52474 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

DEPARTMENT OF HEALTH AND 12420 Parklawn Dr., Rockville, MD 350 mg. Interested persons were invited HUMAN SERVICES 20857. to submit written comments by July 7, The agency’s proposed regulation, in 1992. Food and Drug Administration the form of a tentative final monograph, In the Federal Register of November for OTC anticaries drug products was 24, 1992 (57 FR 55199), the agency also 21 CFR Parts 310, 355, and 369 published in two segments. The first reopened the administrative record to [Docket No. 80N±0042] segment was published in the Federal obtain public comment on whether the Register of September 30, 1985 (50 FR labeling of OTC fluoride-containing RIN 0910±AA01 39854). It addressed general issues on drug products should include the OTC anticaries drug products, the quantity of fluoride, i.e., the specific Anticaries Drug Products for Over-the- switch of prescription anticaries drug amount of fluoride present in the Counter Human Use; Final Monograph products to OTC status, specific product. Interested persons were invited AGENCY: Food and Drug Administration, anticaries active ingredients, dosages for to submit written comments by January HHS. anticaries active ingredients, and 25, 1993. In the Federal Register of labeling of anticaries drug products. January 26, 1993 (58 FR 6102), the ACTION: Final rule. Interested persons were invited to file agency extended the comment period to SUMMARY: The Food and Drug by November 29, 1985, written March 26, 1993. Administration (FDA) is issuing a final comments, objections, or requests for This final rule encompasses all of the rule in the form of a final monograph oral hearing on the proposed regulation above segments. Final agency action on establishing conditions under which before the Commissioner of Food and all OTC anticaries drug products occurs over-the-counter (OTC) anticaries drug Drugs (the Commissioner). Interested with the publication of this final rule products (products that aid in the persons were invited to file comments establishing a monograph for OTC prevention of dental cavities) are on the agency’s economic impact anticaries drug products. generally recognized as safe and determination by January 28, 1986. New The OTC drug procedural regulations effective and not misbranded. FDA is data could have been submitted until (§ 330.10) provide that any testing issuing this final rule after considering September 30, 1986, and comments on necessary to resolve the safety or public comments on the agency’s the new data until December 1, 1986. effectiveness issues that formerly proposed regulation, which was issued The agency stated in the advance resulted in a Category III classification, in the form of a tentative final notice of proposed rulemaking that the and submission to FDA of the results of monograph, and all new data and Panel’s recommended Laboratory that testing or any other data, must be information on OTC anticaries drug Testing Profiles (LTP’s) represented a done during the OTC drug rulemaking products that have come to the agency’s new concept with many technical issues process before the establishment of a attention. This final monograph is part yet to be resolved. Thus, the LTP’s were final monograph. Accordingly, FDA is of the ongoing review of OTC drug not included in the first segment of the no longer using the terms ‘‘Category I’’ products conducted by FDA. tentative final monograph. The agency (generally recognized as safe and mentioned in the tentative final effective and not misbranded), EFFECTIVE DATE: October 7, 1996. monograph (50 FR 39854) that an open ‘‘Category II’’ (not generally recognized FOR FURTHER INFORMATION CONTACT: public meeting was held on September as safe and effective or misbranded), William E. Gilbertson, Center for Drug 26 and 27, 1983, to discuss unresolved and ‘‘Category III’’ (available data are Evaluation and Research (HFD–810), technical issues concerning the LTP’s. insufficient to classify as safe and Food and Drug Administration, 5600 The LTP’s were subsequently discussed effective, and further testing is required) Fishers Lane, Rockville, MD 20857, in the second segment of the tentative at the final monograph stage. In place of 301–594–5000. final monograph, published in the Category I, the term ‘‘monograph SUPPLEMENTARY INFORMATION: In the Federal Register of June 15, 1988 (53 FR conditions’’ is used; in place of Category Federal Register of March 28, 1980 (45 22430). This amendment of the tentative II or III, the term ‘‘nonmonograph FR 20666), FDA published, under final monograph addressed final conditions’’ is used. § 330.10(a)(6) (21 CFR 330.10(a)(6)), an formulation testing for monograph As discussed in the proposed advance notice of proposed rulemaking active ingredients in dentifrice regulation for OTC anticaries drug to establish a monograph for OTC formulations and issues relating to this products (50 FR 39854), the agency anticaries drug products, together with testing. Interested persons were invited advised that the conditions under which the recommendations of the Advisory to file by October 13, 1988, written the drug products that are subject to this Review Panel on OTC Dentifrice and comments, objections, or requests for monograph will be generally recognized Dental Care Drug Products (the Panel), oral hearing on the proposed regulation as safe and effective and not misbranded which was the advisory review panel before the Commissioner. Interested (monograph conditions) will be effective responsible for evaluating data on the persons were invited to file comments 12 months after the date of publication active ingredients in this drug class. on the agency’s economic impact in the Federal Register. Therefore, on or Interested persons were invited to determination by October 13, 1988. New after October 7, 1996, no OTC drug submit comments by June 26, 1980. data could have been submitted until product that is subject to the monograph Reply comments in response to June 15, 1989, and comments on the and that contains a nonmonograph comments filed in the initial comment new data until August 15, 1989. condition, i.e., a condition that would period could be submitted by July 28, In a notice published in the Federal cause the drug to be not generally 1980. Register of May 8, 1992 (57 FR 19823), recognized as safe and effective or to be In accordance with § 330.10(a)(10), the agency reopened the administrative misbranded, may be initially introduced the data and information considered by record to include data and information or initially delivered for introduction the Panel, after deletion of a small in support of a request to increase the into interstate commerce unless it is the amount of trade secret information, package size limitation for fluoride subject of an approved application or were placed on display in the Dockets dentifrice drug products from not more abbreviated application (hereinafter Management Branch (HFA–305), Food than 260 milligrams (mg) of total called application). Further, any OTC and Drug Administration, rm. 1–23, fluorine per package to not more than drug product subject to this monograph Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52475 that is repackaged or relabeled after the supported the proposed revision of the 3. One comment noted that interested effective date of the monograph must be exclusivity policy and discussed a persons must file new data within 1 in compliance with the monograph number of constitutional and policy year after publication of a tentative final regardless of the date the product was concerns about the agency’s labeling monograph per 21 CFR 330.10(a)(7)(iii). initially introduced or initially policies for OTC drug products. For this reason, the comment contended delivered for introduction into interstate The agency notes that the comments that it is important that persons commerce. Manufacturers are in the current rulemaking were submitting comments or objections to encouraged to comply voluntarily with submitted before the agency published a the tentative final monograph be the monograph at the earliest possible final rule changing its labeling policy provided with early feedback from FDA date. for stating the indications for use of so that sufficient time will remain to In response to the proposed rule, the OTC drug products in the Federal allow any necessary additional testing amended proposed rule, and the two Register of May 1, 1986 (51 FR 16258). or market research. The comment reopenings of the administrative record The comments’ concerns were requested that the agency provide for OTC anticaries drug products, 19 addressed by the agency’s change in its feedback on requests no later than 6 drug manufacturers, 2 drug labeling policy for stating indications months following the submission of manufacturers associations, 2 health for use. Under the new policy in comments or objections to the proposed care professionals, 1 health care § 330.1(c)(2) (21 CFR 330.1(c)(2)), the rule. The comment also asked that the professional society, and 3 academic label and labeling of OTC drug products agency’s regulations for the OTC drug institutions submitted comments. are required to contain in a prominent review be amended to contain this Copies of the comments are on public and conspicuous location, either: (1) provision. display in the Dockets Management The specific wording on indications for The agency is unable to make a Branch (address above.) Additional use established under an OTC drug specific commitment to provide information that has come to the monograph, which may appear within a feedback on all comments and agency’s attention since the publication boxed area designated ‘‘APPROVED objections received in this and other of the proposed rule, amended proposed USES’’; (2) other wording describing OTC drug rulemakings within a specific rule, and notices to reopen the such indications for use that meets the time frame, as requested by the administrative record is also on display statutory prohibitions against false or comment. Competing priorities and the in the Dockets Management Branch. misleading labeling, which shall neither constraints of limited resources make All ‘‘OTC Volumes’’ cited throughout appear within a boxed area nor be this impossible to do. However, the this document refer to the submissions designated ‘‘APPROVED USES’’; or (3) agency does review all comments and made by interested persons pursuant to the approved monograph language on objections and tries to provide timely feedback as the situation requires and as the call-for-data notice published in the indications, which may appear within a workloads permit. Federal Register of August 9, 1972 (37 boxed area designated ‘‘APPROVED 4. The Public Health Service Ad Hoc FR 16029) or to additional information USES’’; plus alternative language that has come to the agency’s attention Subcommittee on Fluoride of the describing indications for use that is not Committee to Coordinate Environmental since publication of the advance notice false or misleading, which shall appear of proposed rulemaking. The volumes Health and Related Programs (the elsewhere in the labeling. Subcommittee) discussed dental are on public display in the Dockets 2. One comment contended that OTC Management Branch. fluorosis resulting from fluoride intake drug monographs are interpretive, as in its report entitled ‘‘Review of I. The Agency’s Conclusions on the opposed to substantive, regulations. The Fluoride: Benefits and Risks’’ (Ref. 1). Comments comment referred to statements on this The Subcommittee stated that dental issue submitted earlier to other OTC fluorosis only occurs during tooth A. General Comments on Anticaries drug rulemaking proceedings. Drug Products formation and becomes apparent upon The agency addressed this issue in eruption of the teeth. Dental fluorosis 1. One comment noted its continuing paragraphs 85 through 91 of the ranges from very mild (symmetrical position that FDA could not legally and preamble to the procedures for whitish areas on teeth) to severe (pitting should not, as a matter of policy, classification of OTC drug products, of the enamel, frequently associated prescribe exclusive lists of terms from published in the Federal Register of with brownish discoloration). The which indications for use for OTC drug May 11, 1972 (37 FR 9464 at 9467 to Subcommittee recommended that products must be drawn.The comment 9472); in paragraph 3 of the preamble to manufacturers of dental products stated that FDA could not legally the tentative final monograph for OTC explore whether the levels of fluoride in prohibit alternative OTC indications for antacid drug products, published in the their products can be reduced while use in terminology that is otherwise Federal Register of November 12, 1973 preserving clinical effectiveness. truthful and not misleading. The (38 FR 31260); and in paragraph 1 of the (However, the Subcommittee did not comment added that its views on this preamble to the tentative final suggest an acceptable fluoride exposure subject were presented in oral and monograph in the present proceeding level.) In response to the written testimony submitted to FDA in (50 FR 39854 at 39855). FDA reaffirms Subcommittee’s recommendation, the connection with the September 29, the conclusions stated in those agency asked a professional dental 1982, FDA hearing on the exclusivity documents. Court decisions have association and two manufacturers policy. The comment noted that a confirmed the agency’s authority to associations (Refs. 2, 3, and 4) for proposed revision to the exclusivity issue substantive regulations by information on dentifrices containing policy had been published on April 22, informal rulemaking. (See, e.g., National low levels of fluoride, particularly for 1985 (50 FR 15810). The comment Nutritional Foods Association v. use by children 2 to under 6 years of mentioned that it had submitted its Weinberger, 512 F.2d 688, 696–698 (2d age. views in response to that proposal and Cir. 1975) and National Association of The dental association stated that it is was incorporating those views into the Pharmaceutical Manufacturers v. FDA, not currently considering a low fluoride rulemaking for OTC anticaries drug 487 F. Supp. 412 (S.D.N.Y. 1980), aff’d, toothpaste, but would evaluate such a products. A second comment strongly 637 F.2d 887 (2d Cir. 1981).) product if one were to be submitted. 52476 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

The association indicated that such a References and inappropriate. The comment product would be accepted if clinical (1) Department of Health and Human recommended that this section be data demonstrating effectiveness were Services, ‘‘Review of Fluoride Benefits and revised to more clearly emphasize the available. Risks: Report of the Ad Hoc Subcommittee intended therapeutic function of these The two manufacturers associations on Fluoride, of the Committee to Coordinate dosage forms. For example, ‘‘an provided a joint response, in which they Environmental Health and Related anticaries drug product is one which reviewed the report and relevant Programs,’’ February, 1991, in OTC Vol. No. aids in the prevention or treatment of clinical and epidemiological literature, 08AFM, Docket No. 80N–0042, Dockets dental caries (decay, cavities) and may Management Branch. be formulated as an abrasive-containing with the following conclusions: (1) (2) Comment No. LET15, Docket No. 80N– There is a lack of scientific support for 0042, Dockets Management Branch. dentifrice, paste, or powder, a cause and effect relationship between (3) Comment No. LET16, Docket No. 80N– nonabrasive gel, liquid rinse, or the ingestion of fluoride from dentifrice 0042, Dockets Management Branch. effervescent powder or tablets.’’ products and the subsequent (4) Comment No. LET17, Docket No. 80N– The agency has reviewed the Panel’s development of enamel fluorosis; (2) the 0042, Dockets Management Branch. evaluation of the definition of different reported increase in enamel fluorosis, 5. One comment stated that the fluoride dosage forms and concludes which ranges from very mild to mild, proposed definitions for dentifrice, that there is a significant difference appears to be a result of factors other treatment gel, and treatment rinse in between dentifrices and nonabrasive than dentifrice use, while, importantly, § 355.3(d), (g), and (h), respectively, dental gels and rinses. A dentifrice dentifrice use has been the principal should be revised to exclude discussion formulation contains an abrasive that is contributor to the caries decline over the of the ‘‘cosmetic function or included in the formulation to clean the past 20 years; and (3) manufacturing nonfunction’’ of these treatment teeth (45 FR 20666 at 20671), while changes to reduce the fluoride content categories. The comment noted, for nonabrasive dental gels and rinses do of baby formulas, as well as cautionary example, that the first sentence in the not (45 FR 20666 at 20671). advice to physicians about the definition for dentifrice, ‘‘A substance The agency agrees with the comments administration of fluoride supplements used with a toothbrush to clean the that OTC drug monographs should not regulate cosmetic claims and are limited to young children, are steps that have accessible surfaces of the teeth,’’ refers to only drug claims. The monograph already been initiated and may well to a cosmetic function and should be deleted. The comment proposed definitions are intended to refer to the counteract the increase of the very mild modifying the definitions for dentifrice therapeutic uses of the dosage forms to mild forms of enamel fluorosis that and treatment gel to be consistent with defined. Accordingly, the agency is have been reported, as new the definition for a treatment rinse as deleting any references to a ‘‘cosmetic epidemiologic data become available in follows: A dentifrice is an abrasive- function’’ (e.g., cleaning) from the the future. containing dosage form for delivering an proposed definitions. In the definition The manufacturers associations anticaries drug to the teeth, a treatment for dentifrice, the first sentence (‘‘A recommended that there be no gel is a gel dosage form for delivering an substance used with a toothbrush to reduction in the 850- to 1,150-parts per anticaries drug to the teeth, and a clean the accessible surfaces of the million (ppm) theoretical total fluorine treatment rinse is a liquid dosage form teeth.’’) is deleted. The second sentence levels proposed in the tentative final for delivering an anticaries drug to the is revised to read ‘‘An abrasive- monograph for OTC anticaries drug teeth. The comment suggested the containing dosage form for delivering an products, contending that any reduction following alternative definition for the anticaries drug to the teeth.’’ In the in this range could have serious public entire category of anticaries drug definition for treatment gels, the words health consequences in terms of products rather than defining individual ‘‘and are not intended for use in reducing the current level of anticaries dosage forms: ‘‘an anticaries drug cleaning the teeth’’ are deleted. Other protection in young children. The product is one which aids in the definitions mentioned by the comment associations noted that data from prevention or treatment of dental caries. (treatment rinse, treatment rinse studies evaluating low-potency (250 to It may be formulated as an abrasive- concentrated solution, treatment rinse 550 ppm) fluoride dentifrices were containing paste or powder, effervescent tablets, and treatment rinse contradictory and very sparse in nonabrasive-containing gel, liquid rinse, powder) do not need to be revised children 2 to 6 years of age. or other appropriate product types.’’ because they do not contain any The agency agrees that there is not The comment concluded that this ‘‘cosmetic functions’’ language. enough evidence available at this time alternative definition more clearly 6. One comment recommended that to support the safety and effectiveness emphasizes the intended use of these the definition of an ‘‘anticaries drug,’’ of a low-fluoride dentifrice for children products rather than emphasizing the proposed in § 355.3(b) as ‘‘a drug that 2 to under 6 years of age, or to dosage form. aids in the prevention of dental cavities determine an appropriate fluoride Another comment requested that (decay, caries),’’ be revised to include concentration for a low-level dentifrice. some proposed definitions of OTC ‘‘treatment’’ in addition to ‘‘prevention’’ As noted by the Subcommittee, dental anticaries dosage forms be revised to of dental cavities. The comment also fluorosis does not compromise oral delete those terms that refer to both requested that the definition of health or tooth function as do dental therapeutic and cosmetic functions. The ‘‘anticaries drug’’ reflect the various caries. Therefore, the risk of dental comment specifically referred to the product dosage forms by adding the caries from inadequate fluoride definitions in § 355.3(a) (abrasive), (d) following sentence to the definition: ‘‘It protection is a greater health hazard (dentifrice), (g) (treatment gel), (h) may be formulated as an abrasive- than the cosmetic detriment of fluorosis. (treatment rinse), (i) (treatment rinse containing paste or powder, Until adequate data become available, concentrated solution), (j) (treatment nonabrasive-containing gel, liquid rinse, the agency is not able to generally rinse effervescent tablets), and (k) or other appropriate product type.’’ The recognize a low-fluoride dentifrice as (treatment rinse powder). The comment comment indicated that the expanded safe and effective. If data become contended that the combination of definition more clearly defines an available, the agency will consider therapeutic and cosmetic functions in anticaries drug and encompasses the them. these definitions would be confusing various product dosage forms. Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52477

