301 Part 355—Anticaries Drug Products for Over-The

Food and Drug Administration, HHS § 355.3

modification or alternative procedure § 355.3 Definitions. shall be submitted as a petition in ac- As used in this part: cord with § 10.30 of this chapter. The petition should contain data to support (a) Abrasive. Solid materials that are the modification or data dem- added to dentifrices to facilitate me- onstrating that an alternative proce- chanical removal of dental plaque, de- dure provides results of equivalent ac- bris, and stain from tooth surfaces. curacy. All information submitted will (b) Anhydrous glycerin. An ingredient be subject to the disclosure rules in that may be prepared by heating glyc- part 20 of this chapter. erin U.S.P. at 150 –C for 2 hours to drive off the moisture content. PART 355—ANTICARIES DRUG (c) Anticaries drug. A drug that aids in the prevention and prophylactic PRODUCTS FOR OVER-THE- treatment of dental cavities (decay, COUNTER HUMAN USE caries). (d) Dental caries. A disease of calcified Subpart A—General Provisions tissues of teeth characterized by Sec. demineralization of the inorganic por- 355.1 Scope. tion and destruction of the organic ma- 355.3 Definitions. trix. (e) Dentifrice. An abrasive-containing Subpart B—Active Ingredients dosage form (gel, paste, or powder) for delivering an anticaries drug to the 355.10 Anticaries active ingredients. teeth. 355.20 Packaging conditions. (f) Fluoride. The inorganic form of the Subpart C—Labeling chemical element fluorine in combina- tion with other elements. 355.50 Labeling of anticaries drug products. (g) Fluoride ion. The negatively 355.55 Principal display panel of all fluoride charged atom of the chemical element rinse drug products. fluorine. 335.60 Professional labeling. (h) Fluoride supplement. A special treatment rinse dosage form that is in- Subpart D—Testing Procedures tended to be swallowed, and is pro- 355.70 Testing procedures for fluoride den- moted to health professionals for use in tifrice drug products. areas where the water supply contains

AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 0 to 0.7 parts per million (ppm) fluoride 360, 371. ion. (i) Preventive treatment gel. A dosage SOURCE: 60 FR 52507, Oct. 6, 1995, unless form for delivering an anticaries drug otherwise noted. to the teeth. Preventive treatment gels EDITORIAL NOTE: Nomenclature changes to are formulated in an anhydrous glyc- part 355 appear at 69 FR 13717, Mar. 24, 2004. erin base with suitable thickening agents included to adjust viscosity. Subpart A—General Provisions Preventive treatment gels do not contain abrasives. § 355.1 Scope. (j) Treatment rinse. A liquid dosage (a) An over-the-counter anticaries form for delivering an anticaries drug drug product in a form suitable for top- to the teeth. ical administration to the teeth is gen- (k) Treatment rinse concentrated solu- erally recognized as safe and effective tion. A fluoride treatment rinse in a and is not misbranded if it meets each concentrated form to be mixed with condition in this part and each general water before using to result in the ap- condition established in § 330.1 of this propriate fluoride concentration speci- chapter. fied in the monograph. (b) References in this part to regu- (l) Treatment rinse effervescent tablets. latory sections of the Code of Federal A fluoride treatment rinse prepared by Regulations are to chapter I of title 21 adding an effervescent tablet (a con- unless otherwise noted. centrated solid dosage form) to water

