Food Labeling: Health Claims; Dietary Sugar Alcohols and Dental Caries

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. 97P-0206]

Food Labeling: Health Claims; Dietary Sugar Alcohols and Dental

Caries

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the regulation that authorized a health claim on sugar alcohols and

dental caries to include the sugar alcohol erythritol. FDA is proposing

this action in response to a petition filed by the Cerestar Holding

B.V., Mitsubishi Chemical Corp., and Nikken Chemicals Co. The agency

has tentatively concluded that, based on the totality of publicly

available scientific evidence presented in the petition, erythritol

does not promote dental caries. Therefore, FDA is proposing to amend

the sugar alcohol and dental caries health claim to include erythritol.

DATES: Written comments by September 22, 1997. The agency is proposing

that any final rule that may issue based upon this proposal become

effective upon its publication in the Federal Register.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),

Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,

MD 20857.

FOR FURTHER INFORMATION CONTACT: Joyce J. Saltsman, Center for Food

Safety and Applied Nutrition (HFS-165), Food and Drug Administration,

200 C St. SW., Washington, DC 20204, 202-205-5483.

SUPPLEMENTARY INFORMATION:

I. Background

Register.

ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),

Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,

MD 20857.

FOR FURTHER INFORMATION CONTACT: Joyce J. Saltsman, Center for Food

Safety and Applied Nutrition (HFS-165), Food and Drug Administration,

200 C St. SW., Washington, DC 20204, 202-205-5483.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of August 23, 1996 (61 FR 43433), the

agency adopted a final rule to authorize the use, on food labels and in

food labeling, of health claims on the association between sugar

alcohols and dental caries (hereinafter referred to as the sugar

alcohol final rule) (Sec. 101.80 (21 CFR 101.80)). FDA adopted this

regulation in response to a petition filed under section

403(r)(3)(B)(i) of the Federal Food, Drug, and Cosmetic Act (the act)

(21 U.S.C. 343(r)(3)(B)(i)). Section 403(r)(3)(B)(i) of the act states

that the Secretary of Health and Human Services (and, by delegation,

FDA) shall issue regulations authorizing health claims only if he or

she determines, based on the totality of publicly available scientific

evidence (including evidence from well-designed studies conducted in a

manner which is consistent with generally recognized scientific

procedures and principles), that there is significant scientific

agreement, among experts qualified by scientific training and

experience to evaluate such claims, that the claim is supported by such

evidence (see also Sec. 101.14(c) (21 CFR 101.14(c))).

The sugar alcohol final rule sets out the circumstances in which a

sugar alcohol is eligible to be the subject of a health claim

(Sec. 101.80(c)(2)(ii)). Section 101.80(c)(2)(ii)(A) states that the

food must meet the requirement for a sugar free food defined in 21 CFR

101.60(c)(1)(i)

luate such claims, that the claim is supported by such

evidence (see also Sec. 101.14(c) (21 CFR 101.14(c))).

The sugar alcohol final rule sets out the circumstances in which a

sugar alcohol is eligible to be the subject of a health claim

(Sec. 101.80(c)(2)(ii)). Section 101.80(c)(2)(ii)(A) states that the

food must meet the requirement for a sugar free food defined in 21 CFR

101.60(c)(1)(i). Section 101.80(c)(2)(ii)(B) lists the sugar alcohols

that are eligible to bear the claim, xylitol, sorbitol, mannitol,

maltitol, isomalt, lactitol, hydrogenated starch hydrolysates,

hydrogenated glucose syrups, or a combination of these. Section

101.80(c)(2)(ii)(C) states that:

[W]hen fermentable carbohydrates are present in the sugar

alcohol-containing food, the food shall not lower plaque pH below

5.7 by bacterial fermentation either during consumption, or up to 30

minutes after consumption as measured by the indwelling plaque pH

test found in ``Identification of Low Caries Risk Dietary

Components,'' * * * which is incorporated by reference * * *.