The agency does not agree that the compromising the safety or effectiveness petitioning to amend the monograph to term ‘‘treatment’’ alone should be added of the anticaries drug product. include organic fluoride formulations, to the definition of an anticaries drug. Therefore, the comments recommended but instead require filing an NDA. In the context of this definition, the that the agency delete the second The agency agrees with the comment word ‘‘treatment’’ alone implies that sentence of the definition. that organic fluoride formulations do anticaries drug products could treat an The agency does not agree that the not have a marketing history in the existing caries lesion rather than being second sentence of the definition of a United States. However, the agency is useful as a preventive treatment. The ‘‘treatment gel’’ should be deleted. The currently reevaluating whether foreign Panel recommended and the agency definition in proposed § 355.3(g) was marketing can satisfy the material time previously proposed conditions under based on the only formulation for this and extent criteria for inclusion of an which OTC anticaries drug products dosage form that was submitted to the ingredient in the OTC drug review. The that aid in the prevention of dental Panel for review. The Panel stated that agency intends to address this issue in cavities would be generally recognized stannous fluoride is stable in anhydrous a future issue of the Federal Register. In as safe and effective, and not glycerin (45 FR 20666 at 20688) and the meantime, it would not be in the misbranded (45 FR 20666 at 20690 and defined ‘‘dental gels’’ as being public interest to unduly delay 50 FR 39854 at 39871). Treatment of ‘‘formulated in an anhydrous glycerin publication of the final monograph for dental cavities is generally understood base with suitable thickening agents OTC anticaries drug products while this to be a process by which medical or included to adjust viscosity’’ (45 FR matter is being resolved. dental intervention in the management 20690). The Panel (45 FR 20688) and the Interested persons may submit a of cavities results in either repair or agency have used this definition based petition requesting amendment of the stabilization of tooth decay. Neither the on the results of laboratory and clinical final anticaries monograph to include an Panel nor the agency received data studies that supported the safety and organic fluoride formulation. Such a indicating that fluoridated compounds effectiveness of a specific formulation. petition would be considered in the included in the monograph are effective For greater clarity, the agency is context of the agency’s reevaluation of in treating or stabilizing tooth decay. changing the term ‘‘treatment gel’’ in the marketing history threshold criteria The fluoride drugs included in the § 355.3(i) to ‘‘preventive treatment gel’’ for the OTC drug review. Alternatively, monograph are intended as preventive to make it clear that the product’s an NDA may be filed under part 314 (21 measures against tooth decay and not as intended purpose is prevention of CFR part 314). With either procedure, treatment modalities for the dental cavities. Preventive treatment the manufacturer must submit adequate management of existing dental cavities. gels formulated in bases other than data showing the organic fluoride to be However, if the term ‘‘treatment’’ is anhydrous glycerin could be considered safe and effective for its intended use. expanded to read ‘‘prophylactic for inclusion in the monograph B. Comments on Specific Anticaries treatment,’’ the preventive nature of provided that stability of the fluoride Active Ingredients and Dosage Forms such ‘‘treatments’’ would not compound is demonstrated and the necessarily imply treatment of an available fluoride ion is not adversely 9. One comment requested that the existing caries lesion. Prophylactic affected by the base used in the agency consider the anticaries activities treatment is generally described as the formulation. If such a formulation were of both the stannous and the fluoride act or manner of protection for or found acceptable, the definition of a ions in 0.4 percent stannous fluoride, as prevention of disease. Thus, the agency preventive treatment gel could be well as the combined anticaries effect of is adding the term ‘‘prophylactic revised as necessary to describe such a the total compound, instead of treatment’’ in the definition for formulation. However, the agency considering the fluoride ions alone. The ‘‘anticaries drug’’ in § 355.3(c) of this currently has no data to support such comment contended that the stannous final monograph. formulations. Accordingly, the agency is ions in 0.4 percent stannous fluoride The agency does not agree with the not revising the definition at this time. have significant anticaries properties, by comment that the definition of 8. One comment disagreed with the reducing enamel solubility and through ‘‘anticaries drug’’ should specify various agency’s suggestion in the tentative final antibacterial activity. However, the dosage forms. The definition is only monograph (53 FR 22430 at 22432) that comment did not submit any data to included in the monograph to reflect the interested persons may petition the support its position. intended use of these drug products. agency to amend the anticaries The Panel reviewed extensive data on The agency agrees with the comment monograph to include specific organic stannous fluoride dentifrices, rinses, that an ‘‘anticaries drug’’ can be fluorides as active ingredients for use in and gels (45 FR 20666 at 20684 to 20685 formulated in various dosage forms and dental formulations rather than file to and 20687 to 20688) and attributed has defined numerous dosage forms in obtain an approved new drug effectiveness to the fluoride ion present the final monograph (see § 355.3(e) and application (NDA). The comment stated in the product. The agency is not aware (h) through (m)). These dosage forms that allowing submission of a petition to of any data supporting anticaries include those requested by the include organic fluorides in the activity of stannous ions in stannous comment. monograph presupposes that these fluoride. Without data demonstrating 7. Two comments objected to the active ingredients can be shown to be this activity, the agency has no basis to second sentence of the definition for generally recognized as safe and consider the stannous ions as ‘‘treatment gel’’ in proposed § 355.3(g), effective, and have been used for a contributing to the anticaries effects of which reads: ‘‘Treatment gels are material time and to a material extent. these drug products. formulated in an anhydrous glycerin The comment noted that although 10. Several comments requested that base with suitable thickening agents organic fluoride formulations have been the allowable upper limit of fluoride included to adjust viscosity.’’ The used outside the United States, they do concentration in a dentifrice marketed comments indicated that treatment gels, not meet the conditions for inclusion in under the final monograph be increased including 0.4-percent stannous fluoride the OTC drug review because they have from 1,150 ppm theoretical total treatment gel, may be formulated in never been sold in this country. The fluorine to 1,500 ppm. The comments bases that do not contain any anhydrous comment therefore suggested that the stated that 850 to 1,150 ppm levels of glycerin compound without agency not allow the alternative of fluoride in dentifrice products were 52478 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations established nearly 25 years ago. One one of the two groups. The children potential risk of enamel fluorosis in comment mentioned that, at that time, brushed in the same manner as in the children under 6 years of age using such concentrations of fluoride were set first study. Results of this study higher strength fluoride dentifrices, arbitrarily low because of concerns demonstrated that, even in an area with particularly if the children live in an about fluoride toxicity. The comments optimal water fluoridation, a 1,500-ppm optimally-fluoridated community. indicated that there is sufficient concentration provides greater Another comment cited two reports evidence that much higher fluoride anticaries protection than a 1,000-ppm (Refs. 4 and 5) indicating that the concentrations are safe and effective, theoretical total fluorine concentration. prevalence of dental fluorosis in based on widespread use of such The third clinical study (Ref. 3) children residing in nonfluoridated concentrations in the United States and compared the anticaries effect of three areas has increased appreciably during Europe. With more toxicological data dentifrices containing the following the past decade with more than 20 now available, the comments suggested concentrations of theoretical total percent of the children having mild a higher dosage of fluorides in fluorine: (1) 1,100 ppm (as sodium fluorosis. The comment also cited dentifrices should be available for fluoride), (2) 2,800 ppm (as sodium another study (Ref. 6) suggesting that persons who reside in nonfluoridated fluoride ), and (3) 2,800 ppm (as sodium the use of fluoride dentifrices prior to 2 areas or who have a greater propensity monofluorophosphate). Approximately years of age is a major risk factor for to develop caries. The comments 4,500 school children between 7 and 15 dental fluorosis. The comment pointed contended that such a need has been years of age, whose community water out that modifying the monograph to acknowledged by the agency’s approval supply contained less than 0.3 ppm permit the use of elevated fluoride of an NDA for an ‘‘extra-strength’’ (1,500 fluoride, were assigned at random to concentrations in dentifrices (i.e., 1,500 ppm) fluoride dentifrice. One comment brush unsupervised with one of the to 1,650 ppm) would clearly increase indicated that it manufactures and three dentifrices. Results of the 3-year the risk of children developing dental distributes ‘‘extra-strength’’ fluoride clinical study showed no significant fluorosis. The comment further stated dentifrices in other countries and has difference between the 2,800-ppm that the modest increase in anticaries received no reports of ill effects from sodium monofluorophosphate and the effectiveness attributable to elevated use of these products. positive control (1,100 ppm as sodium fluoride levels in dentifrices may not be The comments submitted several fluoride). However, the study adequate to justify the increased risk of clinical studies (Refs. 1, 2, and 3) demonstrated that the group assigned to developing fluorosis. The comment demonstrating that a dentifrice brush with sodium fluoride containing concluded that the proposed increase of containing 1,500 ppm theoretical total 2,800 ppm theoretical total fluoride fluoride in dentifrices to 1,500 ppm fluorine can provide greater anticaries received an estimated 15 percent fewer would affect the risk/benefit ratio protection than 850- to 1,150-ppm cavities than those subjects who unfavorably. Accordingly, the comment levels. The first study (Ref. 1) was a 3- brushed with the sodium fluoride urged the agency to reject the proposed year, double-blind clinical comparison dentifrice containing 1,100 ppm increase in the fluoride level in of the anticaries effectiveness of a test theoretical total fluoride. dentifrices to 1,500 to 1,650 ppm. dentifrice containing 1.14 percent One comment noted that two of these sodium monofluorophosphate (1,500 clinical studies (Refs. 1 and 2) formed Another comment expressed similar ppm theoretical total fluorine) with a the basis for FDA approval of the 1,500- concern for the potential risk of enamel control dentifrice containing 0.76 ppm ‘‘extra-strength’’ dentifrice under fluorosis in children under 6 years of percent sodium monofluorophosphate an NDA. Based on these data, the age who may use dentifrices containing (1,000 ppm theoretical total fluorine). comment requested that the 1,500-ppm the proposed higher levels of fluoride This study involved 2,415 children, dentifrice be included in the during toothbrushing. The comment primarily 8 to 11 years of age, who monograph. indicated that there exists ample resided in a nonfluoridated community. One comment requested that the documentation that young children The children were randomly assigned to agency specifically include higher swallow a significant amount of one of the two groups. The children strength sodium fluoride dentifrice dentifrice. The comment submitted two brushed normally at home and products (1,500 ppm) in the final published clinical studies (Refs. 7 and participated in a daily supervised monograph. The comment stated its 8) evaluating the significance of fluoride toothbrushing exercise at school. belief that consumers should be dentifrices as a risk factor in dental Results of this study indicated that 48 permitted the widest possible choice of fluorosis. One study (Ref. 7) indicated percent of the subjects who used the safe and effective OTC drugs and that that a portion of the dentifrice 1,000-ppm fluoride dentifrice remained the monograph should be flexible to introduced to the mouth and not caries free and 57 percent of those who permit the use of equivalent fluoride expectorated, but swallowed and used the 1,500-ppm dentifrice remained species. absorbed, ranged from 0 to 100 percent. caries free. The study also suggested Several other comments argued that The study suggested that inadequate that the participants using the 1,000- increasing the fluoride concentration to control of the swallowing reflex by ppm dentifrice would have projected a a level as high as 1,500 to 1,650 ppm younger children accounts for the savings of 639 additional surfaces and would be unwise without adequate excessive ingestion of fluorides, 344 teeth if they had received the 1,500- scientific support to justify the particularly from dentifrices and ppm dentifrice during the 3-year trial. increased risk of developing fluorosis. mouthrinses. The other study (Ref. 8) The second study (Ref. 2) was also a One comment indicated that clinical indicated that, on average, children 3-year, double-blind clinical trials using higher strength fluoride- used 0.662 gram (g) of dentifrice and comparison of two sodium containing dentifrices have ingested 0.299 g per brushing. Results monofluorophosphate dentifrices, one demonstrated no adverse experiences or from this study indicated: (1) The containing 1,500 ppm and the other changes of any consequence with younger the children, the more likely containing 1,000 ppm theoretical total respect to soft tissue aberrations in they are to swallow a greater proportion fluorine. The study involved 1,913 children 8 to 12 years of age. However, of dentifrice; and (2) young children children between 6 and 11 years of age. the comment added that there has not who rinse their mouths and expectorate The subjects were randomly assigned to been sufficient attention paid to the properly after brushing ingest less Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52479 dentifrice. The comment predicted that 6 years of age is increasing in the United fluorine level above 1,500 ppm. if manufacturers are allowed to market States. The agency does not believe that Accordingly, the agency is not including an increased level of fluoride without the increased risk of fluorosis outweighs dentifrices with such theoretical total requiring an agency-approved the benefit of using an extra-strength fluorine levels in the monograph. application, routine use of these extra fluoride dentifrice in children under 6 strength dentifrices would increase the years of age. The agency has determined References potential risk of enamel fluorosis in from the results of the submitted (1) Conti, J. A. et al., ‘‘A 3-year Clinical younger children. However, the clinical studies that the enhanced Trial to Compare Efficacy of Dentifrices comment did not indicate how or why benefit of using an extra-strength Containing 1.14 Percent and 0.76 Percent the routine use of NDA-approved extra dentifrice product does not present Sodium Monofluorophosphate,’’ Community strength dentifrice products would additional risk to children above 6 years Dental Oral Epidemiology, 16:135–138, 1988. prevent an increased risk of enamel of age and to adults, particularly for (2) Fogels, H. R. et al., ‘‘A Clinical fluorosis in younger children. those with a greater propensity to Investigation of a High-Level Fluoride In the tentative final monograph for develop cavities or for those who live in Dentifrice,’’ Journal of Dentistry for Children, OTC anticaries drug products (53 FR communities with nonfluoridated water. 55(3):210–215, 1988. 22430 at 22432), the agency stated that As discussed in the tentative final (3) Lu, K. H. et al., ‘‘A Three-year Clinical a 1,500-ppm theoretical total fluoride monograph (50 FR 39854 at 39864), Comparison of a Sodium Monofluorophosphate Dentifrice with level is safe, but indicated that general developing teeth of children under 6 Sodium Fluoride Dentifrices on Dental Caries recognition of the effectiveness of this years of age may show objectionable in Children,’’ Journal of Dentistry for strength fluoride dentifrice must be dental fluorosis from repeated ingestion Children, 54(4):241–244, 1987. based on adequate published or publicly of excessive amounts of fluoride. (4) Woolfolk, M. W. et al., ‘‘Relation of available medical and scientific data. However, epidemiological and clinical Sources of Systemic Fluoride to Prevalence Two clinical studies (Refs. 1 and 2) that findings indicate that the formative state of Dental Fluorosis,’’ Journal of Public Health formed the basis of an agency NDA of the teeth of children 6 years of age Dentistry, 49:78–82, 1989. approval of this strength sodium and older (excepting third molars) is too (5) Leverett, D. H., ‘‘Fluorides and the monofluorophosphate dentifrice have advanced to be affected by the amount Changing Prevalence of Dental Caries,’’ now been included in the public record and frequency of use of fluoride Science, 217:26–30, 1982. for this rulemaking by the NDA holder. dentifrices. (6) Osuji, O. O. et al., ‘‘Risk Factors for Results of these studies indicate an The agency is including sodium Dental Fluorosis in a Fluoridated enhanced anticaries benefit derived over monofluorophosphate dentifrices that Community,’’ Journal of Dental Research, a 3-year period from the use of the contain 1,500 ppm theoretical total 67(12):1488–1492, 1988. higher fluoride sodium fluorine in this final monograph. (7) Whitford., G. M., D. W. Allmann, and monofluorophosphate dentifrice (1,500 Because of concerns about dental A. R. Shahed, ‘‘Topical Fluorides: Effects on ppm) when compared to the positive fluorosis, the agency is requiring that Physiologic and Biochemical Processes,’’ control fluoride dentifrice (1,000 ppm). dentifrice products with these fluorine Journal of Dental Research, 66(5):1072–1078, The studies also indicated that children concentrations be clearly labeled for use 1987. who are at increased risk to develop (8) Simard, P. L. et al., ‘‘The Ingestion of only by children above 6 years of age. Fluoride Dentifrice by Young Children,’’ caries and those with erupting Accordingly, the agency is including the Journal of Dentistry for Children, 56:177–181, premolars and second molars may following directions in § 355.50(d)(1)(ii): 1989. derive more benefit from a 1,500-ppm Paste dosage form with a theoretical total dentifrice than a 1,000-ppm dentifrice. fluorine concentration of 1,500 ppm 11. One comment (from the holder of The agency has not received any identified in § 355.10(b)(2). Adults and the only approved NDA for a 1,500-ppm clinical or available fluoride ion data on children 6 years of age and older: brush teeth fluoride dentifrice) provided data any 1,500-ppm sodium fluoride thoroughly, preferably after each meal or at indicating that the lowest available least twice a day, or as directed by a dentist fluoride ion concentration measured dentifrice comparable to the information or doctor. Instruct children under 12 years of for 1,500-ppm sodium age in good brushing and rinsing habits (to during the 3-year clinical trial of its monofluorophosphate dentifrice. minimize swallowing). Supervise children as 1,500-ppm sodium Therefore, the agency is not including necessary until capable of using without monofluorophosphate dentifrice higher strength (1,500 ppm) sodium supervision. Children under 6 years of age: product was 1,295 ppm, with an fluoride dentifrice drug products in this Do not use unless directed by a dentist or analytical variability of ± 20 ppm (Refs. final monograph at this time. doctor. 1 and 2). The agency believes that extra- As noted above, comments expressed Based on the available fluoride ion concern that an increase of theoretical strength fluoride dentifrice products may be beneficial to consumers who data for this product, the agency has total fluorine to 1,500 ppm could determined at this time that all 1,500- increase the incidence of dental have a greater propensity to develop cavities, and that manufacturers may ppm sodium monofluorophosphate fluorosis in children. The agency agrees dentifrices must provide an available that for children under 6 years of age a wish to promote these products for this purpose. Therefore, the agency is fluoride ion concentration equal to or risk/benefit analysis indicates that greater than 1,275 ppm. Accordingly, levels of fluoride in dentifrices should expanding § 355.50(f)(2) to include an optional additional labeling statement the agency is including higher strength not exceed the currently accepted OTC (1,500 ppm) sodium level of 1,150 ppm (see discussion of for these products as follows: For dentifrice products containing 1,500 monofluorophosphate dentifrice fluorosis in comment 23). Although an products in § 355.10(b)(2) of this final NDA was approved in 1986 for an extra- ppm theoretical total fluorine. Adults and children over 6 years of age may wish to use monograph as follows: strength fluoride dentifrice (1,500 ppm) this extra-strength fluoride dentifrice if they Dentifrices containing 1,500 ppm whose labeling allowed for use in reside in a nonfluoridated area or if they have theoretical total fluorine in a paste dosage children above 2 years of age, the a greater tendency to develop cavities. form. Sodium monofluorophosphate 1.153 agency recognizes that more recent data Finally, the agency does not find that percent with an available fluoride ion = ± (Refs. 4 and 8) suggest that the sufficient data exist to support the safety concentration (consisting of PO3F and F incidence of fluorosis in children under and effectiveness of a theoretical total combined) ≥ 1,275 ppm. 52480 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