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before using to result in the appro- 0.02-percent or 0.05-percent aqueous so- priate fluoride concentration specified lution with a pH of approximately 7. in the monograph. (b) Sodium monofluorophosphate—(1) (m) Treatment rinse powder. A fluoride Dentifrices containing 850 to 1,150 ppm treatment rinse prepared by adding the theoretical total fluorine in a gel or paste powder (a concentrated solid dosage dosage form. Sodium monofluoro- form) to water before using to result in phosphate 0.654 to 0.884 percent with an the appropriate fluoride concentration available fluoride ion concentration = ¥ specified in the monograph. (consisting of PO3 F and F combined) ≥ 800 ppm. [60 FR 52507, Oct. 6, 1995, as amended at 61 FR 52286, Oct. 7, 1996] (2) Dentifrices containing 1,500 ppm theoretical total fluorine in a gel or paste dosage form. Sodium monofluoro- Subpart B—Active Ingredients phosphate 1.153 percent with an available fluoride ion concentration (con- § 355.10 Anticaries active ingredients. = ¥ sisting of PO3 F and F combined) ≥ The active ingredient of the product 1,275 ppm. consists of any of the following when (c) Stannous fluoride—(1) Dentifrices used in the concentration and dosage containing 850 to 1,150 ppm theoretical form established for each ingredient: total fluorine in a gel or paste dosage (a) Sodium fluoride—(1) Dentifrices con- form. (i) Stannous fluoride 0.351 to 0.474 taining 850 to 1,150 ppm theoretical total percent with an available fluoride ion fluorine in a gel or paste dosage form. So- concentration ≥ 700 ppm for products dium fluoride 0.188 to 0.254 percent with containing abrasives other than cal- an available fluoride ion concentration cium pyrophosphate. ≥ 650 parts per million (ppm). (ii) Stannous fluoride 0.351 to 0.474 (2) Dentifrices containing 850 to 1,150 percent with an available fluoride ion ppm theoretical total fluorine in a pow- concentration ≥ 290 ppm for products dered dosage form. Sodium fluoride 0.188 containing the abrasive calcium to 0.254 percent with an available fluo- ≥ pyrophosphate. ride ion concentration of 850 ppm for (2) Preventive treatment gel. Stannous products containing the abrasive so- fluoride 0.4 percent in an anhydrous dium bicarbonate and a poured-bulk glycerin gel, made from anhydrous density of 1.0 to 1.2 grams per milli- glycerin and the addition of suitable liter. thickening agents to adjust viscosity. (3) Treatment rinses. (i) An aqueous so- (3) Treatment rinse. Stannous fluoride lution of acidulated phosphate fluoride concentrate marketed in a stable form derived from sodium fluoride and containing adequate directions for acidulated with a mixture of sodium mixing with water immediately before phosphate, monobasic, and phosphoric using to result in a 0.1-percent aqueous acid to a level of 0.1 molar phosphate solution. ion and a pH of 3.0 to 4.5 and which yields an effective fluoride ion con- [60 FR 52507, Oct. 6, 1995, as amended at 61 FR centration of 0.02 percent. 52286, Oct. 7, 1996] (ii) An aqueous solution of acidulated phosphate fluoride derived from so- § 355.20 Packaging conditions. dium fluoride acidulated with a mix- (a) Package size limitation. Due to the ture of sodium phosphate, dibasic, and toxicity associated with fluoride active phosphoric acid to a pH of 3.5 and ingredients, the following package size which yields an effective fluoride ion limitations are required for anticaries concentration of 0.01 percent. drug products: (iii) Sodium fluoride 0.02 percent (1) Dentifrices. Dentifrice (toothpastes aqueous solution with a pH of approxi- and tooth powders) packages shall not mately 7. contain more than 276 milligrams (mg) (iv) Sodium fluoride 0.05 percent total fluorine per package. aqueous solution with a pH of approxi- (2) Preventive treatment gels and treat- mately 7. ment rinses. Preventive treatment gel (v) Sodium fluoride concentrate con- and treatment rinse packages shall not taining adequate directions for mixing contain more than 120 mg total fluo- with water before using to result in a rine per package.

