[Federal Register Volume 68, Number 103 (Thursday, May 29, 2003)]
[Proposed Rules]
[Pages 32232-32287]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-12783]



[[Page 32231]]

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Part III





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 356



Oral Health Care Drug Products for Over-the-Counter Human Use; 
Antigingivitis/Antiplaque Drug Products; Establishment of a Monograph; 
Proposed Rules

  Federal Register / Vol. 68, No. 103 / Thursday, May 29, 2003 / 
Proposed Rules  

[[Page 32232]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 356

[Docket No. 81N-033P]
RIN 0910-AA01


Oral Health Care Drug Products for Over-the-Counter Human Use; 
Antigingivitis/Antiplaque Drug Products; Establishment of a Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is issuing an advance 
notice of proposed rulemaking that would establish conditions under 
which over-the-counter (OTC) drug products for the reduction or 
prevention of dental plaque and gingivitis are generally recognized as 
safe and effective and not misbranded. This notice is based on the 
recommendations of the Dental Plaque Subcommittee of the 
Nonprescription Drugs Advisory Committee (NDAC) and is part of FDA's 
ongoing review of OTC drug products.

DATES: Submit written or electronic comments by August 27, 2003. Submit 
reply comments by October 27, 2003.

ADDRESSES: Submit written and reply comments to the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Robert L. Sherman, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION: In accordance with part 330 (21 CFR part 
330), FDA received on December 3, 1998, a report on OTC antigingivitis/
antiplaque drug products from the Dental Plaque Subcommittee (the 
Subcommittee). FDA regulations (Sec.  330.10(a)(6)) provide that the 
agency issue in the Federal Register a proposed rule containing: (1) 
The monograph recommended by the Subcommittee, which establishes 
conditions under which OTC antigingivitis/antiplaque drug products are 
generally recognized as safe and effective and not misbranded; (2) a 
statement of the conditions excluded from the monograph because the 
Subcommittee determined that they would result in the drugs not being 
generally recognized as safe and effective or would result in 
misbranding; (3) a statement of the conditions excluded from the 
monograph because the Subcommittee determined that the available data 
are insufficient to classify these conditions under either (1) or (2) 
of this paragraph; and (4) the conclusions and recommendations of the 
Subcommittee.
    The unaltered conclusions and recommendations of the Subcommittee 
are issued to stimulate discussion, evaluation, and comment on the full 
sweep of the Subcommittee's deliberations. The report has been prepared 
independently of FDA, and the agency has not yet fully evaluated the 
report. The Subcommittee's findings appear in this document to obtain 
public comment before the agency reaches any decision on the 
Subcommittee's recommendations. This document represents the best 
scientific judgment of the Subcommittee, but does not necessarily 
reflect the agency's position on any particular matter contained in it.
    The Subcommittee was asked for its general recommendations on 
combination products in which antigingivitis/antiplaque ingredients are 
combined with other oral health care ingredients. The Subcommittee 
recommended the following as rational oral health care combination 
products: (1) An antigingivitis/antiplaque active ingredient combined 
with an anticaries active ingredient, (2) an antigingivitis/antiplaque 
active ingredient combined with a tooth desensitizer active ingredient, 
and (3) an antigingivitis/antiplaque active ingredient combined with an 
anticaries active ingredient and a tooth desensitizer active 
ingredient.
    However, the agency is not aware of any marketing history of such 
combination products eligible for the OTC drug review, nor were such 
combinations submitted to the Subcommittee. Therefore, the agency is 
dissenting from these recommendations at this time. Data are needed to 
establish the safety and effectiveness of these combination products. 
Accordingly, none of the combination products described above may be 
marketed OTC at this time under this advance notice of proposed 
rulemaking. The agency invites supporting data and information 
demonstrating that these combination products can be generally 
recognized as safe and effective for OTC use.
    Based on proposals from industry, the Subcommittee also made 
general recommendations on testing requirements for final product 
formulations to be considered effective. The agency is seeking specific 
information from interested parties on testing protocols, effectiveness 
criteria, and statistical methods employed to analyze the data from 
these tests.
    The agency notes that the Subcommittee concluded that an active 
ingredient could be either an antigingivitis agent or an 
antigingivitis/antiplaque agent. While an ingredient may also be 
effective in reducing plaque, the Subcommittee stated that the 
therapeutic endpoint for both antigingivitis and antigingivitis/
antiplaque active ingredients is a significant reduction in gingivitis, 
which can be measured using gingival index scores (see section II.C of 
this document).
    The Subcommittee concluded that there is an association between 
plaque and gingivitis. The Subcommittee agreed, however, that the exact 
relationship between plaque and gingivitis cannot be quantified. 
Because the data submitted to support the effectiveness of stannous 
fluoride in reducing plaque were inconclusive, the Subcommittee 
proposed an ``antigingivitis'' statement of identity for this 
ingredient. However, the Subcommittee's proposed indication for this 
ingredient includes a reference to plaque reduction.
    Although it did not require that antigingivitis ingredients also be 
effective in reducing plaque, the Subcommittee agreed that ingredients 
that work primarily by means other than plaque reduction would be 
inappropriate for use in OTC antigingivitis drug products because these 
products may mask the symptoms of a more serious condition and cause 
consumers to delay seeking the advice of a dentist. Because the 
Subcommittee believed that none of the submitted active ingredients 
acted other than by reducing plaque, this issue was not further 
discussed.
    Therefore, the agency is seeking comment on the basis for allowing 
an antigingivitis active ingredient that has not demonstrated 
effectiveness in reducing plaque to bear labeling statements relating 
to plaque reduction. More importantly, because of the safety concern 
that antigingivitis ingredients that work by a mechanism other than 
plaque reduction (e.g., anti-inflammatory) may give consumers a false 
sense of security by masking symptoms of a more serious disease, the 
agency is also seeking comment on whether products that are solely 
antigingivitis agents, i.e., products that do not significantly reduce 
plaque,

[[Page 32233]]

constitute appropriate OTC drug products.
    After reviewing all comments submitted in response to this 
document, FDA will issue in the Federal Register a tentative final 
monograph (TFM) for OTC drug products for the reduction or prevention 
of dental plaque and gingivitis. Under the OTC drug review procedures, 
the agency's position and proposal are first stated in the TFM, which 
has the status of a proposed rule. Final agency action occurs in the 
final monograph, which has the status of a final rule.
    In accordance with Sec.  330.10(a)(2), the Subcommittee and FDA 
have held as confidential all information concerning OTC drug products 
for the reduction or prevention of dental plaque and gingivitis 
submitted for consideration by the Subcommittee. All submitted 
information will be put on public display in the Dockets Management 
Branch (see ADDRESSES) after June 30, 2003, except to the extent that 
persons submitting it demonstrate that it falls within the 
confidentially provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 
section 301(j) of the Federal Food, Drug, and Cosmetic Act (the act) 
(21 U.S.C. 331(j)). Requests for confidentiality should be submitted to 
Robert L. Sherman, Center for Drug Evaluation and Research (see FOR 
FURTHER INFORMATION CONTACT).
    The agency advises that the conditions under which the drug 
products that are subject to this monograph would be generally 
recognized as safe and effective and not misbranded (monograph 
conditions) will be effective 12 months after the date of publication 
of the final monograph in the Federal Register. On or after that date, 
no OTC drug products that are subject to the monograph and that contain 
nonmonograph conditions, i.e., conditions that would cause the drug to 
be not generally recognized as safe and effective or to be misbranded, 
may be initially introduced or initially delivered for introduction 
into interstate commerce unless they are the subject of an approved new 
drug application (NDA) or abbreviated new drug application (ANDA). 
Further, any OTC drug products subject to this monograph that are 
repackaged or relabeled after the effective date of the monograph must 
be in compliance with the monograph regardless of the date the product 
was initially introduced or initially delivered for introduction into 
interstate commerce unless they are the subject of an NDA or ANDA. 
Manufacturers are urged to comply voluntarily with the monograph at the 
earliest possible date.
    A proposed review of the safety, effectiveness, and labeling of all 
OTC drugs by independent advisory review panels was announced in the 
Federal Register of January 5, 1972 (37 FR 85). The final regulations 
providing for this OTC drug review under Sec.  330.10 were published 
and made effective in the Federal Register of May 11, 1972 (37 FR 
9464). In accordance with these regulations, a request for data and 
information on all active ingredients used in OTC drug products bearing 
antiplaque and antiplaque-related claims was issued in the Federal 
Register of September 19, 1990 (55 FR 38560). These claims included the 
reduction or prevention of plaque, tartar, calculus, film, sticky 
deposits, bacterial buildup, gingivitis, diseased, inflamed, or swollen 
gums, pyorrhea, Vincent's disease, periodontal disease, and tooth-
destroying acids.
    The Commissioner of Food and Drugs appointed the following members 
of the Dental Products Panel (the Panel) to review the information 
submitted and to prepare a report under Sec.  330.10(a)(1) and (a)(5) 
on the safety, effectiveness, and labeling of those products:
    Paul B. Robertson, Chairperson
    Charles N. Bertolami (resigned March 24, 1997)
    William H. Bowen (term ended October 31, 1995)
    Carlos E. del Rio (resigned December 14, 1994)
    Julianne Glowacki (term ended October 31, 1994)
    Deborah Greenspan
    Richard D. Norman
    Burton Rosan
    Christine D. Wu
    The Subcommittee, comprised of two members from the Panel plus five 
nonvoting consultants to the Panel, was subsequently formed to evaluate 
the submitted data and report its findings on the safety and 
effectiveness of ingredients for the reduction or prevention of dental 
plaque and gingivitis. Each of the following was a voting member of the 
Subcommittee:
    William H. Bowen, Chairperson (term ended April 1995)
    Robert J. Genco, Chairperson (from April 1995 to December 3, 1998)
    Ralph D'Agostino
    Max A. Listgarten
    Shelia M. McGuire
    Eugene D. Savitt
    Stanley R. Saxe
    Jorgen Slots (resigned April 12, 1995)
    Christine D. Wu
    Several nonvoting liaison representatives served on the 
Subcommittee. P. Jean Frazier, served as the consumer liaison until 
June 6, 1996, followed by Susan Cohen, until May 1997, and Donald S. 
Altman, on May 27, 1998. Frederick A. Curro, served as industry liaison 
(drug) until October 31, 1995, followed by Lewis P. Cancro. Gerald N. 
McEwen, Jr., served as industry liaison (cosmetic) until October 31, 
1996.
    On August 27, 1997, oversight of the Subcommittee was transferred 
from the Panel in the Center for Devices and Radiologic Health (CDRH) 
to the Nonprescription Drugs Advisory Committee in the Center for Drug 
Evaluation and Research (CDER).
    The following FDA employees assisted the Subcommittee:
    Carolyn Tollendi served as CDRH Executive Secretary to the Panel 
until June 7, 1996. Kennerly K. Chapman served as CDER Executive 
Secretary to the Subcommittee until December 17, 1996, followed by 
Andrea Neal until May 9, 1997, followed by Rhonda Stover (interim) 
until May 1998, followed by Kathleen Reedy. Jeanne L. Rippere served as 
CDER liaison to the Subcommittee until June 7, 1996, followed by Robert 
L. Sherman. Stephanie A. Mason served as special assistant to the 
Subcommittee until June 7, 1996.
    The Panel and the Subcommittee were first convened on August 2 and 
3, 1993, for a joint organizational meeting. Working meetings of the 
Subcommittee were held on December 16 and 17, 1993; June 28 and 29, 
October 11, and December 5, 6, and 7, 1994; April 10, 11, and 12, 
August 14 and 15, and December 4 and 5, 1995; June 6 and 7, and 
December 16 and 17, 1996; October 29 and 30, 1997; May 27, 28, and 29, 
October 22, and December 2 and 3, 1998. Joint meetings of the Panel and 
the Subcommittee were held on August 2 and 3, 1993, and December 6, 
1994. Minutes of most Subcommittee meetings are on public display in 
the Dockets Management Branch (see ADDRESSES).
    The following individuals appeared before the Panel and/or the 
Subcommittee at their own or at the Panel's or Subcommittee's request 
to discuss drug products for the reduction or prevention of plaque and 
gingivitis: Gariela Adam-Rodwell, Sam Amer, Daniel M. Bagley, John E. 
Bailey, Michael L. Barnett, Robert D. Bartizek, Kenneth Baumgartner, 
William J. Blot, Nancy L. Buc, Gregory A. Burkhart, Lewis P. Cancro, 
James R. Cheever, Philip Cole, W. Greg Collier, Mark M. Crisanti, 
Catherine C. Davis, Phillip Derfler, John M. DeSesso, Harvey L. 
Dickstein, Jerry A. Douglass, Matthew J. Doyle, W. Gary Flamm, William 
E. Gilbertson, Brian F. Gillespie, David M. Graham, Robert Heller, Jane 
E. Henney,

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Ira D. Hill, Peter B. Hutt, Frederick N. Hyman, Eugene Kamper, Linda M. 
Katz, Bruce Kohut, Surinder Kumar, Anthony C. Lanzaiaco, Mark S. 
Leusch, Debbie L. Lumpkins, Milton V. Marshall, Stephanie A. Mason, 
Stephen F. McClanahan, Stephen H. McNamara, Jerome A. Merski, David 
Morrisson, Kevin P. Mulry, Anne J. Mustafa, Paul J. Okarma, C. Lee 
Peeler, Julie H. Rhee, David I. Richardson, Jeanne L. Rippere, Norman 
A. See, James M. Serafino, Samuel Shapiro, Robert L. Sherman, Chakwan 
Siew, Gregory Singleton, James Skiles, Thomas J. Slaga, R. William 
Soller, Steven D. Stellman, George K. Stookey, Howard Strassler, 
Stanley Tarka, Jr., John M. Treacy, Jack Vincent, Frank A. Volpe, 
Michael Weintraub, Clifford W. Whall, Jr., Donald J. White, Robert 
White, Charles Wiggins, David Williams, Gary M. Williams, Deborah Winn, 
Roy Witkin, and Patrice Wright. No person who so requested was denied 
an opportunity to appear before the Panel or Subcommittee.
    The Subcommittee has thoroughly reviewed the literature and data 
submissions, listened to additional testimony from interested persons, 
and considered all pertinent data and information submitted through 
December 3, 1998, in arriving at its conclusions and recommendations. 
The Subcommittee wishes to thank the American Dental Association's 
(ADA) Council on Scientific Affairs for its assistance in providing 
data, information, and testimony during the course of the 
Subcommittee's deliberations. The ADA also provided its ``Guidelines 
for Acceptance of Chemotherapeutic Products for the Control of 
Supragingival Plaque and Gingivitis'' to the Subcommittee for 
consideration in making its recommendations on the requirements for 
safe and effective OTC antigingivitis/antiplaque ingredients.
    In accordance with the OTC drug review regulations in Sec.  330.10, 
the Subcommittee reviewed OTC drug products for the reduction or 
prevention of dental plaque and gingivitis with respect to the 
following three categories:
    Category I--Conditions under which OTC drugs for the reduction or 
prevention of dental plaque and gingivitis are generally recognized as 
safe and effective and are not misbranded.
    Category II--Conditions under which OTC drugs for the reduction or 
prevention of dental plaque and gingivitis are not generally recognized 
as safe and effective or are misbranded.
    Category III--Conditions for which the available data are 
insufficient to permit final classification at this time.

