caries

In proposed § 101.80(a), FDAdescribes the relationship between sugaralcohols and dental caries. Dental cariesis a multifactorial disease, characterizedby the demineralization of the surface oftooth enamel by acid-forming organismsin dental plaque. It is well establishedthat the relationship between sugarsconsumption and dental caries is one ofcause and effect within themultifactorial context (Refs. 71 and 72).The role of sucrose in the etiology ofdental caries is related to its ability tobe metabolized by oral bacteria intoextracellular polymers that adherefirmly to the tooth surfaces, at the sametime forming acids that candemineralize tooth enamel (Ref. 7). Theextracellular polymers that adhere totooth surfaces (i.e., plaque) facilitate thefurther attachment of additional plaqueto teeth and the proliferation of bacteria.Although saliva can help neutralizeplaque acids and influence theattachment of oral bacteria to the toothsurface (Ref. 7), it has limited access tothe acids generated at the tooth surfacebeneath the plaque.

Diets in the United States tend to behigh in sugars. Although there has beena decline in the prevalence of dentalcaries in the United States, there hasbeen no decline in the consumption ofsugars. Furthermore, the incidence ofdental caries is still widespread (Ref. 7).

Sugar alcohols are used as sweetenersand bulking agents to replace dietarysugars in foods. Because of theircomposition, sugar alcohols are not asfermentable by plaque bacteria assucrose and are, therefore, lesscariogenic than dietary sugars.Replacing dietary sugars with sugaralcohols helps to maintain dentalhealth.

B. Significance of Sugar Alcohols in theCaries Process

As explained in section IV of thisdocument, based on the totality of thepublicly available evidence, FDA hastentatively concluded that there issignificant scientific agreement amongexperts qualified by training andexperience to evaluate such claims thatthere is adequate scientific evidence toconclude that the sugar alcohols xylitol,sorbitol, mannitol, maltitol, isomalt,lactitol, HSH, and HGS are lesscariogenic than sucrose and do notpromote dental caries. In proposed§ 101.80(b), FDA discusses thesignificance of the relationship betweensugar alcohols and dental caries.

Sugar alcohols have been shown inhuman and animal studies to benonfermentable (i.e., xylitol) or slowlyfermentable (i.e., sorbitol, maltitol,mannitol, isomalt, lactitol, HSH, andHGS) by S. mutans and other acid-forming microorganisms in dentalplaque. Human studies have shown areduced rate of acid production inplaque and, in some studies, a reducedincidence of dental caries from the useof sugar alcohol-containing products.

C. Nature of the ClaimIn new § 101.80(c)(1), FDA is

proposing that all requirements of§ 101.14 be met except, as explainedabove, that sugar alcohol-containingfoods are exempt from § 101.14(e)(6).

Under § 101.14(d)(3), nutritionlabeling in accordance with § 101.9must be provided on the label orlabeling of any food for which a healthclaim is made. Therefore, if FDA adoptsthis proposed regulation, the labeling ofthe amount of sugar alcohol in a servingwill have to be declared on the nutritionlabel in accordance with§ 101.9(c)(6)(iii) when a claim is madeon the label or in labeling about sugaralcohols and dental caries.

In new § 101.80(c)(2)(i), FDA isproposing to authorize a health claim on

the relationship between sugar alcoholsand the nonpromotion of dental caries.This action is consistent with theagency’s review of the scientificevidence, which showed that, althoughsugar alcohols are slowly fermented byS. mutans and can form some acid, theydo not contribute to the promotion ofdental caries.

In new § 101.80(c)(2)(i)(A), the agencyis proposing to require that indescribing the relationship betweensugar alcohols and dental caries, theclaim states ‘‘does not promote,’’‘‘useful in not promoting,’’ or ‘‘expresslyfor not promoting’’ dental caries. FDAfinds that these terms accuratelydescribe the relationship between sugaralcohol consumption and dental caries.

In new § 101.80(c)(2)(i)(B), the agencyis proposing to require that the terms‘‘dental caries’’ or ‘‘tooth decay’’ be usedin specifying the disease. These termsare commonly used in dental anddietary guidance materials and arefamiliar to consumers.

Under § 101.14(d), a health claimmust be complete, truthful, and notmisleading. It must enable the public tocomprehend the information providedand to understand the relativesignificance of such information in thecontext of a total daily diet. In addition,a health claim may not attribute anyspecific degree of reduction in risk ofdisease from consumption of theproduct.

In recognition of these generalrequirements, and in light of the factthat both environmental and geneticfactors, as well as eating behaviors, allaffect a person’s risk of developingdental caries (see proposed§ 101.80(a)(1)), FDA is proposing in§ 101.80(c)(2)(i)(C) that for packages thathave a total surface area available forlabeling of 15 or more square inches, theclaim must state that dental cariesdepends on many factors.