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(3) Exception. Package size limitation into interstate commerce of unap- tions do not apply to anticaries drug proved new drugs in violation of sec- products marketed for professional of- tion 505(a) of the act. fice use only and labeled in accord with (c) Warning. The labeling of the prod- § 355.60. uct contains the following warning (b) Tight container packaging. To min- under the heading ‘‘Warning’’: imize moisture contamination, all fluo- (1) For all fluoride dentifrice (gel, paste, ride powdered dentifrices shall be pack- and powder) products. ‘‘Keep out of aged in a tight container as defined as reach of children under 6 years of age. a container that protects the contents [highlighted in bold type] If more than from contamination by extraneous liq- used for brushing is accidentally swal- uids, solids, or vapors, from loss of the lowed, get medical help or contact a article, and from efflorescence, deli- Poison Control Center right away.’’ quescence, or evaporation under the or- These warnings shall be used in place dinary or customary conditions of han- of the general warning statements re- dling, shipment, storage, and distribu- quired by § 330.1(g) of this chapter. tion, and is capable of tight reclosure. (2) For all fluoride rinse and preventive treatment gel products. ‘‘Keep out of Subpart C—Labeling reach of children. [highlighted in bold type] If more than used for’’ (select ap- § 355.50 Labeling of anticaries drug propriate word: ‘‘brushing’’ or ‘‘rins- products. ing’’) ‘‘is accidentally swallowed, get (a) Statement of identity. The labeling medical help or contact a Poison Con- of the product contains the established trol Center right away.’’ These warn- name of the drug, if any, and identifies ings shall be used in place of the gen- the product as: (select one or both of eral warning statements required by the following: ‘anticavity’ or ‘fluoride’) § 330.1(g) of this chapter. (select one of the following as appro- (d) Directions. The labeling of the priate: ‘‘dentifrice,’’ ‘‘toothpaste,’’ product contains the following state- ‘‘tooth polish,’’ ‘‘tooth powder;’’ (op- ments under the heading ‘‘Directions’’: tional: ‘‘dental’’) ‘‘preventive treat- (1) For anticaries dentifrice products— ment gel;’’ or (optional: ‘‘treatment’’ (i) Gel or paste dosage form with a theo- or ‘‘dental’’)) (select one of the fol- retical total fluorine concentration of 850 lowing: ‘‘rinse,’’ ‘‘concentrated solu- to 1,150 ppm identified in § 355.10(a)(1), tion,’’ ‘‘rinse powder,’’ or ‘‘rinse effer- (b)(1), and (c)(1). Adults and children 2 vescent tablets’’). The word ‘‘mouth- years of age and older: Brush teeth wash’’ may be substituted for the word thoroughly, preferably after each meal ‘‘rinse’’ in this statement of identity if or at least twice a day, or as directed the product also has a cosmetic use, as by a dentist or doctor. Instruct chil- defined in section 201(i) of the Federal dren under 6 years of age in good Food, Drug, and Cosmetic Act (the act) brushing and rinsing habits (to mini- (21 U.S.C. 321(i)). mize swallowing). Supervise children (b) Indication. The labeling of the as necessary until capable of using product states, under the heading ‘‘In- without supervision. Children under 2 dication,’’ the following: ‘‘Aids in the years of age: Consult a dentist or doc- prevention of dental (select one of the tor. following: ‘‘cavities,’’ ‘‘decay,’’ ‘‘caries (ii) Gel or paste dosage form with a the- (decay),’’ or ‘‘caries (cavities)’’). Other oretical total fluorine concentration of truthful and nonmisleading state- 1,500 ppm identified in § 355.10(b)(2). ments, describing only the indication Adults and children 6 years of age and for use that has been established and older: Brush teeth thoroughly, pref- listed in this paragraph (b), may also erably after each meal or at least twice be used, as provided in § 330.1(c)(2) of a day, or as directed by a dentist or this chapter, subject to the provisions doctor. Instruct children under 12 years of section 502 of the Federal Food, of age in good brushing and rinsing Drug, and Cosmetic Act (the act) relat- habits (to minimize swallowing). Su- ing to misbranding and the prohibition pervise children as necessary until ca- in section 301(d) of the act against the pable of using without supervision. introduction or delivery for introduc- Children under 6 years of age: Do not