I. Submission of Data and Information

    Under the notices published in the Federal Register of September 
19, 1990 (55 FR 38650), and March 8, 1991 (56 FR 9915), the following 
firms made submissions regarding OTC drug products that the Panel/
Subcommittee determined contained active ingredients or labeling 
associated with claims relating to the reduction or prevention of 
dental plaque and gingivitis.

A. Submissions by Firms

                 Table 1.--Firms and Submitted Products
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                Firm                          Submitted Products
------------------------------------------------------------------------
American Xyrofin (Morgan, Lewis &    Xylitol All Natural Toothpaste,
 Bockius) Washington, DC 20036        Xytol 32 Dental Cream.
------------------------------------------------------------------------
Amer Co., Montecito, CA 93150        Insadol Toothpaste, Pyoralene
                                      Toothpaste.
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Angus Chemical Co., Northbrook, IL   Hexetidine solution.
 60062
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Chesebrough Pond's USA Co.,          CloseUp Antiplaque Toothpaste,
 Greenwich, CT 06836                  Mentadent P Toothpaste.
------------------------------------------------------------------------
Church & Dwight Co., Inc.,           Arm & Hammer Dental Tooth Powder,
 Princeton, NJ 08543                  Dentifrice, and Gel.
------------------------------------------------------------------------
CIBA-GEIGY Corp., Greensboro, NC     Irgasan DP, Irgacare MP.
 27419
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Clinical Product Research, Inc.,     Prozyme Toothpaste, Anti-Plaquer
 Shreveport, LA 71109                 Oral Rinse, Anti-Plaquer
                                      Toothpaste.
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Colgate-Palmolive Co., Piscataway,   Colgate Tartar Control Toothpaste,
 NJ 08855                             Gelkam Oral Care Rinse, Dentaguard
                                      Toothpaste.
------------------------------------------------------------------------
E. Merck, Frankfurter, Germany       Thera-Med, Cholordont M.
------------------------------------------------------------------------
E. B. Michaels Research Associates,  Therasol Brush & Rinse Antiplaque
 Inc., Milford, CT 06460              Oral Hygiene Solution, Therasol
                                      Brush & Rinse Liquid Dentifrice
                                      Oral Irrigant.
------------------------------------------------------------------------
Leaf, Inc., (Hyman, Phelps &         Xylitol.
 McNamara) Washington DC 20005
------------------------------------------------------------------------
Lion Corp. (America), Memphis, TN    Check-Up Gingival Toothpaste.
 38138
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Madaus Medtech, Inc., (ACC           Parodontax Toothpaste.
 Consulting Group, Inc.) Washington
 DC 20036
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Pfizer Inc, New York, NY 10017       Plax Pre-Brushing Dental Rinse.
------------------------------------------------------------------------
Pierre Fabre, S.A., 81106 Castres    Eligydium Toothpaste, Eludil
 Cedex, France                        Mouthwash.
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Prevention Laboratories (formerly 7- Prevention Mouth Rinse.
 L Corp.), Harrisburg, IL 62947
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Procter & Gamble Co., Cincinnati,    Crest Gum Care Toothpaste.
 OH 45242
------------------------------------------------------------------------

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SmithKline Beecham Consumer Brands   Cepacol Gold and Mint Mouthwashes,
 (Marion Merrell Dow, Inc.),          Gly-oxide Liquid.
 Parsippany, NJ 07054
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Vipont Pharmaceuticals, Fort         Viadent Toothpaste and Oral Rinses.
 Collins, CO 80522
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Warner-Lambert Co., Morris Plains,   Listerine Antiseptic Mouthwash.
 NJ 07950
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WhiteHill Oral Technologies, Inc.,   Omni-Med Brush-On Tooth Medication,
 Hazlet, NJ 07730                     Perio-Med Spray, Take-5 Plaque
                                      Fighter Brushless Dentifrice,
                                      Smokers Take-5 Plaque and Stain
                                      Fighter.
------------------------------------------------------------------------
Witkins, Roy T., Westport, CT 06880  Perimed Oral Hygiene Rinse.
------------------------------------------------------------------------

    In categorizing ingredients as ``active'' and ``inactive,'' the 
advisory review panels relied upon their expertise and understanding of 
these terms. FDA has defined ``active ingredient'' in its current good 
manufacturing practice regulations in Sec.  210.3(b)(7) (21 CFR 
210.3(b)(7)) as:
    [Any] component that is intended to furnish pharmacological 
activity or other direct effect in the diagnosis, cure, mitigation, 
treatment, or prevention of disease, or to affect the structure or 
any function of the body of man or other animals. The term includes 
those components that may undergo chemical change in the manufacture 
of the drug product and be present in the drug product in a modified 
form intended to furnish the specified activity or effect.
    An ``inactive ingredient'' is defined in Sec.  210.3(b)(8) as ``any 
component other than an active ingredient.''

B. Active Ingredients Submitted For Review

    Labeled Ingredients Contained in Marketed Products Submitted to the 
Subcommittee:
    Alkyl dimethyl amine oxide
    Alkyl dimethyl glycine
    Aloe vera
    Bromchlorophene
    Carbamide peroxide
    Cetylpyridinium chloride
    Chlorhexidine digluconate
    Dicalcium phosphate dihydrate
    Eucalyptol
    Hexetidine
    Hydrogen peroxide
    Menthol
    Methyl salicylate
    Peppermint oil
    Polydimethylsiloxane
    Poloxamer
    Povidone iodine
    Sage oil
    Sanguinaria extract
    Sodium bicarbonate
    Sodium citrate
    Sodium lauryl sulfate
    Soluble pyrophosphate
    Stannous fluoride
    Stannous pyrophosphate
    Thymol
    Triclosan
    Unsaponifiable fraction of corn oil
    Xylitol
    Zinc chloride
    Zinc citrate
    Some of these ingredients (bromchlorophene, chlorhexidine 
digluconate, hexetidine, soluble pyrophosphate, triclosan, 
unsaponifiable fraction of corn oil) were not marketed for a material 
time and to a material extent for antigingivitis/antiplaque use in the 
United States. (See 21 U.S.C. 321(p)(2).) Although the Subcommittee 
reviewed data to support the safety and effectiveness of these 
ingredients, they are not eligible for inclusion in the OTC drug review 
as part of this advance notice of proposed rulemaking and, therefore, 
are not discussed in this document. In addition, although xylitol was 
reviewed by the Subcommittee, the two firms that submitted data 
subsequently withdrew xylitol from consideration by the Subcommittee. 
Therefore, xylitol is not discussed.
    The nomenclature used by the Subcommittee for the ingredients 
reviewed in this document was the currently accepted terminology stated 
in the 1996 edition of ``USAN and the USP Dictionary of Drug Names.'' 
Names recommended by FDA were used for any ingredients which did not 
have USAN names.

C. Referenced OTC Volumes

    All ``OTC Volumes'' cited throughout this document refer to 
submissions made by interested persons under the call-for-data notices 
published in the Federal Register of September 19, 1990, and March 8, 
1991. The information included in these volumes, except for those 
deletions made in accordance with the confidentiality provisions in 
Sec.  330.10(a)(2), will be put on public display after June 30, 2003, 
in the Dockets Management Branch (see ADDRRESSES).

II. General Statements and Recommendations

A. Definitions

    The Subcommittee adopted the following definitions as its intended 
meaning of terms specifically used in this document concerning OTC drug 
products for the reduction or prevention of dental plaque and 
gingivitis. The Subcommittee was aware that some degree of variation 
with other definitions of the same term may exist.
    [sbull] Calculus. The hard concretions (i.e., calcified plaque) 
that form on teeth, prostheses, and other hard surfaces. Calculus on 
teeth is clinically classified into supragingival calculus, which is 
located on surfaces not covered by the oral mucosa, and subgingival 
calculus, which is located apical (at the top) to the soft tissue 
margin of the gingiva.
    [sbull] Dental Plaque. Organized coherent gel-like or mucoid masses 
consisting of microorganisms in an organic matrix derived from saliva 
and extracellular bacterial products such as glucans, fructans, 
enzymes, toxins, and acids. Plaque also contains other cells (e.g., 
desquamated epithelial cells) and inorganic components such as calcium 
and phosphate. It adheres to the teeth and other surfaces of the oral 
cavity. It occurs at the orifice of the gingival crevices and in the 
periodontal pockets. Plaques may differ markedly in biochemical or 
microbial composition, and their localization.
    [sbull] Gingival Sulcus. The shallow groove between the tooth and 
the marginal gingiva.
    [sbull] Gingivitis. An inflammatory lesion of the gingiva that is 
most frequently caused by dental plaque. Gingivitis is characterized by 
tissue swelling and redness, loss of stippling (a normal state in which 
the surface of healthy gingiva is comprised of small lobes), glossy 
surface, and increased tissue

[[Page 32236]]

temperature. The gingiva also may bleed upon gentle provocation such as 
toothbrushing or may bleed spontaneously. Gingivitis is usually not 
painful.
    [sbull] Oral Hygiene. Self-administered processes aimed at 
controlling microbial and other deposits in the oral cavity.
    [sbull] Pellicle. A thin, colorless, translucent film derived from 
bacterial products and saliva, which forms rapidly on tooth surfaces 
after natural cleansing or prophylaxis. A few hours after deposition, 
oral bacteria begin to adhere to the pellicle. These processes 
represent the earliest stages of plaque formation.
    [sbull] Periodontitis. A disease condition of the periodontium 
characterized by inflammation of the gingiva, increasing probing depth, 
and destruction of the periodontal ligament and the adjacent supporting 
alveolar bone.
    [sbull] Tartar. A synonymous term for calculus.

B. Background and General Discussion of Terms

1. Background
    The Subcommittee was charged with the evaluation of the safety and 
effectiveness of ingredients or combinations of ingredients for the 
reduction or prevention of plaque and gingivitis as claimed in the 
labeling of OTC drug products in light of present-day knowledge and 
standards used in pharmacology, pharmacodynamics, therapeutics, and 
toxicology.
    In making its evaluation, the Subcommittee relied upon factual data 
found in standard textbooks and scientific articles published by 
independent investigators in medical, dental, and other scientific 
journals. Manufacturers included some of these scientific articles in 
their submissions to FDA to provide a scientific basis for claims made 
for the safety and effectiveness of their ingredients. Data supplied by 
manufacturers in unpublished reports of studies performed by private 
laboratories under contract to the manufacturer or in manufacturers' 
laboratories were also used by the Subcommittee in making judgments. 
The Subcommittee also gave due consideration to data from marketing 
experience and widespread clinical usage when in agreement with basic 
data from controlled studies and scientific facts.
2. Plaque
    Plaque, also known as dental plaque and/or microbial plaque, has 
been examined for several decades with most of the information 
explained in the past 25 years. Plaque has a critical etiological role 
in the development of dental caries, gingivitis, and periodontal 
disease. It is now clear that dental plaque is a variable biologic 
community made up of bacteria and a bacterially synthesized matrix. 
While dental plaque may be combined with other materials such as food 
particles and sloughed epithelial cells, the combination of these 
components is called materia alba and is no longer considered plaque.
    The precise genera and species of microorganisms in each dental 
plaque may differ from individual to individual, site to site in the 
same individual, and within a specific site over time. Plaque from 
sites of similar clinical health within individual subjects tends to be 
more similar in composition than plaque from sites in different 
subjects. Even though there is considerable variation within dental 
plaques, the composition of plaque is influenced by several factors. 
The composition of dental plaques is currently known to be affected by 
plaque age, dietary intake of sucrose and other foods, and other 
factors (e.g., friction of mastication, oral health, and salivary 
flow).
    Plaque composition is also affected by its location above or below 
the gingiva. Dental plaques are subdivided into supragingival plaque 
and subgingival plaque. The distinction resides in the location of 
dental plaque as either coronal (toward the crown) or apical (toward 
the root tip) to the soft tissue margin. The microbial populations may 
differ in plaque from the two locations.
    The extracellular matrix synthesized by the bacteria is a 
significant component of plaque. Because the matrix provides plaque 
organisms with strong adhesive and cohesive properties, plaque is not 
easily removed. The tenacity of plaque to adhere to the surfaces of 
oral structures can be used to distinguish plaque from debris, in that 
plaque is not removed by flushing the mouth with water.
    Plaques differ not only quantitatively but qualitatively in their 
bacterial composition. For example, microorganisms found in dental 
plaque include Actinomyces species, Streptococcus sanguis, S. mutans, 
and other Streptococcus species, Spirochetes, Porphyromonas gingivalis, 
Bacteroides forsythus, and other Bacteroides species, Campylobacter 
recta, Peptostreptococcus micros, Eikenella corrodens, Actinobacillus 
actinomycetemcomitans, Eubacterium species, Fusobacterium species, 
Capnocytophaga species, and Prevotella species. This difference in 
bacterial composition has a major effect on its pathogenic potential 
both for periodontal diseases and caries. Some dental plaques are not 
pathogenic or associated with disease, whereas others are etiologic 
factors for caries and periodontal diseases. However, the two types of 
plaque cannot be distinguished visually. The pathogenic potential is 
dependent upon the microbial composition, including the metabolic 
products of microbes, dietary patterns, and the intrinsic resistance of 
the host. It may be prudent to treat all plaques as having pathogenic 
potential.
3. Calculus
    Calculus is a hard concretion that forms on the teeth or dental 
prostheses through deposition of mineral salts in dental plaques. Human 
calculus is essentially mineralized dental plaque, which is almost 
always covered on its external surface by vital, tightly adherent, 
nonmineralized soft plaque. There may also be loosely held materials 
associated with calculus such as materia alba, shed bacteria, 
desquamated epithelial cells, and blood cells. In germ-free animals, 
calcified deposits may occur in the absence of bacterial accumulation 
(Ref. 1). However, in humans, virtually all calculus seen clinically 
likely results from the deposition of calcium and phosphates within 
bacterial plaques. Calculus formation occurs in an orderly fashion, 
beginning after 1 or 2 weeks of plaque formation and resulting in full 
calcification of plaque after 2 to 4 weeks. The process occurs more 
rapidly in some persons than in others.
    Calculus may form subgingivally and is often stained and 
tenaciously attached to the crown and/or root of the tooth. Calculus 
may also form supragingivally, coronal (toward the crown) to the 
gingival margin. Supragingival calculus is found in greater amounts on 
tooth surfaces adjacent to the openings of the ducts of the major 
salivary glands. Both subgingival and supragingival calculus are often 
stained; supragingival calculus can be unsightly, particularly when 
formed in abundance on labial (facing the lips) surfaces. Although 
subgingival calculus is a contributing factor in the development of 
gingivitis, and can also be associated with the progression of 
gingivitis, periodontitis, and periodontal abscesses, the exact nature 
of the role of supragingival calculus in gingivitis is not clear. 
Supragingival calculus can accumulate plaque and act as a nidus (nest) 
for plaque formation, which can lead to gingivitis.
    Calculus facilitates the retention of dental plaque in close 
proximity to the periodontal tissues. It reduces the