FDA is aware that many sugaralcohol-containing chewing gum andconfectionery products have a totalsurface area available for labeling of lessthan 15 square inches, however. Such asmall area would preclude the use of ahealth claim that included all of therequired elements. Many of theseproducts, packaged in small packages,have used the claim ‘‘useful only in notpromoting dental caries’’ on their labelsfor more than 15 years. Because of thepotential dental health benefits toconsumers resulting from a positiveaction on this proposal and given theunique history of this claim, the agencytentatively finds that continued use ofan abbreviated claim on packages withless than 15 square inches of surfacearea will not be misleading or confusing


to consumers of these products.However, the agency continues tobelieve that the fact that dental cariesare multifactorial in their etiology isfundamental to an understanding of theclaim. Therefore, the agency tentativelyconcludes that this fact is a materialfact, and that it must be disclosed onpackages with space available forlabeling of 15 or more square inches. In§ 101.80(c)(2)(i)(D), given the uniquecircumstances surrounding this claim,FDA is proposing to exempt packageswith a total surface area available forlabeling of less than 15 square inchesfrom the provisions of§ 101.80(c)(2)(i)(C).

In proposed § 101.80(c)(2)(i)(E), FDAstates that the claim must not attributeany degree of nonpromotion of dentalcaries to the use of the sugar alcohol-containing food. Based on the agency’sreview of human and animal studies inthis document, none of the studiesprovide a basis for determining thepercent reduction in risk of dental cariesfrom consuming sugar alcohol-containing foods. This requirement isalso consistent with the generalrequirements for health claims in§ 101.14(d), and those health claimsauthorized under part 101, subpart E.

D. Nature of the Food

In § 101.80(c)(2)(ii)(A), FDA isproposing to require that the foodbearing this health claim meet therequirement in § 101.60(c)(1)(i) withrespect to sugars content, that is, qualifyto bear the claim ‘‘sugar free.’’ Thisrequirement is consistent with thescientific evidence showing that foodswith a mixture of sugar alcohols andsugars are still acidogenic (Ref. 38) andcariogenic (Refs. 52, 55, and 56, forexamples).

In new § 101.80(c)(2)(ii)(B), theagency is proposing that the sugaralcohols be limited to xylitol, sorbitol,mannitol, maltitol, isomalt, lactitol,HSH, HGS, or a combination of these.This requirement reflects the availablescientific evidence on the sugar alcoholsand their effects on the promotion ofdental caries.

Sugar alcohols in combination withhigh intensity sugar substitutes, such asaspartame and saccharin, are also usedto replace sucrose. The agency notesthat under proposed § 101.80(c)(2)(ii)(A)and (c)(2)(ii)(B), a sugar alcohol anddental caries claim could appear on afood that contains a combination ofsugar alcohols and high intensitysweeteners but no sugars. The agencynotes that high intensity sweeteners arenot considered fermentable by oralbacteria (Ref. 75).

The agency is not specifying a level ofsugar alcohols in the food productbecause these ingredients are being usedas a substitute for sugars. Therefore, theamount of the substance required is thatneeded to achieve a desired level ofsweetness.

In new § 101.80(c)(2)(ii)(C), theagency is proposing that to qualify tobear a claim, the sugar alcohol-containing food, when tested for itseffects on plaque pH using in vivomethods, must not lower plaque pHbelow 5.7. Based on the agency’s reviewof the scientific evidence, foods thatlowered plaque pH below 5.5 werecontributing to an acidic environment inthe mouth that is detrimental to toothenamel. Although a ‘‘critical’’ plaque pHhas not been defined, changes in pH toa minimum that is above 5.5 aregenerally considered above the levelwhere enamel decalcification would bepromoted (Refs. 8, 75, 86, and 87).

In its review of the scientificevidence, the agency noted that sugaralcohol-containing chewing gum andconfectioneries, such as mints, that donot contain fermentable carbohydrates,did not lower plaque pH below 5.5.However, in one study that evaluatedthe cariogenic potential of anexperimental licorice that contained soyflour, the soy flour was shown to behighly fermentable and dropped plaquepH to below 5.5 (Ref. 43). The agencyis concerned that use of sugar alcoholsin a food product that contains aningredient, such as refined flour, thatwould cause plaque pH to drop below5.5 would thus cause the food to becariogenic.