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use unless directed by a dentist or doc- Children under 6 years of age: consult a tor. dentist or doctor. (iii) Powdered dosage form with a theo- (3) For stannous fluoride treatment retical total fluorine concentration of 850 rinse products. (i) ‘‘Use immediately to 1,150 ppm identified in § 355.10(a)(2). after preparing the rinse.’’ Adults and children 6 years of age and (ii) For powder or effervescent tablets older: Apply powder to a wet tooth- used to prepare treatment rinses. ‘‘Do not brush; completely cover all bristles. use as a rinse until all the’’ (select one Brush for at least 30 seconds. Reapply of the following: ‘‘powder’’ or ‘‘tablet’’) powder as before and brush again. ‘‘has dissolved.’’ Rinse and spit out thoroughly. Brush (4) For anticaries preventive treatment teeth, preferably after each meal or at gel products. Adults and children 6 least twice a day, or as directed by a years of age and older: Use once a day dentist or doctor. Instruct children after brushing your teeth with a tooth- under 12 years of age in good brushing paste. Apply the gel to your teeth and and rinsing habits (to minimize swal- brush thoroughly. Allow the gel to re- lowing). Supervise children as nec- main on your teeth for 1 minute and essary until capable of using without then spit out. Do not swallow the gel. supervision. Children under 6 years of Do not eat or drink for 30 minutes after age: Do not use unless directed by a brushing. Instruct children under 12 dentist or doctor. years of age in the use of this product (2) For anticaries treatment rinse prod- (to minimize swallowing). Supervise ucts—(i) For acidulated phosphate fluo- children as necessary until capable of ride solution containing 0.02 percent fluo- using without supervision. Children ride ion, sodium fluoride 0.05 percent, so- under 6 years of age: consult a dentist dium fluoride concentrate, and stannous or doctor. fluoride concentrate identified in (5) For all concentrated treatment rinse § 355.10(a)(3)(i), (a)(3)(iv), (a)(3)(v), and solutions, powders, and effervescent tab- (c)(3). Adults and children 6 years of lets. The following statement shall ap- age and older: Use once a day after pear as the first statement under direc- brushing your teeth with a toothpaste. tions: ‘‘Do not use before mixing with Vigorously swish 10 milliliters of rinse water.’’ between your teeth for 1 minute and (e) Additional labeling statements for then spit out. Do not swallow the rinse. anticaries drug products. The following Do not eat or drink for 30 minutes after statements need not appear under rinsing. Instruct children under 12 warnings, but are required to appear on years of age in good rinsing habits (to the label of anticaries drugs products minimize swallowing). Supervise chil- as applicable. dren as necessary until capable of (1) For all preventive treatment gels. using without supervision. Children ‘‘This is a(n)’’ (select one or both of the under 6 years of age: Consult a dentist following: ‘‘anticavity’’ or ‘‘fluoride’’) or doctor. ‘‘preventive treatment gel, not a tooth- (ii) For acidulated phosphate fluoride paste. Read directions carefully before solution containing 0.01 percent fluoride using.’’ ion and sodium fluoride 0.02 percent aque- (2) For all stannous fluoride treatment ous solution identified in § 355.10(a)(3)(ii) rinse, preventive treatment gel, and den- and (a)(3)(iii). Adults and children 6 tifrice products. ‘‘This product may years of age and older: Use twice a day produce surface staining of the teeth. after brushing your teeth with a tooth- Adequate toothbrushing may prevent paste. Vigorously swish 10 milliliters of these stains which are not harmful or rinse between your teeth for 1 minute permanent and may be removed by and then spit out. Do not swallow the your dentist.’’ rinse. Do not eat or drink for 30 min- (f) Optional additional labeling state- utes after rinsing. Instruct children ments—(1) For fluoride treatment rinses under 12 years of age in good rinsing and preventive treatment gels. The fol- habits (to minimize swallowing). Su- lowing labeling statement may appear pervise children as necessary until ca- in the required boxed area designated pable of using without supervision. ‘‘APPROVED USES’’: ‘‘The combined