[[Page 32237]]

effectiveness of overall hygiene methods to control dental plaque 
accumulation. Subgingival calculus interferes with the regeneration of 
lost periodontal attachment.
    The removal of calculus is considered a basic step in the 
prevention and treatment of inflammatory periodontal diseases. The 
formation of supragingival calculus can be limited through mechanical 
or chemical methods. Preventing subgingival calculus formation, if 
possible, would not necessarily reduce gingivitis, because a surface 
currently free of calculus can still harbor plaque. Present methods do 
not allow for the predictable prevention of subgingival calculus.
4. Gingivitis
    Gingivitis, an inflammation of the gingiva, affects most of the 
population at one time or another. The signs of gingivitis are tissue 
swelling and redness, loss of stippling, glossy surface, and increased 
tissue temperature. The gingiva may also bleed upon gentle provocation, 
such as toothbrushing, or may bleed spontaneously. Some signs of 
gingivitis, such as bleeding, can be identified by lay persons.
    Gingivitis is a response to injury, often resulting in localization 
of tissue damage and neutralization of the effects of injurious agents. 
If the injurious agents cannot be adequately neutralized or eliminated, 
they may lead to chronic inflammation of the soft tissue and 
periodontitis. While most cases of periodontitis are believed to start 
with gingivitis, most cases of gingivitis do not progress to 
periodontitis. Histologically, gingivitis is characterized by 
inflammatory exudate or infiltrate, loss of collagen of the gingival 
connective tissue, and proliferation of the epithelium into the 
infiltrated tissue. Sometimes the epithelium lining the sulcus (crevice 
bounded by the tooth and free gingiva) may develop microulcerations. In 
gingivitis, the junctional epithelium usually is at or near the 
cementoenamel junction (junction of the tooth crown and root).
    Gingivitis, especially when severe, may be self-diagnosable because 
people can recognize some of the signs of gingivitis, such as bleeding, 
gingival discoloration, and swelling, which gives rise to pseudopockets 
(pocket-like structure caused by inflammation of the gingiva without 
effecting the sulcus base). In the early stages of gingivitis when 
there is little or no pseudopocket formation, only noncalcified plaque, 
and little or no calculus, thorough daily oral hygiene may resolve the 
disease. Under these conditions, self-treatment of gingivitis is 
appropriate. When OTC drug products for the prevention and control of 
plaque-associated gingivitis are used as part of a program of good oral 
hygiene, including regular dental checkups, they can help consumers 
maintain their gingival health.
    The most common form of gingivitis is termed marginal gingivitis 
and occurs in all individuals at some time. It is limited to the 
gingivae around the collar of the tooth. However, people are seldom 
easily able to detect sites with mild gingivitis because there may be 
no pain or bleeding. Plaque-associated gingivitis, an inflammation of 
the interdental and marginal gingiva, can be controlled or prevented by 
removal or inhibition of microbial plaque accumulation. 
Chemotherapeutic agents can enhance the benefits of traditional methods 
of oral cleansing by toothbrushing with a dentifrice and regular use of 
dental floss and other cleaning aids.
    Readily available OTC drug products for the prevention and control 
of plaque-associated gingivitis are intended to play a significant 
public health role. However, the effects of these products in 
periodontitis have not been determined in large scale studies. OTC drug 
products are useful adjuncts to, but do not replace, regular 
professional care.
    In the later stages of gingivitis with the formation of 
pseudopockets and calculus, it becomes more difficult for people to 
resolve the gingivitis. Therefore, self-treatment has limited potential 
for resolution of severe gingivitis, which should be treated as part of 
a regular professional care program. Gingivitis can progressively 
worsen and lead to the development of pockets that can be difficult for 
people to clean.
5. The Interrelationship Between Plaque and Gingivitis
    Dental plaque can be causally related to gingivitis. A critical 
plaque mass at the gingival margin for a particular length of time can 
initiate change. However, the Subcommittee has no knowledge of any 
studies where the volume, mass, or amount of plaque can be closely 
equated with the extent of gingival inflammation. There is a general, 
positive relationship between supragingival plaque levels and levels of 
gingivitis. For example, with little or no supragingival plaque 
accumulation, most often there is gingival health, whereas heavy levels 
of plaque accumulation, especially at the gingival margin, are often 
associated with gingivitis.
    Plaque forms readily on tooth surfaces in individuals with poor 
oral hygiene. It takes, histologically, about 3 to 4 days with no oral 
hygiene in periodontally healthy subjects to develop microscopic 
evidence of gingivitis. This evidence consists of infiltration of the 
gingival epithelium, especially the junctional epithelium, with 
inflammatory cells (including neutrophils), infiltration of the 
gingival connective tissue with lymphocytes, and beginning loss of 
collagen.
    The Subcommittee does not know how long plaque must be present 
before gingivitis spontaneously appears. When distinguishing between 
experimentally induced gingivitis and spontaneous gingivitis 
(developing under conditions of normal oral hygiene) the following are 
found: (1) Most subjects over a period of 1 to 3 weeks of cessation of 
oral hygiene developed gingivitis measurable with clinical indices, and 
(2) subjects must accumulate a certain level of plaque before clinical 
signs of gingivitis are apparent. In addition, mature plaque with 
complex flora appears to be correlated with gingivitis. However, mature 
plaque, comprised of a complex gram-positive and gram-negative flora 
with motile organisms, is often associated with spontaneous gingivitis.
    The Subcommittee accepts that gingivitis is associated with an 
accumulation of plaque along the gingival margin but is unaware of any 
evidence that shows that there is a close correlation between the 
amount of plaque and the induction of gingivitis, as can be assessed 
using present day methods. It should be noted that the relationship 
between the quantity of plaque present and the degree of gingivitis is 
sufficiently complex such that reductions in plaque mass alone are 
inadequate to conclude that a therapeutic effect on gingivitis could be 
expected. Therefore, gingivitis reductions must be measured directly.
6. Periodontitis
    Most cases of periodontitis are believed to start with gingivitis, 
although not all cases of gingivitis lead to periodontitis. 
Periodontitis is characterized clinically by gingivitis of varying 
severity, loss of periodontal attachment, increased probing depth, and 
radiographically detectable loss of alveolar and supporting bone. In 
advanced disease, the teeth may become increasingly mobile. Progression 
of gingivitis and the relationship of gingivitis to the onset of 
periodontitis are not well understood. However, one approach to 
addressing this relationship comes from human studies in which 
meticulous oral hygiene leading to excellent plaque control and control 
of gingivitis appears to prevent the onset of

[[Page 32238]]

periodontitis (Ref. 2). It is not clear whether this prevention was due 
to reduction of supragingival plaque associated with gingivitis, or to 
meticulous oral hygiene, which also prevents colonization of the 
subgingival area by periodontal pathogens that are responsible for the 
onset of periodontitis. What is clear, however, is that in most 
instances meticulous plaque control appears to lead to reduction of 
gingivitis and suppression of the onset or rate of progression of 
periodontitis. Despite periodontal treatment, loss of periodontal 
attachment and loss of bone often persists. Moreover, people treated 
for periodontitis may suffer from recurrent gingivitis, root 
sensitivity, and increased susceptibility to root caries. Periodontitis 
appears to progress in alternating cycles of exacerbation, which are 
often asymptomatic and localized, followed by periods of remission. 
Population studies indicate that systemic conditions such as diabetes 
mellitus and neutrophil disorders, as well as smoking, increase the 
risk for developing periodontitis (Refs. 3 and 4).
    Histologically, the gingiva becomes inflamed, and the sulcus is 
deepened to form a pocket which is lined with a pathologically altered 
epithelial lining, the pocket epithelium. The junctional epithelium is 
displaced apically. The pocket is largely filled with a subgingival 
microbiota that is in contact with the adjacent denuded root surface or 
adherent subgingival calculus deposits. The alveolar process (portion 
of the upper and lower jaws that forms and supports the tooth sockets) 
shows evidence of destruction in a ``horizontal'' or ``vertical'' 
pattern with concomitant loss of the connective tissue attachment to 
the root.
    There are several variants of the disease, including adult 
periodontitis, early-onset periodontitis (which includes localized 
juvenile), periodontitis associated with systemic diseases, necrotizing 
ulcerative periodontitis, and refractory and recurrent periodontitis. 
Of these, adult periodontitis is the most common form of the disease, 
and it responds most predictably to scaling, root planing, and plaque 
control.
7. Oral Hygiene
    The Subcommittee's definition of oral hygiene in this document 
represents the self-administered processes aimed at controlling 
microbial and other deposits in the oral cavity. Regular oral hygiene, 
by interfering with plaque accumulation and maturation, favors 
facultative (able to grow or live with or without oxygen) over 
anaerobic (growing or living in the absence of oxygen) bacteria. In the 
process, regular oral hygiene promotes clean dentition and fresh 
breath, and decreases the risk of plaque-mediated inflammatory changes 
in the oral cavity. Today, mechanical plaque removal with assorted 
devices is the primary method for maintaining good oral hygiene. 
Chemical plaque control (e.g., antiseptic or surfactant mouthrinses) is 
used primarily as an adjunct to mechanical methods and may be 
particularly useful for the treatment of surfaces that are not readily 
accessible to mechanical cleansing, for postsurgical plaque control, 
and for oral care of handicapped persons. Antibiotics may be used as 
adjuncts to oral hygiene to suppress or eliminate specific segments of 
the bacterial population not readily accessible to mechanical 
cleansing.

C. Drug/Cosmetic Status

    The current statutory definitions of ``drug'' and ``cosmetic'' 
require some consideration when applying them to products for the 
reduction or prevention of plaque and gingivitis. According to the act, 
a ``drug'' includes any article ``intended for use in the diagnosis, 
cure, mitigation, treatment, or prevention of disease,'' or any article 
``intended to affect the structure or any function of the body * * * 
.'' (See 21 U.S.C. 321(g).) According to the act, a ``cosmetic'' 
includes an article or component thereof ``intended to be rubbed, 
poured, sprinkled, or sprayed on, introduced into, or otherwise applied 
to the human body or any part thereof for cleansing, beautifying, 
promoting attractiveness, or altering the appearance * * *.'' (See 21 
U.S.C. 321(i).)
    Some products may not clearly fall under one definition or the 
other. Therefore, another consideration in classifying a product is the 
``intended use'' of the product, which is largely dependent on the 
claims made for the product and the accompanying labeling.\1\ In 
attempting to accurately describe a product's benefits, one of the 
guiding principles should be to avoid misleading the public with 
ambiguous claims. Unfortunately, in the case of mouthrinse products, it 
is easy to make claims that suggest a drug-like benefit, while staying 
within the guidelines for cosmetic products. Much of the controversy 
regarding the ``drug'' versus ``cosmetic'' issue for these products 
revolves around the use of the word ``dental plaque'' or its synonyms 
(plaque, bacterial deposits, etc.).
---------------------------------------------------------------------------

    \1\The legal opinions of this scientific panel in this area may 
not and do not necessarily reflect FDA's position.
---------------------------------------------------------------------------

1. Antiplaque Products
    It is the position of the ADA and the American Academy of 
Periodontology that the control of dental plaque is a therapeutic 
procedure basic to the prevention and treatment of caries and 
periodontal diseases, particularly the latter. The well-established 
association between dental plaque accumulation and gingivitis demands 
that effective control of gingivitis be accompanied by effective 
control of dental plaque. ``Nonspecific'' plaque control involves 
decreasing the entire microbial mass in a nonspecific manner, i.e., 
without any attempt at differentially removing or suppressing any 
particular bacterial species, although shifts in bacterial composition 
may occur. It is the primary therapy for preventing and controlling 
periodontal infections that may lead to periodontal inflammatory 
lesions.
    ``Specific'' plaque control implies the control of specific 
pathogens, using strategies that will preferentially suppress certain 
species or categories of microorganisms. This approach generally 
requires the use of antimicrobial agents, typically antibiotics, with a 
specific antimicrobial spectrum. Ideally, the microbial composition of 
the dental plaque should be assessed before and after treatment to 
insure that the antimicrobial agents used are appropriate and that the 
therapy has the desired effect.
    The nonspecific control of dental plaque needs to be thorough in 
order to achieve clinically significant therapeutic benefits. While 
some OTC oral health care products may be able to reduce the rate of 
plaque formation to a statistically significant degree, the inhibitory 
effect on plaque is often insufficient to be considered of therapeutic 
benefit. It is also highly unlikely that the marginal control of 
bacterial deposits has a significant relationship to most, if not all, 
of the cosmetic claims. Outcome variables such as taste and ``feel'' 
are more likely to be affected by flavoring agents and products that 
reduce surface tension than by minor variations in plaque accumulation.
    The claim that a product significantly reduces dental plaque 
(statistically speaking) may mislead people into thinking that the 
reduction is therapeutically significant. Thus, people may purchase a 
product with the mistaken notion that a therapeutic benefit may be 
derived from its use, instead of seeking effective care for

[[Page 32239]]

potential signs and symptoms of disease.
    Therefore, the Subcommittee proposes that any reference to the 
control of dental plaque or its equivalents, with or without 
qualifications, should be interpreted as a drug claim. In addition, the 
Subcommittee proposes that an OTC drug product making any reference to 
the reduction or prevention of dental plaque also must demonstrate a 
clinically significant effect on gingivitis. Thus, antiplaque claims 
should not stand alone.
2. Tartar Products
    The Subcommittee proposes that any reference to supragingival 
tartar (calculus) be interpreted as a cosmetic claim. The Subcommittee 
did not make any reference to subgingival tartar.