In the Swiss ‘‘zahnschonend’’program, if a food does not promote adrop in plaque pH, using intraoralplaque pH telemetric tests, below 5.7 bybacterial fermentation either duringconsumption or up to 30 min later, thefood is considered ‘‘safe for teeth’’ andmay be labeled as such (Ref. 75). Theintraoral plaque pH telemetric test is anin vivo method that measures theacidogenicity of foods and dietarypatterns. Based on experience andexperimentation, foods judged by theSwiss program to be safe for teeth arethose that have been shown not topromote dental decay in animal orhuman model systems (Ref. 75).

In this proposed rule, FDA isproposing to require in§ 101.80(c)(2)(ii)(C) that to be eligible tobear the claim, the food product notlower plaque pH below 5.7, based on invivo measurements, during the timefood is consumed and for up to 30 minafter the food is consumed. The agencyis proposing a more conservative valuethan pH 5.5 because such a value gives

assurance that, consistent with thehealth claim, the food will not promotedental caries.

The methods that have been describedas the most suitable for assessing plaqueacidity of dietary constituents inhumans are indwelling electrodesystems, such as the intraoral plaque pHtelemetric test used in the Swissprogram (Refs. 8 and 75). ICT’s (Ref. 88),which incorporate enamel blocks intodental appliances for the production ofcarious lesions when used incombination with intraoral plaque pHtelemetry, are also good methods forassessing changes in plaque pH inresponse to food. The agency is askingfor comments on whether establishing aminimum plaque pH that is measured invivo during consumption and up to 30min following consumption is areasonable approach to use to determinewhether a sugar alcohol-containingfood, other than sugar alcohol-containing chewing gum andconfectioneries, that contains othercarbohydrate ingredients is incompliance with any final rule resultingfrom this proposal.

E. Optional Information

FDA is proposing in new§ 101.80(d)(1), consistent with theregulations that have authorized otherhealth claims, that health claims aboutthe relationship between sugar alcoholsand dental caries may provideadditional information that is drawnfrom proposed § 101.80 (a) and (b).

In new § 101.80(d)(2), the agency isproposing that when referring tosucrose, the claim may use the term‘‘sucrose’’ or ‘‘sugar.’’ The use of eitherof these terms is consistent with FDA’sregulation that affirms that use of thissubstance is GRAS (§ 184.1854).

FDA is proposing in § 101.80(d)(3),consistent with the health claims that ithas already authorized under part 101,subpart E, to allow manufacturers toprovide additional information aboutrisk factors associated with thedevelopment of dental caries. Althoughsugars consumption and infection withS. mutans are often identified as thecause of dental caries, there are severalrisk factors that play significant roles inthe etiology of this disease (Ref. 71).These factors include frequentconsumption of sucrose or otherfermentable carbohydrates, presence oforal bacteria capable of fermentingsugars, length of time sugars are incontact with the teeth, lack of exposureto fluoride, individual susceptibility,socioeconomic and cultural factors, andcharacteristics of tooth enamel, saliva,and plaque (Refs. 7, 71, and 89).


F. Model Health ClaimsIn proposed § 101.80(e), FDA is

providing model health claims toillustrate the requirements of new§ 101.80. FDA emphasizes that thesemodel health claims are illustrativeonly. If the agency authorizes claimsabout the relationship between sugaralcohols and dental caries,manufacturers will be free to designtheir own claim so long as it isconsistent with § 101.80(c).

VII. Environmental ImpactThe agency has determined under 21

CFR 25.24 (a)(11) that this action is ofa type that does not individually orcumulatively have a significant effect onthe human environment. Therefore,neither an environmental assessmentnor an environmental impact statementis required.

VIII. Analysis of ImpactsFDA has examined the impacts of the

proposed rule under Executive Order12866 and the Regulatory Flexibility Act(Pub. L. 96–354). Executive Order 12866directs agencies to assess all costs andbenefits of available regulatoryalternatives and, when regulation isnecessary, to select regulatoryapproaches that maximize net benefits(including potential economic,environmental, public health and safety,and other advantages; distributiveimpacts; and equity). The agencybelieves that this proposed rule isconsistent with the regulatoryphilosophy and principles identified inthe Executive Order. In addition, theproposed rule is not a significantregulatory action as defined by theExecutive Order and so is not subject toreview under the Executive Order.

The Regulatory Flexibility Actrequires agencies to analyze regulatoryoptions that would minimize anysignificant impact of a rule on smallentities. Because it enables firms tomake claims that they would otherwisebe prohibited from making, the agencycertifies that the proposed rule will nothave a significant economic impact ona substantial number of small entities.Therefore, under the RegulatoryFlexibility Act, no further analysis isrequired.

IX. Effective DateFDA is proposing to make these

regulations effective 30 days after thepublication of a final rule based on thisproposal.