References infected with highly virulent strains of (fluorapatite) different than the active (1) Comment LET18, Docket No. 80N– cariogenic bacteria. In one study (Ref. ingredient found in the comment’s 0042, Dockets Management Branch. 2), a group of rats infected with sodium fluoride dentifrice product, the (2) Comment LET20, Docket No. 80N– Streptococcus sobrinus that was treated study supported the anticaries 0042, Dockets Management Branch. topically with sodium fluoride/sodium effectiveness of a powdered dentifrice 12. One comment requested that the bicarbonate powdered dentifrice dosage form. In this study, 150 medical active ingredient listings for sodium experienced 42 percent fewer caries students brushed daily with one of three fluoride treatment rinses in proposed lesions than a control group treated only dentifrices containing: (1) 71.4 percent § 355.10(b)(3), (b)(4), and (b)(5) be with distilled water. Rats exposed to fluorapatite, (2) an ion-free ‘‘synthetic combined as follows: ‘‘Sodium fluoride either the tooth powder or 10 ppm apatite’’ consisting of hydroxyapatite 0.02 to 0.05 percent in a final solution fluoridated drinking water produced with a surface layer of fluorapatite (total with a pH of approximately 7.’’ The similar reduction in caries (42 and 47 fluorine content, 0.25 percent), or (3) a comment stated that this would provide percent, respectively). control powdered dentifrice not a range of allowable concentrations for In another study (Ref. 3), rats infected containing fluoride. Results of this these rinses without affecting the with S. mutans were treated with a 1:2 study indicated that the group that technical accuracy of the monograph. part slurry of sodium bicarbonate-based brushed with the fluorapatite powder The agency disagrees with the powdered dentifrice containing 0.22 and the group that bushed with the comment. The active ingredient listings percent sodium fluoride (1,000 ppm) in ‘‘synthetic apatite’’ paste developed an in § 355.10(b)(3), (b)(4), and (b)(5) water for 1 minute daily for 3 weeks. average of 38 and 67 percent fewer specify particular concentrations for Results indicated a 51-percent caries cavities, respectively, than those sodium fluoride in a rinse dosage form. reduction in infected rats treated with students who brushed with the The monograph is not intended to the tooth powder as compared to the nonfluoride tooth powder. provide a range of concentrations for group of rats treated with distilled Another study (Ref. 6) compared these products. The 0.02- and 0.05- water. Rats treated with an equal human enamel uptake of fluoride from percent sodium fluoride concentrations concentration of sodium fluoride a sodium fluoride/sodium bicarbonate were included in the monograph based aqueous solution without other inactive dentifrice in a powdered and a paste on separate, independent clinical ingredients developed a 36-percent dosage form. In this study, human studies, as discussed for the 0.05- reduction in cavities as compared to the enamel was ground and polished flat to percent concentration in the Panel’s control group. The data also indicated provide a uniform surface and then report (45 FR 20666 at 20686) and for that no significant difference in the demineralized to create a simulated the 0.02-percent concentration in the incidence of cavities was observed in white-spot caries lesion. Several enamel agency’s tentative final monograph (50 the group of rats treated topically with slabs were exposed continuously for 30 FR 39854 at 39863). More importantly, sodium fluoride/sodium bicarbonate minutes at body temperature to a tooth the directions for 0.02 percent sodium powdered dentifrice and the group of powder (with a poured-bulk density of fluoride in a neutral dental rinse (pH of rats receiving no other treatment except 1.0 to 1.2 g/milliliter (mL) and available approximately 7) are for use twice daily 10 ppm fluoride in their drinking water fluoride ion concentration equal to or and for 0.05 percent sodium fluoride (51 percent versus 54 percent). greater than 850 ppm) and a toothpaste rinse are for use only once a day. These In another animal study (Ref. 4), rats containing sodium fluoride/sodium dosage regimens are each supported by infected with S. sobrinus were treated bicarbonate with an available fluoride separate, independent clinical data. with an undiluted sodium bicarbonate- ion concentration equal to or greater There are no data to support directions base powdered dentifrice containing than 650 ppm. Results of this study for other concentrations. Accordingly, 0.22 percent sodium fluoride. Results of indicated that both the powder and there is no basis to combine the active this study indicated a 47-percent paste dosage forms demonstrated ingredient listings for the sodium reduction in cavities as compared to the comparable enamel uptake of fluoride fluoride treatment rinses included in control group. This reduction in cavities ions. this final monograph. was not statistically different from the The comment concluded by stating 13. One comment requested that 43-percent reduction in total cavities that the data demonstrate the safety and sodium fluoride/sodium bicarbonate obtained by topical treatment with an effectiveness of a powdered dentifrice powdered dentifrices be included in the undiluted sodium bicarbonate-based containing sodium fluoride and show final monograph for OTC anticaries drug toothpaste containing the same level of that such a product can provide products. In response to the agency’s sodium fluoride. effectiveness equivalent to a toothpaste concerns discussed in the tentative final The comment also submitted several containing a similar abrasive system. monograph (53 FR 22430 at 22443) clinical studies that evaluated the The comment urged the agency to about the safety and effectiveness of anticaries effectiveness of fluoridated include sodium fluoride/sodium powdered fluoride dentifrices, the and nonfluoridated powdered bicarbonate powdered dentifrices in the comment submitted several analytical dentifrices. However, the studies final monograph for OTC anticaries drug and biological studies (Ref. 1). The involving nonfluoridated powdered products. comment contended that these studies dentifrices were not related to and do The agency has reviewed the data demonstrate the effectiveness and not support the effectiveness of the provided by the comment and comparable bioavailability of a comment’s dentifrice product that determined that sufficient data have powdered fluoride dentifrice with a contains sodium fluoride as the active been provided to generally recognize as toothpaste containing a similar abrasive ingredient. safe and effective powdered dentifrices system and an equivalent concentration The comment submitted a 1-year containing sodium fluoride with a of theoretical total fluorine. clinical study (Ref. 5) that demonstrated sodium bicarbonate abrasive. However, The comment submitted several the anticaries effectiveness of tooth the agency points out that several of the animal studies (Refs. 2, 3, and 4) that powders containing fluorapatite studies submitted measured the determined the anticaries effect of a (essentially calcium fluoride). Although anticaries effectiveness of dentifrices sodium fluoride/sodium bicarbonate the powdered dentifrice used in this containing active agents (fluorapatite, powdered dentifrice in rats that were study contained an active ingredient carbamide-urease, and fluoridated table Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52481 salt) different than the active ingredient Journal of Dental Research, 66(3):791–794, fluoride. The comment stated that the contained in the comment’s tooth March, 1987. two poured-bulk density ranges were powder (sodium fluoride). Although the (3) Tanzer, J. M. et al., ‘‘Bicarbonate-based based on the assumption that equal Dental Powder, Fluoride, and Saccharin volumes of tooth powder and toothpaste data from one study provide some Inhibition of Dental Caries Associated with indication of cariostatic effectiveness of Streptococcus mutans Infection of Rats,’’ are applied in a single application to the a fluorapatite dentifrice, the agency does Journal of Dental Research, 67(6):969–972, brush; however, that assumption may not find these studies pertinent to the June, 1988. no longer be correct because of the determination of the safety and (4) McMahon, T. et al., ‘‘Caries Inhibition difference in consistency of the two effectiveness of the comment’s sodium by Bicarbonate-based Dental Powder in S. dosage forms. The comment mentioned fluoride/sodium bicarbonate powdered mutans 10449S-infected Rats,’’ Journal of that more toothpaste than tooth powder dentifrice. Dental Research, 67:343, 1988. can be applied to a brush without falling (5) McClendon, J. F., and W. C. Foster, off; thus, the level of fluoride delivered The agency considers the biological ‘‘Prevention of Dental Caries by Brushing The studies submitted by the comment as Teeth With Powders Containing to the teeth in one application is greater demonstrating that the bioequivalence Fluorapatite,’’ Journal of Dental Research, with a toothpaste than with a tooth and bioavailability of fluoride ions are 26:233–239, 1947. powder, assuming comparable comparable for sodium fluoride/sodium (6) Letter from J. J. Hefferren, J. J. Hefferren theoretical total fluorine. bicarbonate powdered and paste Resources, Inc., to T. Winston, Church & The comment submitted a study (Ref. dentifrices containing the same Dwight Co., Comment No. C00066 1) that measured the weight of tooth concentration of theoretical total (Attachment 1), Docket No. 80N–0042, powder and toothpaste applied in a Dockets Management Branch. single application to a tooth brush. fluorine. Results of several well- 14. One comment responded to the designed animal caries studies (Refs. 2, Subjects were instructed to generously agency’s concern expressed in the pour tooth powder onto a wet 3, and 4) demonstrate that rats tentative final monograph (53 FR 22430 inoculated with cariogenic bacteria and toothbrush so that the bristles were at 22444) that several possible methods completely covered. The subjects were fed a caries promoting diet developed of applying a powdered dosage form to 42 to 51 percent fewer cavities when also instructed to apply to a similar size a toothbrush may lead to significant brush an amount of toothpaste they treated with a topical application of variations of fluoride ion delivered to sodium fluoride/sodium bicarbonate would normally use during brushing. the teeth. The comment agreed that The weight of dental powder in a single powdered dentifrice than rats in a directions for using powdered products control group. In addition, the agency application was determined by have been varied. However, the weighing the toothbrush (plus a piece of concludes that the results of the comment indicated that this is not a submitted human enamel uptake study paper used to catch spillage) before and reason to determine that a sodium after application; whereas the weight of (Ref. 6) indicate that the measured fluoride powdered dentifrice would not human enamel uptake of fluoride from the toothpaste was determined by be safe and effective. The comment weighing the package before and after a powder containing sodium fluoride/ added that after several years of sodium bicarbonate with a fluoride ion applying a single dose to a toothbrush. marketing a powdered dentifrice, it has The results of this study indicated that concentration of 1,000 ppm was better found that pouring a powdered than the fluoride uptake of a similar consumers applied an average of 0.8 g dentifrice from a container with a flip- of powdered dentifrice and 1.46 g of dentifrice paste formulation. Although top spout provides a cleaner and the agency does not believe that this paste to the same type of toothbrush. simpler application of the product with Results of this study indicated that two system is comparable to real-life a uniform dosage of fluoride. development of early dental caries or applications of a powdered dentifrice The comment claimed that the product of poured-bulk density 1.1 g/ that a one-time exposure of enamel slabs available fluoride ion obtained from two ° mL provides a level of fluoride continually for 30 minutes at 37 C applications of a tooth powder simulates real-life conditions of short, comparable to a single application of a containing a minimum of 850 ppm fluoridated toothpaste containing the intermittent exposures during a month’s soluble (available) fluoride ion will be usage, the agency does believe that same fluoride concentration. equal to or greater than the Panel’s The data were further analyzed (Ref. fluoride uptake is a marker of potential recommended 650 ppm available 2) to determine what dosage of fluoride anticaries effectiveness and considers fluoride ion for sodium fluoride would be provided if two applications the two fluoride dosage forms at least dentifrices. The comment based the of tooth powder with an available equivalent. need for two applications of tooth fluoride concentration of 850 to 1,100 Accordingly, the agency is including powder on its recommendation that ppm were placed on a toothbrush. The sodium fluoride/sodium bicarbonate sodium fluoride/sodium bicarbonate comment stated that, assuming two powdered dentifrices in § 355.10(a)(2) of powdered dentifrices have a poured- applications of tooth powder and one of this final monograph as follows: bulk density of 1.0 to 1.2 g/mL and an Dentifrices containing 850 to 1,150 ppm toothpaste, the extrapolated amount of theoretical total fluorine in a powdered available fluoride ion concentration available fluoride ion delivered to the dosage form: Sodium fluoride 0.188 to 0.254 equal to or greater than 850 ppm. The teeth by the tooth powder is comparable percent with an available fluoride ion comment responded to several concerns to the amount of soluble fluoride ion concentration of ≥ 850 ppm for products raised by the agency in the tentative provided by a toothpaste. Based on containing the abrasive sodium bicarbonate final monograph (53 FR 22430 at these data, the comment recommended and a poured-bulk density of 1.0 to 1.2 grams 22443). These concerns involved that the directions specify two per milliliter. previous recommendations that two applications of fluoride powder References poured-bulk density ranges (0.5 to 0.99 dentifrices containing 850 to 1,100 ppm g/mL and 1.0 to 1.7 g/mL) were theoretical total fluorine and a poured- (1) Comment No. C00066, Docket No. 80N– necessary for powdered fluoride 0042, Dockets Management Branch. bulk density range of between 1.0 and (2) Tanzer, J. M. et al., ‘‘Effects of dentifrices and that two applications per 1.2 g/mL. Bicarbonate-based Dental Powder, Fluoride, brushing with a powdered dentifrice in One comment discussed directions for and Saccharin on Dental Caries and on the lower poured-bulk density range use of powdered fluoride dentifrices by Streptococcus sobrinus Recoveries in Rats,’’ would provide an appropriate dose of children under 12 years of age. In the 52482 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations tentative final monograph (53 FR 22430 toothpaste with an available fluoride ion important to prevent moisture at 22444), the agency had stated that concentration equal to or greater than contamination of a powdered dentifrice, children under 12 years of age may 650 ppm. Accordingly, the agency is particularly in areas where the humidity require greater manual dexterity to including directions in this final is high due to showering and bathing. properly use a powdered dentifrice than monograph that provide for two The comment indicated that its is needed to correctly use a toothpaste. applications of fluoride powdered powdered dentifrice product is sold in The agency expressed concern about the dentifrices. The agency is also including a plastic bottle with a flip top cap and, potential for young children to in the LTP tables a poured-bulk density therefore, quite effectively prevents accidentally consume a toxic amount of range of 1.0 to 1.2 g/mL for powdered moisture contamination. fluoride when using a tooth powder dentifrices (see section I.F., comment 37 As discussed in the tentative final compared to a toothpaste. The comment of this document). monograph (53 FR 22444), the agency contended that powdered dentifrices do Regarding the use of powdered agrees with the comment that powdered not pose any greater risk over pastes for fluoride dentifrices by children, the fluoride dentifrices would probably accidental overdoses by children. The agency does not believe that powdered remain more stable for a longer period comment added that, while it believes fluoride dentifrices pose a greater threat of time than the paste form because that children between 6 and 12 years of for accidental ingestion than fluoride there would be less interaction between age can use a powdered dentifrice toothpaste. Also, the agency does not dry ingredients during storage of the properly, it has no objection to the believe that children 6 years of age and dentifrice. However, the agency monograph providing that powdered older are likely to consume a toxic recognizes that the storage conditions of dentifrices not be labeled for use by amount of fluoride from a dentifrice a powdered fluoride dentifrice would children under 6 years of age and powder. In most instances, such have a significant impact on whether requiring labeling that states use by products will be used under adult the product would remain stable longer children 6 to under 12 years of age supervision. Further, existing than the paste form. Storage of the should be only with adult supervision. regulations (§ 310.201(a)(10)(iv)) powdered product in areas where the However, the comment expressed establish package size limitations for humidity is high due to showering and concern that such labeling might give sodium fluoride preparations. bathing would require that the container the false impression that there is an The agency agrees with the comment be resistant to moisture contamination. inherent unsafe quality with the that these products should not be A ‘‘tight container,’’ as defined in the product, rather than merely a difficulty labeled for use by children under 6 United States Pharmacopeia (U.S.P.), for children to use the product properly. years of age, and should be labeled for would meet this criterion. The U.S.P. The comment suggested the monograph use with adult supervision by children defines a ‘‘tight container’’ (Ref. 1) as a include the following directions and 6 to under 12 years of age. Accordingly, container that ‘‘protects the contents from contamination by extraneous labeling for powdered fluoride the agency is adding the following liquids, solids, or vapors, from loss of dentifrices to prevent any such false directions for powdered dentifrices in the article, and from efflorescence, impressions: ‘‘Since a powdered § 355.50(d)(1)(iii): deliquescence, or evaporation under the fluoride dentifrice may be difficult for Powdered dosage form with a theoretical ordinary or customary conditions of children to use, this product is not total fluorine concentration of 850 to 1,150 handling, shipment, storage, and recommended for children under 6. ppm identified in § 355.10(b)(2). Adults and children 6 years of age and older: Apply distribution, and is capable of tight re- Children between the ages of 6 and 12 powder to a wet toothbrush; completely closure.’’ should use this product under adult cover all bristles. Brush for at least 30 In addition, § 211.94 (21 CFR 211.94) supervision.’’ seconds. Reapply powder as before and brush of the FDA current good manufacturing The agency has reviewed the data again. Rinse and spit out thoroughly. Brush practice (GMP) regulations addresses (Refs. 1 and 2) and determined that the teeth, preferably after each meal or at least drug product containers and closures. twice a day, or as directed by a dentist or directions for use of fluoride powdered Section 211.194(a) states: ‘‘Drug product dentifrices with a poured-bulk density doctor. Instruct children under 12 years of age in good brushing and rinsing habits (to containers and closures shall not be of 1.0 to 1.2 g/mL and an available minimize swallowing). Supervise children as reactive, additive, or absorptive so as to fluoride ion concentration equal to or necessary until capable of using without alter the safety, identity, strength, greater than 850 ppm must specify two supervision. Children under 6 years of age: quality, or purity of the drug beyond the applications to deliver a comparable Do not use unless directed by a dentist or official or established requirements.’’ amount of fluoride as a fluoride doctor. Section 211.194(b) states: ‘‘Container toothpaste of the same strength. One The agency believes that these closure systems shall provide adequate study (Ref. 1) showed that in a single directions will not give consumers a protection against foreseeable external application 45 percent less tooth false impression that there is any factors in storage and use that can cause powder than toothpaste was applied to inherent unsafe quality with these deterioration or contamination of the a similar size brush. Because spillage products. drug product.’’ that occurred during the weighing References Therefore, based on § 211.94 of the procedure was included in the final FDA GMP regulations and the U.S.P. applied weight of powder, even less (1) J. Ross Associates, ‘‘A Dentifrice Use standard for a ‘‘tight container,’’ the tooth powder than toothpaste was Test,’’ draft of unpublished study, Comment agency is adding a new paragraph in actually placed on the brush. Thus, the No. C00066 (Attachment I, Exhibit 5), Docket § 355.20(b) that reads: ‘‘Tight container No. 80N–0042, Dockets Management Branch. agency agrees with the comment that (2) J. Ross Associates, ‘‘A Dentifrice Use packaging. To minimize moisture consumers who use two applications of Test,’’ draft of unpublished study, Comment contamination, all fluoride powdered a fluoride tooth powder with a poured- No. C00066 (Attachment I, Exhibit 7), Docket dentifrices shall be packaged in a tight bulk density of 1.0 to 1.2 g/mL No. 80N–0042, Dockets Management Branch. container, which is defined as a containing 850 to 1,100 ppm available 15. One comment agreed with the container that protects the contents from fluoride ion receive an amount of agency’s concern expressed in the contamination by extraneous liquids, fluoride ion comparable to using a tentative final monograph (53 FR 22430 solids, or vapors, from loss of the article, single application of a sodium fluoride at 22444) that proper packaging is and from efflorescence, deliquescence, Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52483 or evaporation under the ordinary or respondents. Further, the survey terms ‘‘treatment’’ and ‘‘dental’’ are both customary conditions of handling, involved only women between the ages appropriate statements of identity for shipment, storage, and distribution, and of 18 and 49 years of age. There were various anticavity product dosage forms is capable of tight reclosure.’’ no men in the survey nor women above and that other equally truthful and 49 years of age; these people might also nonmisleading identifiers are also Reference have reasons for wanting to know the appropriate. The comment made two (1) The United States Pharmacopeia 23— fluoride content. In addition, the survey recommendations: (1) The term The National Formulary 18, United States did not attempt to assess the relative ‘‘treatment’’ be retained as an optional Pharmacopeial Convention, Inc., Rockville, understanding by the respondents of the statement of identify for gels, rinses, MD, p. 10, 1994. various methods of expressing concentrated rinses, rinse powders, or C. Comments on Labeling of OTC quantities of fluoride. Contextual rinse effervescent tablets, and (2) the Anticaries Drug Products material could have been used to clarify term ‘‘dental’’ also be listed as optional, 16. One comment responded to the the meaning of the measures used, such as in connection with a agency’s question whether consumers making it more likely that consumers professionally promoted ‘‘dental would benefit in having OTC fluoride- could make use of the information treatment gel.’’ The comment concluded containing drug products labeled to provided, regardless of the type of that its suggested revisions to state their fluoride levels. The comment measurements used. § 355.50(a) would provide for truthful Nonetheless, the survey provides and accurate statements of identity. objected to fluoride level labeling for some useful information. It Another comment suggested that the OTC anticaries drug products and demonstrates that more consumers agency delete the term ‘‘treatment’’ from provided the results of a consumer chose a dentifrice labeled with the the statement of identity and permit survey as support (Ref. 1). The survey higher net fluoride content, based on the ‘‘anticavity dental rinse’’ or ‘‘fluoride was conducted in shopping malls in concept that ‘‘more fluoride is better.’’ dental rinse’’ as a statement of identity, eight different geographic areas and Rather than emphasizing fluoride because the term ‘‘treatment’’ does not included a sample of 200 women concentration numbers, the agency appropriately describe the activity of between the ages of 18 and 49. The believes that labeling would be more these products. The comment stated that women routinely purchased dentifrice beneficial if it informs consumers who these rinse products provide their products for their households. In have a greater propensity to develop anticaries benefits primarily through a addition, 150 women with children cavities of the need to use a higher prophylactic mode of action and are between 1 and 5 years of age were strength fluoride dentifrice. Therefore, perceived by consumers as preventive interviewed to determine the habits and in this final rule, the agency is including prophylactic measures rather than practices of women with children in § 355.50(f)(2) the following optional therapeutic treatments. The mechanism regarding the use of fluoride dentifrices. additional labeling statement for of fluoride action is well recognized in The comment stated that the results of dentifrice products containing 1,500 the scientific community and was the survey indicate that: (1) Consumers ppm theoretical total fluorine: ‘‘Adults addressed in the Panel’s report (45 FR believe that fluoride in dentifrice and children over 6 years of age may 20666 at 20672). According to the products is important in preventing wish to use this extra-strength fluoride comment, the Panel noted that fluoride cavities, (2) regardless of the unit of dentifrice if they reside in a increases enamel resistance to acid measurement, e.g., ppm, percent, or nonfluoridated area or if they have a solubility, making the teeth less milligrams per inch (mg/in), used to greater tendency to develop cavities.’’ susceptible to plaque acid attack, label the fluoride concentration, Because of concerns about dental thereby producing its cariostatic effect. consumers believe ‘‘more is better’’ fluorosis occurring in children under 6 The comment concluded this is when choosing a dentifrice because they years of age, the agency is requiring primarily a preventive mode of action as consistently selected dentifrices labeled extra-strength fluoride dentifrice contrasted to a therapeutic action. The with the higher net fluoride, indicating products to state in their labeling that comment thus proposed that the agency that consumers believe that there are the product should not be used by delete the term ‘‘treatment’’ from the differences in the effectiveness of children under 6 years of age unless statement of identity and permit fluoride dentifrice products, (3) most directed by a doctor or dentist. (See ‘‘anticavity dental rinse’’ or ‘‘fluoride consumers know how to use fluoride section I.B., comment 10 of this dental rinse’’ as a statement of identity. dentifrices, (4) most consumers are document.) The comment concluded that these aware of the fluoride ingredient in the In conclusion, no comments, data, or statements of identity are more toothpaste, and (5) most parents take an information were submitted in support descriptive and meaningful to interest in and supervise their children’s of fluoride level labeling. Accordingly, consumers and more accurately define brushing habits. Based on these results, this final monograph does not contain a the therapeutic benefit of an anticaries the comment concluded that labeling requirement that fluoride-containing drug product. fluoride-containing products to state dentifrice products label the quantity of The agency discussed the use of the their fluoride levels is not useful to fluoride. However, it does provide an term ‘‘treatment’’ as part of the consumers and could be misleading. optional additional labeling statement statement of identity for nonabrasive The comment recommended that such that manufacturers may use for these gels and rinses in the tentative final labeling not be required for OTC products. monograph (50 FR 39854 at 39866) in fluoride drug products. response to a comment that pointed out The agency has evaluated the Reference that some current dentifrice (abrasive- consumer survey and determined that it (1) Comment No. C0097, Docket No. 80N– containing) products are transparent or has some methodology deficiencies. The 0042, Dockets Management Branch. translucent and are called gels by major deficiency is an inadequate 17. One comment objected to the manufacturers and consumers. Two respondent sample size. In order to inclusion of the term ‘‘treatment’’ as the other comments also expressed concern generalize the findings of this study to single recommended term in the that the use of the term ‘‘gel’’ alone for the general population, it would be proposed statement of identity in a nonabrasive 0.4-percent stannous necessary to have a larger number of § 355.50(a). The comment stated that the fluoride product could be confusing to 52484 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations the consumer in distinguishing between a cosmetic use, as defined in section 201(i) statement of identity what it is and what abrasive and nonabrasive fluoride gels; of the Federal Food, Drug, and Cosmetic Act it does. these comments suggested the term (the act) (21 U.S.C. 321(i)). One comment maintained that the ‘‘nonabrasive dental gel.’’ The agency 18. One comment requested revisions agency’s labeling policy set forth in a agreed with the comments that it is in the proposed statement of identity for proposal to amend the statement of important to provide labeling that fluoride-containing products in identity requirements for OTC drugs would allow consumers to easily § 355.50(a). The comment contended published in the Federal Register of distinguish between a nonabrasive and that a fluoride-containing liquid product April 17, 1986 (51 FR 13023), along an abrasive-containing fluoride gel, but labeled both to prevent cavities and to with the agency’s exclusivity and label stated that the term ‘‘nonabrasive’’ may freshen the breath should be identified separation policies, make it impossible not be meaningful for consumers. The as an ‘‘anticavity or fluoride for a manufacturer to comply with both mouthwash,’’ whereas a fluoride rinse agency also stated that because the drug and cosmetic labeling that makes no cosmetic claims should nonabrasive fluoride gels had not been requirements set forth in the statute and properly be identified as an ‘‘anticavity widely marketed, consumers were not regulations. The comment pointed out or fluoride rinse.’’ that existing FDA regulations require familiar with the use of the term ‘‘dental Several other comments requested gel’’ to identify such products, that the statement of identity for both that the statement of identity for drug and cosmetic products appear on particularly in the context of widely anticaries drug products include the marketed abrasive-containing fluoride the principal display panel of the terms ‘‘tooth powder’’ and ‘‘tooth product. The comment contended that dentifrices labeled as gels. Thus, the polish.’’ The comments stated that these agency proposed that the term the effect of the agency’s drug-cosmetic terms are commonly recognized and label separation policy is that the ‘‘treatment’’ be included in the have been used in dentifrice product statement of identity for all nonabrasive cosmetic statement of identity may not labeling for many years. be placed on the principal display OTC fluoride products to clearly The agency agrees that a fluoride- distinguish between a dentifrice and a panel. containing liquid product represented The comment argued that cosmetic nonabrasive fluoride product. both to prevent cavities and to freshen The agency agrees with the comment terminology should be allowed the breath can properly be identified as anywhere in the labeling of an anticaries that the term ‘‘treatment’’ can be an ‘‘anticavity or fluoride mouthwash.’’ optional for fluoride dental rinses, but dentifrice that is also a cosmetic product Further, the agency agrees that a so long as it does not render the disagrees with making this term fluoride rinse with no cosmetic claims optional for nonabrasive fluoride gels. product’s labeling false or misleading. in its labeling is appropriately identified The comment argued that consumers As discussed in section I.A., comment 7 as a ‘‘rinse.’’ The agency also agrees that of this document, the agency has added would not be misled by the inclusion of the terms ‘‘tooth polish’’ and ‘‘tooth both kinds of labeling on an anticaries the word ‘‘preventive’’ to the definition powder’’ are suitable for use as part of of a ‘‘treatment gel.’’ The comments did drug product. On the contrary, the the statement of identity for anticaries comment stated that consumers would not discuss the possibility that drug products. The word ‘‘tooth’’ consumers could be confused in more likely be misled if the drug and indicates the site of usage; ‘‘powder’’ is cosmetic statements of identity and distinguishing a nonabrasive fluoride a dosage form; and ‘‘polish’’ has been treatment gel from an abrasive- other claims were to appear on entirely used in labeling of these products for different portions of the label. The containing dentifrice gel. The comment many years without consumer also did not explain how such labeling comment concluded that there is no confusion. The word ‘‘polish’’ indicates legal or policy justification for this label would distinguish a nonabrasive a cosmetic usage. As discussed in fluoride gel from an abrasive fluoride separation policy. comment 19, the agency’s OTC drug If a product covered by this dentifrice. In order for consumers to be regulations do not prohibit placing a rulemaking is marketed for both drug better able to make this distinction, the cosmetic statement of identity of a drug/ and cosmetic use, it must conform to the agency is requiring that the term cosmetic product on the principal requirements of the final OTC drug ‘‘preventive treatment’’ be included in display panel. Accordingly, the agency monograph and bear appropriate the statement of identity for nonabrasive is including the terms ‘‘mouthwash’’ (if labeling for cosmetic uses in accord fluoride gels. Because a distinction is the product also has a cosmetic use), with section 602 of the act (21 U.S.C. not needed for fluoride dental rinses, ‘‘tooth polish,’’ and ‘‘tooth powder’’ in 362) and the provisions of 21 CFR parts the agency is providing that the phrase § 355.50(a) in this final rule. (For further 701 and 740. ‘‘preventive treatment’’ be optional in discussion of the statement of identity, Sections 201.61 and 701.11 of the CFR the statement of identity for these see section I.C., comments 17 and 19 of require that the statement of identity for products. The statement of identity for this document.) OTC drug and cosmetic products each OTC anticaries drug products in 19. Two comments noted that many appear on the principal display panel of § 355.50(a) of this final monograph anticaries drug products also properly the product. The agency’s OTC drug reads as follows: contain cosmetic ingredients and regulations do not prohibit placing the The labeling of the product contains the include cosmetic labeling. The cosmetic statement of identity of a drug/ established name of the drug, if any, and identifies the product as the following: comments contended that cosmetic product on the principal ‘‘anticavity fluoride’’ (select one of the manufacturers must be permitted to display panel. However, in accordance following as appropriate: ‘‘dentifrice,’’ label such products with statements of with the revised labeling requirements ‘‘toothpaste,’’ ‘‘tooth polish,’’ ‘‘tooth identity that include truthful drug/ for OTC drug products, cosmetic claims powder;’’ (optional: ‘‘dental’’) ‘‘preventive cosmetic terminology. For example, the may not appear within the boxed area treatment gel;’’ or (optional: ‘‘preventive comments stated that the same product designated ‘‘APPROVED USES.’’ (See treatment’’ or ‘‘dental’’)) (select one of the may be used both as an anticaries section I.A., comment 1 of this following: ‘‘rinse,’’ ‘‘concentrated solution,’’ ‘‘rinse powder,’’ or ‘‘rinse effervescent dentifrice and as a cleaning and breath document.) As discussed in the final tablets’’). The word ‘‘mouthwash’’ may be freshening toothpaste. The comment rule on the agency’s ‘‘exclusivity substituted for the word ‘‘rinse’’ in this maintained that such a product should policy’’ (51 FR 16258 at 16264 statement of identity if the product also has be able to truthfully declare in its (paragraph 14)), cosmetic terminology is Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52485 not reviewed and approved by FDA in benefits. The comment requested the information should be displayed on the the OTC drug monographs and therefore agency to delete the statement in principal display panel. Therefore, the can not be placed in the boxed portion proposed § 355.50(e)(2) that says ‘‘This agency is including in this final of the label. Cosmetic terminology can, is a(n)’’ (select one or both of the monograph new § 355.55 as follows: however, be placed outside the box and following: ‘‘anticavity’’ or ‘‘fluoride’’) ‘‘Principal display panel of all fluoride on the product’s principal display ‘‘treatment rinse, not a mouthwash.’’ rinse drug products. In addition to the panel. In addition, cosmetic claims may In the tentative final monograph for statement of identity required in appear elsewhere in the labeling should OTC anticaries drug products, the § 355.50, the following statement shall manufacturers choose the labeling agency expressed concern that, because be prominently placed on the principal alternative provided in § 330.1(c)(2)(i) or fluoride dental rinses and cosmetic display panel: ‘IMPORTANT: Read (c)(2)(iii) for labeling drug/cosmetic mouthwashes are similar in appearance, directions for proper use’.’’ products. Although the agency does not consumers might confuse such products Reference specifically prohibit commingled drug (50 FR 39854 at 39869). The agency and cosmetic labeling other than in the stated that proper labeling is an (1) Labeling for Scope, OTC Vol. 08AFM, product’s indications section, such important aid to preventing consumer Docket No. 80N–0042, Dockets Management claims should be appropriately confusion as to the use of these Branch. described so that consumers will be products. Therefore, the agency 21. One comment disagreed that the readily able to differentiate the drug proposed labeling, including the heading ‘‘Indication’’ proposed in aspects from the cosmetic aspects of labeling statement ‘‘* * * not a § 355.50(b) was needed in the labeling such labeling. If commingled drug and mouthwash * * *’’ in § 355.50(e)(2), to of OTC fluoride dentifrice products. The cosmetic labeling claims are confusing minimize confusion and to help comment contended that the function of or misleading, the product’s labeling consumers distinguish between dental a fluoride toothpaste is generally could be misleading within the meaning rinses and cosmetic mouthwashes. known, and consumers have safely and of sections 502(a) and 602(a) of the act The agency sees no reason why an correctly used these products for years (21 U.S.C. 352(a) and 362(a)). appropriately labeled OTC fluoride without the heading ‘‘Indication’’ in the 20. One comment objected to the first rinse cannot also be used for freshening labeling of these products. The portion of the agency’s proposed the breath. Such a product can properly comment added that the consuming additional labeling statement for be identified as an anticavity or fluoride public probably does not consider fluoride dental rinses in § 355.50(e)(2), rinse or mouthwash (see section I.C., fluoride toothpaste to be a drug in the which states: ‘‘This is a(n)’’ (select one comment 18 of this document). same sense as other common OTC drug or both of the following: ‘‘anticavity’’ or However, the agency believes that products; thus, consumers could be ‘‘fluoride’’) ‘‘treatment rinse, not a proper labeling of OTC fluoride rinses is confused by this new labeling mouthwash. Read directions carefully an important factor in helping to ensure requirement. The comment suggested before using.’’ The comment contended the safe and effective use of these that § 355.50(b) be revised to make use that a properly formulated and labeled products. of the heading ‘‘Indication’’ optional. product could be legally and accurately The agency is concerned that, based The agency does not agree that the promoted as both an anticavity dental upon familiarity with cosmetic heading ‘‘Indication(s)’’ should be rinse and a cosmetic mouthwash. The mouthwash use, a consumer might optional. All OTC drug monographs in comment added that requiring the ‘‘not overuse and/or misuse an OTC fluoride parts 331 through 358 (21 CFR 331 a mouthwash’’ statement on fluoride rinse. For example, directions for use of through 358) have been promulgated dental rinses is not consistent with the fluoride rinses are notably different with a standard ‘‘Indications’’ paragraph agency’s well-established policy from directions for use of cosmetic requiring that the labeling of the regarding OTC drugs that claim both mouthwashes. Cosmetic mouthwashes product state its FDA approved use(s) therapeutic and cosmetic benefits. The are often labeled for multiple use during under the heading ‘‘Indication(s).’’ comment stated that dual drug/cosmetic the day (e.g., ‘‘first thing in the morning, However, two general OTC drug product labeling is permitted in other product after meals, and before social labeling provisions, which were categories (e.g., antiperspirants, engagements’’) (Ref. 1). Fluoride rinses promulgated after the comment was dentifrices, and antidandruff are labeled for use once or twice a day submitted, provide alternatives. Section shampoos), and that the agency does not (§ 355.50(d)(2)). Cosmetic mouthwash 330.1(c)(2)(i) provides that, at the option require similar labeling statements for labeling directs consumers to ‘‘rinse or of the manufacturer, the ‘‘Indications’’ such products. The comment contended gargle 30 seconds’’ (Ref. 1). The may be designated ‘‘APPROVED USES’’ that requiring an anticavity dental rinse/ directions for use of fluoride rinses state or given a similar designation as mouthwash product to display the ‘‘not that consumers should ‘‘* * * swish * permitted in that paragraph of the a mouthwash’’ labeling statement is * * between your teeth for 1 minute * regulations. Section 330.1(i)(8) provides inconsistent with agency policy for * * Do not eat or drink for 30 minutes that ‘‘indications’’ or ‘‘uses’’ may be these other OTC products and could be after rinsing’’ (§ 355.50(d)(2)). used interchangeably. confusing to consumers who have been Based on the above discussion, the Although the comment claims that receiving both benefits from previous agency has determined that the ‘‘not a consumers may not be accustomed to use of these products. mouthwash’’ statement need not be reading such information on dentifrice The comment argued that the agency’s required labeling for OTC fluoride product labels, the agency believes that proposal would adversely affect the rinses. Accordingly, the agency is not consumers should be aware that these truthful promotion of OTC anticavity including proposed § 355.50(e)(2) in this products are drugs. This same principle dental rinses, and that consumers final monograph. However, in order to would apply to other OTC products that desiring both anticavity and breath maximize the safe and effective use of consumers might not consider to be freshening activity would have to OTC fluoride rinses, the agency drugs because they have not contained purchase two separate products (i.e., an concludes that these products must such labeling in the past, e.g., anticavity dental rinse and a cosmetic contain labeling that clearly instructs antiperspirants and sunscreens. The mouthwash) instead of purchasing one consumers to read the directions. The comment did not provide any evidence product that would provide both agency also believes that this that consumers would be confused by 52486 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations reading this type of labeling, which has from 1985 to 1992 for reports related to meal, and, for reasons of practicality, appeared for years on many widely used fluoride rinses, gels, and dentifrices brushing at least twice a day—after OTC drug products. The agency finds (Ref. 1). In the 0- to 9-year age group, breakfast and in the evening. The that informative headings such as there were 22 reports for fluoride rinses comments indicated that they are ‘‘Indications’’ or ‘‘Uses’’ (as well as and gels, but no reports for fluoride unaware of any data that suggest ‘‘Warnings’’ and ‘‘Directions’’) are dentifrice products. In addition, the brushing once a day is adequate, and useful to consumers and provide agency has reviewed available data therefore urged the agency not to refer uniformity to OTC drug product concerning exposures to fluoride to any minimum number of times for labeling. Therefore, the agency is not toothpastes and fluoride rinses brushing. (2) The contraindication for making use of the heading (mouthwash) in annual reports of the the use of fluoride dentifrices by ‘‘Indication(s)’’ optional. American Association of Poison Control children under 2 years of age is 22. One comment noted that Centers for the years 1989 to 1991 (Refs. unwarranted because children that age § 330.1(g) (21 CFR 330.1(g)) requires that 2, 3, and 4). For children under 6 years have many teeth requiring anticaries all drugs, unless exempted, be labeled of age, the number of accidental protection. The comments stated that with the warning ‘‘Keep this and all exposures averaged approximately 1,200 early instruction of children regarding drugs out of the reach of children.’’ The per year for fluoride toothpastes and dental care minimizes the risk of comment stated that OTC anticaries almost 1,000 per year for fluoride rinses. fluorosis due to ingestion of fluoride dentifrices and rinses obviously should However, fluoride toothpaste usage is dentifrice and encourages good oral not be subject to the general warning estimated to be 300 times that of health care habits. because they bear directions for use by fluoride rinses. Thus, the accidental The Panel reviewed several clinical children. The comment requested that ingestion rate for fluoride toothpaste is studies that showed fluoride-containing OTC anticaries drug products be much lower than for fluoride liquid dentifrices effectively increase exempted from the requirement to bear products. Therefore, the available data resistance to enamel solubility and this warning. strongly support a requirement that therefore reduce dental decay when The agency agrees, in part, with the fluoride rinses and gels be labeled in comment. The agency recognizes that applied to the teeth at least once a day accord with the general warning in (Refs. 1, 2, and 3). Radike (Ref. 3) fluoride dentifrices are generally kept § 330.1(g), without any modifications. within the reach of children to describes three 1-year clinical studies This requirement appears in with a similar design conducted to encourage use on a regular basis. The § 355.50(c)(2) of this final monograph. agency is concerned that the general determine whether the frequency of warning ‘‘Keep this and all drugs out of References application affects the anticariogenic effect of a stannous fluoride dentifrice. the reach of children’’ could discourage (1) Food and Drug Administration, Center or inhibit parents from keeping fluoride for Drug Evaluation and Research, Adverse Each study used similar stannous dentifrices within easy reach of children Reaction Summary Listing for Fluoride fluoride dentifrices, but the subjects 6 years of age and older who are able Rinses, Gels, and Dentifrices for years 1985 (school children) were assigned one of to use dentifrice products safely and to 1992, OTC Vol. O8AFM, Docket No. 80N– three different brushing procedures: (1) effectively. However, these products 0042, Dockets Management Branch. Unsupervised brushing, (2) supervised (2) Litovitz, T. L. et al., ‘‘1989 Annual should not be within easy reach of brushing once-a-day after the noon Report of the American Association of Poison meal, and (3) supervised brushing three children under 6 years of age, who Control Centers National Data Collection should be supervised and instructed in System,’’ The American Journal of times a day (after breakfast and dinner the proper use of these products and Emergency Medicine, 8:421, 1990. and before retiring). Each brushing who are vulnerable to dental fluorosis. (3) Litovitz, T. L. et al., ‘‘1990 Annual regimen was assigned approximately the Thus, in § 355.50(c) of this final Report of the American Association of Poison same number of control subjects as test monograph, the agency is modifying the Control Centers National Data Collection subjects. Subjects in a control group § 330.1(g) warning to read as follows for System,’’ The American Journal of assigned to a specific brushing Emergency Medicine, 9:488, 1991. fluoride dentifrice products: ‘‘Keep out procedure brushed with a nonfluoride- (4) Litovitz, T. L. et al., ‘‘1991 Annual containing dentifrice. In the study in of the reach of children under 6 years Report of the American Association of Poison of age.’’ Control Centers National Data Collection which no toothbrushing instructions The agency disagrees with the System,’’ The American Journal of were given and the subjects were comment with respect to fluoride rinses Emergency Medicine, 10:480, 1992. allowed to follow their usual brushing and gels. The agency believes that these 23. Two comments disagreed with the habits, the fluoride dentifrice subjects dosage forms should not be within easy directions proposed in § 355.50(d)(1) for developed 23 percent fewer new caries reach of any children. These products anticaries dentifrices, which state: than those in the control group. In the are not indicated for use in children ‘‘Adults and children 2 years of age and study with one supervised brushing in under 6 years of age on an OTC basis. older: brush teeth thoroughly at least the school room after the noon meal, the For children 6 to under 12 years of age, once daily or as directed by a dentist or fluoride dentifrice subjects developed the products must be labeled for use doctor. Children under 6 years of age 34 percent fewer caries than those in the under the supervision of an adult. These should be supervised in the use of this control group. In the third study with fluoride dosage forms are potentially product.’’ The comments disagreed in supervised brushing three times a day more toxic than fluoride dentifrice two major areas: (1) The agency’s (after breakfast and dinner and before products because they do not contain an reference to brushing at least once daily retiring), the fluoride dentifrice subjects abrasive that can bind some the fluoride may be misinterpreted by the public as developed 57 percent fewer new caries ion and because a child under 6 is more being adequate and, therefore, may lead than those in the control group. The likely to drink a flavored liquid than eat to less brushing and poor oral health results from these studies clearly large amounts of toothpaste, which may care. The comments indicated that there suggest that simply cleansing the teeth contain up to 40 percent by weight of is no clear consensus within the dental with an abrasive containing inert abrasive ingredients. profession as to the number of times nonfluoridated dentifrice is not as The agency has reviewed its adverse teeth should be brushed each day. Many effective in reducing the incidence of reaction data base covering the period dentists recommend brushing after each caries as brushing with a fluoride- Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52487 containing dentifrice. The data also Clinical results after 1 year indicated The agency disagrees with the show that more frequent topical that brushing thoroughly immediately comments suggesting that the applications of fluoride significantly after the ingestion of food resulted in a contraindication for children under 2 enhance anticaries protection. 63-percent reduction in caries activity years of age is unwarranted. Very young Supervised brushing with a fluoride in the experimental group when children cannot be expected to dentifrice once-a-day after the noon compared to the control group. rationally interpret and consistently meal resulted in 33 percent fewer A more recent 1982 study (Ref. 8) follow the instructions involving proper cavities than unsupervised brushing. reviewed the prevention control of oral toothbrushing; nor do they have the Further, subjects who brushed three diseases and recommended at least two manual dexterity to use the fluoride times a day with a fluoride dentifrice daily brushings with a fluoride dentifrice product properly. Children experienced: (1) 40 percent fewer new dentifrice as effective in reducing the under 2 years of age do not have control cavities than those who brushed with a incidence of dental cavities. The study of their swallowing reflex and do not fluoride dentifrice only once-a-day, further stated that because have the skills to expectorate the even under supervision, and (2) 60 toothbrushing is intended to remove toothpaste properly (50 FR 39854 at percent fewer cavities than those whose food debris and dental plaque from the 39867). Although the prevalence of brushing was unsupervised. The results teeth, brushing after meals and sweet dental caries is decreasing, some reports of these three studies indicate that fewer snacks is commonly recommended in suggest the incidence of mild fluorosis caries occur as frequency of supervised dental health messages to the public. (a permanent, mottled discoloration of brushing and brushing after meals is The agency agrees with the comments the teeth) in young children is increased. and with many dentists that brushing increasing in the United States due to properly and thoroughly more often Several additional studies (Refs. 4 the increase of fluoride in our food than once daily will promote better oral chain (Ref. 9). Excessive ingestion of through 7) also indicate that brushing health care. Reducing cariogenic activity immediately after meals is the most fluoride by young children increases the by brushing more often than once a day, risk of fluorosis during the critical time favorable time to reduce the number of particularly after meals, can be cariogenic bacteria from all tooth of anterior teeth development and can explained by the synergistic effect of the interfere with the successful surfaces. Two review studies (Refs. 4 antienzymatic properties of fluoride (45 and 6) discussed the role nutrition plays development of other emerging teeth FR 20666 at 20672) along with the (Ref. 10). Toothbrushing for children in the etiology of dental disease. Both mechanical removal of food debris. The studies concluded that one preventative under 2 years of age when teeth are first Panel recognized that three factors are emerging may also cause minor injury to measure to effectively reduce the necessary for caries to occur (45 FR number of cariogenic bacteria present in the soft tissue in the mouth. The agency 20666 at 20672): (1) The teeth must be recognizes that young children are most the mouth is to brush thoroughly after susceptible to caries, (2) acid-producing susceptible to mild fluorosis as a result each meal with a fluoride-containing bacteria of the mouth must colonize on of improper use and swallowing of a dentifrice. Forty years ago, another the teeth, and (3) a substrate must be fluoride dentifrice product. Based on study (Ref. 7) indicated that many present for bacteria to proliferate and to the above, the agency concludes that it dentists and health workers strongly produce acid for demineralization of the is appropriate to include in the labeling recommend that toothbrushing be teeth. Effective anticaries protection is of fluoride dentifrice drug products performed immediately after the achieved by exposing the tooth enamel containing 1,000 ppm theoretical total ingestion of sugar-containing food if to fluoride ions and by the mechanical fluorine the following sentence: brushing is to be effective in reducing removal of dental plaque and food ‘‘Children under 2 years of age: Consult dental cavities. The study also included debris from tooth surfaces and gingival a clinical investigation evaluating the tissue areas. Both objectives are better a dentist or doctor.’’ The agency is effectiveness of reducing dental cavities accomplished by toothbrushing more including this sentence in the directions by brushing the teeth with one of three often than once daily, preferably after in § 355.50(d)(1)(i) of this final types of nonfluoridated dentifrices meals. The mechanical removal of food monograph. The agency is also immediately after the ingestion of food. debris from teeth and gingival areas including a similar statement in the This report (Ref. 7) dealt with only one decreases the availability of metabolized directions for dentifrices containing of the dentifrices, the neutral paste. carbohydrate sources, which are 1,500 ppm theoretical total fluorine for Subjects in the experimental group were required for caries development. children under 6 years of age (see instructed individually to brush their The agency agrees with the Panel that section I.B., comment 10 of this teeth thoroughly within 10 minutes after brushing with a fluoride-containing document). each ingestion of food or sweets and, dentifrice at least once daily effectively References when brushing was not possible, to renders the teeth less susceptible to rinse the mouth thoroughly with water. dental cavities. The agency also (1) Council on Dental Therapeutics, Toothbrushes and dentifrice were Accepted Dental Therapeutics, 37th ed., recognizes, however, that anticaries American Dental Association, Chicago, p. supplied to all experimental subjects. protection could be enhanced by 303, 1977. Subjects in the control group were not brushing more than once a day, (2) Council on Dental Therapeutics, supplied with dentifrices or brushes, preferably after each meal to remove the ‘‘Evaluation of Super Stripe Toothpaste,’’ but were instructed to continue their food particles that provide the substrate Journal of the American Dental Association, customary oral hygiene habits of necessary for bacteria to proliferate and 71:930–931, 1966. brushing only on arising and before produce acid in the development of (3) Radike, A. W., ‘‘Current Status of retiring, rather than after the ingestion dental caries (Ref. 3). Therefore, the Research on the Use of a Stannous Fluoride of food. When this study was conducted agency is revising part of the directions Dentifrice,’’ in OTC Vol. 080099. (4) Massler, M., ‘‘Nutrition and Dental in 1950, fluoridated toothpastes were for all OTC fluoride dentifrices to read: Decay,’’ Food and Nutrition News, 39:1–4, not available in the marketplace; thus, ‘‘* * * brush teeth thoroughly, 1968. the control subjects would not have preferably after each meal or at least (5) Nikiforuk, G., and J. B. MacDonald, ‘‘An used a fluoridated dentifrice as a part of twice a day, or as directed by a dentist Evaluation of Dentifrices in the Prevention of their customary oral hygiene habits. or doctor.’’ Dental Caries and Gingivitis,’’ Journal of the 52488 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