D. Labeling of Antigingivitis/Antiplaque Drug Products

    Having reviewed the submitted labels of antigingivitis/antiplaque 
drug products, the Subcommittee recommends that labeling include the 
following:
1. Ingredients
    Antigingivitis/antiplaque agents should contain only active 
ingredients plus such inactive ingredients as may be necessary for 
formulation. The label should state the name and quantity of each 
active ingredient in appropriate units as specified later in this 
document.
    For various reasons, including allergic reactions, safety concerns, 
and personal preference, individuals may wish to avoid using certain 
inactive ingredients. It is impossible to make a free choice in this 
regard unless all the components of drug products are listed on the 
labels. Therefore, the Subcommittee strongly recommends that all 
inactive ingredients be listed on the label in descending order of 
quantity. However, the product should not imply or claim that its 
inactive ingredients have a therapeutic benefit. The Subcommittee 
recognizes that although full disclosure of flavoring and coloring 
ingredients is desirable, this may be impractical and confusing because 
of the large number of ingredients that may be involved. Thus, 
flavoring and coloring ingredients may be listed in accordance with 
present regulations for labeling such ingredients in cosmetic products 
(21 CFR 701.3).
2. Statement of Identity
    The labeling must indicate the principal intended action of the 
active ingredient as well as the indication for use of the product. The 
Subcommittee recommends that the statement of identity for active 
ingredients that demonstrate an antigingivitis effect should be 
``antigingivitis.'' The recommended statement of identity for active 
ingredients that also demonstrate an antiplaque effect should be 
``antigingivitis/antiplaque.''
3. Indications
    The indications for antigingivitis/antiplaque drug products should 
be simply and clearly stated, inform the user of the general 
pharmacological action of the product, and provide a reasonable 
expectation of results to be anticipated from use of the product. The 
indications should be specific and confined to the conditions for which 
the product is recommended. The labeling for any product that contains 
an active ingredient for which no claim is made would be misleading.
    a. For all antigingivitis products. The Subcommittee's recommended 
indication for OTC drug products containing antigingivitis active 
ingredients is: ``helps (select one of the following: `control,' 
`reduce,' or `prevent') (select one or more of the following: 
`gingivitis,' `gingivitis, an early form of gum disease,' or `bleeding 
gums').''
    b. For antigingivitis products containing stannous fluoride. The 
Subcommittee's recommended indication for OTC antigingivitis drug 
products containing stannous fluoride is the statement in paragraph a. 
above and/or the following: ``helps interfere with harmful effects of 
plaque associated with gingivitis.''
    c. For all antigingivitis/antiplaque products. The Subcommittee's 
recommended indication for OTC drug products containing antigingivitis/
antiplaque active ingredients is: ``helps (select one of the following: 
`control,' `reduce,' `prevent,' or `remove') plaque that leads to 
(select one or more of the following: `gingivitis,' `gingivitis, an 
early form of gum disease,' or `bleeding gums').''
    d. For antigingivitis/antiplaque products containing the fixed 
combination of eucalyptol, menthol, methyl salycilate, and thymol. The 
Subcommittee's recommended indication for OTC drug products containing 
the fixed combination of eucalyptol, menthol, methyl salycilate, and 
thymol is the statement in paragraph c. above and/or the following: 
``helps (select one of the following: `control,' `inhibit,' or `kill') 
plaque bacteria that contribute to the development of (select one or 
more of the following: `gingivitis,' `gingivitis, an early form of gum 
disease,' or `bleeding gums').''
4. Directions for Use
    The directions for use should be clear, direct, and provide 
sufficient information to permit safe and effective use of the product. 
The product labeling should include a clear statement of the smallest 
usually effective dose and, where applicable, maximum doses (or 
concentration if more appropriate) per time interval. If dosage varies 
by age, the directions should be broken down by age groups. The 
Subcommittee used directions from the supportive clinical trials as the 
basis for its recommended directions for use.
    a. For antigingivitis or antigingivitis/antiplaque dentifrice 
products. The directions for use for antigingivitis or antigingivitis/
antiplaque dentifrice drug products should be consistent with the 
directions required in the final monograph for OTC anticaries drug 
products in 21 CFR 355.50(d)(1).
    b. For antigingivitis/antiplaque oral rinse products. ``Adults and 
children 12 years of age and older: Vigorously swish 20 milliliters of 
rinse between your teeth twice a day for 30 seconds and then spit out. 
Do not swallow the rinse. Children 6 years to under 12 years of age: 
supervise use. Children under 6 years of age: do not use.''
5. Warnings
    Labeling of antigingivitis and antigingivitis/antiplaque products 
should include warnings against unsafe use, side effects, and adverse 
reactions.
    a. For all antigingivitis and antigingivitis/antiplaque products. 
``If more than used for brushing (rinsing) is accidentally swallowed, 
get medical help or contact a Poison Control Center right away. If 
gingivitis, bleeding, or redness persists for more than 2 weeks, see 
your dentist. See your dentist immediately if you have painful or 
swollen gums, pus from the gum line, loose teeth, or increasing spacing 
between the teeth. These may be signs or symptoms of periodontitis, a 
serious form of gum disease.''
    b. For antigingivitis products containing stannous fluoride. ``Keep 
out of the reach of children under age 6.''
6. Additional Labeling Statements
    For stannous fluoride dentifrice drug products. In addition to 
warning statements, the following statements should appear on the label 
of antigingivitis dentifrice drug products containing stannous 
fluoride: ``This product may produce surface staining of the teeth. 
Adequate tooth brushing may prevent these stains which are not

[[Page 32240]]

harmful or permanent and may be removed by a dentist.''

E. Combination Drug Products

1. General Combination Policy
    The Subcommittee recognizes that there may be a reason for 
combining active ingredients in certain OTC drug products. However, 
such combinations must be based on a sound and logical scientific 
rationale. The Subcommittee applied the OTC drug review regulation in 
Sec.  330.10(a)(4)(iv) in developing a combination policy for 
antigingivitis/antiplaque drug products. The Subcommittee believes that 
it is rational to combine oral health care ingredients that meet the 
regulatory requirements as well as the criteria adopted by the 
Subcommittee, together with suitable inactive ingredients, provided 
that: (a) Each active ingredient makes a contribution to the claimed 
effect, (b) the active ingredients are safe and effective and combining 
the ingredients does not decrease the effectiveness of any individual 
ingredient, (c) combining the ingredients does not decrease the safety 
of the combination compared to a single ingredient, (d) the inactive 
ingredients are safe and do not interact with or otherwise inhibit the 
effectiveness of the active ingredients, (e) there is a significant 
target population that can benefit from the use of the combination, and 
(f) the combination contains adequate directions for use and is labeled 
with adequate warnings against unsafe use.
    The Subcommittee concludes that the same general principles apply 
when an active ingredient from a different pharmacological class 
reviewed by another OTC drug advisory panel is combined with an active 
ingredient reviewed by this Subcommittee. The rationale for such 
combinations should be evaluated by FDA according to the combination 
policy set forth in the reports of both advisory panels and in 
accordance with the agency's regulations.
2. Criteria for Category I Combination Products
    The Subcommittee recommends that each claimed active ingredient in 
a combination product must make a significant contribution to the 
claimed effects of the product. Further, two Category I active 
ingredients from different pharmacological groups may be combined to 
treat different symptoms concurrently if each Category I active 
ingredient is present within its established dosage range, the 
combination is rational, there is a significant target population that 
suffers from the concurrent symptoms, and the combination is as safe 
and as effective as each individual active ingredient used alone.
3. Category I Combination Antigingivitis/Antiplague Drug Products
    The Subcommittee considers it rational to combine antigingivitis/
antiplaque agents with an anticaries agent. It is also rational to 
combine antigingivitis/antiplaque agents with a tooth desensitizing 
agent. In addition, the Subcommittee considers it rational to combine 
an antigingivitis/antiplaque agent with an anticaries agent and a tooth 
desensitizer in a single drug product. Further, the Subcommittee 
believes that although it has been presented with no scientific basis 
to recommend the combination of two or more antigingivitis ingredients, 
two or more antigingivitis/antiplaque ingredients, or combinations of 
antigingivitis and antigingivitis/antiplaque ingredients, it is 
theoretically reasonable to combine such ingredients, provided it is 
demonstrated that each ingredient contributes to the claimed effect and 
does not decrease the safety or effectiveness of another active 
ingredient.

F. Testing of Antigingivitis/Antiplaque Drug Products

    The Subcommittee concludes that the single active ingredients and 
the fixed combination of eucalyptol, menthol, methyl salicylate, and 
thymol placed in Category I have been shown through clinical trials to 
be safe and effective for OTC use in the control of gingivitis and 
plaque. However, because product formulation can have a significant 
impact on the effectiveness of these active ingredients, the 
Subcommittee recommends that OTC antigingivitis/antiplaque drug 
products demonstrate their effectiveness through the testing described 
below. Based on the varying mechanisms of action of the Category I 
active ingredients, the Subcommittee recommends testing specific to 
each of the Category I active ingredients to demonstrate their 
effectiveness in traditional dosage forms (dentifrice, gel, paste, or 
rinse).
1. Changes in Traditional Dosage Forms
    The Subcommittee recommends that drug products containing Category 
I active ingredients formulated in dosage forms other than those 
reviewed by the Subcommittee be required to demonstrate antigingivitis/
antiplaque effectiveness by a single 6-month, randomized, controlled, 
clinical trial.
2. Final Formulation Testing
    The following testing should be conducted on the product 
formulation, a standard formulation with effectiveness documented by 
clinical trials, and a negative control. In general, for a product to 
be considered effective it must demonstrate that it is statistically 
substantially equivalent to the standard formulation and statistically 
superior to the negative control as assessed by reasonable statistical 
analyses. For validation of the study, the standard must be 
statistically superior to the negative control. However, during the 
rulemaking process, the criteria appropriate for these tests should be 
provided by the product manufacturers.
    a. Cetylpyridinium Chloride Rinse.
    [sbull] Determine the in vitro antimicrobial activity of the 
product against representative plaque organisms commonly associated 
with gingivitis. Representative organisms include, but are not limited 
to, typed stains of: Actinomyces viscosus, F. nucleatum, P. gingivalis, 
Prevotella intermedia, Bacteroides forsythus, Candida species, S. 
mutans, and gram negative enteric rods. Testing to determine a 
product's in vitro antimicrobial activity should include minimal 
inhibitory concentration (MIC) assays, or 30-second kill-time studies, 
as appropriate.
    [sbull] Demonstrate the availability of the active ingredient using 
a Disk Retention Assay (DRA). A suggested method for this assay is 
included in a submission to the Subcommittee (Ref. 5).
    [sbull] Demonstrate the biological activity of the formulation 
using an ex vivo Plaque Glycolysis and Regrowth Model (PGRM). A 
suggested protocol for this assay is included in a submission to the 
Subcommittee (Ref. 5).
    b. Stannous Fluoride Dentifrice.
    [sbull] An in vitro determination of antimicrobial activity against 
representative plaque organisms commonly associated with gingivitis 
(described in paragraph F.2.a. of this document) is recommended. 
Testing to determine a product's in vitro antimicrobial activity should 
include MIC assays, 30-second kill-time studies, or plaque biofilm 
assays, as appropriate.
    [sbull] Demonstrate the biological activity of the formulation 
using ex vivo PGRM (protocol for assay, Ref. 5).
    c. Fixed Combination of Eucalyptol (0.092 percent), Menthol (0.042 
percent), Methyl Salicylate (0.060 percent), and Thymol (0.064 percent) 
Rinse.
    [sbull] Determine the in vitro antimicrobial activity using 30-
second kill-time studies with both standard laboratory

[[Page 32241]]

strains and wild-type organisms obtained from saliva sampling. 
Representative organisms are listed in paragraph F.2.a of this 
document. Conduct kill-time testing using an exposure time of 30 
seconds in the presence of exogenous protein. Use an initial inoculum 
of 1-percent transmission.
    [sbull] Demonstrate the in vivo activity of the formulation through 
a short-term experimental gingivitis study of at least 2 weeks 
duration. A representative protocol, comparing the test product, a 
clinically tested standard, and a negative control, is included in a 
submission to the Subcommittee (Ref. 6). The criterion for study 
validation is statistically significant differences in plaque and 
gingivitis scores between the clinically tested standard and the 
negative control. To establish comparability to the standard mouthrinse 
in this test (or another generally accepted statistical test of 
clinical comparability), the new mouthrinse formulation must satisfy 
the ``at least as good as'' statistical criteria for both plaque and 
gingivitis scores, i.e., at least statistically significantly 
comparable or equivalent to the clinically tested standard.