X. CommentsInterested persons may, on or before

October 3, 1995, submit to the DocketsManagement Branch (HFA–305), Food

and Drug Administration, rm. 1–23,12420 Parklawn Dr., Rockville, MD20857, written comments regarding thisproposal. Two copies of any commentsare to be submitted, except thatindividuals may submit one copy.Comments are to be identified with thedocket number found in brackets in theheading of this document. Receivedcomments may be seen in the officeabove between 9 a.m. and 4 p.m.,Monday through Friday.

XI. References

The following references have beenplaced on display in the DocketsManagement Branch (address above)and may be seen by interested personsbetween 9 a. m. and 4 p. m., Mondaythrough Friday.

1. Drozen, Melvin S., ‘‘Health claimpetition regarding the noncariogenicityof sugar alcohols,’’ August 31, 1994.

2. Drozen, Melvin S., ‘‘Objections andrequest for a hearing by Working Groupof sugar alcohol manufacturers to therevocation of 21 C.F.R. section105.66(f),’’ Docket No. 91N–384L,Dockets Management Branch, FDA,Rockville, MD.

3. Saltsman, Joyce J., CFSAN, FDA,Letter to Melvin S. Drozen, September15, 1994.

4. Saltsman, Joyce J., CFSAN, FDA,Letter to Melvin S. Drozen, October 7,1994.

5. Drozen, Melvin S., Letter to FDA,November 15, 1994.

6. Saltsman, Joyce J., CFSAN, FDA,Memorandum of telephoneconversation, December 8, 1994.

7. DHHS, Public Health Service(PHS), ‘‘The Surgeon General’s Reporton Nutrition and Health,’’ U.S.Government Printing Office,Washington, DC, 1988.

8. Harper, D. S., D. C. Abelson, and M.E. Jensen, ‘‘Human plaque aciditymodels,’’ Journal of Dental Research, 65(Special Issue):1503–1510, 1986.

9. Ten Cate, J. M., ‘‘Demineralizationmodels: Mechanistic aspects of thecaries process with special emphasis onthe possible role of foods,’’ Journal ofDental Research, 65 (SpecialIssue):1511–1515, 1986.

10. Curzon, M. E. J., ‘‘Integration ofmethods for determining the cariogenicpotential of foods: Is this possible withpresent technologies?,’’ Journal ofDental Research, 65 (SpecialIssue):1520–1524, 1986.

11. Stookey, G. K., ‘‘Considerations indetermining the cariogenic potential offoods: How should existing knowledgebe combined?,’’ Journal of DentalResearch, 65(Special Issue):1525–1527,1986.

12. Working Group Consensus Report,‘‘Integration of methods,’’ Journal ofDental Research, 65(SpecialIssue):1537–1539, 1986.

13. DePaola, D. P., ‘‘Executivesummary,’’ Scientific ConsensusConference on Methods for Assessmentof the Cariogenic Potential of Foods,Journal of Dental Research, 65(SpecialIssue)1540–1543, 1986.

14. LSRO, FASEB, ‘‘Dietary Sugars inHealth and Disease, II. Xylitol,’’Bethesda, MD, July, 1978.

15. LSRO, FASEB, ‘‘Dietary Sugars inHealth and Disease, III. Sorbitol,’’Bethesda, MD, July, 1978.

16. LSRO, FASEB, ‘‘Dietary Sugars inHealth and Disease, IV. Mannitol,’’Bethesda, MD, July, 1978.

17. Working Group Consensus Report,‘‘Animal caries,’’ Journal of DentalResearch, 65:1528–1529, 1986.

18. Working Group Consensus Report,‘‘Human plaque acidity,’’ Journal ofDental Research, 65:1530–1531, 1986.

19. Working Group Consensus Report,‘‘Demineralization/remineralization,’’Journal of Dental Research, 65:1532–1536, 1986.

20. Moller, I. J., and S. Poulsen, ‘‘Theeffect of sorbitol-containing chewinggum on the incidence of dental caries,plaque and gingivitis,’’ CommunityDental and Oral Epidemiology, 1:58–67,1973.

21. Banozcy, J., E. Hadas, I. Esztary, I.Marosi, and J. Nemes, ‘‘Three-yearresults with sorbitol in clinicallongitudinal experiments,’’ Journal ofthe International Association ofDentistry in Children, 12:59–63, 1981.

22. Kandelman, D., and G. Gagnon,‘‘Clinical results after 12 months from astudy of the incidence and progressionof dental caries in relation toconsumption of chewing-gumcontaining xylitol in school preventiveprograms,’’ Journal of Dental Research,66:1407–1411, 1987.

23. Rekola, M., ‘‘Changes in buccalwhite spots during two-year totalsubstitution of dietary sucrose withxylitol,’’ Acta OdontologicaScandinavica, 44:285–290, 1986.