Canadian Dental Association, 21:557–565, for dentifrices containing 1,000 ppm the children between 2 and 3 years of 1955, Abstracted in Dental Abstracts, theoretical total fluorine, but requested age could perform mouthrinsing 1(4):227, 1956. the agency to expand § 355.50(d)(1) to without swallowing the fluid. The 3- (6) Finn, S. B., and R. B. Glass, ‘‘Sugar and read: ‘‘To prevent swallowing, children and 4-year-old children could, as a rule, Dental Decay,’’ World Review of Nutrition and Dietetics, 22:318–320, 1975. under 6 years of age should be keep the fluid in their mouths for 30 (7) Fosdick, L. S., ‘‘The Reduction of the supervised in the use of toothpaste seconds. The 5- and 6-year-old children Incidence of Dental Caries. 1. Immediate (mouthrinse).’’ The comment stated that could all perform the rinse for 1 minute; Tooth-Brushing with a Neutral Dentifrice,’’ young children should be educated in these children had considerably less The Journal of the American Dental the proper manner of toothbrushing so individual variation in expectorated Association, 40(2):133–143, 1950. as to help enhance proper brushing volumes. Based on these data, the (8) Council on Dental Therapeutics, technique as well as appropriate agency finds that suggesting to parents Accepted Dental Therapeutics, 39th ed., product use (i.e., using small portions that swallowing can be prevented may American Dental Association, Chicago, pp. 335–337, 1982. and spitting the dentifrice out after use, cause unnecessary alarm when they (9) Leverett, D. H., ‘‘Fluorides and the rather than ingestion). The comment observe a young child swallow small Changing Prevalence of Dental Caries,’’ stated that the Council on Dental amounts of dentifrice during the Science, 217:26–30, 1982. Therapeutics of the American Dental learning process. Accordingly, the (10) Simard, P. L. et al., ‘‘The Ingestion of Association (ADA) has recently adopted agency is using the word ‘‘minimize’’ Fluoride by Young Children,’’ Journal of this statement and directed its use on all instead of ‘‘prevent’’ in this final Dentistry for Children, 56:177–181, 1989. labeling for Council-accepted fluoride- monograph. The revised direction 24. Three comments objected to the containing dentifrices and statement in § 355.50(d)(1)(i) reads: directions proposed in § 355.50(d)(1) for mouthwashes. ‘‘Instruct children under 6 years of age anticaries products marketed in a The agency agrees with the in good brushing and rinsing habits (to dentifrice dosage form (containing 1,000 comments. The Panel recommended minimize swallowing). Supervise ppm theoretical total fluorine), which that fluoride dentifrices be labeled to children as necessary until capable of states: ‘‘Children under 6 years of age indicate that children under 6 years of using without supervision.’’ should be supervised in the use of this age should be supervised in the use of product.’’ The comments contended that these products. In the tentative final Reference this is the type of language that is monograph for OTC anticaries drug (1) Ericsson, Y., and B. Forsman, ‘‘Fluoride customarily used for products or products (50 FR 39854 at 39867), the Retained from Mouthrinses and Dentifrices activities that are dangerous, thus the agency interpreted the Panel’s statement in Preschool Children,’’ Caries Research, language is needlessly alarmist. The to mean that all children under 6 years 3:290–299, 1969. comments explained that ‘‘supervision’’ of age should be properly instructed and 25. One comment objected to the part in this usage connotes watchfulness to supervised in the use of a dentifrice, but of the proposed directions in prevent any action by the child that the amount of supervision may vary § 355.50(d)(2)(i) for anticaries products could lead to harm. The comments depending on a child’s skills. If a child marketed for use as treatment rinses, claimed that a parent reading this has fairly good toothbrushing skills, which states: ‘‘Children under 12 years direction for use might infer that parents may allow unsupervised of age should be supervised in the use toothpaste has some dangerous hidden brushing, but may wish to check the of this product.’’ The comment stated toxicity. The comments emphasized that child’s toothbrushing techniques that the Panel recommended that the important point is that children periodically. The agency did not intend children under 6 years of age be should be trained how to brush their that every toothbrushing event until age supervised in the use of fluoride teeth so that they will obtain the desired 6 should be supervised. As the dentifrices (45 FR 20666 at 20673), but benefit of toothbrushing without comments suggested, the important did not mention children above 6 years swallowing excessive amounts of point is for parents to assure themselves of age. The comment suggested that the toothpaste, which would increase their that their children are learning the Panel’s recommendation was made in risk of fluorosis. One comment stated proper use of dentifrices, and once they order to limit daily fluoride ingestion that the proposed labeling implies that are assured of this, supervision is no and thereby avoid possible dental even after good brushing habits are longer required. The agency agrees that fluorosis. The comment cited the acquired, every toothbrushing event the labeling should make this point Panel’s discussion of epidemiological until age 6 should be supervised by a without being unnecessarily and clinical findings that indicated that parent. The comments requested that overcautious or alarmist. teeth of children 6 years of age and the directions be revised to read: Regarding the request to expand older are ‘‘(excepting third molars) * * ‘‘Instruct children under 6 years of age § 355.50(d)(1) to include the language * too advanced to be affected by in good brushing and rinsing habits as ‘‘To prevent swallowing * * * ,’’ the excessive daily fluoride ingestion.’’ The recommended by your dentist.’’ The agency agrees that the objective of comment mentioned the Panel’s comments argued that implicit in the instruction and supervision is to avoid discussion (45 FR 20666 at 20673) that concept of instruction is supervision excessive ingestion of the dentifrice. children 6 years of age and older have until the parent is satisfied that the However, the agency believes that the developed control of their swallowing child can follow the instruction word ‘‘prevent’’ may be too strong a reflexes and are able to rinse for 1 correctly. The comments concluded that term and that prevention of some minute and expectorate properly. The the term ‘‘instruction’’ rather than swallowing of dentifrices is comment stated that if the agency is ‘‘supervision’’ provides the correct unachievable in young children. The concerned that children between 6 and emphasis, provides useful guidance amount of dentifrice ingested varies 12 years of age using the product for the adequate to deal with the concern about with the age and skill of the child. The first time may not be able to follow label fluorosis, and does so without Panel reviewed a study (Ref. 1) directions without instruction from a stimulating unwarranted parental involving children 2 to 6 years of age parent or other adult, then limited concern. that showed large individual variations directions about supervision might be Another comment did not object to in expectorated volumes after useful. However, the comment the term ‘‘supervised’’ in the direction mouthrinsing with water. Only a few of expressed concern that continuing Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52489 supervision each time the product is warnings to the directions for use fluoride dentifrice formulation marketed used did not appear warranted and that section. This statement is to appear as in the United States. This comment this unnecessarily overcautious labeling the first statement under the directions stated that no incidence of surface could discourage use of these products. for use for concentrated treatment rinse staining was found that would justify The agency agrees. As discussed in solutions, powders, and effervescent such a labeling statement. comment 24, the agency interpreted the tablets. It should then be followed by One comment suggested that the Panel’s statement to mean that children the proper directions for preparing the tendency of stannous fluoride products under 6 years of age should be properly diluted rinse product. The part of the to cause staining of the teeth is directly instructed and supervised in the use of proposed warning that stated ‘‘Read the related to a number of factors. It may be a dentifrice, not because of any directions carefully.’’ is not needed highly dependent on the formulation of particular hazard, but to ensure that the when this revised labeling format is the product and/or the brushing habits child is developing adequate used. of the user. The comment stated that the toothbrushing skills and is using the 27. Several comments objected to the stability of the fluoride and the stannous product correctly. Instruction and agency’s proposed labeling statement in ions in a product have an effect on supervision serve the same purpose for § 355.50(e)(3) for OTC stannous whether or not the product causes tooth fluoride rinses (i.e., to assure proper use fluoride-containing dentifrices, staining. For example, a product that of these products) and are not intended treatment gels, and treatment rinses, contains a high level of stannous ions to discourage use of fluoride rinses by which states: ‘‘This product may may be more likely to stain teeth than children. Once the parent is certain that produce surface staining of the teeth. a product that is stabilized and, the child is using the product correctly, Adequate toothbrushing may prevent therefore, does not contain many unsupervised use may be allowed. these stains which are not harmful or stannous ions. The comment asserted Therefore, the agency is revising part of permanent and may be removed by your that stable stannous fluoride products the directions statement to read: dentist.’’ In support of their objections (e.g., dental gels) are not likely to cause ‘‘Instruct children under 12 years of age to this statement, one comment cited discernible staining. The comment in good rinsing habits (to minimize five published studies (Refs. 1 through concluded that the labeling statement swallowing). Supervise children as 5) and another comment submitted an about tooth staining should not be necessary until capable of using without unpublished study of the incidence of imposed indiscriminately on all supervision.’’ stained teeth in school children who stannous fluoride products without 26. One comment disagreed with the used a stannous fluoride dentifrice (Ref. regard to the stability of the product. agency’s proposal to include the 6). Stating that the evidence regarding One comment contended that following statement in § 355.50(c) as a the propensity of stannous fluoride requiring the labeling statement about warning for concentrated treatment products to stain teeth is equivocal, tooth staining on stannous fluoride rinse solutions, powders, and another comment argued that the dentifrice products would cause undue effervescent tablets: ‘‘Do not use before labeling statement should be required concern among consumers. The mixing with water. Read the directions only on those stannous fluoride comment was concerned that the carefully.’’ The comment stated that products that have been scientifically proposed warning would cause users to neither the Panel in the advance notice proven to cause substantial and avoid safe and effective stannous of proposed rulemaking (45 FR 20666) discernible staining on the teeth of fluoride products in favor of other nor the agency in the tentative final users. The comment urged the agency to products that do not bear such a monograph for OTC anticaries drug abandon or strictly limit its proposal to warning. Another comment stated that products identified a compelling safety require a teeth staining labeling requiring such a labeling statement hazard that warrants including the statement on OTC stannous fluoride without reliable scientific support is information in the warnings section dentifrice products. damaging to consumers who may place rather than in the directions for use. The Three comments noted that the Panel undue emphasis on the possibility of comment contended that the safe use of specifically stated in its discussion of some transient staining. The first these concentrated products is amply stannous fluoride dentifrice drug comment added that requiring the ensured by including the quoted products (45 FR 20666 at 20685) that ‘‘* labeling statement regardless of whether language in the directions for use. The * * the frequency and intensity of or not a product caused staining of the comment requested that this staining with the level of tin present in teeth would handicap stannous fluoride information be included in the these formulations does not appear to products that could be shown not to directions section only, because it present any significant problem; cause a greater amount of staining than concerns proper use of a product rather therefore, no labeling statement on any other fluoride product. than cautioning to prevent possible staining shall be required for stannous Another comment contended that the dangers of misuse. fluoride dentifrice formulations * * *.’’ data used by the agency to support the In the tentative final monograph, the Two of the comments stated that the tooth staining labeling statement (50 FR agency stated that, in order to alert agency failed to offer any new evidence 39854 at 39865 and 39866) are flawed consumers that dental rinse products in that would make the findings of the and do not support the agency’s concentrated form (solutions, powders, expert panel inappropriate. One of the decision to require this statement on and effervescent tablets) must be diluted comments asserted that all the studies stannous fluoride products. Stating that or dissolved in water before using, the cited by the agency in support of the none of the studies attempted to relate agency is proposing the warning stated proposed labeling statement for the incidence of staining to any element above for these dosage forms. The stannous fluoride dentifrice products of the dentifrice other than stannous agency agrees with the comment that (50 FR 39854 at 39865 and 39866) were fluoride, the comment asserted that consumers could equally be alerted if cited previously by the Panel as support interaction between the polishing agent this information appeared in the for its conclusion that no labeling (abrasive) and the fluoride moiety may directions for use section. Accordingly, statement about tooth staining was be responsible for any staining in this final monograph, the agency is necessary (45 FR 20666 at 20685). observed. The comment noted that the moving the statement ‘‘Do not use Another comment mentioned extensive polishing agent in the stannous fluoride before mixing with water.’’ from the experience with the first stannous dentifrices in some studies was sodium 52490 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations metaphosphate. The comment that tooth staining is related to any Dentistry and Oral Epidemiology, 5:55–60, maintained that it is impossible to know individual polishing agent. However, 1977. whether similar results would have based on the information available from (6) Katayama, T., ‘‘Incidence of Stained occurred if a different polishing agent the studies, the agency is unable to Teeth on School Children Who Have Used Stabilized SnF2 Toothpaste for Three Years,’’ had been used. The comment concluded determine if staining is a formulation unpublished study in Comment No. C63, that these data show that stannous specific problem. The agency believes Docket No. 80N–0042, Dockets Management fluoride contained in a dentifrice base of that the information submitted clearly Branch. sodium metaphosphate can cause mild demonstrates that stannous fluoride 28. One comment requested that the staining in some subjects when dental products (i.e., dentifrices, nses, professional labeling in § 355.60 be analyzed by investigators in blind, and gels) have the potential to produce modified to require that only dental controlled settings. surface staining of the teeth. The agency rinse formulations composed of The comment added that the studies is not aware that such staining results ingredients suitable for swallowing be used by the agency to support the from the use of any other commonly used as fluoride supplements intended proposed staining statement (50 FR utilized fluoride ingredients. for ingestion in areas where the water 39854 at 39865 and 39866) did not The agency reaffirms its conclusion supply is nonfluoridated. The comment compare the reported incidence of tooth that a labeling statement regarding tooth stated that this section, as proposed, staining with consumer perception of staining should be required on all does not mention that fluoride rinses such staining. The comment maintained stannous fluoride products. The agency promoted to health professionals and that these studies demonstrate that tooth believes that: (1) Consumers should be not offered to the general public are staining caused by stannous fluoride advised that staining of the teeth may be specially formulated with ingredients products is barely perceptible by caused by stannous fluoride products, suitable for ingestion. These products consumers and is of little importance to including dentifrices, and (2) that are intended to be swallowed. The the vast majority of people under adequate brushing or dental prophylaxis comment mentioned that dental rinse normal conditions of daily use. The may prevent the stains. The agency does products not intended to be swallowed comment and another comment not believe that one comment’s are formulated differently and contain mentioned a study by Ness, Rosekrans, suggested labeling statement about tooth other ingredients. and Welford (Ref. 5) that also staining has any advantage over the The agency agrees that further demonstrates that staining is barely statement proposed by the agency in the explanation of the term ‘‘supplement’’ perceptible and not important to tentative final monograph. The would help to reduce possible consumers. comment’s suggested statement uses confusion. Therefore, the agency is One comment agreed with the Panel words like ‘‘occasionally’’ and ‘‘minor’’ modifying the introductory language in that a labeling statement about tooth and is more ambiguous than the the professional labeling in § 355.60 as staining is unnecessary for stannous agency’s proposed statement. The follows: ‘‘The labeling for anticaries fluoride dentifrices. However, the agency’s statement conveys a more fluoride treatment rinses identified in comment asserted that, if the agency meaningful message using the phrase § 55.10 that are specially formulated so determines that such a labeling ‘‘may produce surface staining.’’ In they may be swallowed (fluoride statement is necessary, the data support addition, the agency’s statement advises supplements) and are provided to health only a limited labeling statement for the consumer that the staining is not professionals (but not to the general stannous fluoride dentifrice products in harmful or permanent. The agency public) may contain the following which sodium metaphosphate is the considers its proposed statement to be additional dosage information: * * *.’’ polishing agent. In addition, the more informative than the comment’s Also, the agency is including a comment requested that this labeling suggested statement and more helpful to definition of fluoride supplement in statement be modified to reflect the consumers. Therefore, the agency is § 355.3 as follows: ‘‘Fluoride underlying data as follows: ‘‘This including its proposed labeling supplement. A special treatment rinse product may occasionally produce statement in § 355.50(e)(2) of this final dosage form that is intended to be minor temporary surface staining of monograph. swallowed, and is promoted to health teeth. Adequate toothbrushing will professionals for use in areas where the prevent these stains and they may be References water supply contains 0 to 0.7 parts per easily removed by your dentist.’’ (1) Jackson, D., and P. Sutcliffe, ‘‘Clinical million fluoride ion.’’ The agency does not believe that the Testing of a Stannous Fluoride-Calcium studies submitted by the comments D. Comments on the Switch of Pyrophosphate Dentifrice in Yorkshire Prescription Anticaries Drug Products to support eliminating the labeling School Children,’’ British Dental Journal, statement regarding tooth staining from 123:40–48, 1967. OTC Status stannous fluoride dentifrice products. (2) James, P. M. C., and R. J. Anderson, 29. One comment objected to the Although two of the six studies ‘‘Clinical Testing of a Stannous Fluoride- proposed prescription-to-OTC switch of submitted do not show significant Calcium Pyrophosphate Dentifrice in 0.4 percent stannous fluoride gel staining caused by stannous fluoride Buckinghamshire School Children,’’ British products for economic and labeling Dental Journal, 123:33–39, 1967. dentifrice products (Refs. 5 and 6), four (3) Naylor, M. N., and R. D. Emslie, reasons. The comment indicated that of the six studies (Refs. 1 through 4) ‘‘Clinical Testing of Stannous Fluoride and currently only small manufacturers demonstrate that test groups using Sodium Monofluorophosphate Dentifrices in make and market these products on a stannous fluoride dentifrice products London School Children,’’ British Dental prescription basis. The comment had significantly more tooth staining Journal, 123:17–23, 1967. asserted that OTC status would than groups using dentifrice products (4) Slack, G. L. et al., ‘‘Clinical Testing of disadvantage these small companies by without fluoride. Three of these studies a Stannous Fluoride-Calcium Pyrophosphate forcing them into the OTC marketplace (Refs. 1, 2, and 4) used a dentifrice with Dentifrice in Essex School Girls,’’ British with obvious competitive and marketing Dental Journal, 123:26–33, 1967. calcium pyrophosphate as the abrasive (5) Ness, L., D. L. Rosekrans, and J. F. expenses. According to the comment, agent. Sodium metaphosphate was the Welford, ‘‘An Epidemiological Study of promoting its products through health- abrasive agent used in the other study Factors Affecting Extrinsic Staining of Teeth care professionals is less costly than (Ref. 3). These studies do not indicate in an English Population,’’ Community promoting the products to the general Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52491 public on an OTC basis. The comment this document. The agency considers fluoride industry without endangering contended that OTC status creates a the statement for dental gel products to public safety. labeling problem that does not exist be important to their safe OTC use. In the tentative final monograph (50 when these products are marketed as The agency concludes that the OTC FR 39854 at 39857), the agency prescription drugs. The comment availability of 0.4 percent stannous concurred with the Panel’s identified this problem as a‘‘negative fluoride dental gel products provides recommendation that the package size statement’’ required in the product’s benefit to consumers and poses very of OTC preventive treatment gel labeling, i.e., ‘‘not a toothpaste.’’ The little risk of misuse when the products products be limited to 120 mg total comment concluded by suggesting that are packaged and labeled properly. fluorine because of possible safety the interests of the consuming public Therefore, the agency is including 0.4 concerns. The Panel was concerned and ‘‘small’’ entities are best served by percent stannous fluoride dental gel about the significant differences in the not including 0.4 percent stannous products in this final monograph. amount of fluorine available for fluoride gel in the OTC drug monograph 30. One comment objected to the 120- pharmacological or toxicological action and by continuing its prescription mg package size limitation for fluoride between dentifrices (abrasive- status. treatment gels proposed in § 55.20. The containing) and nonabrasive treatment The agency does not agree with the comment requested that a 7-ounce (oz) gels and rinses. Available fluoride in a comment. The Panel recommended that package size for 0.4 percent stannous dentifrice is dependent upon the certain fluoride dental rinses and gels, fluoride preventive treatment gels chemical reactivity of the fluoride ion which had previously been restricted to (containing 192 mg total fluorine) with the abrasive (45 FR 20675 to prescription use, be made available OTC remain in the marketplace, at least as a 20677), while all of the fluoride ion in provided that they conform to package prescription drug product for use under the nonabrasive preventive treatment size limitations and proper labeling to the supervision and direction of the gel is available. There are potential avoid misuse (45 FR 20666 at 20666, dental profession. The comment noted safety concerns (i.e., ingestion of an 20674, and 20691). (Package size that its decision to market a 7-oz entire package that could cause serious effects, particularly for a small child) limitations are discussed in section I.G., package size of 0.4 percent stannous comment 46.) The Panel reviewed four when the 120-mg total fluorine package fluoride treatment gel was partially published studies on stannous fluoride size limitation for a preventive based on the 7-oz package size of 0.4 dental gels containing 0.4 percent treatment gel is exceeded. This package percent stannous fluoride dentifrice stannous fluoride in an anhydrous size limitation appears in § 355.20 of products marketed at the time its glycerin gel (45 FR 20682) and this final monograph. Although the product was introduced into the concluded that these studies provide package size will vary depending on the marketplace. The comment noted that, sufficient documentation of the safety concentration of the fluoride ingredient in the tentative final monograph (50 FR and effectiveness of this dental gel in the product, the maximum OTC 39854 at 39857), the agency cited the dosage form for OTC use. In the package size of a 0.4-percent stannous position and experience since 1958 of tentative final monograph (50 FR 39854 fluoride preventive treatment gel at 39858), the agency concurred with the ADA concerning package size product is 4.375 oz. The agency has no the Panel’s recommendation that 0.4 limitations for OTC rinses and gels in objection to larger size packages being percent stannous fluoride in an support of the proposal in § 355.20 to available as prescription drug products. anhydrous glycerin gel be switched to limit package sizes for dental rinses and However, if a manufacturer wishes to OTC status and labeled with proper gels. market a 0.4-percent stannous fluoride directions for use (45 FR 20688). The comment mentioned over 10 preventive treatment gel product in a The agency is aware that the change years of safe prescription marketing of larger package size on a prescription of 0.4 percent stannous fluoride dental its 7-oz product with a child-proof basis, the manufacturer must obtain an gels from prescription-to-OTC status safety closure. The comment contended approved NDA under section 505 of the will lead to different marketing that consumer use is different with act (21 U.S.C. 355) and part 314 of the strategies and promotional activities. regard to the safe handling of regulations. However, the agency has determined prescription drug products, as compared The comment provided no data or that such a product can be generally to OTC drug products. The comment information in support of its contention recognized as safe and effective and noted that the agency concluded in the that the general public handles marketed as an OTC product. This OTC tentative final monograph that a toxic prescription drugs differently than OTC status does not prevent a manufacturer dose of fluorine via a dentifrice drug drugs. The agency believes that more from continuing to promote the use of product could not be ingested without potent prescription drug products such products through health-care vomiting, although the agency did not generally are handled differently than professionals, who then would instruct address the effect of glycerin (which is most OTC drugs. However, the agency is their patients to purchase and use the used in the treatment gel) with regard to unaware of any data that suggest that products. vomiting. The comment stated that the consumers handle prescription In response to the comment’s 7-oz package size of this product anticaries gels and treatment rinses objection to the proposed labeling of its represents over 50 percent of its dollar differently than OTC anticaries fluoride product with the statement ‘‘This is not volume and its discontinuance would mouthwashes and rinses. a toothpaste,’’ the agency indicated in represent a hardship. The comment The agency indicated in the tentative the tentative final monograph (50 FR requested reconsideration of the OTC final monograph (50 FR 39857) that the 39869) that a nonabrasive dental gel status of the 7-oz package size for its safety of dentifrice pastes containing up packaged in a conventional tube can be 0.4-percent stannous fluoride treatment to 260 mg fluoride can be attributed to: confused with a conventional abrasive- gel. The comment stated that, at a (1) The decreased amount of fluoride containing dentifrice. There is also a minimum, allowing this product to actually available for absorption because safety concern because dentifrices remain in the marketplace on a of the reactivity of fluoride with the contain an abrasive, while these dental prescription basis would best serve the abrasive in dentifrice pastes; and (2) the gels do not. This safety concern is interests of the dental profession and likelihood that the amount of dentifrice discussed in section I.G., comment 46 of small businesses in the stannous that contains a toxic dose of fluoride 52492 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations could not be ingested without vomiting. comment requested that the agency sodium monofluorophosphate, provides The comment provided no information include this combination product in the a rational combination that has an or data on the effect of glycerin in a final monograph for OTC anticaries drug enhanced therapeutic effect and satisfies dental gel with regard to vomiting in products. the agency’s combination policy in support of its contention that larger The agency agrees that 0.05 percent § 30.10(a)(4)(iv) (21 CFR package sizes be allowed for the gel sodium fluoride and 1.5 percent 330.10(a)(4)(iv)). dosage form. Without data, the agency hydrogen peroxide may be a rational One comment submitted two clinical cannot determine glycerin’s role on combination for concurrent therapy in studies (Refs. 1 and 2) to support the vomiting if large amounts of a dental gel orthodontic patients. However, as the combination of two fluoride ingredients were to be ingested. In conclusion, the agency discussed in the tentative final in a dentifrice. The first study (Ref. 1) agency does not consider the comment’s monograph for OTC oral health care was a 3-year double-blind, randomized arguments supportive of its requests that drug products, the Advisory Review clinical study involving 799 children 14 0.4 percent stannous fluoride gels Panel on OTC Oral Health Care Drug to 15 years old. Two combination remain prescription drugs or that the Products (Oral Cavity Panel) was dentifrices, each containing 0.76 percent 120-mg package size be increased for concerned about the chronic use of sodium monofluorophosphate (1,000 such products marketed on an OTC hydrogen peroxide in products such as ppm theoretical total fluorine) and 0.10 basis. antimicrobial mouthwashes (53 FR 2436 percent sodium fluoride (455 ppm at 2446 and 2447). The agency further theoretical total fluorine) (to provide a E. Comments on Combination theoretical total fluorine level of 1,455 Anticaries Drug Products stated in this discussion that the effects of long-term OTC use of hydrogen ppm) were compared with a fluoride- 31. One comment submitted new data peroxide would be considered as part of free control dentifrice and with a and information to support the safety the antiseptic segment of the oral health positive control 0.76 percent sodium and effectiveness of a combination drug care drug products rulemaking. monofluorophosphate dentifrice (1,000 product containing 0.05 percent sodium After that tentative final monograph ppm theoretical total fluorine). One of fluoride and 1.5 percent hydrogen was published, the agency published a the two experimental combination peroxide. The comment stated that this call-for-data for OTC antiplaque drug fluoride dentifrices had an alumina combination drug product, which was products in the Federal Register of abrasive system. The other had a not considered in the tentative final September 19, 1990 (55 FR 38560). The dicalcium phosphate abrasive system. monograph for OTC anticaries drug data submitted to the agency as a result The combination dentifrices reduced products, is targeted for once-daily use of this call-for-data will be evaluated by the incidence of dental caries by in an orthodontic population. The the Dental Products Panel. That Panel approximately 26 percent compared comment contended that this will consider, among other things, the with the fluoride-free placebo dentifrice, combination of ingredients provides safety of the long-term oral use of and by approximately 15 percent rational, concurrent therapy as an oral hydrogen peroxide solutions. The compared with the positive control 0.76 cleanser and anticaries agent for agency believes that the Dental Products percent sodium monofluorophosphate orthodontic patients for two reasons: (1) Panel is the appropriate forum to dentifrice with an alumina abrasive Orthodontic appliances occasionally consider whether a combination system. cause minor irritation or injury to the product containing 0.05 percent sodium The second study (Ref. 2) was a 3-year oral mucosa and the product cleanses fluoride and 1.5 percent hydrogen clinical trial that involved school these irritations or injuries, and (2) the peroxide can be generally recognized as children who resided in an area with configuration of the orthodontic safe and effective for long-term OTC use nonfluoridated water. Two combination appliance and its duration of use may in the oral cavity. The agency has dentifrices containing sodium cause decalcification of teeth in informed the manufacturer that it monofluorophosphate and sodium orthodontic patients and the product considers the combination product to be fluoride, either 1,450 or 2,000 ppm reduces tooth decalcification. a new drug that may not be introduced theoretical total fluorine, were The comment stated that the safety of or delivered for introduction into compared to a sodium the 0.05-percent sodium fluoride monofluorophosphate dentifrice interstate commerce without an component of the product was containing 1,000 ppm theoretical total approved NDA (Ref. 2). The agency has recognized by FDA in the tentative final fluorine. Results indicated that after 3 deferred this product to the Dental monograph for OTC anticaries drug years of unsupervised brushing, the Products Panel and will address the products (50 FR 39854 at 39872). The children who used either the 1,450- or submitted data as part of the OTC oral comment submitted data (Ref. 1) from 2,000-ppm fluoride dentifrice health care rulemaking applicable to an enamel solubility reduction test and combinations developed fewer cavities antiplaque drug products. an enamel fluoride uptake test to than those who brushed with the 1,000- support the effectiveness of the sodium References ppm sodium monofluorophosphate fluoride in the combination product. dentifrice. No significant difference in The comment also submitted a clinical (1) Comment No. C80, Docket No. 80N– 0042, Dockets Management Branch. caries reduction between the 1,450-ppm study of the combination product to (2) Letter from R. J. Chastonay, FDA, to R. and 2,000-ppm fluoride dentifrices was support the safety of daily exposure of Finn, Chesebrough-Pond’s USA Co., in OTC reported. the oral mucosa to 1.5 percent hydrogen Vol. 08AFM, Docket No. 80N–0042, Dockets Another comment submitted peroxide for an 18-month period (Ref. Management Branch. laboratory and clinical data (Ref. 3) to 1). The comment added that the 32. Two comments requested the support the safety and effectiveness of a effectiveness of up to 3 percent agency to include the combination of dentifrice containing sodium fluoride hydrogen peroxide as an oral cleanser sodium fluoride with sodium (1,000 ppm) and sodium was established in the tentative final monofluorophosphate in a dentifrice in monofluorophosphate (420 ppm). In one monograph for OTC oral health care the final monograph. The comments study, enamel specimens exposed for 24 drug products published in the Federal contended that the combination of two hours to a suspension of sodium Register of January 27, 1988 (53 FR Category I fluoride ingredients, monofluorophosphate alone or in 2436). Based on these data, the particularly sodium fluoride and combination with sodium fluoride had Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52493 greater fluoride uptake with the available in the United States for many The comment maintained that the combination fluorides than with sodium years. The comment stated that this fluoride ion is the effective anticaries monofluorophosphate alone. In another combination occurs as a result of the moiety, and it is irrelevant whether the study, a nearly three-fold reduction in hydrolysis of sodium fluoride ion comes from one fluoride enamel solubility was shown with the monofluorophosphate during contact salt or a combination of two fluoride combination of sodium fluoride and with the tooth surface and during the salts, as long as the fluoride ion is sodium monofluorophosphate aging process of the fluoride dentifrice present in safe and effective quantities. compared to sodium formulation itself. The comment The comment concluded that these data monofluorophosphate alone. The indicated that as the dentifrice ages, demonstrate the safety and effectiveness comment also provided a graph of sodium monofluorophosphate of the combination of sodium fluoride enamel solubility reduction data from undergoes hydrolysis resulting in a and sodium monofluorophosphate in a dentifrices containing sodium fluoride significant increase of sodium fluoride dentifrice product. The comment urged or sodium monofluorophosphate alone within the sodium the agency to include the combination or various combinations of sodium monofluorophosphate formulation. The of sodium fluoride with sodium monofluorophosphate and sodium comment added that in the oral monofluorophosphate in a 3 to 1 ratio fluoride. The comment noted that a environment sodium fluoride may as a dentifrice in the final monograph. combination containing 75 percent represent more than 50 percent of the The agency has reviewed the available sodium fluoride and 25 percent sodium hydrolyzed fluoride species in contact data and concludes that they do not monofluorophosphate would be with the tooth surface as a result of the support the comments’ claims. The data optimal. The comment contended that hydrolysis of sodium do not demonstrate the cariostatic this combination produces twice as monofluorophosphate alone. The superiority of combination dentifrices much reduction in enamel solubility as comment included several studies containing sodium fluoride and sodium either of the ingredients alone at showing that sodium monofluorophosphate compared to comparable fluoride concentrations. monofluorophosphate undergoes rapid conventionally formulated 0.76 percent The comment included an animal hydrolysis in saliva and even more sodium monofluorophosphate study in which male rat pups were rapid hydrolysis in the presence of dentifrices. The data do not show that inoculated with streptococci (strain not plaque microorganisms. In one study the effect of the sodium fluoride/sodium provided) and placed on a standard (Ref. 3), during a short period of monofluorophosphate combination is cariogenic diet for 3 weeks. During this greater than the effect achieved by the period, the teeth were brushed with a toothbrushing, the levels of fluoride ions in saliva were initially much lower individual active ingredients alone at sodium monofluorophosphate/sodium comparable fluoride ion concentrations. fluoride dentifrice combination or a with the sodium monofluorophosphate dentifrice than with the comparable A combination drug product control fluoride dentifrice (active containing Category I active ingredients ingredient and strength not specified). sodium fluoride preparation. However, after 10 minutes in saliva, both from the same therapeutic category must The results of this study indicated that satisfy the criteria in § 330.10(a)(4)(iv). the combination of sodium fluoride and dentifrice formulations provided almost similar levels of fluoride ions. The The ‘‘General Guidelines for OTC Drug sodium monofluorophosphate was Combination Products, September significantly more ‘‘cariostatic’’ than the comment stated that the uncontrolled hydrolysis of the two fluoride agents 1978’’ give clarifying examples single fluoride dentifrice. regarding the combination policy (Ref. The comment also mentioned a 3-year results in an important, but suboptimal, increase in the bioavailability of 4). Paragraph 3 of these guidelines clinical study involving 573 school states: children. This study was designed to fluoride ions. The comment indicated that a combination of fluoride Category I active ingredients from the same determine the anticaries effect of a therapeutic category that have the same dentifrice containing a sodium ingredients may provide greater product mechanism of action should not ordinarily be monofluorophosphate/sodium fluoride stability if the agency allows combined unless there is some advantage combination (1,420 ppm) with a manufacturers the opportunity to over the single ingredients in terms of comparable control toothpaste control the ratio of these two fluoride enhanced effectiveness, safety, patient containing only sodium ingredients in the dentifrice acceptance, or quality of formulation. They monofluorophosphate (1,315 ppm). formulation. According to the comment, may be combined in selected circumstances After 2 and 3 years of unsupervised this would be better than relying on the to treat the same symptoms or conditions if brushing, the number of new decayed, unpredictable chemical process of the combination meets the OTC combination hydrolysis to create a fluoride policy in all respects, the combination offers missing, or filled (DMF) surfaces was 12 some advantage over the active ingredients to 50 percent lower in the combination combination product. The comment used alone, and the combination is, on a fluoride group than in the sodium asserted that its dentifrice product benefit-risk basis, equal to or better than each monofluorophosphate control group. controls the process of hydrolysis by of the active ingredients used alone at its Based on the results of this study, the providing a combination fluoride therapeutic dose. comment concluded that the dentifrice with a fluoride ingredient The agency has not received sufficient combination of sodium fluoride and ratio of 3 to 1 (sodium fluoride to data to conclude that the use of a sodium monofluorophosphate is sodium monofluorophosphate), thereby combination fluoride product has an significantly more effective than sodium enhancing the therapeutic effect of the advantage over or is more effective in monofluorophosphate alone in reducing anticaries product. However, the controlling the incidence of dental the incidence of dental cavities. comment did not indicate how it caries than a product containing a single The comment acknowledged that proposed to control the hydrolysis of fluoride active ingredient at comparable combinations of fluoride active the one-quarter proportion of sodium fluoride ion concentrations. ingredients have not been marketed in monofluorophosphate in its product. In the clinical studies submitted by the United States. The comment stated, This information is particularly the comment, there was no comparison however, that the combination of significant if the hydrolysis of sodium of a combination and single ingredient sodium fluoride and sodium monofluorophosphate occurs as rapidly product at comparable fluoride monofluorophosphate has been widely in the mouth as the comment indicated. concentrations. The agency notes that 52494 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations the higher levels of fluoride hours. The agency questions the Results after Two Years,’’ Caries Research, concentration in the combination relevancy of a 24-hour exposure time 21:149–157, 1987. dentifrices, 1,455 ppm (Ref. 1) and 1,450 when the exposure time to a dentifrice F. Comments on Testing Guidelines or 2,000 ppm (Ref. 2), as compared to formulation in the mouth during actual the fluoride levels in the positive toothbrushing is a few minutes only. In 33. One comment agreed with the control single fluoride ingredient the animal study measuring the effect of agency’s conclusion that laboratory test dentifrice (1,000 ppm), most likely three dentifrices on the incidence of data are not adequate to establish account for the enhanced effectiveness caries in rats, no details were given comparative claims of effectiveness for anticaries active ingredients (53 FR of the combination products. Because of regarding the active ingredients or the 22430 at 22446). However, the comment these higher concentrations, the fluoride concentrations in the contended that the agency should presence of two sources of fluoride ions dentifrices tested. Regarding hydrolysis recognize the possibility that, in certain may be unrelated to the observed during the aging process of sodium cases, claims of superior performance in increase in effectiveness. monofluorophosphate products, the a laboratory test may be desirable. As a The agency has also evaluated two Panel stated that sodium hypothetical example, the comment other clinical studies (Refs. 6 and 7) that monofluorophosphate exists in water in stated that it may be important to a compared comparable fluoride dynamic equilibrium with sodium dental professional that (1) one active concentrations (1,000 ppm) for a single- fluoride, and with the various ions ingredient provides more rapid fluoride ingredient sodium produced by the hydrolysis of the uptake than another and (2) this monofluorophosphate dentifrice and a compound (45 FR 20666 at 20674). The performance could promote hardening combination containing sodium fluoride agency does not consider this reaction of enamel in certain instances. The and sodium monofluorophosphate. In as producing a combination drug comment suggested that such claims these studies, the two dentifrices were product. The agency considers the could be made in professional labeling comparably effective. One study (Ref. 6) sodium monofluorophosphate without needing clinical studies for was a 31-month, double-blind clinical compound as a single active ingredient, support. study involving 1,027 school-aged even though it is aware that the children. The anticaries effectiveness of The agency reiterates its conclusion compound always contains some that the extension of laboratory test data a single fluoride ingredient dentifrice amounts of sodium fluoride. containing sodium to a comparative evaluation of In conclusion, the agency has monofluorophosphate (1,000 ppm effectiveness between different fluoride theoretical total fluorine) was compared determined that the submitted products or fluoride active ingredients with a combination fluoride dentifrice information and data do not is inappropriate (53 FR 22446). In containing sodium fluoride and sodium demonstrate the cariostatic superiority general, the agency does not believe that monofluorophosphate (1,000 ppm of combination dentifrices containing claims of superior performance in a theoretical total fluorine, with 500 ppm sodium fluoride and sodium laboratory test are appropriate for use in contributed by each fluoride ingredient). monofluorophosphate relative to single- either the consumer or professional During this study, the children brushed ingredient fluoride dentifrices with a labeling of OTC anticaries drug products daily in school under supervision and comparable fluoride ion concentration. unless that superior performance has were clinically and radiologically Accordingly, these fluoride been shown to have clinical examined annually. After 31 months of combinations are not included in this significance. However, the agency will use, no statistically significant final monograph. evaluate any such laboratory test data difference in the incidence of dental References submitted on a case-by-case basis. caries was observed between children in 34. One comment (from an agency the two dentifrice groups. (1) Hodge, H. C. et al., ‘‘Caries Prevention dental reviewing officer) objected to the In the second study (Ref. 7), the by Dentifrices Containing a Combination of use of Laboratory Testing Profiles Sodium Monofluorophosphate and Sodium (LTP’s) for final formulation testing for effectiveness of three dentifrices was Fluoride,’’ British Dental Journal, 149:201– compared over a 2-year period. The 204, 1980. Category I active ingredients in fluoride study involved 2,769 children; a nearly (2) Diodati, R. R. et al., ‘‘Clinical Anticaries dentifrice formulations. The comment equal number did unsupervised Effect of Various Fluoride Dentifrices,’’ expressed unawareness of any data brushing at home with one of the Abstract No. 258, Journal of Dental Research, submitted to the agency demonstrating following dentifrices: (1) Sodium 65:198, 1986. that the results from the biological test monofluorophosphate (1,000 ppm), (2) a (3) Comment No. C00059, Docket No.80N– requirements in the LTP’s were combination of sodium fluoride and 0042, Dockets Management Branch. correlated with adequate and well- sodium monofluorophosphate (4) Food and Drug Administration controlled anticaries clinical studies. containing equimolar amounts of each ‘‘General Guidelines for OTC Drug The comment did not submit any data Combination Products, September 1978,’’ active ingredient (theoretical total Docket No. 78D–0322, Dockets Management demonstrating that the LTP’s do not fluorine of 1,000 ppm), or (3) a Branch. correlate with clinical studies. combination of sodium fluoride and (5) Conti, A. J. et al., ‘‘A 3-Year Clinical Two comments (from manufacturers) sodium monofluorophosphate Trial to Compare Efficacy of Dentifrices concurred with the agency’s proposal containing equimolar amounts of each Containing 1.14 Percent and 0.76 Percent that the LTP’s be used to ensure the active ingredient (theoretical total Sodium Monofluorophosphate,’’ Community effectiveness of abrasive-containing fluorine of 2,500 ppm). The results of Dental Oral Epidemiology, 16:135–138, 1988. fluoride drug products. One of the this study indicated no significant (6) Juliano, G. F. et al., ‘‘Clinical Study comments contended that, based on the differences in caries inhibition among Comparing the Anticaries Effect of Two current state of dental research, it is not Fluoride Dentifrices,’’ Abstract No. 131, the dentifrices tested. Journal of Dental Research, 64:189, 1985. necessary to do clinical studies to verify In most of the in vitro studies (7) Ripa, L. W. et al., ‘‘Clinical Comparison anticaries performance except in certain submitted (Ref. 3), exposure times of the of the Caries Inhibition of Two Mixed NaF- situations, such as the introduction of a tooth enamel surface to suspensions of Na2PO3F Dentifrices Containing 1,000 and new anticaries active ingredient. dentifrice were for lengthy periods of 2,500 ppm F Compared to a Conventional Regarding the comment questioning time ranging from 30 minutes to 24 Na2PO3F Dentifrice Containing 1,000 ppm F: whether the LTP’s were correlated with Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52495 adequate and well-controlled clinical pursuant to the monograph is that the Stannous Ion,’’ by inserting a statement testing, the agency notes that the Panel product must meet the final formulation indicating that the test dilution for the based its recommendations on the test requirements (LTP’s) included in silica abrasive should remain 1:10 as results of actual biological tests § 355.70. stated in the tentative final monograph performed on fluoride dentifrices that 36. One comment stated that all (45 FR 20666 at 20681). The second had been shown to be clinically toothpaste advertised as containing comment indicated that the appropriate effective in preventing caries (45 FR fluoride should be tested for stannous values for soluble fluoride should 20666 at 20677). Thus, the Panel’s fluoride concentration, per unit volume discriminate between dentifrices using recommendations were based on the or weight. The comment contended that insoluble sodium metaphosphate and correlation of laboratory testing results this is necessary to ensure that the silica abrasives. The comment indicated concentration of stannous fluoride is not with clinical results. that in Table 3 for stannous fluoride The agency considers the LTP final being reduced. dentifrices (45 FR 20681) under ‘‘I. formulation test requirements in this There are a number of requirements final monograph to be adequate to applicable to fluoride dentifrices that Soluble Fluoride Ion,’’ the test values ensure the safety and effectiveness of will ensure the fluoride concentration of for fluoride ion listed for the silica dentifrices containing fluoride active the product. While toothpastes can abrasive formulation should be 600 ppm ingredients included in the monograph. contain one of several different fluoride for the fresh value and 500 ppm for the In the tentative final monograph (53 FR ingredients, the LTP’s included in the aged minimal value with a test dilution 22430 at 22433), the agency stated final monograph are intended to ensure of 1:10, rather than 700 ppm for the reasons why it concurred with the available fluoride ion in the final fresh value and 650 ppm for the aged Panel’s recommended laboratory testing products. The aged minimal fluoride ion minimal value. The comment stated that requirements, as set forth in the Panel’s values in the LTP tables are used to this revision would discriminate LTP tables (45 FR 20666 at 20679 to determine the product’s expiration date. between dentifrices using insoluble 20681) for Category I fluoride This date provides consumers relevant sodium metaphosphate and those using ingredient/abrasive combinations. Thus, information regarding use of the silica abrasives. the agency concludes that lengthy product. In addition, § 211.166 of the The agency recognizes that the data clinical trials are not necessary to agency’s current good manufacturing the Panel used to establish the LTP ensure the safety and effectiveness of practice regulations (21 CFR 211.166) tables were developed by industry and dentifrices containing monograph contains stability testing requirements submitted to the Panel to provide a basis for drug products, including fluoride ingredients. for the LTP tables. The agency has 35. One company asked whether the toothpastes. Accordingly, these reviewed the industry’s corrections of monograph would preclude FDA’s requirements address the comment’s the LTP tables as noted above and accepting valid clinical trials in lieu of concern. LTP’s. The comment noted the agency’s 37. Two comments requested that the agrees that these corrections should be statement in the tentative final agency revise LTP Table 3 to include made. However, the agency does not monograph that the use of LTP’s to corrected test values submitted by the find it necessary to insert an additional establish efficacy should not in any way industry for stannous fluoride clarification statement in the corrected preclude the option of clinical testing as dentifrices (45 FR 20666 at 20681). One LTP tables as requested by one a final demonstration of efficacy for comment noted that the agency’s comment. Instead, the agency has those companies that prefer to use this revisions in the LTP tables discussed in revised the LTP tables to reflect the method (53 FR 22430 at 22434). the tentative final monograph (53 FR changes made to the tables in the The monograph does not preclude 22430 at 22435 and 22436) omitted a tentative final monograph (53 FR 22435 manufacturers from performing clinical correction mentioned in an earlier and 22436) and in this final monograph testing to ensure the effectiveness of a comment concerning stannous fluoride (see section I.B., comments 10, 13, 14, fluoride dentifrice. However, the that was made to this rulemaking. The and 15 of this document, and section regulatory requirement for all fluoride comment requested that the agency I.F., comments 38, 39, and 42 of this dentifrice drug products marketed revise Table 3 under ‘‘II. Soluble document) as follows:

TABLE 1.ÐACCEPTABLE TEST VALUES FOR 1,000 PPM THEORETICAL TOTAL FLUORINE SODIUM FLUORIDE DENTIFRICES IN A PASTE DOSAGE FORM I. Soluble Fluoride Ion (F±)

Abrasive Fresh F± value1 Aged minimal F± value 1,2 Test dilution (w/w)

High-beta-phase calcium pyrophosphate 648 ppm 403 ppm 1:3

II. Hydrogen Ion Concentration (pH)

Abrasive Test value Test dilution (w/w)

High-beta-phase calcium pyrophosphate 6.5 to 8.0 1:3 1 Values listed are parts of the measured substance per million parts of the whole dentifrice. 2 Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective. 52496 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

TABLE 2.ÐACCEPTABLE TEST VALUES FOR 1,000 PPM THEORETICAL TOTAL FLUORINE SODIUM MONOFLUOROPHOSPHATE DENTIFRICES IN A PASTE DOSAGE FORM = ± 1 I.Soluble Fluoride Ions (PO3F and F )

Aged minimal Abrasive Ion Fresh value2 Test dilution (w/w) value2,3

= 4 Applicable to all abrasives PO3F 650 ppm Half total 1:10 = (PO3F and F±) value F± 10 to 150 ppm 10 ppm to 1:10 = PO3F value = Total (PO3F 800 ppm 600 ppm 1:10 and F±)

II.Hydrogen Ion Concentration (pH)

Abrasive Test value Test dilution (w/w)

Alumina 6.4 to 9.0 1:10 Calcium carbonate 7.0 to 10.0 1:10 Calcium pyrophosphate 5.0 to 5.4 1:10 Dicalcium phosphate 6.3 to 7.6 1:10 Insoluble sodium metaphosphate 5.6 to 6.9 1:10 Silica 5.5 to 7.4 1:10

1 = ± For the compound sodium monofluorophosphate in a dentifrice formulation, fluoride ion exists as a combination of the ions PO3F and F . = ± Values are given for each of these ions as well as the ``Total'': combination of PO3F plus F . 2 Values listed are parts of the measured substance per million parts of the whole dentifrice. 3 Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective. 4 ± Soluble PO3 is derived either by direct analytical measurement or by subtracting soluble fluoride ion (F ) from total soluble available fluoride = ± (PO3F plus F ).