G. Inactive Ingredients

1. Alcohol in Oral Health Care Drug Products
    Many OTC mouthrinses contain alcohol (up to 26 percent or more). 
Concerns were raised when published reports and other information 
appeared to show a possible risk of developing oropharyngeal cancers 
from daily use of mouthrinses containing high concentrations of 
alcohol. After reviewing the available data, the Subcommittee has the 
following comments concerning high alcohol-content mouthrinses and 
cancer of the buccal cavity and pharynx (oral).
    a. Oral cancer. Based on the 1993 statistics for oral cancer in the 
United States (Ref. 7), the buccal cavity and pharynx are the eighth 
most common site of cancer, representing approximately 3 percent of all 
cancers reported. Approximately 30,000 people per year develop oral 
cancer. The ratio of men to women developing oral cancer is about 2 to 
1. The 5-year survival rate for persons with oral cancer is about 33 
percent for African-Americans and 50 percent for Caucasians.
    Alcohol consumption and tobacco smoking/chewing account for 
approximately three-fourths of oral cancers in the United States (Refs. 
8 through 13). Other less clearly established causal factors include 
poor dental conditions, oral infections, nutritional deficiencies, and 
possibly high alcohol-content mouthrinses (Refs. 14 through 19).
    b. Adverse reactions associated with mouthrinses. A drug that 
ordinarily causes no adverse effects with short-term exposure may 
produce pathologic tissue changes after chronic usage. Prolonged usage 
of a drug and/or its metabolites combined with various compounds in the 
mouth may result in cumulative effects in oral tissues. Mouthrinses 
should be evaluated for chronic, long-term usage and resulting 
manifestations (Ref. 20).
    Mucous membranes of the mouth can absorb mouthrinse ingredients, 
which may pass systemically into the bloodstream. The literature 
describes local adverse reactions from mouthrinse usage, ranging in 
severity from irritancy and sensitization to cancer (Refs. 21, 22, and 
23).
    Some case-control studies suggest a causal association between 
mouthrinse use and oral cancer risk, most recently in the largest study 
to date by the National Cancer Institute (Ref. 24). The cancer risk 
seems to be greater in females (60 percent) than in males (40 percent) 
and varies in proportion to dose, tending to increase with increasing 
duration and frequency of use and the alcohol concentration of the 
mouthrinse (Ref. 24). Other researchers have found no evidence of an 
increased cancer risk associated with mouthrinses (Refs. 25, 26, and 
27).
    The reported risk of oral cancer pertains to mouthrinses with 
alcohol-contents of 25 percent or higher. However, since these 
mouthrinses also contain other active ingredients, such as essential 
oils with lipophilic, membranotropic effects, some high alcohol-content 
mouthrinses may affect tissues by a variety of mechanisms.
    Studies that have evaluated the potential for alcohol in 
mouthrinses to cause cancer have a number of shortcomings: (1) 
Investigations based on subject accounts without benefit of medical 
records or other written documentation, (2) unreliable classification 
of exposure to known risk factors such as alcohol and tobacco in study 
subjects, (3) lack of consistent dose-response relationships based on 
frequency and/or duration of mouthrinse use, and (4) combining cases of 
cancer of the buccal cavity and pharynx despite the fact that 
mouthrinses are in direct contact only with the mucosa of the buccal 
cavity.
    c. Alcohol and oral cancer. Although consumption of alcoholic 
beverages is a known risk factor for oral cancer, pure alcohol does not 
show a direct carcinogenic action in laboratory animals or humans. The 
cancer associated with alcoholic beverages is probably related to 
contaminating carcinogens. These include urethane produced from urea 
reacting with ethyl alcohol during yeast fermentation of fruit juices, 
and n-nitrosamine compounds catalyzed from precursor nitrite and 
amines, amides, or other nitrosatable agents. Commercial mouthrinses 
contain distilled ethanol free of these contaminating carcinogens. 
Other findings suggest an ability of ethanol to enhance the conversion 
of procarcinogens to mitogens, and of ethanol's metabolite acetaldehyde 
to produce deoxyribonucleic acid (DNA) abnormalities in human cells.
    Animal studies have indicated that ethanol may also function as a 
cocarcinogen, in association with other substances that are true 
carcinogens (Ref. 28). Alcohol may act by facilitating the penetration 
of carcinogens into the mucosa (Refs. 29 through 33). Weak carcinogenic 
nitrosamines and other compounds have been shown to have enhanced 
carcinogenicity in the presence of alcohol (Ref. 33). Alcohol may act 
directly on epithelial cells by altering intracellular metabolism and 
rendering cells more susceptible to carcinogens (Ref. 28).
    Based on these studies, the Subcommittee recommends that further 
studies on the possible cancer risk associated with high alcohol-
content mouthrinses be conducted. These studies should include testing 
various components of the mouthrinse and pertinent dietary ingredients.
    d. Abuse and misuse of mouthrinses. Although some OTC mouthrinses 
contain alcohol, the potential for development of drug tolerance and 
addiction due to use of these products seems negligible. However, 
misuse of any mouthrinse product may occur if the product gives the 
user a false sense of security, diminishing the users's desire to seek 
professional advice. This problem may be particularly acute for 
mouthrinses that may subdue signs and symptoms of a gingivitis 
infection without resolving a more severe, underlying periodontitis 
infection. A label warning should alert the consumer to this danger.
    e. Alcohol as a facilitator. While the Subcommittee recognizes that 
the combination of alcohol and tobacco is associated with a marked 
increase in the incidence of oral cancer as compared to exposure to 
tobacco alone, it concludes that the mechanism of this synergism is 
unknown. Animal studies (Ref. 28) have shown that alcohol has a topical

[[Page 32242]]

potentiating effect in the production of squamous cell carcinoma in 
animal cheek pouches treated with 7,12-dimethylbenz(a)-anthracene 
(DMBA). Decreased latency and larger tumors were observed as compared 
to controls.
    Other animal studies (Refs. 29, 30, 32, and 33) have demonstrated 
similar effects. These studies were older and implied a model that is 
not comparable to what happens in humans. Moreover, some carcinogens 
are extremely species-specific, and limited information is available on 
direct experiments performed on the human mucosa.
    If the synergistic effect of alcohol in causing an increased risk 
of oral cancer is attributed to a topical effect, as noted in the 
animal studies, then daily use of oral rinses containing a high 
concentration of alcohol may have a tissue altering effect. Whether 
this may be as significant as alcoholism in the epidemiology of oral 
cancer warrants continued investigation.
    One of the few mechanistic evidences for a local alcohol effect has 
been demonstrated by permeability studies. In the presence of nicotine, 
alcohol had a greater relative effect on penetration of carcinogens in 
and across the floor of the oral mucosa (floor of the mouth, oral 
mucosa) (Ref. 34). Also, pharmaceutical studies have demonstrated that 
the oral mucosa can have a reservoir effect, so that compounds are 
rapidly taken up and held in the oral epithelium, extending the 
duration of their effect (Ref. 35). This mechanism has recently been 
utilized in a formulation using alcohol to increase permeability, 
thereby obtaining systemic delivery of proprietary drugs after only a 
mucosa exposure.
    It is clear that further research is needed to investigate the role 
of alcohol as an enhancer of the penetration of carcinogens through the 
oral mucosa. In addition, the threshold of alcohol concentration 
necessary to achieve this phenomena needs to be investigated.
2. The Subcommittee's Conclusions and Recommendations Regarding Alcohol 
Content in Mouthrinses
    On June 6, 1996, the Subcommittee, along with other scientific 
experts (e.g., epidemiologists and statisticians) held a workshop (Ref. 
36) to further consider whether alcohol-containing mouthrinses 
contributed to oral cancers. Although some studies have implicated high 
alcohol-content mouthrinses as a possible cause of oral/pharyngeal 
cancer, the relationship between high alcohol-content mouthrinses and 
oral/pharyngeal cancer is not clear. The findings of various studies 
are contradictory and do not show a consistent dose-response 
relationship. A major difficulty in deciding cause and effect in these 
studies is the possibility of confounding by known risk factors, such 
as high alcoholic beverage consumption and tobacco use.
    The Subcommittee reviewed new data consisting of a specificity 
analysis (Ref. 37) using data from the Winn et al. study (Ref. 24) and 
a preliminary analysis from an unpublished study of laryngeal, 
esophageal, and oral cancer (Ref. 38). In addition, the Subcommittee 
reviewed seven case-control studies, published between 1979 and 1991 
(Refs. 12, 13, and 23 through 27), of the association between 
mouthrinse use and oral cancer. These studies are described below.
    Weaver et al. (Ref. 23) reported the use of alcohol-containing 
mouthrinses among 11 subjects with oropharyngeal cancer who indicated 
that they did not smoke or drink alcoholic beverages. These cases 
became part of a case-control study regarding an association between 
alcohol-containing mouthrinses and oropharyngeal cancer. Although the 
study was unevaluable, it generated the hypothesis that led to 
subsequent studies.
    A 1983 case-control study by Wynder et al. (Ref. 12) evaluated the 
relationship between mouthrinses and oropharyngeal cancer. No positive 
findings were reported for men. In women, the relative risk, unadjusted 
for smoking and alcoholic beverage consumption, was statistically 
significant for daily use of mouthrinses. However, there was no 
consistent relationship for duration or frequency of use. Further, a 
refined analysis using a multiple logistic model indicated no 
association between mouthrinse use and oropharyngeal cancer. The 
investigators concluded that, due to the absence of a dose-response 
relationship and the possibility of confounding by tobacco and 
alcoholic beverage use, it was not possible to attribute an association 
between daily mouthrinse use and oral cancer in women.
    A 1983 case-control study by Blot et al. (Ref. 13) included female 
subjects from a previous study of snuff use. A relative risk of 1.94 
was reported for women who used a mouthrinse but did not use tobacco 
products. However, this was not statistically significant (confidence 
interval = 0.8 to 4.7), and there were no consistent dose-response 
relationships for years of use, frequency of use, time retained in the 
mouth, or concentration (i.e., diluted vs. full strength). Because 
dose-response relationships are important in considering whether there 
is an association between mouthrinse use and oral cancer, the 
Subcommittee concludes that this study does not support a causal 
association between alcohol-containing mouthrinses and oropharyngeal 
cancer.
    The Subcommittee reviewed three additional case-control studies 
published between 1985 and 1989 (Refs. 25, 26, and 27). One study by 
Kabat et al. (Ref. 26) is of particular interest because, although 
mouthrinses were not associated with increased oral cancer risk in 
terms of frequency or duration of use, cases were significantly more 
likely than controls to state that mouthrinses were used to disguise 
breath odors caused by alcoholic beverages or tobacco. In contrast, 
similar proportions of cases and controls reported using a mouthrinse 
to conceal food odors or for mouth infections or dental problems. The 
Subcommittee concludes that these findings indicate that mouthrinse use 
may be serving as a surrogate for underreported drinking and/or 
smoking.
    A 1991 study by Winn et al. (Ref. 24) was the largest case-control 
study among the seven published studies evaluating mouthrinses (866 
cases and 1,249 controls). Odds-ratios for oropharyngeal cancer risk 
after adjusting for tobacco and alcoholic beverage use were 1.4 
(confidence interval 1.0 to 1.8) in men and 1.6 (confidence interval 
1.1 to 2.3) in women. Dose-response relationships, such as duration of 
use, frequency of use, and age when use started, were questionable, 
with no trend analysis of these relationships reported. This study also 
showed a decreased odds-ratio for dental X-rays. There is no 
biologically plausible reason to expect X-rays to be protective against 
oral cancer, and the negative association is likely a reflection of 
less frequent visits for dental care by cases versus controls. However, 
the negative association could not be eliminated by adjustment for 
factors that are relevant to quality of dental care (e.g., education).
    Thus, this study was capable of producing a statistically 
significant noncausal association that could not be eliminated by 
adjustment of the data. Further, regarding the odds ratio for 
mouthrinse use, confounding due to underreported use of tobacco and 
alcoholic beverages, both strong risk factors for oropharyngeal cancer, 
could result in an artificially elevated odds ratio. Such a false 
association can be produced even though the extent of underreporting is 
the same in both the case and control groups (Ref. 39). Information in 
the published literature indicates that especially drinking and 
sometimes smoking are underreported (Refs. 40 through 44). The

[[Page 32243]]

Subcommittee concludes that these studies do not support a causal 
relationship between the use of alcohol-containing mouthrinses and 
oropharyngeal cancer.
    The Subcommittee reviewed unpublished new data that included a 
specificity analysis (Ref. 37) of the data from the Winn et al. study 
(Ref. 24). This analysis excluded 75 cases (38 men and 37 women) who 
did not have oropharyngeal cancer (i.e., epithelial cell cancer of the 
mouth) based on evaluation of the International Classification of 
Diseases codes. The excluded cases consisted primarily of tumors of the 
minor salivary glands and sarcomas and lymphomas that happened to occur 
within the oral cavity. Excluding these cases left 535 and 256 cases of 
oropharyngeal cancer in men and women, respectively. Evaluation of 
smoking and alcoholic beverage use indicated that both of these risk 
factors were more strongly associated with the included cases than with 
the total number of cases (included plus excluded). Neither smoking nor 
alcoholic beverage use were associated with the excluded cases. This 
analysis indicated that the excluded cases may not have the same 
etiology as the included cases and, therefore, should not have been 
included in the original analysis conducted by Winn et al. (Ref. 24) to 
evaluate risk associated with mouthrinse use.
    When odds ratios for mouthrinse use in women were calculated for 
the included cases, they were decreased relative to the odds ratios for 
total cases originally reported by Winn et al. (Ref. 24). This was true 
for a number of subanalyses, including duration of use, frequency of 
use, age when use began, and alcohol concentration. Higher odds ratios 
for mouthrinse use among the excluded cases suggested that mouthrinse 
use was more strongly associated with excluded cases than with included 
cases. However, there is no biologically plausible explanation for this 
finding since the excluded cases represent a variety of tumor types 
whose origins cannot be presently explained by topical exposure to 
ethanol via mouthrinse use. In addition, the data were inconsistent 
with a dose-response with respect to duration of use, frequency of use 
and age when mouthrinse use started, which suggests that this finding 
may be related to information bias rather than a causal association. 
The specificity analysis among male cases was less informative than for 
females and supports neither a causal hypothesis nor information bias 
as the explanation for the weak association with mouthrinse use (odds 
ratio 1.4) originally reported by Winn et al. (Ref. 24). The limited 
value of the specificity analysis in males is likely related to the 
fact that: (1) The excluded male cases represented a smaller percentage 
of the total male cases and (2) the odds ratio for mouthrinse use in 
males is smaller than it is in females. Both of these factors make it 
difficult to detect any shifts in odds ratios. The Subcommittee 
concludes that, overall, the specificity analysis of the Winn et al. 
study (Ref. 24) indicates that this study does not support a causal 
association between mouthrinse use and oropharyngeal cancer (Ref. 37).
    Preliminary analyses from an unpublished case-control study of 
laryngeal, esophageal, and oral cancer (Ref. 38) showed that the odds 
ratio for mouthrinse use in males and females combined (adjusted for 
cigarette and alcoholic beverage use) was 1.4 (confidence interval 1.0 
to 2.0). However, the analyses of frequency, duration, and age when use 
started showed inconsistencies that question a causal relationship. In 
addition, when the data were evaluated with respect to alcohol content, 
the highest odds ratio (unadjusted for smoking and alcoholic beverage 
use) was found among users of mouthrinses containing no alcohol (e.g., 
salt water, vinegar, baking soda in water). The Subcommittee concludes 
that this finding differs from the Winn et al. study (Ref. 24) results 
showing that odds ratios were elevated only for mouthrinses having the 
highest alcohol content and is inconsistent with the hypothesis of a 
causal association between alcohol-containing mouthrinses and oral 
cancer.
    An unpublished review of the literature concerning possible 
mechanisms of alcoholic beverage consumption and oral cancer risk was 
submitted to the Subcommittee (Ref. 45). Although alcoholic beverage 
consumption is a known risk factor for oral cancer and the literature 
on experimental mechanistic studies (e.g., in vitro and animal studies) 
raises speculations concerning how the biological effects of alcohol 
may modulate cancer risk, the Subcommittee concludes that the relevance 
of these studies to mouthrinse use in humans has not been established.
    Based on the studies reviewed, the Subcommittee concludes that the 
available data do not support a causal relationship between the use of 
alcohol-containing mouthrinses and oral cancer. The vote was unanimous 
with the Chairman abstaining. The Subcommittee acknowledges that 
epidemiologic research on oropharyngeal cancer will continue, and that 
the conclusion reached by the Subcommittee is based on the data 
available at the time of its deliberations. However, because some 
studies did report a relationship between the use of high alcohol-
content mouthrinses and pharyngeal cancer, the Subcommittee agrees that 
further studies should be conducted to determine the relationship 
between high alcohol-content mouthrinses and oral/pharyngeal cancers. 
In addition, the Subcommittee recommends that all mouthrinses should be 
labeled in a readily readable manner with the alcohol concentration in 
percent, e.g., ``Contains -- % alcohol'' on the principal display 
panel.