In the sugar alcohol final rule, the agency stated that for other

sugar alcohols to be included in Sec. 101.80(c)(2)(ii)(B), a petitioner

must show how the substance conforms to the requirements of

Secs. 101.14(b) and 101.80 (61 FR 43433 at 43442). FDA stated:

For those substances that are to be consumed at other than

decreased dietary levels, the petitioner must demonstrate to FDA's

satisfaction that the substance is safe and lawful under the

applicable food safety provisions of the act

(Sec. 101.14(b)(3)(ii)). Likewise, the petitioner would need to

provide evidence that the sugar alcohol will not lower plaque pH

below 5.7. Therefore, before a claim can be made for a new sugar

alcohol, it must be shown to meet the requirements for Sec. 101.80.

When this is demonstrated, FDA will take action to add the substance

to the list in this regulation, which has been renumbered as

Sec. 101.80(c)(2)(ii)(B)

). Likewise, the petitioner would need to

provide evidence that the sugar alcohol will not lower plaque pH

below 5.7. Therefore, before a claim can be made for a new sugar

alcohol, it must be shown to meet the requirements for Sec. 101.80.

When this is demonstrated, FDA will take action to add the substance

to the list in this regulation, which has been renumbered as

Sec. 101.80(c)(2)(ii)(B).

The present rulemaking is in response to a petition to amend

Sec. 101.80(c)(2)(ii)(B) to include erythritol as one of the sugar

alcohols that is eligible to bear the sugar alcohol and dental caries

health claim.

II. Petition for Health Claim on Erythritol and the Nonpromotion of

Dental Caries

A. The Petition

On April 4, 1997, the petitioners submitted a petition to FDA

requesting that the agency amend Sec. 101.80(c)(2)(ii)(B) to authorize

a claim to authorize a noncariogenicity dental health claim for the

sugar alcohol erythritol. On May 16, 1997, the agency sent the

petitioner a letter stating that it had completed its initial review of

the petition, and that the petition would be filed in accordance with

section 403(r)(4) of the act (see Docket 97P-0206, Letter 1). The

following is a review of the health claim petition and of whether

erythritol satisfies the requirements of Secs. 101.80(c)(2)(ii) and

101.14(b) and (c) of FDA's regulations.

B. Preliminary Requirements

1. The Substance That Is the Subject of the Petition

Erythritol is a 4-carbon, monosaccharide polyhydric alcohol. It

occurs naturally in a wide variety of plants (e.g., watermelons,

melons, grapes, and mushrooms) and animals (e.g., humans, dogs, and

cows). Erythritol is also a product of the fermentation by yeasts and

molds of sugars (Ref. 1, p. 27).

2. The Substance Is Associated With a Disease for Which the U.S

Is the Subject of the Petition

Erythritol is a 4-carbon, monosaccharide polyhydric alcohol. It

occurs naturally in a wide variety of plants (e.g., watermelons,

melons, grapes, and mushrooms) and animals (e.g., humans, dogs, and

cows). Erythritol is also a product of the fermentation by yeasts and

molds of sugars (Ref. 1, p. 27).

2. The Substance Is Associated With a Disease for Which the U.S.

Population Is at Risk

In the preamble to the proposed sugar alcohol and dental caries

rule (60 FR 37507 at 37509, July 20, 1995) and in the regulation

authorizing the claim on sugar alcohols and dental caries

(Sec. 101.80(a)(3)), FDA established that dental caries is a disease

for which the U.S. population is at risk. The agency stated:

Dental caries is recognized in The Surgeon General's Report on

Nutrition and Health * * * as a disease or health-related condition

for which the United States population is at risk * * *. The overall

prevalence of dental caries imposes a substantial burden on

Americans. Of the 13 leading health

problems in the United States, dental diseases rank second in direct

costs * * *.

Dental caries continues to affect a large proportion of

Americans. Although there has been a decline in the prevalence of

dental caries among children in the United States, the disease

remains widespread throughout the population * * *.