24. Makinen, K. K., and A. Scheinin,‘‘Turku sugar studies. VI. Theadministration of the trial and thecontrol of the dietary regimen,’’ ActaOdontologica Scandanavia, 33:105–127,1975.

25. Rekola, M., ‘‘Approximal cariesdevelopment during 2-year totalsubstitution of dietary sucrose withxylitol,’’ Caries Research, 21:87–94,1987.

26. Scheinin, A., J. Banoczy, J. Szoke,I. Esztari, K. Pienihakkinen, U.Scheinin, J. Tiekso, P. Zimmerman, andE. Hadas, ‘‘Collaborative WHO xylitol


field studies in Hungary. I. Three-yearcaries activity in institutionalizedchildren,’’ Acta OdontologicaScandinavica, 43:327–347, 1985.

27. Banoczy, J., A. Scheinin, R. Pados,G. Ember, P. Kertesz, and K.Pienihakkinen, ‘‘Collaborative WHOxylitol field studies in Hungary. II.General background and control of thedietary regimen,’’ Acta OdontologicaScandinavica, 43:349–357, 1985.

28. Scheinin, A., K. Pienihakkinen, J.Tiekso, J. Banoczy, J. Szoke, I. Esztari,P. Zimmerman, and E. Hadas,‘‘Collaborative WHO xylitol fieldstudies in Hungary. VII. Two-year cariesincidence in 976 institutionalizedchildren,’’ Acta OdontologicaScandinavica, 43:381–387, 1985.

29. Barmes, D., J. Barnaud, S.Khambonanda, and J. Sardo Infirri,‘‘Field trials of preventive regimes inThailand and French Polynesia,’’International Dental Journal, 35:66–72,1985.

30. Kandelman, D., A. Bar, and A.Hefti, ‘‘Collaborative WHO xylitol fieldstudy in French Polynesia. I. BaselinePrevalence and 32-month cariesincrement,’’ Caries Research, 22:1–10,1988.

31. Frostell, G., L. Blomlof, I.Blomqvist, G. M. Dahl, S. Edward, A.Fjellstrom, C. O. Henrikson, O. Larje, C.E. Nord, and K. J. Nordenvall,‘‘Substitution of sucrose by Lycasin incandy. ‘The Roslagen study’,’’ ActaOdontologica Scandinavica, 32:235–253, 1974.

32. Glass, R. L., ‘‘A two year clinicaltrial of sorbitol gum,’’ Caries Research,17:365–368, 1983.

33. Ikeda, T., K. Ochiai, Y. Doi, T.Mukasa, and S. Yagi, ‘‘Maltitol andSE58 in rats and decalcification ashuman intraoral substrate, NihonUniversity Journal of Oral Science,25:1–5, 1975.

34. Yagi, S., ‘‘Effects of maltitol oninsoluble glucan synthesis by S. mutansand change of enamel hardness,’’ NihonUniversity Journal of Oral Science,4:136–144, 1978.

35. Leach, S. A., G. T. R. Lee, and W.M. Edgar, ‘‘Remineralization of artificialcaries-like lesions in human enamel insitu by chewing sorbitol gum,’’ Journalof Dental Research, 68:1064–1068, 1989.

36. Rundegren, J., T. Koulourides, andT. Ericson, ‘‘Contribution of maltitoland Lycasin to experimental enameldemineralized in the human mouth,’’Caries Research, 14:67–74, 1980.

37. Creanor, S. L., R. Strang, W. H.Gilmour, R. H. Foye, J. Brown, D. A. M.Geddes, and A. F. Hall, ‘‘The effect ofchewing gum use on in situ enamellesion remineralization,’’ Journal ofDental Research, 71:1895–1900, 1992.

38. Bibby, B. G., and J. Fu, ‘‘Changesin plaque pH in vitro by sweeteners,’’Journal of Dental Research, 64:1130–1133, 1985.

39. Birkhed, D., and S. Edwardsson,‘‘Acid production from sucrosesubstitutes in human dental plaque,’’Proceedings of ERGOB Conference, pp.211–217, 1978.

40. Birkhed, D., S. Edwardsson, B.Svensson, F. Moskovitz, and G. Frostell,‘‘Acid production from sorbitol inhuman dental plaque,’’ Archives of OralBiology, 23:971–975, 1978.

41. Birkhed, D., S. Edwardsson, M. L.Ahlden, and G. Frostell, ‘‘Effects of 3 mofrequent consumption of hydrogenatedstarch hydrolysate (Lycasin), maltitol,sorbitol and xylitol on human dentalplaque,’’ Acta OdontologicaScandinavica, 37:103–115, 1979.