H. General Guidelines on Safety and Effectiveness

1. General Statement
    The Subcommittee arrived at its conclusions and recommendations 
regarding the safety and effectiveness of all active ingredients after 
considering all pertinent data and information submitted. The 
Subcommittee adopted the following general ``points to consider.'' 
These are not intended to restrict investigators, but are 
recommendations for studies recognized as desirable approaches to 
determine the safety and effectiveness of OTC antigingivitis/antiplaque 
active ingredients. In some cases, other methods may be equally 
applicable, or newer methods may be preferable. Also, these recommended 
studies may not produce all information necessary to determine that an 
ingredient is generally recognized as safe and effective.
2. Guidelines
    An OTC drug included in a monograph is described in Sec.  330.10 as 
generally recognized among qualified experts as safe and effective for 
use and as not misbranded. Proof of the safety of an OTC drug 
ingredient consists of adequate tests by methods reasonably applicable 
to show the drug is safe under the prescribed, recommended, or 
suggested conditions of use. This proof shall include results of 
significant human experience during marketing. General recognition of 
safety shall ordinarily be based upon published studies which may be 
corroborated by unpublished studies and other data. Proof of 
effectiveness of an OTC drug ingredient consists of controlled clinical 
investigations as defined in Sec.  314.126(b) (21 CFR 314.126b)) by 
qualified experts to show that the drug provides clinically significant 
relief of the type claimed in its labeling. The latter requirement may 
be waived if it is not reasonably applicable to the drug in question or

[[Page 32244]]

essential to the validity of the investigation and an alternative 
method of investigation is adequate to substantiate effectiveness. 
Effectiveness may be corroborated by partially controlled or 
uncontrolled studies, and reports of significant human experience 
during marketing. General recognition of effectiveness shall ordinarily 
be based upon published studies that may be corroborated by unpublished 
studies and other data.
    The characteristics of adequate and well-controlled studies have 
been developed over a period of years and are described in Sec.  
314.126. Studies supporting the safety and effectiveness of OTC drug 
ingredients should provide sufficient details of study design, conduct, 
and analysis to allow a critical evaluation of the data in relationship 
to the above characteristics.
    In several proposed and final monographs, the agency has stated 
that, in order for an active ingredient to be included in an OTC drug 
monograph, it is necessary that the ingredient be adequately 
characterized and that these standards be published in an official 
compendium such as the United States Pharmacopeia (USP) or the National 
Formulary (NF) (58 FR 28194 at 28284). Such specifications are 
necessary to assure the identity, strength, quality, and purity of the 
active ingredient. Therefore, the Subcommittee recommends that a full 
description of the ingredient, including its physical and chemical 
characteristics and stability, be provided, and that manufacturers 
contact and work with the USP to develop monographs for ingredients 
that are not currently included in that compendium. For ingredients 
that are currently included in an official compendium, reference to the 
current edition of the USP or the NF may satisfy this requirement.
    a. Safety. The Subcommittee's determination of the safety of single 
ingredients and ingredient combinations is based on the following 
criteria: (1) The incidence and risk of adverse reactions and 
significant side effects when the ingredient was used according to 
adequate directions in the labeling, (2) the margin of safety under 
conditions of normal use and the potential for harm that might result 
from abuse or misuse under conditions of widespread OTC availability, 
(3) the potential for inducing untoward effects on the oral tissues, 
including irritation, ulceration, inflammation, erosion, and minor 
effects such as discoloration of the teeth, restorations, and 
prostheses, etc., and (4) assessment of the benefit-to-risk ratio. The 
Panel further states that microbial safety should be determined through 
clinical evaluation of changes in representative oral microbial 
populations (e.g., the possible emergence of opportunistic organisms or 
potential pathogens), in order to assure that there is no adverse 
change in the balance of the oral microflora under conditions of 
expected OTC use.
    i. Toxicological studies. A variety of toxicological data can be 
obtained to demonstrate that an active ingredient is safe. The 
Subcommittee recommends that manufacturers conduct the applicable 
studies discussed below and emphasizes that these recommendations do 
not preclude the use of alternative comparable methods that are 
currently available or better methods that may be developed in the 
future. The Subcommittee recommends that the following data be 
available for the active ingredient(s) intended for use on the mucous 
membranes of the mouth and throat.
    Testing the effects of various ingredients on animal subpopulations 
that can reflect human subpopulations should be considered (e.g., 
hyposalivation studies in nonsalivating animals). Adequate, acceptable, 
controlled in vivo studies of acute and chronic toxicity in several 
species of animals should be available. Such studies may include 
single-dose gavage studies, repeat-dose gavage studies, oral irritation 
studies, pharmacokinetic/biodistribution studies, and dermal 
sensitization studies. Information regarding the genetic, reproductive 
toxicologic, and carcinogenic potential should be considered for 
ingredients that are going to be used daily on a long-term basis. It is 
not necessary to determine the LD50 (lethal dose for 50 
percent of the test animals) of the ingredient. However, information 
about the minimal lethal dose would be useful.
    All or some of the recommended toxicological studies may not be 
necessary for all active ingredients. Some circumstances that might 
preclude an ingredient from the above testing are: (1) It is already 
generally recognized as safe, (2) it is a direct food additive, (3) it 
has been used previously in approved dental drug products, or (4) it is 
the subject of an OTC drug monograph with a different but similar or 
related use at a similar concentration and for a similar time period. 
Published articles may be considered in lieu of the testing recommended 
above.
    One of the Subcommittee's primary concerns regarding 
antigingivitis/antiplaque ingredients is whether or not swallowing the 
active ingredient presents a threat to the user. The Subcommittee 
recommends that gavage studies be used to address concerns about 
potential systemic toxicity unless applicable published or unpublished 
studies have been conducted using a dietary admixture mode of 
administration and comparable toxicokinetics can be shown between 
gavage and dietary modes of administration. Single administration 
gavage studies are typically performed using a limit-value test in the 
rat at a specified high dose to evaluate acute toxicity potential 
(Refs. 46, 47, and 48). In the absence of adequate dietary admixture 
studies, repeat dose gavage studies may be employed to evaluate 
systemic toxicity from multiple exposures. The test article is 
administered to rats on a number of consecutive days.
    Where there is a concern that antigingivitis/antiplaque active 
ingredients may induce untoward effects on the oral mucosa, the dosage 
to be used for these studies should be justified based on the 
concentration of human exposure levels. An appropriate dosage range may 
extend, for example, from a low dose comparable to swallowing a single 
dose of mouthrinse or the amount remaining following expectoration of a 
mouthrinse to a high dose that either causes dose-limiting toxicity or 
is several orders of magnitude greater than the clinical exposure 
levels. Such studies usually use four applications per day for a period 
of 28 consecutive days. The oral irritation should include both a 
negative and a positive control group. All test articles should be 
applied in an identical manner. A negative control group may consist of 
animals that are treated with either water or saline, and the positive 
control is a group of animals that are treated with the solution that 
is known to cause a minimal degree of irritation without being inhumane 
to the animals (e.g., 5-percent solution of sodium lauryl sulfate).
    The Subcommittee recommends that the study include abraded mucosa 
in order to determine whether the test ingredient delays or prevents 
the healing of oral lesions. The parameters to include are any gross 
observations of changes in the oral tissue, such as sloughing, 
ulceration, or bleeding. Following the sacrifice of each animal, the 
histopathology of oral tissues should be examined.
    ii. Studies in older adults. The Subcommittee is concerned that 
older adults might be at greater risk for potential systemic toxicity 
from the use of antigingivitis/antiplaque active ingredients. This is 
of particular concern because of the continually

[[Page 32245]]

increasing size of the older adult population, who are retaining more 
natural teeth and becoming a significant population for use of 
antiplaque/antigingivitis products.
    Publications have described differences in drug responses in the 
elderly. Changes in pharmacokinetics have been reviewed (Ref. 49). 
Absorption can theoretically be altered by noted changes in 
gastrointestinal function, but the majority of studies have shown no 
difference in rate or extent of absorption of the drug examined. 
Distribution of a drug within the body is affected because fat content 
of body weight increases and intracellular water decreases. For 
example, albumin concentration is reduced and drugs which bind to 
albumin are more free to distribute to the rest of the body. Hepatic 
metabolism may be altered. Reduction of blood flow to the liver will 
decrease clearance of some drugs. Renal excretion is affected in some 
older adults by loss of renal mass and functional nephrons.
    Russell (Ref. 50) noted that despite numerous reports in the 
literature of impaired GI function with aging, most functions remain 
relatively intact because of the large reserve capacity of the 
intestine, pancreas, and liver. In a review critically analyzing 
available information on age-related changes in the digestive and 
absorptive GI physiology of lipids, data suggested lipid digestion and 
absorption are well-preserved in the aging. However, intercurrent 
illness or experimental stress may produce impairment in aging animals 
and humans that is not seen in younger controls (Ref. 51).
    Atillasoy and Holt (Ref. 52) noted that the GI tract represents an 
organ system characterized by rapid proliferation. Contrary to 
generally held prejudices, the authors write, a state of 
hyperproliferation, not hypoproliferation, occurs in the epithelial 
cells of the stomach, small intestine, and large intestine of stable-
fed, aged rodents when compared to young adult rodents.
    In a gavage study (Ref. 53) Yamada et al. investigated renal 
ammoniagenesis in isolated nephron segments from control, acidotic 
senescent (exhibiting deteriorating teeth due to aging), and young 
adult rats. No significant difference was seen in glutamine-dependent 
ammonia production in the segments. However, ammonia production in 
glomeruli from old rats was significantly greater than in young rats.
    There appear to be no available consistent findings to warrant that 
additional gavage studies of antigingivitis/antiplaque active 
ingredients in older animals will produce more meaningful findings 
relative to older adults than the usual gavage studies in adult 
animals. This is due to the great diversity which exists in the health 
and fitness status of the elderly population. The Subcommittee 
considers a comment by Ahronheim (Ref. 54) appropriate:
    Although much has been written about age-related alterations in 
drug disposition, there is disagreement as to the extent and 
inevitability of these changes. Studies focusing on aged individuals 
suffer from several problems. Cross-sectional studies comparing 
young and old subjects sometimes compare young, healthy individuals 
with aged subjects gathered from hospitals or nursing homes. If the 
aged subjects are ``healthy'' they may nonetheless have subclinical 
disease, which can alter outcomes in studies that seek to determine 
a drug's disposition and effects. However, aged subjects that are 
truly healthy may represent an elite minority so that the study's 
results may not be applicable to the general elderly population. 
Longitudinal studies are almost impossible to complete and data is 
sparse, but recent findings indicate that the geriatric population 
is, indeed, heterogeneous.
    In addition to these pitfalls, it is not known how 
generalizations about aging physiology, even if they are true, can 
be applied to drug disposition, since most drugs have not been 
subjected to exhaustive age-specific testing and few conclusions can 
be reached based on pharmacokinetic data. Even less is known about 
pharmacodynamic changes because the study of age-related tissue 
receptor density, activity, and sensitivity is in its infancy. We 
must therefore rely on clinical observations to a large extent when 
drawing conclusions about efficacy and potential toxicity of various 
agents in use. The Subcommittee concludes that the results of the 
usual gavage studies are adequate.
    iii. Irritation and delayed contact sensitization studies in 
humans. Observations during adequate clinical studies are sufficient to 
demonstrate the irritation and sensitization potential of an ingredient 
or ingredient combination. However, if necessary, a number of methods 
embodying the use of patch testing have proven of value in determining 
skin irritancy and systemic sensitization. The Subcommittee recommends 
one of the following three methods of patch testing to address concerns 
of irritancy and sensitivity:
    [sbull] Draize testing. In the Draize human skin irritancy and 
sensitization tests or one of its various modifications (Ref. 55), the 
testing should be performed on the skin of the subject's back or arm.
    [sbull] Method of Shelanski and Shelanski. In this method (Ref. 
56), the active ingredients or the formulation under study are applied 
at frequent intervals of 1 or 2 days to the test site for 3 or 4 weeks. 
After a rest period of 2 weeks, a single dose of the drug is applied as 
a challenge. The preliminary applications are made to detect primary 
skin irritants and provoke sensitization in susceptible individuals. 
The challenging dose detects whether or not the drug is a skin 
sensitizer.
    [sbull] Maximization procedure of Kligman. This procedure (Ref. 57) 
or one of its modifications uses an irritant applied over a desquamated 
test site. Desquamation is performed by using a rubbing technique that 
facilitates penetration, thereby hastening and accentuating the skin-
sensitizing potential of the substance. Other validated human models 
may be used.
    iv. Microbiologic evaluation. The Subcommittee is concerned about 
the potential of antigingivitis/antiplaque ingredients with 
antimicrobial effects to allow emergence of opportunistic pathogens, 
induce resistance in oral microorganisms, or allow an oral overgrowth 
of inherently resistant potential pathogens. Representative microbial 
species and their relative proportion to the total cultivable 
microflora in supragingival plaque and saliva should be monitored over 
at least a 6-month period of continuous use of the antiplaque product 
to determine if a shift in the oral flora has occurred that might 
result in the proliferation of pathogenic microorganisms, which may 
include Candida species and other yeast, Staphylococcus aureus and 
other Staphylococcus species, beta-hemolytic Streptococci, and enteric 
gram-negative rods. Additionally, for those antigingivitis/antiplaque 
ingredients where the mechanism of action is suspected to be 
antimicrobial, an assessment of changes in microorganisms associated 
with gingival disease should be carried out. One determination should 
be made prior to the start of use, one at the conclusion of the study, 
and one at an intermediate time. In vitro minimum inhibitory 
concentrations should be assessed for representative species to 
determine the development of increased resistance after prolonged 
antimicrobial therapy.
    b. Effectiveness. The Subcommittee's determination of the 
therapeutic effectiveness of ingredients and combinations of 
ingredients for antigingivitis/antiplaque use is based on published and 
unpublished studies containing pharmacological data considered by the 
Subcommittee to be scientifically valid and pertinent. Clinical 
criteria for proof of effectiveness of a single ingredient or 
combination of ingredients were determined by evaluating data from 
valid controlled studies and by calling on the clinical expertise of 
the