TABLE 3.ÐACCEPTABLE TEST VALUES FOR 1,000 PPM THEORETICAL TOTAL FLUORINE STANNOUS FLUORIDE DENTIFRICES IN A PASTE DOSAGE FORM I. Soluble Fluoride Ion (F±)

Aged minimal F± Abrasive Fresh F± value1 Test dilution (w/w) value1,2

Insoluble sodium metaphosphate 700 ppm 650 ppm 1:3 Silica 600 ppm 500 ppm 1:10 Calcium pyrophosphate 288 ppm 108 ppm3 1:3

II. Soluble Stannous Ion (Sn∂∂)

Aged minimal Abrasive Fresh Sn∂∂ value1 Test dilution (w/w) Sn∂∂ value1,2

Insoluble sodium metaphosphate 2,000 ppm Qualitatively de- 1:10 tectable Silica Qualitatively detectable Qualitatively de- 1:10 tectable Calcium pyrophosphate 900 ppm Qualitatively de- 1:3 tectable

III. Hydrogen Ion Concentration (pH)

Abrasive Test value Test dilution (w/w)

Insoluble sodium metaphosphate 4.2 to 5.4 1:4 Silica 4.6 to 5.1 1:4 Calcium pyrophosphate 4.4 to 5.1 1:3 1 Values listed are parts of the measured substance per million parts of the whole dentifrice. 2 Values listed are intended for use in determining expiration dating for fluoride dentifrices covered by the final monograph. These values are not intended to be used to determine if a dentifrice meets monograph requirements, i.e., is safe and effective. 3 Value corresponds to that of aged product found clinically effective.

TABLE 4.ÐACCEPTABLE TEST VALUES FOR ALL OTC FLUORIDE DENTIFRICES IN A PASTE DOSAGE FORM

I. Theoretical Total Fluorine1 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52497

TABLE 4.ÐACCEPTABLE TEST VALUES FOR ALL OTC FLUORIDE DENTIFRICES IN A PASTE DOSAGE FORMÐContinued

A. 850 to 1,150 ppm for all active ingredients B. 1,500 ppm for sodium monofluorophosphate

II. Available Fluoride Ion Concentration1

Active Ingredient Minimum Available Fluoride Ion1 A. For 850 to 1,150 ppm Dentifrices: Sodium fluoride ≥ 650 ppm = ± Sodium monofluorophosphate ≥ 800 ppm (consisting of PO3F and F combined) Stannous fluoride/calcium ≥ 290 ppm pyrophosphate Stannous fluoride/with abrasive other ≥ 700 ppm than calcium pyrophosphate B. For 1,500 ppm Dentifrices: = ± Sodium Monofluorophosphate ≥ 1,275 ppm (consisting of PO3F and F combined)

III. Total Fluorine in Milligram Per Milliliter Dentifrice

A. For 850 to 1,150 ppm Dentifrices: 0.935 to 1.955 B. For 1,500 ppm Sodium Monofluorophosphate Dentifrices: 1.650 to 2.550 1 Values listed are parts of the measured substance per million parts of the whole dentifrice.

TABLE 5.ÐACCEPTABLE TEST VALUES FOR SODIUM FLUORIDE/SODIUM BICARBONATE POWDERED DENTIFRICES CONTAINING 1,000 PPM THEORETICAL TOTAL FLUORINE

I. Theoretical Total Fluorine1 850 to 1,150 ppm II. Minimum Available Fluoride Ion1 850 ppm III. Poured-bulk Density Range in Gram Per Milliliter Dentifrice 1.0 to 1.2 1 Values listed are parts of the measured substance per million parts of the whole dentifrice.

TABLE 6ÐBIOLOGICAL TESTING REQUIREMENTS FOR ALL DENTIFRICES IN PASTE AND POWDER DOSAGE FORMS

I. Animal Caries Reduction and, II. One of the Following Tests: A. Enamel Solubility Reduction B. Fluoride Enamel Uptake

38. One comment concurred with the in drug manufacturing, but the CGMP pH, specific gravity, stannous ion agency’s statement (53 FR 22430 at regulations do not provide test methods concentration, or maximum test 22435) that measurements such as or acceptable values of measurement. dilutions from the provisions of the specific gravity, pH, stannous ion The comment provided the following monograph means that manufacturers content, maximum test dilution, and example: If control of pH is important may set these specifications as they see lower limit of available fluoride at the in manufacturing a dentifrice, the CGMP fit. expiration date should not be included regulations provide that it is necessary However, the comment added that in the final monograph. The comment to institute and document procedures there are other statements in the agreed that these measurements are for ensuring accurate recording, control agency’s discussion of LTP’s that cast adequately addressed in the current of pH during the process, and doubt on the above interpretation. As an good manufacturing practices (CGMP) acceptable checking of equipment. example, the comment cited the phrase regulations. The comment stated that However, the comment stated that the ‘‘the allowable range for specific gravity the CGMP regulations in part 211 (21 regulations do not specify equipment, (1.1 to 1.7) and theoretical total fluoride CFR part 211) provide for acceptable measurements, or the proper pH range. (850 to 1,150 ppm) * * *’’ (53 FR 22430 outcomes of the performing, validating, The comment contended that one could at 22437). The comment noted that, recording, and reporting of procedures reasonably conclude that omission of even though these ranges are given 52498 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations equal force in this discussion, final monograph are considered The agency also acknowledges that theoretical total fluoride is specified in essential by the agency and must be changes in specific gravity result in a proposed § 355, while specific gravity is met. In the preamble to the tentative corresponding change in the amount of not. The comment also mentioned the final monograph (53 FR 22435 and fluoride contained in a given volume of Panel’s recommendations regarding 22436), the agency revised the Panel’s dentifrice if the concentration of the specific pH guidelines (53 FR 22443) recommended testing guidelines for a fluoride is expressed as a weight-to- and the agency’s statement that ‘‘* * * number of testing parameters. The weight measurement, such as ppm. manufacturers should use the aged agency intended that these testing The agency also indicated that a minimal fluoride ion limits provided in values be used solely as guidance for fluoride range of 0.935 to 1.955 mg per the LTP Tables * * * to determine the fulfilling CGMP requirements. mL of dentifrice might be appropriate. expiration dates for fluoride dentifrices In this document, the agency has These weight-to-volume measurements * * *’’ (53 FR 22445). The comment further revised the proposed testing correspond directly to allowable ranges added that the third agency change in guidelines for parameters other than for specific gravity (1.1 to 1.7) and the Panel’s recommendations states that available fluoride ion and biological test theoretical total fluorine (850 to 1,150 the agency is proposing the LTP values requirements (see section I.F., ppm). The agency presented the of pH and specific gravity (but not comments 35 and 39 of this document). following guidelines for dentifrices: The stannous ion levels, maximum test These revised parameters are also lower limits of 850 ppm theoretical total dilutions, or aged minimal fluoride intended only as guidance, e.g., for use fluorine and a specific gravity of 1.1 levels) as guidelines of appropriate in determining expiration dating. The convert to a lower limit of 0.935 mg testing limits. The comment requested agency is including a revised LTP chart fluorine per mL toothpaste. The upper that the agency clarify its position on in the preamble of this document for limits of 1,150 ppm theoretical total these matters. informational purposes (see section I.F., fluorine and a specific gravity of 1.7 The agency’s proposal (53 FR 22430 at comment 37 of this document). convert to an upper limit of 1.955 mg 22434 and 22435) states that fluoride 39. One comment stated its approval fluorine per mL toothpaste. This dentifrices shall: (1) Meet or exceed the of the agency’s proposed modification of provides a range of 0.935 to 1.955 mg soluble fluoride ion level specified for the Panel’s recommended ranges for fluorine per mL toothpaste. This range each particular fluoride ingredient listed theoretical total fluorine. The proposal ensures that fluoride dentifrices with in the monograph, and (2) meet the set out a range of 0.935 to 1.955 mg different specific gravities, due to requirements for biological testing. The theoretical total fluorine per mL for changes in the abrasive system, will agency included these criteria in the dentifrices with a specific gravity lower contain the same range of total fluoride proposed monograph. Furthermore, the than 1.1 or higher than 1.7 (53 FR 22430 per volume of dentifrice as specified in agency is including requirements at 22438). The comment indicated that the LTP tables. This fluoride range also pertaining to available fluoride content the proposed modification reflects the will provide flexibility to accommodate and biological testing in this final dynamic nature of dental research and the development of new abrasive monograph. (See section I.F., comment provides innovation without systems. 40 of this document.) These compromising the required amount of The agency indicated in an earlier requirements must be satisfied for an fluoride ion available to the teeth with comment (see section I.B., comment 10 anticaries dentifrice to be considered each brushing. The comment added that of this document) that it is including generally recognized as safe and this single required range of theoretical extra-strength sodium effective. total fluorine values more accurately monofluorophosphate dentifrices (1,500 The agency stated in the tentative defines the amount of fluoride ions ppm) in this final monograph as final monograph (53 FR 22430 at 22435) available to the teeth during each generally recognized as safe and that certain recommended requirements brushing. For that reason, the proposed effective dentifrice products. Therefore, in the LTP tables are adequately range is more descriptive of products the agency is also providing a range of addressed in the CGMP regulations (21 that have been proven clinically 1.65 to 2.55 mg per mL of dentifrice for CFR part 211) and need not be effective. The comment suggested that a higher strength dentifrices (1,500 ppm). specifically addressed in the single theoretical total fluorine range This range corresponds directly to the monograph. These included parameters would be better than the two previous allowable ranges for specific gravity (1.1 such as specific gravity and pH, which proposed ranges of specific gravity and to 1.7). relate to inactive ingredients and theoretical total fluorine. The comment The agency concludes that fluoride appropriate manufacturing procedures. contended that a single range would ranges of 0.935 to 1.955 mg (for all 850 The CGMP regulations require ensure consumers that the active to 1,150 ppm dentifrices) and 1.6 to 2.55 establishing and following test methods ingredient in dentifrice products mg (for 1,500 ppm sodium and specifications that are appropriate delivers the required concentration of monofluorophosphate dentifrices) and scientifically sound. These required fluoride ion, thus providing the desired theoretical total fluorine per mL methods and specifications may be anticaries effect. toothpaste are appropriate for these found in a variety of sources (e.g., the In the tentative final monograph for Category I fluoride dentifrice United States Pharmacopeia/National OTC anticaries drug products (53 FR formulations, irrespective of their Formulary or codified monographs). 22430 at 22437), the agency proposed a specific gravity. The agency is including The discussion about testing range of 850 to 1,150 ppm for theoretical these ranges in the revised LTP tables. parameters not specifically included in total fluorine and a specific gravity (See also section I.F., comment 37 of the monograph (such as pH, specific range of 1.1 to 1.7. This range of values this document.) gravity (w/v), stannous ion was intended to accommodate the 40. Several comments addressed the concentration, aged minimal fluoride newer, less dense abrasive systems use of LTP’s, rather than clinical trials, ion values, and test dilution) was without compromising the effectiveness to predict the anticaries effectiveness of intended as guidance only. While these of fluoride dentifrices. The agency monograph fluoride dentifrices parameters are important to the indicated that these ranges are intended formulated with ‘‘new’’ abrasive manufacturer’s product, only those for formulation purposes and not as a systems or with anticalculus agents. requirements specifically set out in the variation for quality control purposes. One comment (from a professional Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52499 dental association) objected to the decalcification process associated with adequate to ensure the effectiveness of agency’s proposal in the tentative final caries. The comment submitted three dentifrices containing monograph monograph (53 FR 22430 at 22442) to clinical studies (Refs. 1, 2, and 3) to fluoride ingredients. The agency allow LTP’s for this testing. The demonstrate that the inclusion of indicated that the Panel based its comment contended that all fluoride- anticalculus agents in fluoride- development of LTP’s on laboratory containing dentifrice products should containing dentifrices does not interfere testing results from studies on fluoride either be clinically tested or should be with the anticaries effectiveness of these dentifrice formulations that had actually equivalent to clinically tested products. products. The comment noted that three been clinically tested and found The comment stated that the agency’s clinically proven anticalculus agents effective. The agency agreed with the proposed LTP’s would permit marketing (pyrophosphate salts, zinc chloride, and Panel’s view that a monograph fluoride of any dentifrice product containing an zinc citrate) are currently marketed in ingredient/abrasive system in a established fluoride agent regardless of dentifrices in the United States. dentifrice formulation not specifically whether or not the abrasive system had According to the comment, these agents reviewed by the Panel, must contain an been clinically tested. The comment have been shown not to adversely affect amount of available fluoride ion equal argued that, because of the very limited fluoride activity in three biological tests to or greater than the highest available nature of the monograph LTP’s, there is that were included in the tentative final fluoride ion value recommended for the no assurance of the availability of monograph (53 FR 22430 at 22447). The specific fluoride ingredient. This fluoride ions during the time of comment objected to the dental requirement applies to fluoride brushing. The comment added that association’s position concerning the dentifrices that contain a monograph abrasives can play a very critical role in validity of using LTP’s to predict the fluoride ingredient and either (1) a new the rate of release/availability of the anticaries effectiveness of fluoride abrasive ingredient (not previously active ingredient. Furthermore, the dentifrices with an anticalculus agent, included in marketed dentifrices) or (2) comment stated that the LTP’s proposed contending that the dental association’s an abrasive ingredient included in in the tentative final monograph assess concern is not warranted by existing previously marketed dentifrices in a the steady state level of release of the scientific data. The comment indicated combination not specifically reviewed active species. This value, according to that it would be a waste of scarce by the Panel (53 FR 22430 at 22441). the comment, has no meaning in resources and funds to require further The agency proposed that fluoride examining the potential efficacy of clinical testing when laboratory tests dentifrices must meet or exceed the fluoride dentifrice products. The can accurately determine whether or not soluble fluoride ion level specified for comment maintained that only anticalculus agents interfere with each particular fluoride ingredient listed clinically tested fluoride/abrasive fluoride efficacy. The comment in the monograph and meet the test systems should be eligible for review requested that the agency continue to requirements of any two of the under the OTC drug monograph system. require only LTP’s as set forth in the following biological tests: (1) Enamel The comment added that any fluoride tentative final monograph (53 FR 22430 solubility reduction (ESR), (2) fluoride dentifrice with an untested abrasive at 22434). uptake by enamel, and/or (3) animal system should be required to supply The agency recognizes that inactive caries reduction (53 FR 22430 at 22434). clinical data demonstrating ingredients, such as abrasives and effectiveness. The comment stated that anticalculus agents, can play an The agency does not agree that one of its association had established testing important role in the rate of release/ the clinical studies (Ref. 1) submitted by guidelines designed to demonstrate availability of fluoride from a fluoride one comment adequately demonstrates equivalency of fluoride agents provided compound during the time period of whether or not an anticalculus additive that the formulations have a fluoride/ toothbrushing. Although the analytical affects the anticaries effectiveness of a abrasive system similar to a clinically tests do not directly measure the dentifrice. The study did not include a effective product. availability of fluoride ions during the positive control (Category I) fluoride The comment also contended that time of toothbrushing, the biological toothpaste in the experimental design. fluoride dentifrices containing agents tests indicate that the fluoride ion is Instead, a fluoride/anticalculus that inhibit calculus formation, thus active in preventing dental caries. In dentifrice was compared to a negative influencing the calcification/ addition, one of the biological tests, the control toothpaste (not containing either decalcification process associated with animal caries reduction, directly fluoride or anticalculus agent). caries, should be required to submit a measures the anticaries effectiveness of However, the two other studies (Refs. 2 more extensive LTP than the agency had a fluoride dentifrice product in an and 3) submitted by the comment proposed in the tentative final animal model in vivo after a limited clearly indicate that the anticaries monograph (53 FR 22430 to 22448). The brushing time. The severity of caries in effectiveness of the dentifrice comment recommended that either each group is computed, and a favorable formulations tested was not adversely animal caries or remineralization result for the test sample indicates that affected by the anticalculus agents used studies be required for these products. the fluoride ion has activity. The test in the studies. In one study (Ref. 2), The comment stated that such studies sample is compared with a U.S.P. three dentifrices containing 1,000, would evaluate the potential fluoride dentifrice reference standard 1,500, or 2,500 ppm fluoride (as sodium inactivation of the fluoride agent by a that has been proven effective in clinical monofluorophosphate) and an secondary nontherapeutic additive. studies. anticalculus agent (0.5 percent zinc A comment from a manufacturers’ In the tentative final monograph (53 citrate trihydrate) were compared with association objected to the first FR 22430 at 22433 and 22440, dentifrices that contained the same comment’s position, contending that no comments 4 and 11), the agency fluoride concentrations but no data or other information were discussed why lengthy clinical trials are anticalculus agent. At the conclusion of submitted to rebut the agency’s LTP no longer warranted. The comments did the 3-year study, no clinically proposal. The comment also disagreed not provide any new data or information significant difference was observed with the dental association’s contention to alter that conclusion. The agency between the fluoride dentifrices with or that calculus inhibiting agents can determined that appropriate laboratory without the anticalculus agent. influence the calcification/ testing, including biological testing, is However, a dose-response effect was 52500 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations observed at varying fluoride monofluorophosphate dentifrices Although the agency encourages the concentrations. In the other clinical provided high levels of available active development of additional testing study (Ref. 3), three dentifrices fluoride ions but produced only small procedures, such as remineralization containing 1,000 or 1,100 ppm of reductions in enamel solubility. Thus, tests, the agency considers the three fluoride (as sodium fluoride and sodium this study indicated that the animal biological tests recommended by the monofluorophosphate) and different caries reduction studies gave the most Panel as sufficient at this time to anticalculus ingredients (3.3 percent complete assessment of effectiveness of demonstrate anticaries effectiveness. soluble pyrophosphate, 2 percent zinc the dentifrices tested compared with the Demineralization/remineralization chloride, and 1.25 percent unspecified test results from the two in vitro tests studies in humans may also be zinc compound) were evaluated. The (ESR and enamel uptake of fluoride). predictive of anticaries effectiveness. three dentifrices produced anticaries Therefore, the agency concludes that However, the agency has not received protection similar to a control sodium both animal and human studies provide sufficient data to correlate specifically monofluorophosphate toothpaste a more complete assessments of the results of remineralization tests with containing 1,000 ppm fluoride, but anticaries effectiveness. clinical studies that demonstrate without an anticalculus ingredient. The agency has thoroughly reviewed anticaries effectiveness of fluoride These two clinical studies corroborate the comments, the clinical studies dentifrices. The agency would consider that these anticalculus agents do not involving anticalculus agents added to such tests as an option to animal caries interfere with the anticaries dentifrice products containing reduction tests if adequate data were effectiveness of the fluoride active monograph fluoride ingredients, and submitted to the agency in the form of ingredients sodium fluoride and sodium data comparing the results of in vitro a petition to amend the monograph. monofluorophosphate. biological tests with in vivo animal The agency is concerned that newer caries tests. Based on this evaluation, References abrasives and anticalculus agents may the agency concludes that biological (1) Lu, K. H. et al., ‘‘The Effect of a reduce the availability of fluoride ions, testing is necessary for all clinically Fluoride Dentifrice Containing an and that this reduction may not be untested dentifrice products to ensure Anticalculus Agent on Dental Caries in detected by the chemical tests suggested fluoride ion availability. Therefore, the Children,’’ Journal Of Dentistry For Children, 52(6):449–451, 1985. in the LTP’s. These chemical tests may agency is revising the biological testing (2) Stephen, K. W. et al., ‘‘A 3-Year Oral not always reflect the true anticaries requirements in this final monograph to Health Dose-Response Study of Sodium effectiveness of fluoride dentifrices with require that all OTC anticaries dentifrice Monofluorophosphate Dentifrices with and or without additives in situ when drug product formulations not without Zinc Citrate: Anti-Caries Results,’’ diluted in the mouth by saliva or specifically reviewed by the Panel be Community Dentistry and Oral exposed to the subtle reactions between tested in an animal caries reduction test. Epidemiology, 16:321–325, 1988. dentifrice ingredients and salivary This type of biological test will be (3) Triol, C. W. et al., ‘‘A Clinical Study of components. Although these in vitro required rather than optional, as the Anticaries Efficacy of Three Fluoride Dentifrices Containing Anticalculus tests may show positive results that are proposed in the tentative final Ingredients: One and Two Year Results,’’ The predictive of anticaries activity, during monograph (53 FR 22430 at 22434). Journal of Clinical Dentistry, 1(2):48–50, actual use in the mouth the product may Based upon a review of all the available 1988. not provide the same expected level of data, the agency still concludes that (4) Pader, M. et al., ‘‘The Evaluation of anticaries effectiveness. The limitations long-term clinical trials are not needed Fluoride Dentifrices,’’ Journal of the Society of in vitro tests are particularly for different or new dentifrice products of Cosmetic Chemistry, 28:681–694, 1977. significant in evaluating fluoride containing a monograph fluoride 41. One comment stated that it is toothpastes that contain additives that ingredient/abrasive system, including unclear what the reference standards may affect fluoride ion availability untested abrasive systems or new will be for the required analytical and under in situ conditions. For that additives. The agency considers fluoride biological testing of fluoride dentifrices. reason, the agency considers them to be availability as well as ESR and fluoride The comment contended that it is only markers of potential effectiveness, uptake studies to be good predictors of difficult to comment on the whole not actual proof. potential effectiveness of a fluoride program without knowing what the During one study (Ref. 4), several toothpaste. However, the in vivo animal standards are. The comment suggested laboratory tests (including ESR, enamel caries reduction test provides further that an additional period of time be uptake of fluoride, and animal caries assurance that the dentifrice is active permitted to allow interested groups to reduction tests) were investigated as against dental caries. The biological comment on the acceptability of the indicators of the compatibility of an portion of the recommended testing actual United States Pharmacopeia abrasive system and a fluoride source. provides an important assurance that, in (U.S.P.) reference standards when they Dentifrices containing 1,000 ppm of addition to being chemically available are established. fluoride (as sodium fluoride, stannous as demonstrated by the analytical In the tentative final monograph, the fluoride, or sodium portion of the testing recommendations, agency stated that it was coordinating monofluorophosphate) were formulated the fluoride is also bioavailable in that establishment of the fluoride dentifrice with abrasives known either to interact it will alter tooth structure in the reference standard formulations with or not interact with particular fluorides. biological tests to make the tooth the United States Pharmacopeial The in vitro tests measured fluoride resistant to caries. Convention (U.S.P.C.) (53 FR 22430 at uptake for a considerably longer time Accordingly, the agency is revising 22439). Since then, industry has worked period than would be experienced the first sentence in § 355.70 of the with the U.S.P.C. to establish reference during actual intermittent use. The testing procedures for fluoride dentifrice standards, through the joint authors claimed that the in vitro tests drug products to read: ‘‘A fluoride Nonprescription Drug Manufacturers provide valuable information. They also dentifrice drug product shall meet the Association and Cosmetic, Toiletry and stated that the results of the ESR test did biological test requirements for animal Fragrance Association task force. not correlate well with the animal caries caries reduction and one of the Information about the reference assay results. Furthermore, the authors following tests: Enamel solubility standards was made public in U.S.P.’s noted that the sodium reduction or fluoride enamel uptake.’’ Pharmacopeial Forum in 1990 (Ref. 1), Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52501 and interested parties had an to test methods as long as the changes the alternative testing procedure opportunity to comment at that time. are scientifically validated and produce provides results that are equivalent to Reference standards have been available accurate and reliable results. the currently required biological test from U.S.P.C. since 1990. The agency does not agree that the methods. Based on the public availability and specific biological testing procedures for 43. Two comments objected to use of these U.S.P. fluoride dentifrice fluoride dentifrices should be fluoride dentifrice reference standards reference standards by the industry considered as test guidelines only. The being provided through the U.S.P.C. The since 1990, the agency concludes that it agency indicated in the tentative final comments suggested that exact is not necessary to provide an additional monograph (53 FR 22430 at 22443) that specifications for these reference comment period. the availability of the fluoride ion in a standards (including levels of dentifrice formulation and meeting the ingredients, source of raw materials, Reference biological testing requirements are the product specifications, and detailed (1) The United States Pharmacopeial most important testing criteria for production directions) be provided as Convention, Inc., ‘‘Headquarters Column,’’ predicting the effectiveness of a fluoride part of the U.S.P. monograph system so Pharmacopeial Forum, 16:3–4, 1990. dentifrice product. The agency that manufacturers could prepare their 42. Two comments requested that the considers demonstration of the own fresh reference standards when agency refrain from mandating specific bioavailability of the fluoride ion in the needed. One comment contended that, biological test procedures in the final biological tests listed in § 355.70 as given sufficient detailed specifications, monograph for OTC anticaries drug necessary to ensure the anticaries manufacturers would certainly be as products. Instead, the two comments effectiveness of fluoride dentifrices. The qualified to produce properly prepared requested that the biological test agency points out that the required standards as the U.S.P.C. procedures proposed in § 355.70 be biological tests are based on the results Following publication of the tentative considered as guidelines only. The of actual biological testing procedures final monograph, FDA and industry comments agreed with the agency that performed on fluoride dentifrices that developed procedures for introduction the substitution of a new test, such as had been shown to be clinically of new or modified commercial remineralization, for one of the three effective in preventing caries. These dentifrice formulations without full qualifying biological tests should testing procedures are a regulatory clinical testing, provided that require a petition for FDA approval. standard that supports general bioavailability/bioequivalence of the However, the comments strongly recognition of the safety and formulation was demonstrated against disagreed with the need for a petition effectiveness of fluoride dentifrices. an appropriate reference standard (Ref. for minor modifications in the biological The agency has had a similar petition 1). Six U.S.P. fluoride dentifrice testing protocols when the results are at procedure for many years for reference standards were initially least as valid, reliable, and accurate as modifications to the in vitro test for established for use in the biological the current test procedures. One OTC antacid drug products (see 21 CFR testing of fluoride dentifrices: (1) comment added that, without this 331.29). The agency has processed these Sodium fluoride-calcium flexibility, the acceptance by the agency petitions in a timely manner. pyrophosphate (high beta-phase), (2) of even minor changes may take an Accordingly, the agency is including the sodium fluoride-silica, (3) sodium inordinate period of time without biological testing procedures in § 355.70 monofluorophosphate-calcium helping to protect the dentifrice user as required tests for any fluoride carbonate, (4) sodium from an ineffective product. The dentifrice drug product marketed monofluorophosphate-dicalcium comment suggested that if the agency pursuant to this monograph. phosphate, (5) sodium continues to maintain control over The agency finds no basis to agree monofluorophosphate-silica, (6) changes in test procedures, approval of with the comment’s suggestion that stannous fluoride-silica (Ref. 2). These the changes should be timely and a list requiring these specific biological reference standards are prepared by of criteria should be provided so that testing procedures interferes with the manufacturers of dentifrice drug manufacturers can be assured that advancement of science and technology. products and provided to the U.S.P.C. changes will be accepted by the agency. The agency does not intend for the for distribution. Thus, the agency agrees The second comment indicated that testing procedures to preclude the with one comment that manufacturers mandating specific test protocols tends application of new, advanced are qualified to produce these reference to discourage scientific experimentation technology in testing fluoride standards. Based on the development of and the application of advanced dentifrices. The agency agrees with the these reference standards by technology in method development. The two comments that as technology manufacturers of OTC dentifrice drug comment noted that advances in continues to evolve, modifications to products, neither the agency nor the technology alone will result in changes the existing testing procedures may U.S.P.C. sees a need to include exact in test protocols and the precision, result in more sensitive, reliable, and specifications for these reference sensitivity, and accuracy of various accurate measurements. However, there standards in the U.S.P. monograph measurements. Therefore, the comment should be a consensus in the scientific system. Furthermore, the U.S.P. requested that the agency designate the community that these new procedures monograph system does not include biological testing procedures as are generally accepted. The agency exact specifications for other reference guidelines only and explicitly indicate encourages the development of new standards the U.S.P.C. provides. that other valid, reproducible methods testing technology and methods for The agency had a meeting with are acceptable. The comment indicated fluoride dentifrices and has provided in U.S.P.C. and industry representatives on that requiring a petition to modify and the monograph the opportunity for May 20, 1993 (Ref. 3), to discuss the improve a procedure would not only be interested persons to propose existing U.S.P. program for dentifrice time consuming, but also would be modifications or alternative testing reference standards and to determine if expensive and thus not in the interest of procedures through the petition process any changes were needed once the final consumers. The comment concluded in 21 CFR 10.30. Any petition should monograph for OTC anticaries drug that companies should have the contain sufficient data to support the products is issued. Additional opportunity to make minor modification modification and to demonstrate that procedures to assure continued 52502 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations availability of these dentifrice reference and sodium fluoride/sodium chosen reference standard must be the standards from the U.S.P.C. were bicarbonate combinations, all of which same as the fluoride ingredient in the developed. The U.S.P.C.’s current have been proven effective in clinical dentifrice formulation being tested; supply of dentifrice reference standards trials. According to one comment, however, it is not necessary that the were subsequently tested to monitor providing all of these standards would abrasive be the same as the abrasive stability (Refs. 4 through 7). ensure the exclusion of ineffective contained in the reference standard. The Manufacturers of each reference combinations without unfairly agency is aware that several standard have committed to retest excluding dentifrices that are effective manufacturers use the U.S.P. reference stability every 18 months and to make but fail to meet the performance of an standards, sodium fluoride/calcium every effort to resupply the U.S.P.C. inappropriate standard. pyrophosphate or sodium fluoride/ with additional reference standards The agency agrees with the comments silica, in the biological testing of their when supplies are depleted (Ref. 3). that the availability of appropriate sodium fluoride/sodium bicarbonate This should occur within 1 to 2 months U.S.P. reference standards is essential to dentifrice products (Ref. 2). A after the U.S.P.C. makes a request. The conduct the biological testing included manufacturers’ association has recently U.S.P.C. will provide information in this final monograph for OTC informed the agency that a new supply concerning the reference standards’ anticaries drug products. In the tentative of one of the U.S.P. reference standards, stability profile (including total fluoride, final monograph (53 FR 22430 at sodium fluoride/calcium pyrophosphate available fluoride ions, pH, and specific 22439), the agency stated that it was (high-beta phase), will not be gravity) that is provided by each coordinating with U.S.P.C. to establish manufactured when the current supply manufacturer to any purchaser upon fluoride dentifrice reference standards at U.S.P.C. is exhausted (Ref. 3). When written request. The agency believes that would be made available to this sodium fluoride/calcium that the availability of this information manufacturers interested in pyrophosphate dentifrice reference adequately addresses the comments’ manufacturing fluoride dentifrices. standard is no longer available, concerns about specifications for these Subsequently, U.S.P. fluoride dentifrice manufacturers should use the sodium dentifrice reference standards. Other reference standards have been fluoride/silica dentifrice reference information of concern, such as source established for Category I fluoride standard in its place to conduct the of raw materials and detailed ingredient/abrasive combinations that biological tests. Thus, in response to the production directions, are considered had been reviewed by the Panel and comment’s suggestion that a reference confidential commercial information or determined by clinical trials to be standard be established for a sodium trade secret information. The agency effective anticaries drug products. These fluoride/sodium bicarbonate dentifrice, concludes that distribution of dentifrice reference standards include the fluoride it is sufficient that the formulation meet reference standards by the U.S.P.C. is dentifrice combinations suggested by the biological testing requirements using appropriate. the comments, i.e., sodium fluoride/ a reference standard containing sodium calcium pyrophosphate and sodium References fluoride, and the available fluoride ion fluoride/silica, as well as sodium concentration of the dentifrice be equal (1) The United States Pharmacopeial monofluorophosphate/calcium to or greater than 650 ppm. Convention, Inc., ‘‘Headquarters Column,’’ carbonate, sodium Pharmacopeial Forum, 16:3–4, 1990. monofluorophosphate/dicalcium References (2) The United States Pharmacopeial phosphate, sodium Convention, Inc., ‘‘Reference Standards (1) OTC Vol. 08BTPRS, Docket No. 80N– Catalog,’’ Pharmacopeial Forum, 17:2458, monofluorophosphate/silica, and 0042, Dockets Management Branch. 1991. stannous fluoride/silica (see section I.F., (2) Memoranda of telephone conversations (3) Minutes of meeting between FDA, comment 43 of this document). A list of between C. Martin, FDA, and W. Cooley, U.S.P.C., and industry representatives, May U.S.P. reference standards available as Procter & Gamble Co., dated February 8, 20, 1993, identified as MM6, Docket No. of the date of this final rule is on file 1993; P. Okarma, Colgate-Palmolive Co., 80N–0042, Dockets Management Branch. dated February 9, 1993; and D. Worrell, in the Dockets Management Branch (Ref. Church & Dwight Co., dated February 17, (4) Comment No. RPT4, Docket No. 80N– 1). 0042, Dockets Management Branch. 1993, OTC Vol. 08AFM, Docket No. 80N– The U.S.P. reference standards that 0042, Dockets Management Branch. (5) Comment No. RPT5, Docket No. 80N– have been established include only 0042, Dockets Management Branch. (3) Comment No. RPT4, Docket No. 80N– (6) Comment No. RPT6, Docket No. 80N– those dentifrice formulations that have 0042, Dockets Management Branch. been demonstrated to be clinically 0042, Dockets Management Branch. G. Comments on Package Size effective and that were reviewed by the (7) Comment No. RPT7, Docket No. 80N– Limitation 0042, Dockets Management Branch. Panel. At the time of the Panel’s 44. Two comments suggested that deliberation, no clinical data supporting 45. One comment requested that the several U.S.P. reference standards for the effectiveness of a sodium fluoride/ agency increase the fluoride dentifrice dentifrices should be provided for each sodium bicarbonate dentifrice were package size limitation from 260 mg of Category I fluoride ingredient and submitted for review. Consequently, a total fluorine per package to 350 mg to abrasive combination for which clinical U.S.P. reference standard for this accommodate the increased amount of proof of effectiveness has been dentifrice formulation has not been fluoride contained in dentifrices submitted. The comments stated that established. containing 1,500 ppm. The comment the types and sources of abrasives and The agency indicated in the tentative noted that dentifrice products marketed other ingredients present in dentifrice final monograph (53 FR 22430 at 22443) pursuant to the proposed OTC drug reference standards could have a that any Category I fluoride compound monograph contain less than 1,150 ppm significant effect on the results of formulated with an appropriate abrasive fluoride and are marketed in 9-oz bioavailability tests. As an example, the can be marketed provided the dentifrice package sizes to adhere to the 260-mg comments suggested that U.S.P. meets the biological testing total fluorine package size limitation. dentifrice reference standards for requirements in § 355.70 and contains The comment indicated that FDA had sodium fluoride products should the amount of available fluoride ion obviously reconsidered the 260-mg include sodium fluoride/calcium stated in § 355.10. The particular dentifrice package size limitation in pyrophosphate, sodium fluoride/silica, fluoride ingredient contained in the approving an NDA for an OTC dentifrice Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52503 product containing 1,500 ppm fluoride. After the tentative final monograph size restrictions are inappropriate for According to the comment, the NDA was published in 1985, the agency professional packages used by dental fluoride dentifrice is marketed in 8.2 evaluated and approved an NDA (19– practitioners in their practice. The and 6.4 oz package sizes that contain 518) for an OTC fluoride dentifrice comment stated that dentists routinely 350 and 272 mg theoretical total containing 1,500-ppm theoretical total administer these products to their fluorine, respectively. The comment fluoride (Ref. 2). As part of that patients as part of their treatment and, added that these package sizes do not evaluation, the agency reconsidered, as thus, require a larger container than the have any special cautionary labeling noted by the comment, the package size proposed OTC package sizes. The concerning the additional fluoride and limitation of 260 mg total fluorine that comment concluded that professional do not have child-resistant closures. The had been recommended by the Panel package sizes would have limited comment contended that consumers and proposed by the agency in the distribution, would not be available to would not be able to differentiate the tentative final monograph. The agency consumers and, therefore, would not be amount of fluoride contained in approved marketing of a 6.4 oz (actually a safety concern. packages of the 1,150-ppm and the containing 276 mg total fluorine) and a The package size limitations 1,500-ppm products, and thus would 8.2 oz (containing 350 mg total fluorine) established for OTC fluoride dentifrices, not treat or use the products differently. package size. Since that time, the agency treatment rinses, and preventive The comment remarked that there has reviewed the confidential sales treatment gels in § 355.20 of this final appears to have been no concern at all distribution data submitted under the monograph are intended for products that ingestion of the entire package of NDA for the extra-strength dentifrice. used by the general public and not for dentifrice was a real public safety risk. The data indicate extensive marketing products used only under professional The comment concluded that experience for the 6.4 oz package size supervision. The agency does not consumers would benefit from an and limited marketing of the 8.2 oz believe that safety problems will occur increase in the package size fluorine package size. Furthermore, the when a larger package size is distributed limitation because of the added manufacturer of the extra-strength for professional office use only, convenience of a larger package size and dentifrice has discontinued marketing provided the package is not intended to more economical products on a cost per the 8.2 oz package size (Ref. 3). The be distributed by the dentist to the oz basis. agency concludes that it has insufficient consumer for home use. A product The comment stated that the issue in marketing experience and an inadequate marketed in this manner would present establishing a package size limitation is safety profile to support general potential safety problems similar to an to prevent acute toxicity that may result recognition of an 8.2 oz package size OTC product. Therefore, the agency is from a single individual ingesting the containing 350 mg total fluorine per not limiting the package size for entire contents of a fluoride dentifrice package. The agency has sufficient data dentifrices, treatment rinses, and package on a single occasion, rather to support the 6.4 oz package size of preventive treatment gels labeled for than to prevent the long-term adverse 1,500 ppm dentifrice (containing 276 professional office use only. The agency effects of fluoride ingestion. The mg total fluorine). Therefore, the agency is including in § 355.60 of the comment submitted a list of 21 is limiting monograph dentifrices to a monograph (professional labeling) the published animal toxicology studies package size containing no more than following statements for products (Ref. 1) that were submitted in support 276 mg total fluorine per package. marketed to health professionals in of the NDA for the 1,500-ppm fluoride References package sizes larger than those specified dentifrice product. The comment stated in § 355.20: ‘‘For Professional Office Use that a review of its marketing experience (1) Comment No. CP4, Docket No. 85N– Only’’ and ‘‘This product is not records over an 18-month period 0554, Dockets Management Branch. intended for home or unsupervised (2) Copy of FDA-approved Labeling from (during which tubes as small as 1.4 oz consumer use.’’ For clarity, the agency were marketed) indicated that no one in NDA 19–518, OTC Vol. 08AFM, Docket No. 80N–0042, Dockets Management Branch. is adding paragraph (a)(3) to § 355.20 as the United States had ingested an entire follows: ‘‘Package size limitations do tube of toothpaste regardless of size (3) Memorandum of telephone conversation between C. Martin, FDA, and L. not apply to anticaries drug products during that period of time. The Cancro, Consultant to Chesebrough-Pond’s marketed for professional office use comment added that it has marketed a Co., dated August 9, 1993, OTC Vol. 08AFM, only and labeled in accord with 1,450-ppm fluoride (theoretical total Docket No. 80N–0042, Dockets Management § 355.60.’’ fluorine) dentifrice extensively outside Branch. the United States in tube sizes that 46. One comment requested that the II. Summary of Significant Changes exceed the proposed monograph proposed package size limitations for From the Proposed Rule package size limitations without any dentifrices, treatment rinses, and A. Summary of Ingredient Categories special warnings or closures. The treatment gels in § 355.20(a) and (b) not comment stated that no incidents or be limited to 260 mg (dentifrices) and The agency has reviewed all claimed issues have been raised with respect to 120 mg (rinses and gels) total fluorine active ingredients submitted to the the safety of such package sizes. The per package when the products are Panel and to the tentative final comment concluded that the proposed intended for professional use. Noting monograph, as well as other data and 260-mg package size limitation is that the package size limitations were information available at this time. For unnecessary to protect the safety or proposed because of potential toxicity the convenience of the reader, the health of the American public and that that might be caused by accidental following table is a summary of the the limitation should be raised to 350- ingestion of these products, the agency’s categorization of OTC mg. comment contended that these package anticaries active ingredients.