Based on these facts, FDA concludes that, as required in

Sec. 101.14(b)(1), dental caries is a disease for which the U.S.

population is at risk.

3. The Substance Is a Food

In the preamble to the sugar alcohols proposed rule (60 FR 37507 at

37509) and in the final regulation itself (Sec. 101.80(a)(4)), the

agency states that sugar alcohols can be used as sweeteners to replace

dietary sugars, such as sucrose and corn sweeteners, in foods such as

chewing gums and certain confectioneries. Therefore, FDA concludes that

erythritol satisfies the preliminary requirement in

Sec. 101.14(b)(3)(i).

4

alcohols proposed rule (60 FR 37507 at

37509) and in the final regulation itself (Sec. 101.80(a)(4)), the

agency states that sugar alcohols can be used as sweeteners to replace

dietary sugars, such as sucrose and corn sweeteners, in foods such as

chewing gums and certain confectioneries. Therefore, FDA concludes that

erythritol satisfies the preliminary requirement in

Sec. 101.14(b)(3)(i).

4. The Substance Is Safe and Lawful

The petitioner has submitted a petition requesting that FDA affirm

that the use of erythritol is generally recognized as safe (GRAS) (62

FR 10285, March 6, 1997). The agency notes that this GRAS affirmation

petition (GRASP 7G0422) is still under review, and that authorization

of a health claim should not be interpreted as affirmation that the

proposed uses of erythritol are GRAS. Such a determination can be made

only after the agency has completed its review of the GRAS petition. A

preliminary review of the GRAS affirmation petition, however, reveals

that it contains significant evidence supporting the safety of the use

of this substance at the levels necessary to justify a health claim.

In the GRAS affirmation petition, the petitioner relied heavily on

published animal subchronic and chronic toxicity studies and

reproduction studies (GRASP 7G0422, App. IV: C4, C12, D5, D7, D8, D17,

D20, D27, and D30), on human toleration and absorption studies (GRASP

7G0422, App. IV: C9, C19, C27, E2, E6, E8, and E11), and on the

conclusions about the safety of erythritol by a panel of independent

experts qualified by scientific training and experience to evaluate the

safety of foods. The panel of independent scientists based their

conclusions on their review of various published and unpublished

scientific studies which included animal toxicological studies and

clinical studies. In their report entitled, ``Erythritol: A Review of

Biological and Toxicological Studies'' (GRASP 7G0422, App

xperts qualified by scientific training and experience to evaluate the

safety of foods. The panel of independent scientists based their

conclusions on their review of various published and unpublished

scientific studies which included animal toxicological studies and

clinical studies. In their report entitled, ``Erythritol: A Review of

Biological and Toxicological Studies'' (GRASP 7G0422, App. I-1), the

panel concluded that:

The large body of published data supports the conclusion that

the intake of erythritol would not be expected to cause adverse

effects in humans under the conditions of use in food and that other

qualified food safety experts would agree that erythritol is

generally recognized as safe (GRAS) under the conditions of its

intended use in food.

The petitioner also asserted that erythritol occurs endogenously

and naturally in the diet, and that it has a history of safe use in

foods. The petitioner further argued that the safety of erythritol is

supported by its chemical structure, i.e., it is positioned in the

homologous series of sugar alcohols, between glycerol and xylitol, a

series that also includes other common food ingredients such as

sorbitol and mannitol.

Based on the totality of the evidence, the agency is not prepared,

at this time, to take issue with the petitioner's view that the use of

erythritol is safe and lawful. Therefore, FDA tentatively concludes

that the petitioner has provided evidence that satisfies the

requirement in Sec. 101.14(b)(3)(ii) that use of erythritol at the

levels necessary to justify a claim is safe and lawful.

III. Review of Scientific Evidence

vidence, the agency is not prepared,

at this time, to take issue with the petitioner's view that the use of

erythritol is safe and lawful. Therefore, FDA tentatively concludes

that the petitioner has provided evidence that satisfies the

requirement in Sec. 101.14(b)(3)(ii) that use of erythritol at the

levels necessary to justify a claim is safe and lawful.