42. Frostell, G., ‘‘Dental plaque pH inrelation to intake of carbohydrateproducts,’’ Acta OdontologicaScandanavia, 27:3–29, 1969.

43. Toors, F. A., and J. I. B. Herczog,‘‘Acid production from a nonsugarlicorice and different sugar substitutesin Streptococcus mutans monocultureand pooled plaque-saliva mixtures,’’Caries Research, 12:60–68, 1978.

44. Gallagher, I. H., and S. J. Fussell,‘‘Acidogenic fermentation of pentosealcohols by human dental plaquemicroorganisms,’’ Archives of OralBiology, 24:673–679, 1979.

45. Gehring, F., and H. D. Hufnagel,‘‘Intra- and extraoral pH measurementson human dental plaque after rinsingwith some sugar and sucrose substitutesolutions,’’ Oralprophylaxe, 5:13–19,1983.

46. Havenaar, R., J. H. J. Huis In’tVeld, O. Backer Dirks, and J. D. deStoppelaar, ‘‘Some bacteriologicalaspects of sugar substitutes,’’Proceedings from ERGOB Conference,pp. 192–196, 1978.

47. Jensen, M. E., ‘‘Human plaqueacidogenicity studies with hydrogenatedstarch hydrolysates,’’ unpublished.

48. Maki, Y., K. Ohta, I. Takazoe, Y.Matsukubo, Y. Takaesu, V. Topitsoglou,and G. Frostell, ‘‘Acid production fromisomaltulose, sucrose, sorbitol, xylitol insuspensions of human dental plaque,’’Caries Research, 17:335–339, 1983.

49. Park, K. K., B. R. Schemehorn, J.W. Bolton, and G. K. Stookey,‘‘Comparative effect of sorbitol andxylitol mints on plaque acidogenicity,’’presented at the InternationalAssociation for Dental Research, April17–21, 1991.

50. Soderling, E., K. K. Makinen, C.-Y. Chen, H. R. Pape, and P.-L. Makinen,‘‘Effect of sorbitol, xylitol and xylitol/sorbitol gums on dental plaque,’’ CariesResearch, 23:378–384, 1989.

51. Birkhed, D., and G. Skude,‘‘Relation of amylase to starch andLycasin metabolism in human dentalplaque in vitro,’’ Scandinavian Journalof Dental Research, 86:248–258, 1978.

52. Havenaar, R., J. S. Drost, J. D. deStoppelaar, J. H. J. Huis in’t Veld, andO. Backer Dirks, ‘‘Potential cariogenicityof Lycasin 80/55 in comparison tostarch, sucrose, xylitol, sorbitol and L-sorbose in rats,’’ Caries Research,18:375–384, 1984.

53. Havenaar, R., J. S. Drost, J. H. J.Huis in’t Veld, O. Backer Dirks, and J.D. de Stoppelaar,, ‘‘Potentialcariogenicity of Lycasin 80/55 beforeand after repeated transmissions of thedental plaque flora in rats,’’ Archives ofOral Biology, 29:993–999, 1984.

54. Havenaar, R., J. H. J. Huis In’tVeld, J. D. de Stoppelaar, and O. BackerDirks, ‘‘A purified cariogenic diet forrats to test sugar substitutes with specialemphasis on general health,’’ CariesResearch, 17:340–352, 1983.

55. Havenaar, R., J. D. Huis in’t Veld,J. D. J. de Stoppelaar, and O. B. Dirks,‘‘Anti-cariogenic and remineralizingproperties of xylitol in combinationwith sucrose in rats inoculated withStreptococcus mutans,’’ CariesResearch, 18:269–277, 1984.

56. Grenby, T. H., and J. Colley,‘‘Dental effects of xylitol compared withother carbohydrates and polyols in thediet of laboratory rats,’’ Archives of OralBiology, 28:745–758, 1983.

57. Karle, E. J., and F. Gehring,‘‘Kariogenitatsuntersuchungen vonzuckeraustauschstoffen anxerostomierlen ratten. (Studies on thecariogenesis of sugar substitutes inxerostomized rats),’’ DeutscheZahnarztliche Zeitschrift, 34:551–554,1979.

58. Muhlemann, H. R., R. Schmid, T.Noguchi, T. Imfeld, and R. S. Hirsch,‘‘Some dental effects of xylitol underlaboratory and in vivo conditions,’’Caries Research, 11:263–276, 1977.

59. Shyu, K.-W., and M.-Y Hsu, ‘‘Thecariogenicity of xylitol, mannitol,sorbitol and sucrose,’’ Proceedings ofthe National Science Council ROC,4:21–26, 1980.