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daily use of a fluoride preventive treat- Subpart D—Testing Procedures ment’’ (select one of the following: ‘‘rinse’’ or ‘‘gel’’) ‘‘and a fluoride tooth- § 355.70 Testing procedures for fluo- paste can help reduce the incidence of ride dentifrice drug products. dental cavities.’’ (a) A fluoride dentifrice drug product (2) For dentifrice products containing shall meet the biological test require- 1,500 ppm theoretical total fluorine. ments for animal caries reduction and ‘‘Adults and children over 6 years of one of the following tests: Enamel solu- age may wish to use this extra- bility reduction or fluoride enamel up- strength fluoride dentifrice if they re- take. The testing procedures for these side in a nonfluoridated area or if they biological tests are labeled Biological have a greater tendency to develop cav- Testing Procedures for Fluoride ities.’’ Dentifrices; these testing procedures are on file under Docket No. 80N–0042 in [60 FR 52507, Oct. 6, 1995; 60 FR 57927, Nov. 24, the Division of Dockets Management 1995; 61 FR 51187, Oct. 7, 1996; 64 FR 13296, (HFA–305), Food and Drug Administra- Mar. 17, 1999] tion, 5630 Fishers Lane, rm. 1061, Rock- ville, MD 20852, and are available on re- § 355.55 Principal display panel of all quest to that office. fluoride rinse drug products. (b) The United States Pharmacopeia In addition to the statement of iden- fluoride dentifrice reference standards tity required in § 355.50, the following along with reference standard stability statement shall be prominently placed profiles (total fluoride, available fluo- on the principal display panel: ‘‘IM- ride ion, pH, and specific gravity) re- PORTANT: Read directions for proper quired to be used in the biological tests use.’’ are available to any purchaser upon written request to the United States § 355.60 Professional labeling. Pharmacopeial Convention, Inc., 1260 (a) The labeling for anticaries fluo- Twinbrook Parkway, Rockville, MD ride treatment rinses identified in 20852. § 355.10(a)(3) and (c)(3) that are spe- (c) Alternative testing procedures cially formulated so they may be swal- may be used. Any proposed modifica- lowed (fluoride supplements) and are tion or alternative testing procedures provided to health professionals (but shall be submitted as a petition in ac- not to the general public) may contain cord with § 10.30 of this chapter. The petition should contain data to support the following additional dosage infor- the modification or data dem- mation: Children 3 to under 14 years of onstrating that an alternative testing age: As a supplement in areas where procedure provides results of equiva- the water supply is nonfluoridated (less lent accuracy. All information sub- than 0.3 parts per million (ppm)), clean mitted will be subjected to the disclo- the teeth with a toothpaste and rinse sure rules in part 20 of this chapter. with 5 milliliters (mL) of 0.02 percent or 10 mL of 0.01 percent fluoride ion [60 FR 52507, Oct. 6, 1995, as amended at 68 FR rinse daily, then swallow. When the 24879, May 9, 2003] water supply contains 0.3 to 0.7 ppm fluoride ion, reduce the dose to 2.5 mL PART 357—MISCELLANEOUS INTER- of 0.02 percent or 5 mL of 0.01 percent NAL DRUG PRODUCTS FOR fluoride ion rinse daily. OVER-THE-COUNTER HUMAN (b) The labeling for products mar- USE keted to health to health professionals in package sizes larger than those spec- Subpart A [Reserved] ified in § 355.20 shall include the statements: ‘‘For Professional Office Use Subpart B—Anthelmintic Drug Products Only’’ and ‘‘This product is not in- Sec. tended for home or unsupervised con- 357.101 Scope. sumer use.’’ 357.103 Definition. 357.110 Anthelmintic active ingredient.

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