III. Review of Scientific Evidence

The petitioner submitted two scientific studies evaluating the

relationship between erythritol and dental caries: A human study and an

animal study that included an in vitro evaluation.

The human study included an interdental plaque pH telemetry test,

one of the methods described in the text entitled ``Identification of

Low Caries Risk Dietary Components,'' which the agency incorporated by

reference in the sugar alcohol regulation (see

Sec. 101.80(c)(2)(ii)(C)). The test was conducted at the Bioelectronic

Unit of the Clinic of Preventive Dentistry, Periodontology, and

Cariology of the University Dental Institute of Zurich, Switzerland

(Ref. 1, Appendix B-2).

For this test, each subject had a mandibular telemetric prosthesis

incorporating a miniaturized glass pH-electrode placed directly

opposite the interproximal area of an adjacent abutment tooth. Once the

prosthesis was inserted into the subject's mouth, the subject was asked

not to alter his or her eating habits. The prostheses were worn

throughout the 3-to 4-day test period to allow an undisturbed growth of

interdental plaque over the tips of the electrodes. With the exception

of water rinses, the subjects were also asked to refrain from all oral

hygiene measures.

At the end of the 3-to 4-day plaque buildup period, the interdental

plaque pH telemetry test was conducted. Baseline plaque pH was measured

over a 15-minute period after the subjects chewed a piece of paraffin

for 3 minutes. The subjects then sucked on the sugar-free throat

lozenge containing erythritol, followed by plaque pH measurements over

a 30-minute period

m all oral

hygiene measures.

At the end of the 3-to 4-day plaque buildup period, the interdental

plaque pH telemetry test was conducted. Baseline plaque pH was measured

over a 15-minute period after the subjects chewed a piece of paraffin

for 3 minutes. The subjects then sucked on the sugar-free throat

lozenge containing erythritol, followed by plaque pH measurements over

a 30-minute period. The same test procedure was then repeated using a

10-percent sucrose rinse as the control substance in place of the

erythritol lozenge.

The results of this test showed that after the first paraffin chew,

baseline plaque pH measured between 6.9 to 7.0, values that were

similar to earlier tests with the same subjects and plaque ages (Ref.

1, Appendix B-2). Following consumption of erythritol, plaque pH

measured 6.0 to 6.65. The sucrose rinse caused plaque pH to drop to a

range of 4.25 to 4.9, levels that were significantly lower than pH of

plaque during the erythritol period and well below the critical pH

value of 5.7, the level at which demineralization of enamel occurs. The

key finding for this proceeding is that there were no significant

differences in plaque pH between the paraffin and erythritol periods.

Kawanabe and coworkers evaluated the cariogenicity of erythritol in

vitro and in pathogen-free rats (Ref. 1, Appendix B-3). The authors

used microorganisms of various Streptococcus, Lactobacillus, and

Actinomyces species to determine whether the organisms could use

erythritol as a substrate for lactic acid production and plaque

formation. The results of this study showed that erythritol was not

utilized as a substrate for lactic acid production or for plaque

formation by Streptococcus mutans or certain other oral microorganisms.

In the animal study, the rats were randomly divided into six

groups. Three groups of animals were fed modified diets for 5 days.

These diets contained either starch alone, with no sugars or sugar

alcohol; starch plus sucrose; or starch plus erythritol

s not

utilized as a substrate for lactic acid production or for plaque

formation by Streptococcus mutans or certain other oral microorganisms.

In the animal study, the rats were randomly divided into six

groups. Three groups of animals were fed modified diets for 5 days.

These diets contained either starch alone, with no sugars or sugar

alcohol; starch plus sucrose; or starch plus erythritol. Then the

animals were infected with Streptococcus sobrinus, after which they

continued to consume the modified diet for an additional 50 days. In a

similar experiment, the other three groups of animals were fed diets

that contained starch chocolate; sucrose chocolate, or erythritol

chocolate, and the animals were infected with Streptococcus mutans.