[[Page 32246]]

Subcommittee members. Proof of effectiveness of a single ingredient or 
combination of ingredients was determined by evaluating data from 
valid, well-controlled studies demonstrating a significant reduction of 
the symptoms or a therapeutic benefit for the stated indication in the 
labeling.
    Although the OTC drug review is an active ingredient review, not a 
product review, the Subcommittee recognizes that a final product must 
be formulated properly, according to accepted pharmaceutical 
manufacturing practices. If a product is not formulated properly, 
active ingredients may be present in less than the minimum effective 
dose, may be in a form that does not exert the intended therapeutic 
effect(s), or may not be bioavailable. Therefore, the Subcommittee 
considered it important whether or not inert ingredients or other 
active ingredients in a formulation might alter the effect of the 
product's principal active ingredient. The designation of a 
pharmaceutical necessity as an inactive ingredient does not necessarily 
mean that the ingredient is pharmacologically inactive.
    The Subcommittee considers its recommended ``points to consider'' 
acceptable current approaches for arriving at valid conclusions 
concerning the effectiveness of OTC antigingivitis/antiplaque drug 
products. These ``points to consider'' do not preclude the use of 
newer, more refined laboratory or clinical techniques to establish 
effectiveness.
    c. Clinical trials. Acceptable studies should state the specific 
objectives of the study, a review of pertinent literature, and present 
the scientific rationale for the use of the ingredient. The mode, 
frequency, and duration of application should be thoroughly described. 
The indices and variables selected for measuring effectiveness, the 
methods of measurement, and the rationale for such choices should be 
characterized. The Subcommittee believes that the effectiveness of an 
OTC antigingivitis ingredient, antigingivitis/antiplaque ingredient, or 
ingredient combination should be demonstrated by evidence of a 
clinically significant endpoint, specifically a reduction and/or 
prevention of gingivitis. In general, the Subcommittee would also 
expect a reduction of dental plaque mass and/or plaque virulence 
(degree of pathogenicity as indicated by the severity of the disease 
produced). However, the Subcommittee also believes that an ingredient 
can reduce gingivitis without a demonstrated reduction of plaque. Where 
possible, additional evidence for the effectiveness of the agent should 
be provided by demonstrating a shift in the plaque flora.
    i. Design. Studies should measure the difference between reduction 
or prevention of dental plaque and gingivitis resulting from the test 
ingredient as compared to a placebo. Examples of acceptable 
experimental designs include crossover, parallel, factorial, 
sequential, single-blind, and therapeutic equivalency studies. 
Preference should be given to using double-blind studies with a placebo 
control. The placebo is the formulation of the test agent without the 
active ingredient, or some other suitable placebo.
    ii. Subjects. A sufficient number of subjects should be used to 
permit statistical analysis for the data obtained. The number of 
subjects tested should be sufficient to eliminate examiner bias and 
bias introduced by the placebo effect, if applicable, and to allow for 
anticipated dropouts and estimated variability of effect. The subjects 
should be of both genders and within the age groups for which the 
active ingredient is intended. Specific exclusionary criteria should be 
given.
    iii. Conduct of the study. The study should be of sufficient 
duration to demonstrate effectiveness. The duration will depend upon 
the actual use, anticipated effect, potential sustained benefits, and 
any safety considerations. The Subcommittee believes that such studies 
should be at least 6 months in duration to provide sufficient time for 
an ingredient to exert an antigingivitis/antiplaque effect and for 
adverse events to manifest themselves. Six months will also provide 
time to investigate the possibility that an OTC oral ingredient used 
daily over an extended period of time might cause a shift in the oral 
flora that may result in the proliferation of pathogenic 
microorganisms. Scoring and oral health evaluations should be done at 
baseline, at completion, and at appropriate intervals during the study. 
Baseline demographic, medical, historical, and physical data for each 
subject should be obtained and recorded. Such data should include a 
medical history, a complete oral examination, laboratory studies, if 
indicated, and other pertinent data.
    The treatments should be performed on a random basis. The 
randomization procedure should be used so that variables not otherwise 
controlled balance out. The number and frequency of applications of the 
preparation should be in accordance with the method outlined in the 
indication for use and directions in the labeling. The clinical 
investigative team should monitor subjects during the study to detect 
any adverse events and take appropriate action. An evaluation of dose 
response and possible mechanism of action would enhance any submission.
    iv. Appropriate assessments. Appropriate assessments using 
validated or accepted techniques must be used.
    v. Interpretation of data. Investigative methods should be 
described in sufficient detail so that experiments can be repeated by 
another investigator to verify and confirm results. Methods of 
statistical analysis should be determined before starting the study.
    Positive evidence of effectiveness should be obtained from a 
minimum of two studies, each conducted by an independent investigative 
group. In addition to statistical significance, clinical importance 
should be addressed. Strength of effect and concern about statistically 
significant changes not being clinically significant reflect the 
importance of randomized controlled trials of longer duration to 
determine if individuals benefit from proposed agents and 
interventions. Statistical significance can be easily calculated using 
a nominal (categorical) scale such as gingival index scores. A large 
``N'' offers scores with an approximately normal distribution so that 
parametric statistics can be used, as if using exact measures such as 
in an interval or ratio scale. The gingival index, however, is a 
nominal scale and the difference between 0 and 2 is not the same as the 
difference between 1 and 3. Slight differences exist in mean gingival 
index scores which are not clinically obvious and cannot be easily 
discerned in a subject. A product can produce a change in the response 
variable that is statistically significant, yet the question of 
clinical significance remains unanswered.

III. Classification of Active Ingredients

    In addition to carefully reviewing the submitted data, the 
Subcommittee considered all pertinent data and information available in 
arriving at its conclusions and recommendations regarding the active 
ingredients. The following tables summarize the Subcommittee's 
recommended categorization of active ingredients:

          Table 2.--Categorization of Single Active Ingredients
------------------------------------------------------------------------
      Active Ingredients              Safety              Efficacy
------------------------------------------------------------------------
Aloe vera                       III                 III
------------------------------------------------------------------------

[[Page 32247]]

 
Cetylpyridinium chloride        I                   I
------------------------------------------------------------------------
Dicalcium phosphate dihydrate   I                   III
------------------------------------------------------------------------
Hydrogen peroxide               I                   III
------------------------------------------------------------------------
Sanguinaria extract             I                   III
------------------------------------------------------------------------
Sodium bicarbonate              I                   III
------------------------------------------------------------------------
Sodium lauryl sulfate           I                   III
------------------------------------------------------------------------
Stannous fluoride (for          I                   I
 gingivitis)
------------------------------------------------------------------------
Zinc citrate                    I                   III
------------------------------------------------------------------------


     Table 3.--Categorization of Combinations of Active Ingredients
------------------------------------------------------------------------
 Active Ingredient Combination        Safety              Efficacy
------------------------------------------------------------------------
Alkyl dimethyl amine oxide and  III                 III
 alkyl dimethyl glycine
------------------------------------------------------------------------
Eucalyptol, menthol, methyl     I                   I
 salicylate, and thymol
------------------------------------------------------------------------
Hydrogen peroxide and povidone  III                 III
 iodine
------------------------------------------------------------------------
Hydrogen peroxide and sodium    I                   III
 bicarbonate
------------------------------------------------------------------------
Hydrogen peroxide, sodium       I                   III
 citrate, sodium lauryl
 sulfate, and zinc chloride
------------------------------------------------------------------------
Peppermint oil and sage oil     I                   III
------------------------------------------------------------------------
Polydimethylsiloxane and        I                   III
 poloxamer
------------------------------------------------------------------------
Stannous pyrophosphate and      I                   III
 zinc citrate
------------------------------------------------------------------------

A. Category I Conditions

    The Subcommittee recommends Category I labeling for all Category I 
single antigingivitis/antiplaque active ingredients and combinations of 
active ingredients (see section II.D of this document).
1. Category I Single Active Ingredients
    Cetylpyridinium chloride (rinse)
    Stannous fluoride (dentifrice)
    a. Cetylpyridinium chloride (rinse). The Subcommittee concludes 
that cetylpyridinium chloride at concentrations of 0.045 to 0.1 percent 
with at least 72 to 77 percent chemically available cetylpyridinium 
chloride is safe and effective for use in mouthrinse formulations as an 
OTC antigingivitis/antiplaque agent. Cetylpyridinium-containing 
mouthrinses have been used in the United States since 1940. 
Cetylpyridinium chloride 0.025 percent to 0.1 percent has been marketed 
nationally in several products. Products containing cetylpyridinium 
chloride have also been marketed internationally. The more than 55-year 
U.S. marketing history is significant with respect to the ingredient's 
safety.
    Cetylpyridinium chloride is a quaternary nitrogenous compound l-
hexa-decyl pyridinium chloride with antimicrobial activity against many 
microorganisms, including viruses. Its chemical and physical properties 
are well described in the USP (Ref. 58). It is classified as a cationic 
surface-active agent and contains a cetyl radical substituted for 
hydrogen atom on position 1. In hydrochloric acid it forms a chloride 
salt. The cetyl radical renders the molecule lipophilic, contributing 
to the lipophilic/hydrophilic balance which is necessary for the 
antimicrobial activity of such quaternary nitrogenous compounds. The 
antimicrobial activity is dependent upon the positioning of the charged 
molecule with bacterial cells that carry a net negative charge. This 
positioning allows the hydrophilic portion of the cetylpyridinium 
chloride to interact with the cell membrane, resulting in leakage of 
cellular components, disruption of cellular metabolism, inhibition of 
cell growth, and cell death (Refs. 59 through 62). Because the 
positively charged hydrophilic region is critical to antimicrobial 
activity, any formulation that diminishes the activity of this cationic 
group or that competes with this group may inactivate the product. 
Therefore, it is essential to establish that the cetylpyridinium 
chloride in products is sufficiently biologically active to justify an 
antigingivitis claim.
    i. Safety. The Subcommittee believes there are sufficient safety 
data to permit final classification of the safety of cetylpyridinium 
chloride as an OTC antimicrobial agent for topical use in the oral 
cavity when used within the proposed dosage limits set forth below. The 
Subcommittee bases its conclusions on the safety of cetylpyridinium 
chloride mouthrinses used in animal and pharmacokinetic studies, 
assessment of adverse events in randomized, placebo-controlled clinical 
trials, and postmarket spontaneous adverse event data reported to the 
manufacturer and FDA.
    The LD50 of cetylpyridinium chloride is 250 milligrams 
per kilogram (mg/kg) given subcutaneously, 6 mg/kg intraperitoneally, 
30 mg/kg intravenously, and 200 mg/kg given orally as a pure compound 
(Ref. 63). The data (Ref. 64) show that the oral LD50 values 
in the rat from a mouthrinse containing 0.05 percent cetylpyridinium 
chloride were 34 mg/kg to 48 mg/kg of the mouthrinse alone. This lower 
LD50 with the rinse formulation as compared to 
cetylpyridinium chloride in solution is likely due to the other 
components of the mouthrinse, such as the alcohol.
    Subchronic toxicity studies of cetylpyridinium chloride 
administered orally at dose levels ranging from 5 to 500 mg/kg showed 
morbidity and death at 125, 250, and 500 mg/kg. At lower doses, the 
only significant finding in rats and dogs was gastric irritation at 
doses of 50 mg/kg per day and higher (Ref. 65). These studies are 
similar to studies conducted prior to 1950.
    Two chronic exposure safety studies of 6 months and 1 year were 
reported (Ref. 65). Doses administered daily by oral gavage ranged from 
5 to 75 mg/kg. Significant decreases in body weight and weight gain 
were noted in 40- and 75-mg/kg animals of both sexes. At necropsy, GI 
irritation was manifested as thickening of the stomach mucosa observed 
at the 40- and 75-mg/kg level, and in some animals administered 15 mg/
kg.
    Local irritation studies (Ref. 65) included eye irritation tests 
and dermal exposure. Evidence of eye irritation was observed at high 
concentrations but no dermal lesions were observed. Local irritation 
using cetylpyridinium chloride mouthrinse formulations was assessed in 
the canine oral mucosa irritation model (Ref. 65). A cotton plug 
saturated with cetylpyridinium chloride mouthrinse was applied to the 
gingival mucosa three to five times a day for 4 days. Mouthrinse 
formulations containing up to 0.45 percent cetylpyridinium chloride did 
not induce irritation after 20 applications. Lin et al. (Ref. 66) 
evaluated inhalation toxicity in rats and found clinical signs of 
toxicity, including respiratory difficulty, eye irritation, and nasal 
discharge at concentrations of approximately 0.1 mg cetylpyridinium 
chloride/liter and above. However, these nonlethal effects were 
reversible.
    A study of the effects of alcohol and cetylpyridinium chloride on 
the buccal mucosa of hamsters was reported (Ref. 67). Animals received 
daily applications of 0.05 percent cetylpyridinium