60. Bramstedt, F., F. Gehring, and E.J. Karle, ‘‘Comparative study of thecariogenic effects of Palatinit, xylitoland saccharose in animals,’’unpublished, 1976.

61. Izumiya, A., T. Ohshima, and S.Sofue, ‘‘Caries inducibility of varioussweeteners,’’ Academy of Pedodontia, p.65, May 1984.

62. Gehring, F., and E. J. Karle, ‘‘Thesugar substitute Palatinit with specialemphasis on microbiological and caries-preventing aspects,’’ ZeitschriftErnahrungswiss, 20:96–106, 1981.


63. Karle, E. J., and F. Gehring,‘‘Palatinit-A New Sugar Substitute andits Carioprophylactic Assessment,’’Deutsche Zalnarztliche Zeitschrift33:189–191, 1978.

64. Larje, O., and R. H. Larson,‘‘Reduction of dental caries in rats byintermittent feeding with sucrosesubstitutes, Archives of Oral Biology,15:805–816, 1970.

65. Muhlemann, H. R., ‘‘Effect oftopical application of sugar substituteson bacterial agglomerate formation,caries incidence and solution rates ofmolars in the rat,’’ unpublished, 1978.

66. Ooshima, T., A. Izumitani, T.Minami, T. Yoshida, S. Sobue, T.Fujiwari, and S. Hamada, ‘‘Non-cariogenicity of maltitol in SPF ratsinfected with mutans streptococci,’’submitted for publication.

67. Tate, N., S. Wada, H. Tani, and K.Oikawa, ‘‘Experimental studies oncorrelations between progressive cariesand sugar intake,’’ unpublished.

68. Leach, S. A., and R. M. Green,‘‘Effect of xylitol-supplemented diets onthe progression and regression of fissurecaries in the albino rat,’’ CariesResearch, 14:16–23, 1980.

69. Mukasa, T., ‘‘The possibility ofmaltitol and SE 58 as non-cariogenicsweeteners: their utilization byStreptococcus mutans for insolubleglucan synthesis and experimentaldental caries in rats,’’ Nihon UniversityJournal of Oral Science, 3:266–275,1977.

70. Hoeven, J. S. van der,‘‘Cariogenicity of disaccharide alcoholsin rats,’’ Caries Research, 14:61–66,1980.

71. Burt, B. A., and A. I. Ismail, ‘‘Diet,nutrition, and food cariogenicity,’’Journal of Dental Research, 65 (SpecialIssue): 1475–1484, 1986.

72. National Research Council,National Academy of Sciences, ‘‘Dietand Health,’’ National Academy Press,Washington, DC, 1989.

73. Hoeven, J.S. van der, ‘‘Carigenicityof lactitol in program-fed rats,’’ CariesResearch, 20:441–443, 1986.

74. Imfeld, T., and H. R. Muhlemann,‘‘Cariogenicity and acidogenicity offood, confectionery and beverages,’’Pharmacology and TherapeuticDentistry, 3:53–68, 1978.

75. Imfeld, T., ‘‘Identification of LowCaries Risk Dietary Components,’’Monographs in Oral Science, vol. 11,Karger, Basel, Switzerland, pp. 1–8 and117–144, 1983.

76. Grenby, T. H., A. Phillips, and M.Mistry, ‘‘Studies of the dental propertiesof lactitol compared with five other bulksweeteners in vitro,’’ Caries Research,23:315–319, 1989.

77. Grenby, T. H., and A. Phillips,‘‘Dental and metabolic effects of lactitolin the diet of laboratory rats,’’ BritishJournal of Nutrition, 61:17–24, 1989.

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List of Subjects in 21 CFR Part 101Food labeling, Nutrition, Reporting

and recordkeeping requirements.

Therefore, under the Federal Food,Drug, and Cosmetic Act and underauthority delegated to the Commissionerof Food and Drugs, it is proposed that21 CFR part 101 be amended as follows:

PART 101—FOOD LABELING

1. The authority citation for 21 CFRpart 101 is revised to read as follows:

Authority: Secs. 4, 5, 6 of the FairPackaging and Labeling Act (15 U.S.C. 1453,1454, 1455); secs. 201, 301, 402, 403, 409,701 of the Federal Food, Drug, and CosmeticAct (21 U.S.C. 321, 331, 342, 343, 348, 371).

2. New § 101.80 is added to subpart Eto read as follows:

§ 101.80 Health claims: dietary sugaralcohols and dental caries.