Anticaries Active Ingredients Monograph (M) Nonmonograph (NM)

Hydrogen fluoride: ...... 52504 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

Anticaries Active Ingredients Monograph (M) Nonmonograph (NM)

RinseÐIn an appropriate formulation with 0.02 per- cent fluoride ion ...... NM Phosphate preparations: ...... Calcium sucrose phosphate ...... NM Dicalcium phosphate dihydrate ...... NM Disodium hydrogen phosphate ...... NM Phosphoric acid ...... NM Sodium dihydrogen phosphate ...... NM Sodium dihydrogen phosphate monohydrate ...... NM Sodium phosphate ...... NM Sodium phosphate, dibasic anhydrous reagent ...... NM Sodium bicarbonate ...... NM Sodium fluoride: ...... DentifriceÐpaste: 0.188 to 0.254 percent (with ≤ 650 available fluoride ion) ...... M DentifriceÐpowder: 0.188 to 0.254 percent (with ≥ 850 ppm available fluoride ion and poured-bulk density of 1.0 to 1.2 g/mL) ...... M RinseÐ0.05 percent ...... M RinseÐ0.02 percent ...... M RinseÐAcidulated phosphate fluoride with 0.02 percent fluoride ion ...... M RinseÐAcidulated phosphate fluoride with 0.01 percent fluoride ion ...... M Sodium fluoride and hydrogen fluoride: ...... RinseÐAcidulated phosphate fluoride with 1.23 percent fluoride ion ...... MN Sodium monofluorophosphate (850 to 1,150 ppm): .... Dentifrice: 0.654 to 0.884 percent (with ≥ 800 ppm = ± available fluoride ion as PO3F and F combined) M RinseÐ6.0 percent ...... NM Sodium monofluorophosphate (1,500 ppm): ...... NM DentifriceÐ1.153 percent (with ≥ 1,275 ppm avail- = ± able fluoride ion as PO3F and F combined) ...... M ...... Stannous fluoride: ...... DentifriceÐ0.351 to 0.474 with an available fluo- ride ion concentration of: ...... ≥ 700 ppm for products containing abrasive other than calcium pyrophosphate ...... M or ...... ≥ 290 ppm for products containing the abrasive calcium pyrophosphate ...... M RinseÐ0.1 percent ...... M GelÐ0.4 percent in an anhydrous glycerin gel ...... M

B. Summary of the Agency’s Changes 2. The agency is including fluoride products appear in § 355.50(d)(1)(iii). dentifrices that contain 1,500 ppm (See section I.B., comments 13 and 14 1. The agency is revising the theoretical total fluorine in of this document.) definitions proposed for anticaries drug, § 355.10(b)(2) of this final monograph. 4. The agency is increasing the dentifrice, and treatment gel in Because of concerns about dental package size limitations in § 355.20(a) § 355.3(c), (e), and (i), respectively. The fluorosis, the agency is requiring that for dentifrice (toothpastes and tooth agency is adding a definition for dentifrices containing these fluorine powders) packages up to 276 milligrams anhydrous glycerin in § 355.3(b), as concentrations be clearly labeled for use total fluorine per package. The agency is used in § 344.3(a) (21 CFR 344.3(a)) of only by children 6 years of age and also adding a new paragraph in § 355.20 the final monograph for OTC topical older and is including directions for for fluoride powdered dentifrices that otic drug products. Also, in § 355.3(h), adults and children 6 years of age and provides for tight container packaging in the agency is adding a definition for a older in § 355.50(d)(1)(ii) of this final accordance with the definition in the fluoride supplement that is intended to monograph. The agency is also U.S.P. (See section I.B., comment 15 and be swallowed. Because of these including an optional additional section I.G., comment 45 of this additions, proposed § 355.3(b) through labeling statement that will inform document.) (f) have been redesignated as paragraphs consumers of the benefits of these 5. The agency notes that there is a (c) through (g), and § 355.3(g) through products. (See section I.B., comment 10 U.S.P. monograph for Sodium Fluoride (k) have been redesignated as of this document.) and Phosphoric Acid Topical Solution paragraphs (i) through (m), respectively, 3. The agency is adding sodium (Ref. 1). This monograph applies to in this final monograph. (See section fluoride/sodium bicarbonate powdered acidulated phosphate sodium fluoride I.B., comments 5, 6, and 7 of this dentifrices in § 355.10(a)(2) of this final topical solutions having a pH between document.) monograph. Directions for these 3.0 and 4.0. Therefore, this monograph Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52505 would apply to the aqueous solution of products. The agency anticipates that References acidulated phosphate fluoride described this revision will be completed before (1) The United States Pharmacopeia 23— in § 355.10(a)(3)(ii) of the final this final monograph for OTC anticaries The National Formulary 18, United States monograph for OTC anticaries drug drug products becomes effective. In Pharmacopeial Convention, Inc., Rockville, products and could apply to the accord with § 355.50(a) of the final MD, p. 1423, 1994. aqueous solution of acidulated monograph, manufacturers marketing (2) Memorandum of telephone phosphate fluoride described in these products should include the conversation between C. Martin, FDA, and P. Okarma, Colgate-Palmolive Co., dated § 355.10(a)(3)(i) if the pH range of the compendial name, Sodium Fluoride and December 9, 1993, OTC Vol. 08AFM, Docket U.S.P. monograph were to be expanded Phosphoric Acid Topical Solution, as No. 80N–0042, Dockets Management Branch. to 4.5. The agency and an interested the established name in the labeling of 6. The agency is redesignating several manufacturer (Ref. 2) are working with such products. paragraphs and is providing the U.S.P. to develop a revision in the following table of changes for the compendial monograph for these rinse convenience of the reader:

Paragraph number in the tentative final mono- Paragraph number in this final mongraph graph

355.3(b) ...... 355.3(c) through (g) ...... 355.3(b) through (f) 355.3(h) ...... 355.3(i) through (m) ...... 355.3(g) through (k) ...... 355.10(a)(2) ...... 355.10(a)(3)(i) ...... 355.10(b)(1) 355.10(a)(3)(ii) ...... 355.10(b)(2) 355.10(a)(3)(iii) ...... 355.10(b)(3) 355.10(a)(3)(iv) ...... 355.10(b)(4) 355.10(a)(3)(v) ...... 355.10(b)(5) 355.10(b)(1) ...... 355.10(a)(2) 355.10(b)(2) ...... 355.10(c)(1)(i) ...... 355.10(a)(3) 355.10(c)(1)(ii) ...... 355.10(a)(4) 355.10(c)(2) ...... 355.10(c) 355.10(c)(3) ...... 355.10(b)(6) ...... 355.20(a)(1)1 ...... 355.20(a) 355.20(a)(2) ...... 355.20(b) 355.20(a)(3) ...... 355.20(b) ...... 355.50(d)(1)(i) ...... 355.50(d)(1)(i) 355.50(d)(1)(ii) ...... 355.50(d)(2)(i) ...... 355.50(d)(2) 355.50(d)(2)(ii) ...... 355.50(d)(2)(iii) ...... 355.50(d)(2)(ii) 355.50(d)(5) ...... 355.50(e)(2) ...... 355.50(e)(3) 355.50(f)(1)2 ...... 355.50(f) 355.50(f)(2) ...... 355.50(g) 1 Because § 355.20(b) has been revised, the heading of § 355.20 has been changed to ``Packaging conditions.'' 2 Because § 355.50(f)(2) has been added, the word ``statement'' in the heading of § 355.50(f) has been changed to ``statements.''