Mandibular caries scores were determined at 70 days of age in all

groups.

The results of this study showed that the group fed starch plus

erythritol experienced significantly fewer caries compared to the

starch and starch plus sucrose groups. The total caries scores for

groups fed diets of starch, starch

plus sucrose, and starch plus erythritol were 12.5, 60.5, and 3.1,

respectively. Similarly, the group consuming erythritol chocolate

experienced significantly fewer caries compared to the starch chocolate

and sucrose chocolate groups. The caries scores for the starch

chocolate, sucrose chocolate, and erythritol chocolate groups were

18.5, 82.8, and 6.7, respectively. There were no significant

differences in the body weights of the rats between groups.

The authors stated that, although the group fed starch usually

experienced the least dental caries, the caries score for the group fed

starch was significantly higher than that of the group fed starch plus

erythritol. The same trend was reported in the animals consuming the

chocolate diets. The authors suggested that the cariogenicity of starch

in these experiments may be explained by the contamination of mono- and

disaccharides

group fed starch usually

experienced the least dental caries, the caries score for the group fed

starch was significantly higher than that of the group fed starch plus

erythritol. The same trend was reported in the animals consuming the

chocolate diets. The authors suggested that the cariogenicity of starch

in these experiments may be explained by the contamination of mono- and

disaccharides. The main conclusion from this study is that erythritol

did not induce dental caries.

IV. Decision to Propose a Health Claim Relating Erythritol to the

Nonpromotion of Dental Caries

The petition set out the results of an indwelling plaque pH test

and the results of an in vitro and animal study that evaluated the

cariogenicity of erythritol. FDA reviewed this information and has

tentatively concluded that there is significant scientific evidence to

demonstrate that erythritol does not promote dental caries. The results

of the plaque pH test clearly demonstrate that erythritol does not

lower plaque pH below 5.7, and that, therefore, it does not promote the

demineralization of dental enamel. The results of the in vitro and

animal study are consistent with the results of the indwelling plaque

pH study and show that erythritol does not support the growth of oral

microorganisms responsible for producing the acid in plaque and has

little to no cariogenic potential. The results of these studies are

consistent with the results of the studies that investigated the

cariogenic potential of the sugar alcohols listed in

Sec. 101.80(c)(2)(ii)(B). Therefore, FDA tentatively finds that

erythritol has satisfied the requirements set forth in Secs. 101.14(d)

and 101.80, and the agency is proposing to add erythritol to the list

of eligible sugar alcohols.

V. Description of Modifications to Sec. 101.80

sistent with the results of the studies that investigated the

cariogenic potential of the sugar alcohols listed in

Sec. 101.80(c)(2)(ii)(B). Therefore, FDA tentatively finds that

erythritol has satisfied the requirements set forth in Secs. 101.14(d)

and 101.80, and the agency is proposing to add erythritol to the list

of eligible sugar alcohols.

V. Description of Modifications to Sec. 101.80

Section 101.80(c)(2)(ii)(B) lists the sugar alcohols that are

eligible to be the subject of a dental claim. FDA is proposing to amend

Sec. 101.80(c)(2)(ii)(B) to state ``[T]he sugar alcohol in the food

shall be xylitol, sorbitol, mannitol, maltitol, isomalt, lactitol,

hydrogenated starch hydrolysates, hydrogenated glucose syrups,

erythritol, or a combination of these.''

The agency is not specifying a level of erythritol in the food

product because, like the other sugar alcohols, erythritol is being

used as a substitute for sugars. Therefore, the amount of the substance

required is that needed to achieve a desired level of sweetness.

VI. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(11) that this

action is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required. This finding is based on information submitted by the

petitioner in an environmental assessment prepared using the format

described in 21 CFR 25.31a(b)(5).