(a) Relationship between dietary sugaralcohols and dental caries. (1) Dentalcaries, or tooth decay, is a diseasecaused by many factors. Bothenvironmental and genetic factors canaffect the development of dental caries.Risk factors include tooth enamelcrystal structure and mineral content,plaque quantity and quality, salivaquantity and quality, individualimmune response, types and physicalcharacteristics of foods consumed,eating behaviors, presence of acidproducing oral bacteria, and culturalinfluences.

(2) The relationship between dietarysugars consumption and tooth decay iswell established. Sucrose is one of themost, but not the only, cariogenic sugarin the diet. Bacteria found in the mouthare able to metabolize sugars producingacid and forming dental plaque.Prolonged exposure of the tooth enamelto acids from dental plaque causes toothenamel to demineralize, or decay.Frequent between-meal consumption ofsugary foods, particularly foods thateasily stick to the teeth, can cause toothdecay.

(3) U.S. diets tend to be high in sugarsconsumption. Although there has beena decline in the prevalence of dentalcaries in the United States, per capitaconsumption of sugars has not declined,and the disease remains widespreadthroughout the population. Federalgovernment agencies and nationallyrecognized health professionalorganizations recommend decreasedconsumption of sugars.

(4) Dietary sugar alcohols can be usedto replace dietary sugars in food. Sugaralcohols are significantly less cariogenicthan dietary sugars. Thus, replacingdietary sugars with sugar alcohols helpsto maintain dental health.

(b) Significance of the relationshipbetween sugar alcohols and dentalcaries. Sugar alcohols do not promote


dental caries because they are slowlymetabolized by bacteria to form someacid. The rate and amount of acidproduction is significantly less than thatfrom sucrose and does not cause the lossof important minerals from toothenamel.

(c) Requirements. (1) All requirementsset forth in § 101.14 shall be met, exceptthat sugar alcohol-containing foods areexempt from section § 101.14(e)(6).

(2) Specific requirements. (i) Natureof the claim. A health claim relatingsugar alcohols and the nonpromotion ofdental caries may be made on the labelor labeling of a food described in(c)(2)(ii) of this section, provided that:

(A) The claim shall state ‘‘does notpromote,’’ ‘‘useful in not promoting,’’ or‘‘expressly for not promoting’’ dentalcaries.

(B) In specifying the disease, theclaim uses the following terms: ‘‘dentalcaries’’ or ‘‘tooth decay.’’

(C) For packages with a total surfacearea available for labeling of 15 or moresquare inches, the claim shall indicatethat dental caries depends on manyfactors.

(D) Packages with a total surface areaavailable for labeling of less than 15square inches are exempt fromparagraph (C) of this section.

(E) The claim shall not attribute anydegree of nonpromotion of dental cariesto the use of the sugar alcohol-containing food.

(ii) Nature of the food. (A) The foodshall meet the requirement in§ 101.60(c)(1)(i) with respect to sugarscontent.

(B) The sugar alcohol in the food shallbe xylitol, sorbitol, mannitol, maltitol,isomalt, lactitol, hydrogenated starchhydrolysates, hydrogenated glucosesyrups, or a combination of these.

(C) The sugar alcohol-containing foodshall not lower plaque pH below 5.7 bybacterial fermentation either duringconsumption or up to 30 minutes afterconsumption, as measured by in vivotests.

(d) Optional information. (1) Theclaim may include information fromparagraphs (a) and (b) of this section,which describe the relationship betweendiets containing sugar alcohols anddental caries.

(2) In referring to sucrose, the claimmay use the term ‘‘sucrose’’ or ‘‘sugar.’’

(3) The claim may identify one ormore of the following risk factors fordental caries: Frequent consumption ofsucrose or other fermentablecarbohydrates; presence of oral bacteriacapable of fermenting sugars; length oftime sugars are in contact with the teeth;

lack of exposure to fluoride; individualsusceptibility; socioeconomic andcultural factors; and characteristics oftooth enamel, saliva, and plaque.

(e) Model health claim. The followingmodel health claims may be used infood labeling to describe therelationship between sugar alcohol anddental caries.

(1) For packages with total surfacearea available for labeling of less than 15square inches:

(i) Useful only in not promoting toothdecay;

(ii) Does not promote tooth decay; and(iii) [This product] does not promote

tooth decay.(2) For packages with total surface

area available for labeling of 15 or moresquare inches:

(i) Tooth decay is a disease caused bymany factors including frequentbetween meal consumption of sugaryfoods. [Name of sugar alcohol] does notpromote tooth decay.

(ii) [Reserved].Dated: July 7, 1995.

William B. Schultz,Deputy Commissioner for Policy.

Note: The following tables will not appearin the annual Code of Federal Regulations.

BILLING CODE 4160–01–P


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

federal register /vol. 60, no. 139/thursday, july 20, … register/vol. 60, no. 139/thursday, july...

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