7. The agency is revising and 8. The agency has moved the follows for fluoride dentifrice drug expanding § 355.50(a) to provide the statement ‘‘Do not use before mixing products: ‘‘Keep out of the reach of option of using the additional terms with water’’ from the warnings in children under 6 years of age.’’ This ‘‘mouthwash,’’ ‘‘tooth powder,’’ and proposed § 355.50(c) to the directions warning appears in § 355.50(c)(1) of this ‘‘tooth polish’’ in the statement of for use in § 355.50(d)(5) of this final final monograph. However, in identity. The agency is also requiring monograph. This statement is to be the § 355.50(c)(2), the agency continues to that the term ‘‘preventive treatment’’ be first sentence of the directions for require the general warning in § 330.1(g) included in the statement of identity for concentrated treatment rinse solutions, for all other OTC anticaries drug nonabrasive fluoride gels. The agency is powders, and effervescent tablets. (See products. (See section I.B., comment 22 providing that the word ‘‘treatment’’ be section I.C., comment 26 of this of this document.) optional in the statement of identity for document.) 10. The agency is revising the fluoride rinse products. (See section 9. The agency is modifying the directions for anticaries dentifrice drug I.C., comments 17 and 18 of this general warning in § 330.1(g), which products proposed in § 355.50(d) and is document.) states: ‘‘Keep this and all drugs out of including the revised directions in the reach of children,’’ to read as § 355.50(d)(1)(i), (d)(1)(ii), and (d)(1)(iii) 52506 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations of this final monograph. The agency is marketed to professionals in package not generally recognized as safe and also revising the directions for use of sizes larger than those specified in effective for anticaries use, i.e., anticaries preventive treatment gels by § 355.20: ‘‘For Professional Office Use hydrogen fluoride, sodium carbonate, children in § 355.50(d) to read: ‘‘Instruct Only’’ and ‘‘This product is not sodium monofluorophosphate (6 children under 12 years of age in the use intended for home or unsupervised percent rinse), and sodium phosphate. of this product (to minimize consumer use.’’ The agency is also In this final rule, the agency is swallowing). Supervise children as amending § 355.20 by revising amending § 310.545(a)(2) by adding the necessary until capable of using without paragraph (b) to read: ‘‘Package size ingredients calcium sucrose phosphate, supervision.’’ The agency is including limitations do not apply to anticaries dicalcium phosphate dihydrate, the revised directions in § 355.50(d)(4) drug products marketed for professional disodium hydrogen phosphate, in this final monograph. office use only and labeled in accord phosphoric acid, sodium dihydrogen 11. The agency is revising the with § 355.60.’’ (See section I.G., phosphate, sodium dihydrogen directions for use of anticaries treatment comment 46 of this document.) phosphate monohydrate, and sodium rinses by children, proposed in 16. The agency is revising the phosphate, dibasic anhydrous reagent to § 355.50(d)(2)(i), to read: ‘‘Instruct biological testing requirements in this this list of nonmonograph conditions. children under 12 years of age in good final monograph to require that all OTC These ingredients appear in new rinsing habits (to minimize swallowing). anticaries dentifrice drug product § 310.545(a)(2)(ii), while previous Supervise children as necessary until formulations be tested in an animal § 310.545(a)(2) is redesignated capable of using without supervision.’’ caries reduction test rather than § 310.545(a)(2)(i). The agency is including the revised allowing this type of biological test to be The agency is removing the existing directions in § 355.50(d)(2)(i) and optional as proposed in the tentative warning and caution statement required (d)(2)(ii) in this final monograph. (See final monograph (53 FR 22430 at in § 369.21 (21 CFR 369.21) and section I.C., comment 25 of this 22434). Accordingly, the first sentence exemptions for certain drugs limited by document.) in § 355.70 of the testing procedures for NDA’s to prescription sale in 12. The agency is not including fluoride dentifrice drug products reads: § 310.201(a)(10) and (a)(15) (21 CFR proposed § 355.50(e)(2) in this final ‘‘A fluoride dentifrice drug product 310.201(a)(10) and (a)(15)) for anticaries monograph. In its place, the agency is must meet the biological test drug products because most portions of including new § 355.55, as follows: requirements for animal caries those regulations are superseded by the ‘‘Principal display panel of all fluoride reduction and one of the following tests: anticaries final monograph (21 CFR part rinse drug products. In addition to the Enamel solubility reduction or fluoride 355). The items being removed include: statement of identity required in enamel uptake.’’ The agency has further (1) § 310.201(a)(10)(i) through § 355.50, the following statement shall revised the proposed testing guidance (a)(10)(vi); (2) § 310.201(a)(15)(i) be prominently placed on the principal for parameters other than available through (a)(15)(vi); and (3) paragraphs display panel: ′IMPORTANT: Read fluoride ion and biological test in § 369.21 applicable to sodium directions carefully before using’’′. requirements and is citing these revised fluoride dentifrice powder and sodium Because proposed § 355.50(e)(2) is not parameters as testing intended as monofluorophosphate dentifrice included in this monograph, the agency guidance, e.g., for use in determining solution. The agency is reserving is redesignating proposed § 355.50(e)(3) expiration dating. The agency is paragraphs (a)(10) and (a)(15) in as § 355.50(e)(2) in this final including a revised LTP chart in the § 310.201 for future use. monograph. (See section I.C., comment preamble of this document for Any drug product labeled, 20 of this document.) informational purposes. (See section represented, or promoted for use as an 13. The agency is not including I.F., comments 37, 39, and 40 of this OTC anticaries drug product that proposed § 355.50(g) (which states: document.) contains any of the ingredients listed in ‘‘The word ′physician′ may be 17. The agency is revising the testing § 310.545(a)(2) or that is not in substituted for the word ′doctor′ in any procedures in § 355.70 to include conformance with the monograph (21 of the labeling statements in this information about the available U.S.P. CFR part 355) may be considered a new section.’’) in this final monograph fluoride dentifrice reference standards. drug within the meaning of section because the agency has amended § 330.1 (See section I.F., comments 43 and 44 of 201(p) of the act (21 U.S.C. 321(p)) and to permit the interchangeability of this document.) misbranded under section 502 of the act certain terms, including ‘‘physician’’ (21 U.S.C. 352) and may not be III. The Agency’s Final Conclusions on and ‘‘doctor,’’ in all OTC drug marketed for this use unless it is the OTC Anticaries Drug Products monographs. (See 59 FR 3998, January subject of an approved application or 28, 1994.) Based on available evidence, the abbreviated application under section 14. The agency is modifying the agency is issuing a final monograph 505 of the act (21 U.S.C. part 355) and introductory language in the establishing conditions under which part 314 of the regulations (21 CFR part professional labeling in § 355.60 to read: OTC anticaries drug products (aid in the 314). In appropriate circumstances, a ‘‘The labeling for anticaries fluoride prevention of dental cavities) are citizen petition to amend the treatment rinses identified in § 355.10(b) generally recognized as safe and monograph may be submitted under 21 that are specially formulated so they effective and not misbranded. CFR 10.30 in lieu of an application. Any may be swallowed (fluoride Specifically, the agency has determined OTC anticaries drug product initially supplements) and are provided to health that the following active ingredients introduced or initially delivered for professionals (but not to the general meet monograph conditions: Sodium introduction into interstate commerce public) may contain the following fluoride, sodium monofluorophosphate, after the effective dates of additional dosage information: * * *.’’ and stannous fluoride. All other § 310.545(a)(2) or the effective date of (See section I.C., comment 28 of this ingredients considered in this this final rule that is not in compliance document.) rulemaking have been determined to be with the regulations is subject to 15. The agency is including in nonmonograph conditions. Four of regulatory action. § 355.60 (professional labeling) the these ingredients are presently listed in An analysis of the cost and benefits of following statements for products § 310.545(a)(2) (21 CFR 310.545(a)(2)) as this regulation, conducted under Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52507

Executive Order 12291, was discussed 21 CFR Part 355 (a)(6)(ii)(A), (a)(7) (except as covered by in the tentative final monograph of Labeling, Over-the-counter drugs. paragraph (d)(3) of this section), (a)(8)(i), September 30, 1985 (50 FR 39854) and (a)(9) through (a)(10)(iii), (a)(12)(i) in the amendment of the tentative final 21 CFR Part 369 through (a)(12)(iv), (a)(14) through monograph of June 15, 1988 (53 FR Labeling, Medical devices, Over-the- (a)(15)(i), and (a)(16) through (a)(18)(i) 22430). No comments were received in counter drugs. of this section. response to the agency’s request for Therefore, under the Federal Food, * * * * * specific comment on the economic Drug, and Cosmetic Act and under (24) October 7, 1996, for products impact of this rulemaking (50 FR 39854 authority delegated to the Commissioner subject to paragraph (a)(2)(ii) of this at 39871 and 53 FR 22430 at 22447), and of Food and Drugs, 21 CFR chapter I is section. the substance of that analysis has not amended as follows: 4. Part 355 is added to read as follows: changed. Executive Order 12291 has been superseded by Executive Order PART 310ÐNEW DRUGS PART 355ÐANTICARIES DRUG 12866. FDA has examined the impacts PRODUCTS FOR OVER-THE- 1. The authority citation for 21 CFR COUNTER HUMAN USE of the final rule under Executive Order part 310 continues to read as follows: 12866 and the Regulatory Flexibility Act (Pub. L. 96–354). Executive Order 12866 Authority: Secs. 201, 301, 501, 502, 503, Subpart AÐGeneral Provisions directs agencies to assess all costs and 505, 506, 507, 512–516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and Sec. benefits of available regulatory Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 355.1 Scope. alternatives and, when regulation is 353, 355, 356, 357, 360b–360f, 360j, 361(a), 355.3 Definitions. necessary, to select regulatory 371, 374, 375, 379e); secs. 215, 301, 302(a), Subpart BÐActive Ingredients approaches that maximize net benefits 351, 354–360F of the Public Health Service (including potential economic, Act (42 U.S.C. 216, 241, 242(a), 262, 263b– 355.10 Anticaries active ingredients. environmental, public health and safety, 263n). 355.20 Packaging conditions. and other advantages; distributive § 310.201 [Amended] Subpart CÐLabeling impacts; and equity). The agency believes that this final rule is consistent 2. Section 310.201 Exemption for 355.50 Labeling of anticaries drug products. with the regulatory philosophy and certain drugs limited by new-drug 355.55 Principal display panel of all applications to prescription sale is fluoride rinse drug products. principles identified in the Executive amended by removing and reserving 335.60 Professional labeling. Order. In addition, the final rule is not paragraphs (a)(10) and (a)(15). a significant regulatory action as defined 3. Section 310.545 is amended by Subpart DÐTesting Procedures by the Executive Order and, thus, is not redesignating the text of paragraph (a)(2) 355.70 Testing procedures for fluoride subject to review under the Executive as paragraph (a)(2)(i); by adding new dentifrice drug products. Order. (a)(2)(i) heading and paragraphs (a)(2)(ii) Authority: Secs. 201, 501, 502, 503, 505, The Regulatory Flexibility Act and (d)(24); and by revising paragraph 510, 701 of the Federal Food, Drug, and requires agencies to analyze regulatory (d) introductory text and paragraph Cosmetic Act (21 U.S.C. 321, 351, 352, 353, options that would minimize any (d)(1) to read as follows: 355, 360, 371). significant impact of a rule on small entities. All major anticaries drug § 310.545 Drug products containing Subpart AÐGeneral Provisions products already contain monograph certain active ingredients offered over-the- counter (OTC) for certain uses. § 355.1 Scope. ingredients, and no reformulations (a) * * * (a) An over-the-counter anticaries should be necessary. This final rule will drug product in a form suitable for require some relabeling for these (2) Anticaries drug products—(i) Approved as of May 7, 1991. * * * topical administration to the teeth is products. Manufacturers will have 1 generally recognized as safe and year to implement this relabeling. (ii) Approved as of October 7, 1996. Calcium sucrose phosphate effective and is not misbranded if it Accordingly, the agency certifies that Dicalcium phosphate dihydrate meets each condition in this part and the final rule will not have a significant Disodium hydrogen phosphate1 each general condition established in economic impact on a substantial Phosphoric acid1 § 330.1 of this chapter. number of small entities. Therefore, Sodium dihydrogen phosphate (b) References in this part to under the Regulatory Flexibility Act, no Sodium dihydrogen phosphate monohydrate regulatory sections of the Code of further analysis is required. Sodium phosphate, dibasic anhydrous reagent1 Federal Regulations are to Chapter I of The agency has determined under 21 Title 21 unless otherwise noted. CFR 25.24(c)(6) that this action is of a * * * * * type that does not individually or (d) Any OTC drug product that is not § 355.3 Definitions. cumulatively have a significant effect on in compliance with this section is As used in this part: the human environment. Therefore, subject to regulatory action if initially (a) Abrasive. Solid materials that are neither an environmental assessment introduced or initially delivered for added to dentifrices to facilitate nor an environmental impact statement introduction into interstate commerce mechanical removal of dental plaque, is required. after the dates specified in paragraphs debris, and stain from tooth surfaces. (d)(1) through (d)(24) of this section. (b) Anhydrous glycerin. An ingredient List of Subjects (1) May 7, 1991, for products subject that may be prepared by heating to paragraphs (a)(1) through (a)(2)(i), 21 CFR Part 310 glycerin U.S.P. at 150 C for 2 hours to (a)(3) through (a)(4), (a)(6)(i)(A), drive off the moisture content. Administrative practice and (c) Anticaries drug. A drug that aids procedure, Drugs, Labeling, Medical 1 These ingredients are nonmonograph except when used to prepare acidulated phosphate in the prevention and prophylactic devices, Reporting and recordkeeping fluoride treatment rinses identified in § 355.10(a)(3) treatment of dental cavities (decay, requirements. of this chapter. caries). 52508 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations

(d) Dental caries. A disease of 0.188 to 0.254 percent with an available mixing with water immediately before calcified tissues of teeth characterized fluoride ion concentration of ≥ 850 ppm using to result in a 0.1-percent aqueous by demineralization of the inorganic for products containing the abrasive solution. portion and destruction of the organic sodium bicarbonate and a poured-bulk matrix. density of 1.0 to 1.2 grams per milliliter. § 355.20 Packaging conditions. (e) Dentifrice. An abrasive-containing (3) Treatment rinses. (i) An aqueous (a) Package size limitation. Due to the dosage form for delivering an anticaries solution of acidulated phosphate toxicity associated with fluoride active drug to the teeth. fluoride derived from sodium fluoride ingredients, the following package size (f) Fluoride. The inorganic form of the acidulated with a mixture of sodium limitations are required for anticaries chemical element fluorine in phosphate, monobasic, and phosphoric drug products: combination with other elements. acid to a level of 0.1 molar phosphate (1) Dentifrices. Dentifrice (toothpastes (g) Fluoride ion. The negatively ion and a pH of 3.0 to 4.5 and which and tooth powders) packages shall not charged atom of the chemical element yields an effective fluoride ion contain more than 276 milligrams (mg) fluorine. concentration of 0.02 percent. total fluorine per package. (h) Fluoride supplement. A special (ii) An aqueous solution of acidulated (2) Preventive treatment gels and treatment rinse dosage form that is phosphate fluoride derived from sodium treatment rinses. Preventive treatment intended to be swallowed, and is fluoride acidulated with a mixture of gel and treatment rinse packages shall promoted to health professionals for use sodium phosphate, dibasic, and not contain more than 120 mg total in areas where the water supply phosphoric acid to a pH of 3.5 and fluorine per package. contains 0 to 0.7 parts per million (ppm) which yields an effective fluoride ion (3) Exception. Package size limitations fluoride ion. concentration of 0.01 percent. do not apply to anticaries drug products (i) Preventive treatment gel. A dosage (iii) Sodium fluoride 0.02 percent marketed for professional office use form for delivering an anticaries drug to aqueous solution with a pH of only and labeled in accord with the teeth. Preventive treatment gels are approximately 7. § 355.60. formulated in an anhydrous glycerin (iv) Sodium fluoride 0.05 percent (b) Tight container packaging. To base with suitable thickening agents aqueous solution with a pH of minimize moisture contamination, all included to adjust viscosity. Preventive approximately 7. fluoride powdered dentifrices shall be treatment gels do not contain abrasives. (v) Sodium fluoride concentrate packaged in a tight container as defined (j) Treatment rinse. A liquid dosage containing adequate directions for as a container that protects the contents form for delivering an anticaries drug to mixing with water before using to result from contamination by extraneous the teeth. in a 0.02-percent or 0.05-percent liquids, solids, or vapors, from loss of (k) Treatment rinse concentrated aqueous solution with a pH of the article, and from efflorescence, solution. A fluoride treatment rinse in a approximately 7. deliquescence, or evaporation under the concentrated form to be mixed with (b) Sodium monofluorophosphate— ordinary or customary conditions of water before using to result in the (1) Dentifrices containing 850 to 1,150 handling, shipment, storage, and appropriate fluoride concentration ppm theoretical total fluorine in a paste distribution, and is capable of tight specified in the monograph. dosage form. Sodium reclosure. (l) Treatment rinse effervescent monofluorophosphate 0.654 to 0.884 tablets. A fluoride treatment rinse percent with an available fluoride ion Subpart CÐLabeling = prepared by adding an effervescent concentration (consisting of PO3F and F± combined) ≥ 800 ppm. § 355.50 Labeling of anticaries drug tablet (a concentrated solid dosage form) products. to water before using to result in the (2) Dentifrices containing 1,500 ppm (a) Statement of identity. The labeling appropriate fluoride concentration theoretical total fluorine in a paste of the product contains the established specified in the monograph. dosage form. Sodium name of the drug, if any, and identifies (m) Treatment rinse powder. A monofluorophosphate 1.153 percent the product as the following: ‘‘anticavity fluoride treatment rinse prepared by with an available fluoride ion = fluoride’’ (select one of the following as adding the powder (a concentrated solid concentration (consisting of PO3F and ± appropriate: ‘‘dentifrice,’’ ‘‘toothpaste,’’ dosage form) to water before using to F combined) ≥ 1,275 ppm. ‘‘tooth polish,’’ ‘‘tooth powder;’’ result in the appropriate fluoride (c) Stannous fluoride—(1) Dentifrices (optional: ‘‘dental’’) ‘‘preventive concentration specified in the containing 850 to 1,150 ppm theoretical treatment gel;’’ or (optional: ‘‘treatment’’ monograph. total fluorine in a paste dosage form. (i) Stannous fluoride 0.351 to 0.474 percent or ‘‘dental’’)) (select one of the Subpart BÐActive Ingredients with an available fluoride ion following: ‘‘rinse,’’ ‘‘concentrated concentration ≥ 700 ppm for products solution,’’ ‘‘rinse powder,’’ or ‘‘rinse § 355.10 Anticaries active ingredients. containing abrasives other than calcium effervescent tablets’’). The word The active ingredient of the product pyrophosphate. ‘‘mouthwash’’ may be substituted for consists of any of the following when (ii) Stannous fluoride 0.351 to 0.474 the word ‘‘rinse’’ in this statement of used in the concentration and dosage percent with an available fluoride ion identity if the product also has a form established for each ingredient: concentration ≥ 290 ppm for products cosmetic use, as defined in section (a) Sodium fluoride—(1) Dentifrices containing the abrasive calcium 201(i) of the Federal Food, Drug, and containing 850 to 1,150 ppm theoretical pyrophosphate. Cosmetic Act (the act) (21 U.S.C. 321(i)). total fluorine in a paste dosage form. (2) Preventive treatment gel. Stannous (b) Indication. The labeling of the Sodium fluoride 0.188 to 0.254 percent fluoride 0.4 percent in an anhydrous product states, under the heading with an available fluoride ion glycerin gel, made from anhydrous ‘‘Indication,’’ the following: ‘‘Aids in concentration ≥ 650 parts per million glycerin and the addition of suitable the prevention of dental (select one of (ppm). thickening agents to adjust viscosity. the following: ‘‘cavities,’’ ‘‘decay,’’ (2) Dentifrices containing 850 to 1,150 (3) Treatment rinse. Stannous fluoride ‘‘caries (decay),’’ or ‘‘caries (cavities)’’). ppm theoretical total fluorine in a concentrate marketed in a stable form Other truthful and nonmisleading powdered dosage form. Sodium fluoride and containing adequate directions for statements, describing only the Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations 52509 indication for use that has been again. Rinse and spit out thoroughly. (to minimize swallowing). Supervise established and listed in this paragraph Brush teeth, preferably after each meal children as necessary until capable of (b), may also be used, as provided in or at least twice a day, or as directed by using without supervision. Children § 330.1(c)(2) of this chapter, subject to a dentist or doctor. Instruct children under 6 years of age: consult a dentist the provisions of section 502 of the under 12 years of age in good brushing or doctor. Federal Food, Drug, and Cosmetic Act and rinsing habits (to minimize (5) For all concentrated treatment (the act) relating to misbranding and the swallowing). Supervise children as rinse solutions, powders, and prohibition in section 301(d) of the act necessary until capable of using without effervescent tablets. The following against the introduction or delivery for supervision. Children under 6 years of statement shall appear as the first introduction into interstate commerce of age: Do not use unless directed by a statement under directions: ‘‘Do not use unapproved new drugs in violation of dentist or doctor. before mixing with water.’’ section 505(a) of the act. (2) For anticaries treatment rinse (e) Additional labeling statements for (c) Warning. The labeling of the products—(i) For acidulated phosphate anticaries drug products. The following product contains the following warning fluoride solution containing 0.02 statements need not appear under under the heading ‘‘Warning’’: percent fluoride ion, sodium fluoride warnings, but are required to appear on (1) For all fluoride dentifrice 0.05 percent, sodium fluoride the label of anticaries drugs products as (toothpastes and tooth powders) concentrate, and stannous fluoride applicable. products. ‘‘Keep out of the reach of concentrate identified in (1) For all preventive treatment gels. children under 6 years of age.’’ This § 355.10(a)(3)(i), (a)(3)(iv), (a)(3)(v), and ‘‘This is a(n)’’ (select one or both of the warning shall be used in place of the (c)(3). Adults and children 6 years of age following: ‘‘anticavity’’ or ‘‘fluoride’’) first general warning statement required and older: Use once a day after brushing ‘‘preventive treatment gel, not a by § 330.1(g) of this chapter. your teeth with a toothpaste. Vigorously toothpaste. Read directions carefully (2) For all fluoride rinse and gel swish 10 milliliters of rinse between before using.’’ products. The first general warning your teeth for 1 minute and then spit (2) For all stannous fluoride treatment statement in § 330.1(g) of this chapter out. Do not swallow the rinse. Do not rinse, preventive treatment gel, and shall be used. eat or drink for 30 minutes after rinsing. dentifrice products. ‘‘This product may (d) Directions. The labeling of the Instruct children under 12 years of age produce surface staining of the teeth. product contains the following in good rinsing habits (to minimize Adequate toothbrushing may prevent statements under the heading swallowing). Supervise children as these stains which are not harmful or ‘‘Directions’’: necessary until capable of using without permanent and may be removed by your (1) For anticaries dentifrice supervision. Children under 6 years of dentist.’’ products—(i) Paste dosage form with a age: Consult a dentist or doctor. (f) Optional additional labeling theoretical total fluorine concentration (ii) For acidulated phosphate fluoride statements—(1) For fluoride treatment of 850 to 1,150 ppm identified in solution containing 0.01 percent rinses and preventive treatment gels. § 355.10(a)(1), (b)(1), and (c)(1). Adults fluoride ion and sodium fluoride 0.02 The following labeling statement may and children 2 years of age and older: percent aqueous solution identified in appear in the required boxed area Brush teeth thoroughly, preferably after § 355.10(a)(3)(ii) and (a)(3)(iii). Adults designated ‘‘APPROVED USES’’: ‘‘The each meal or at least twice a day, or as and children 6 years of age and older: combined daily use of a fluoride directed by a dentist or doctor. Instruct Use twice a day after brushing your preventive treatment’’ (select one of the children under 6 years of age in good teeth with a toothpaste. Vigorously following: ‘‘rinse’’ or ‘‘gel’’) ‘‘and a brushing and rinsing habits (to swish 10 milliliters of rinse between fluoride toothpaste can help reduce the minimize swallowing). Supervise your teeth for 1 minute and then spit incidence of dental cavities.’’ children as necessary until capable of out. Do not swallow the rinse. Do not (2) For dentifrice products containing using without supervision. Children eat or drink for 30 minutes after rinsing. 1,500 ppm theoretical total fluorine. under 2 years of age: Consult a dentist Instruct children under 12 years of age ‘‘Adults and children over 6 years of age or doctor. in good rinsing habits (to minimize may wish to use this extra-strength (ii) Paste dosage form with a swallowing). Supervise children as fluoride dentifrice if they reside in a theoretical total fluorine concentration necessary until capable of using without nonfluoridated area or if they have a of 1,500 ppm identified in supervision. Children under 6 years of greater tendency to develop cavities.’’ § 355.10(b)(2). Adults and children 6 age: consult a dentist or doctor. years of age and older: Brush teeth (3) For stannous fluoride treatment § 355.55 Principal display panel of all thoroughly, preferably after each meal rinse products. (i) ‘‘Use immediately fluoride rinse drug products. or at least twice a day, or as directed by after preparing the rinse.’’ In addition to the statement of a dentist or doctor. Instruct children (ii) For powder or effervescent tablets identity required in § 355.50, the under 12 years of age in good brushing used to prepare treatment rinses. ‘‘Do following statement shall be and rinsing habits (to minimize not use as a rinse until all the’’ (select prominently placed on the principal swallowing). Supervise children as one of the following: ‘‘powder’’ or display panel: ‘‘IMPORTANT: Read necessary until capable of using without ‘‘tablet’’) ‘‘has dissolved.’’ directions for proper use.’’ supervision. Children under 6 years of (4) For anticaries preventive treatment age: Do not use unless directed by a gel products. Adults and children 6 § 355.60 Professional labeling. dentist or doctor. years of age and older: Use once a day (a) The labeling for anticaries fluoride (iii) Powdered dosage form with a after brushing your teeth with a treatment rinses identified in theoretical total fluorine concentration toothpaste. Apply the gel to your teeth § 355.10(a)(3) and (c)(3) that are of 850 to 1,150 ppm identified in and brush thoroughly. Allow the gel to specially formulated so they may be § 355.10(a)(2). Adults and children 6 remain on your teeth for 1 minute and swallowed (fluoride supplements) and years of age and older: Apply powder to then spit out. Do not swallow the gel. are provided to health professionals (but a wet toothbrush; completely cover all Do not eat or drink for 30 minutes after not to the general public) may contain bristles. Brush for at least 30 seconds. brushing. Instruct children under 12 the following additional dosage Reapply powder as before and brush years of age in the use of this product information: Children 3 to under 14 52510 Federal Register / Vol. 60, No. 194 / Friday, October 6, 1995 / Rules and Regulations years of age: As a supplement in areas for these biological tests are labeled All information submitted will be where the water supply is Biological Testing Procedures for subjected to the disclosure rules in part nonfluoridated (less than 0.3 parts per Fluoride Dentifrices; these testing 20 of this chapter. million (ppm)), clean the teeth with a procedures are on file under Docket No. toothpaste and rinse with 5 milliliters 80N–0042 in the Dockets Management PART 369ÐINTERPRETATIVE (mL) of 0.02 percent or 10 mL of 0.01 Branch (HFA–305), Food and Drug STATEMENTS RE WARNINGS ON percent fluoride ion rinse daily, then Administration, rm. 1–23, 12420 DRUGS AND DEVICES FOR OVER- swallow. When the water supply Parklawn Dr., Rockville, MD 20857, and THE-COUNTER SALE contains 0.3 to 0.7 ppm fluoride ion, are available on request to that office. reduce the dose to 2.5 mL of 0.02 4. The authority citation for 21 CFR (b) The United States Pharmacopeia part 369 continues to read as follows: percent or 5 mL of 0.01 percent fluoride fluoride dentifrice reference standards ion rinse daily. along with reference standard stability Authority: Secs. 201, 301, 501, 502, 503, (b) The labeling for products marketed profiles (total fluoride, available 505, 506, 507, 701 of the Federal Food, Drug, to health to health professionals in fluoride ion, pH, and specific gravity) and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 371). package sizes larger than those specified required to be used in the biological in § 355.20 shall include the statements: tests are available to any purchaser § 369.21 [Amended] ‘‘For Professional Office Use Only’’ and upon written request to the United 5. Section 369.21 Drugs; warning and ‘‘This product is not intended for home States Pharmacopeial Convention, Inc., or unsupervised consumer use.’’ caution statements required by 1260 Twinbrook Parkway, Rockville, regulations is amended by removing the MD 20852. Subpart DÐTesting Procedures entries for ‘‘SODIUM FLUORIDE (c) Alternative testing procedures may DENTIFRICE POWDER’’ and ‘‘SODIUM § 355.70 Testing procedures for fluoride be used. Any proposed modification or MONOFLUOROPHOSPHATE dentifrice drug products. alternative testing procedures shall be DENTIFRICE SOLUTION.’’ (a) A fluoride dentifrice drug product submitted as a petition in accord with shall meet the biological test § 10.30 of this chapter. The petition Dated: September 18, 1995. requirements for animal caries should contain data to support the William K. Hubbard, reduction and one of the following tests: modification or data demonstrating that Acting Deputy Commissioner for Policy. Enamel solubility reduction or fluoride an alternative testing procedure [FR Doc. 95–24693 Filed 10–5–95; 8:45 am] enamel uptake. The testing procedures provides results of equivalent accuracy. BILLING CODE 4160±01±F