VII. Analysis of Impacts

action is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required. This finding is based on information submitted by the

petitioner in an environmental assessment prepared using the format

described in 21 CFR 25.31a(b)(5).

VII. Analysis of Impacts

FDA has examined the economic implications of the proposed rule as

required by Executive Order 12866 and the Regulatory Flexibility Act (5

U.S.C. 601-612). Executive Order 12866 directs agencies to assess all

costs and benefits of available regulatory alternatives and, when

regulation is necessary, to select the regulatory approach that

maximizes net benefits (including potential economic, environmental,

public health and safety effects; distributive impacts; and equity).

Executive Order 12866 classifies a rule as significant if it meets any

one of a number of specified conditions, including having an annual

effect on the economy of $100 million or adversely affecting in a

material way a sector of the economy, competition, or jobs, or if it

raises novel legal or policy issues. If a rule has a significant

economic impact on a substantial number of small entities, the

Regulatory Flexibility Act requires agencies to analyze regulatory

options that would minimize the economic impact of that rule on small

entities. FDA finds that this proposed rule is not a significant rule

as defined by Executive Order 12866 and finds under the Regulatory

Flexibility Act that the proposed rule will not have a significant

impact on a substantial number of small entities.

The establishment of this health claim results in benefits and in

costs only to the extent that food manufacturers elect to take

advantage of the opportunity to use the claim. This rule will not

require that any labels be redesigned, or that any product be

reformulated

latory

Flexibility Act that the proposed rule will not have a significant

impact on a substantial number of small entities.

The establishment of this health claim results in benefits and in

costs only to the extent that food manufacturers elect to take

advantage of the opportunity to use the claim. This rule will not

require that any labels be redesigned, or that any product be

reformulated.

Some manufacturers are using FDA's approved health claim regarding

the benefits of sugar alcohols. This proposed health claim will allow

them to highlight the effects of another sugar alcohol, erythritol. The

benefit of establishing this health claim is to provide for new

information in the market regarding the relationship of erythritol and

dental caries, and to provide consumers with the assurance that this

information is truthful, not misleading, and scientifically valid.

Costs will be incurred by small entities only if they opt to take

advantage of the marketing opportunity presented by this regulation.

FDA cannot predict the number of small entities that will choose to use

the claim. However, no firm, including small entities, will choose to

bear the cost of redesigning labels unless they believe that the claim

will result in increased sales of their product. Therefore, this rule

will not result in either a decrease in revenues or a significant

increase in costs to any small entity. Accordingly, under the

Regulatory Flexibility Act, 5 U.S.C. 605(b), the agency certifies that

this proposed rule will not have a significant economic impact on a

substantial number of small entities.

VIII. Paperwork Reduction Act

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday.

1. Cerestar Holding B. V., Mitsubishi Chemical Corp., and Nikken

Chemicals Co., ``Petition to amend the regulation for 21 CFR

Sec. 101.80 to authorize a noncariogenicity dental health claim for

the sugar alcohol erythritol (1,2,3,4-butanetetrol),'' April 4, 1997

[CP1].

List of Subjects in 21 CFR Part 101

Food and Drug Administration, Food labeling, Nutrition, Reporting

and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR part 101 be amended as follows:

PART 101--FOOD LABELING

1. The authority citation for 21 CFR part 101 continues to read as

follows:

Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act

(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, 701 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342,

343, 348, 371).

2. Section 101.80 is amended by revising paragraph (c)(2)(ii)(B) to

read as follows:

Sec. 101.80 Health claims: dietary sugar alcohols and dental caries.

* * * * *

(c) * * *

(2) * * *

(ii) * * *

(B) The sugar alcohol in the food shall be xylitol, sorbitol,

mannitol, maltitol, isomalt, lactitol, hydrogenated starch

hydrolysates, hydrogenated glucose syrups, erythritol, or a combination

of these.

* * * * *

Dated: June 17, 1997.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 97-17797 Filed 7-8-97; 8:45 am]

BILLING CODE 4160-01-F