[[Page 32248]]

chloride for 21 days on the everted hamster cheek pouch. Abrasion was 
also carried out. No significant differences were found between the 
control and study animals.
    Contact sensitization potential was assessed using a 25-percent 
concentration of cetylpyridinium chloride in petrolatum for 
sensitization and a 10-percent concentration for challenge. No evidence 
of sensitization was observed in any of the 24 participants (Ref. 65).
    Pharmacokinetic studies assessing absorption, distribution, and 
elimination of cetylpyridinium chloride were done in rats and dogs 
(Ref. 65). In the rat study, approximately 85 percent of a single dose 
of radiolabeled cetylpyridinium chloride was detected in the feces and 
about 10 percent in the urine. The dog study was inconclusive, since 
only 56.5 percent of the radiolabeled cetylpyridinium chloride 
administered was recovered from the urine, feces, case rinses, organs, 
and carcass.
    The safety data were systematically collected from several clinical 
trials (Refs. 68, 69, and 70). Adverse events did not differ between 
placebo and control except for tongue and tooth discoloration 
associated with cetylpyridinium chloride. In contrast, Lobene et al. 
(Ref. 71) found that approximately a quarter of the subjects using 
cetylpyridinium chloride reported a slight, transient irritation of the 
gingiva. In one short-term study (Ref. 72), more subjects in the 
cetylpyridinium chloride group were found to have aphthous ulcers than 
the placebo group. Gingival irritation and aphthous ulcers were not 
reported in other randomized controlled clinical trials of 
cetylpyridinium chloride-containing mouthrinses. Further studies of the 
mucosal irritancy potential of cetylpyridinium chloride, especially in 
those with hyposalivation, are warranted.
    Studies (Refs. 65 and 73) showed that there are no significant 
changes in the balance of the human oral flora or in the overgrowth of 
potential pathogens such as Candida. It appears that cetylpyridinium 
chloride has activity in the range of 0.12 to 8 micrograms per 
milliliter ([mu]g/mL) in vitro against S. aureus, S. sanguis, E. 
corrodens, Neisseria, Veillonella parvula, P. gingivalis, F. nucleatum, 
and Candida albicans.
    Data on teratogenic and mutagenic effects are available from in 
vitro and in vivo animal studies (Ref. 65). However, long-term 
cumulative effects on metabolism and teratogenic effects are not 
available from controlled human studies. The FDA spontaneous adverse 
reaction reports and adverse events reports submitted suggest that 
clinical experience following long-term OTC use of the ingredient has 
not revealed overt toxic manifestations. Although the summarized FDA 
spontaneous adverse drug reaction report (Ref. 65) indicates that three 
deaths and six comas occurred after ingestion of cetylpyridinium 
chloride-containing mouthrinses, it is unclear to what extent the 
mouthrinses or other circumstances may have contributed to these severe 
adverse events. The Subcommittee notes that tooth and tongue staining, 
as well as oral irritation, may occur with the use of products 
containing cetylpyridinium chloride.
    In summary, the safety of cetylpyridinium chloride has been 
extensively evaluated in a variety of controlled, clinical and 
nonclinical studies. Based on this information, in addition to adverse 
event data collected during more than 55 years of U.S. marketing of 
mouthrinses containing cetylpyridinium chloride, the Subcommittee 
concludes that cetylpyridinium chloride is safe when used at 
concentrations of 0.045 percent to 0.1 percent in mouthrinse 
formulations.
    ii. Effectiveness. The Subcommittee concludes that cetylpyridinium 
chloride is effective as an OTC antigingivitis/antiplaque ingredient 
within the dosage limits proposed above.
    The Subcommittee evaluated six placebo-controlled, blinded, 
clinical efficacy trials (Ref. 65). In five of the six studies, a 15- 
to 27-percent reduction in supragingival plaque was obtained with 
cetylpyridinium chloride in concentrations ranging from 0.05 to 0.1 
percent. The reduction seems to persist for 6 months. Four 6-month 
trials and several shorter trials were also submitted (Refs. 70 and 
73). All of the studies demonstrated a significant reduction of 
supragingival dental plaque with the use of 0.045 to 0.1 percent 
cetylpyridinium chloride mouthrinse. This is a reproducible finding in 
both short-term and 6-month studies based on the data submitted and in 
the published literature (Ref. 74).
    The results of two 6-month studies (Refs. 68 and 69), a 2-month 
study (Ref. 75), and a 4-month study (Ref. 76) showed reductions in 
gingivitis (based upon gingival index) ranging from 15.7 to 41 percent. 
Although trends were noted, no clear-cut dose response in the 
antigingivitis effect was documented in any one study in that range.
    Data from four other 6-month studies (Ref. 70) (three of which were 
carried out by different research groups) did not demonstrate a 
statistically significant reduction in gingivitis. In the Ciancio study 
(Ref. 77), there was no statistically significant reduction in 
gingivitis, although there was a reduction in plaque. Similarly, in the 
Lobene study (Ref. 78), no differences in gingival index were seen at 
4, 20, or 26 weeks, although there was a statistically significant 
reduction in gingival index at 8 weeks. In two studies (012-035 and 
012-037) by Ackerman and DeGenero (Ref. 79), a mouthrinse containing 
cetylpyridinium chloride showed no effect on gingivitis at 6 months. In 
a 6-week study by Moran (Ref. 80), cetylpyridinium chloride in a 
mouthrinse had no effect on plaque or gingivitis. Although most of the 
formulations reduced plaque, the gingivitis results in these studies 
are not consistent.
    The Subcommittee believes that differences in the results of 
studies on the effectiveness of cetylpyridinium chloride mouthrinse are 
likely explained by the use of different formulations (Refs. 65, 70, 
and 81). Based on the data presented, the biological effectiveness and 
chemical availability of cetylpyridinium chloride in a mouthrinse 
appear to be greatly affected by the particular formulation. 
Cetylpyridinium chloride in mouthrinse formulations all at 
approximately 0.045 percent nominal concentrations were shown to vary 
markedly between 4 and 77 percent. Thus, it is clear that inactivation 
of cetylpyridinium chloride is likely based upon formulation. It is 
recommended that the bioavailability of cetylpyridinium chloride in 
each formulation be determined to reduce the possibility that the 
active ingredient is removed due to chemical reaction, complexing, 
micelle (a colloid particle formed by an aggregation of small 
molecules) formation, or other sources of deactivation. Assessment of 
mouthrinses containing cetylpyridinium chloride in formulations similar 
to those tested in the positive studies (Refs. 68, 69, 76, and 77) show 
that 72 to 76 percent of the cetylpyridinium chloride is available 
(Ref. 82). Therefore, it is reasonable to assume that formulations 
containing 72 to 76 percent available cetylpyridinium chloride are 
active in reducing gingivitis and plaque.
    At the request of the Subcommittee, the manufacturer conducted 
additional analyses demonstrating the effectiveness of cetylpyridinium 
chloride on a site and subject basis, relative to other oral healthcare 
practices, and on the basis of odds-ratio calculations. Specifically, 
using a minimum 33 percent reduction in bleeding criterion, results of 
4 long-term studies were pooled to estimate an

[[Page 32249]]

overall odds ratio for improvement relative to a placebo. After 3 
months of product use, the odds ratio was 3.12 with a 95 percent 
confidence interval of 2.85 to 3.40. After 6 months, the odds ratio was 
3.10 with a 95 percent confidence interval of 2.75 to 3.45. Based on 
the totality of the data, the Subcommittee concludes that 
cetylpyridinium chloride mouthrinse is safe and effective as an OTC 
antigingivitis/antiplaque agent.
    b. Stannous fluoride (dentifrice). The Subcommittee concludes that 
stannous fluoride in a compatible dentifrice base at a concentration of 
0.454 percent is safe and effective for OTC use as an antigingivitis 
active ingredient.
    i. Safety. Stannous fluoride has been used as an OTC caries-
preventive agent in toothpastes in the United States since 1954. Since 
1981, it has been largely replaced by sodium fluoride or sodium 
monofluorophosphate. However, during this 27-year period, it is 
estimated that at least 70 billion doses of stannous fluoride were sold 
in the United States. Thus, a long market history exists to support its 
safety.
    The toxicity of ingesting fluoride from toothpaste has been 
reviewed extensively (Ref. 83). Concern has been expressed over the 
need to supervise the use of fluoridated toothpaste by young children 
because of the potential risk of developing fluorosis (Ref. 84). Acute 
toxicity of stannous fluoride in the rat (LD50) appears to 
range from 31 to 300 mg/kg. Thus, it appears to have an acute toxicity 
comparable to that of sodium fluoride (Refs. 85 and 86). Toxicity 
studies show that a dentifrice formulation containing stannous fluoride 
plus stannous chloride was comparable to other nationally marketed 
fluoride-containing dentifrices.
    Several subchronic toxicity tests of stannous fluoride dentifrice 
formulations have been carried out (Ref. 85). In a study conducted over 
3 months, rats received either 3.3 grams (g) dentifrice/kg/daily (= 
13.2 mg of stannous fluoride/kg/daily) or 8.4 g dentifrice/kg/daily (= 
33.6 mg of stannous fluoride/kg/daily) by gavage. Any observed effects 
were not attributed to stannous fluoride. Two additional 91-day studies 
were conducted in rats. Dentifrice slurries in distilled water were 
administered by gavage. All dentifrice groups revealed microscopic 
alterations in the stomach lining, such as eosinophilic gastritis, 
squamous epithelial hyperplasia, and squamous vacualization. No other 
abnormalities were observed. No tumorigenic effects have been reported 
from studies conducted in male or female rats or mice. Studies 
conducted in human volunteers who received 50 mg a day of the stannous 
ion as stannous chloride revealed that about 3 percent of the dose is 
absorbed.
    Based on results from a 13-week oral toxicity study in rats on 
stannous chloride conducted through the National Toxicology Program 
(NTP), a safety factor of 5,000 exists for potential exposure to 
stannous salts from use of a dentifrice containing 0.454 percent 
stannous fluoride. The safety factor is defined as the ratio between no 
observed adverse effect level (NOAEL) in the NTP study and the 
anticipated exposure to stannous salts from twice daily use of stannous 
fluoride toothpaste.
    The Subcommittee's analyses of clinical studies, including detailed 
examination of soft tissue and microbiological assays, revealed no 
adverse shifts among the oral microbiological populations studied, no 
overgrowth of opportunistic pathogens, and no development of oral 
microbial resistance to stannous fluoride. Significant reductions in S. 
mutans were observed among subjects exhibiting higher levels of this 
organism. Based on these data, the Subcommittee concludes that a 0.454 
percent stannous fluoride dentifrice is safe for long-term use.
    Stannous ion in stannous fluoride dentifrices has been associated 
with staining of tooth surfaces, which in some instances may be severe 
(Refs. 87 and 88). In studies CC-191, CC-238, and CC-247 (Ref. 89), 2.1 
percent of subjects discontinued the trial due to self-perceived tooth 
staining. Oral desquamation was reported by five subjects using a 
stannous fluoride dentifrice. This adverse effect does not appear to be 
an extensive problem because persons with hyposalivation have used 
stannous fluoride gels without adverse effects.
    Because staining is a common phenomenon with the use of stannous 
fluoride, the Subcommittee evaluated data concerning the extent of 
consumer sensitivity to dental staining and the ease with which these 
stains can be removed. Studies demonstrated that dental staining with 
0.454 percent stannous fluoride was noticed by a minority of consumers 
and that staining can be removed from enamel surfaces and dental 
restorations during conventional prophylactic procedures. However, the 
Subcommittee recommends that product labeling include a restriction on 
use by children and a statement concerning the likelihood of tooth 
staining.
    ii. Effectiveness. Stannous fluoride has been incorporated into 
numerous dentifrice formulations that contain a variety of abrasive 
substances, including hydrated silica gels, calcium pyrophosphate, and 
a variety of excipient agents (see the Federal Register of March 28, 
1980, 45 FR 20666 at 20684 to 20688).
    The careful formulation of stannous fluoride dentifrices to prevent 
rapid oxidation and hydrolysis, and thereby inactivation, of stannous 
ions is critical for clinical effectiveness of these dentifrices. 
Oxidation can be prevented in several ways. In one approach, water is 
excluded from the formulation. Another approach involves use of 
chelating agents such as pyrophosphate, citrate, gluconate, gantrez (a 
copolymer of maleic acid and methyl ether) or phytate, which form 
soluble stannous complexes. In addition, incorporation of another 
stannous compound, such as stannous pyrophosphate or stannous chloride, 
provides a steady-state situation in which the concentration of 
bioavailable stannous fluoride is relatively stable. It is essential to 
note that the inclusion of stannous fluoride alone in a dentifrice 
without stabilization is not sufficient to obtain optimum clinical 
effectiveness. Clearly, products containing stannous fluoride may have 
a defined shelf life.
    Stannous fluoride has a long and well-established history as a 
caries-preventive agent (Ref. 90). Stannous fluoride at a 0.4-percent 
concentration results in a concentration of 970 parts per million (ppm) 
fluoride (Ref. 86). Effects of stannous fluoride on plaque formation 
and gingivitis have given mixed results which, in part, reflect the 
duration of the studies, the concentration used, and the type of 
subjects studied.
    The Subcommittee evaluated the results of three primary trials and 
three supportive trials (Refs. 85 and 89) of a stabilized 0.454-percent 
stannous fluoride dentifrice for antiplaque and antigingivitis claims. 
Two of the primary 6-month trials (CC-191 and CC-238) carried out in 
Indiana had results that are consistent with each other (Ref. 89). The 
final assessments were consistent with the interim 3-month assessments. 
The third study (CC-247), conducted in Northfield, lasted for 7 months 
and had results that appeared to differ in some measures from those in 
Indiana (Ref. 89). The Indiana studies had reductions of 18.8 percent 
and 20.5 percent in gingival index, 30.5 percent and 33.4 percent in 
bleeding index, and a nonsignificant reduction of 2.6 percent and 3.1 
percent compared with placebo in plaque. In contrast, the Northfield 
study (one evaluator) reported a 10.7-percent

[[Page 32250]]

reduction in gingivitis in the stannous fluoride group and a 
statistically not significant 6.6-percent increase in the bleeding 
index. There was a 17.8-percent reduction in a Turesky modified 
Quigley-Hein Plaque Index and a 1.1-percent reduction using the Silness 
& Loe Plaque Index system. Two graders were used in this study, and 
they obtained large numerical differences in their assessments at the 
3-month assessment period and the final 7-month assessment. No 
significant shifts in the microbial flora were reported after 3 and 6 
months of product use.
    Three supportive double-blind and independent studies (CC-174, CC-
178, and CC-205) have been reported (Ref. 91). Two studies (CC-174 and 
CC-178) continued for 6 months and the third study (CC-205) for 2 
months. Study CC-174 demonstrated statistically significant differences 
in the indices from the stannous fluoride group compared with the 
negative control at the 1.5- and 3-month grading periods. However, all 
indices were not significant at the 7-month grading period.
    Study CC-178 (Ref. 91) revealed no significant differences in the 
gingival, bleeding, and plaque indices after 2 months use in the 
stannous fluoride group, compared with the control. After 6 months use, 
there was a statistically significant difference in the gingivitis 
index (9.3 percent) in the stannous fluoride group. Significant 
differences were not detected in the bleeding and plaque indices among 
the two groups.
    Study CC-205 (Ref. 91), which was conducted for 2 months only, 
revealed a significant difference (15.4 percent) in the gingivitis 
index of the stannous fluoride group compared with the control. There 
was a reported 23.9 percent difference in the bleeding index. However, 
the scores for both groups were exceptionally low compared with all of 
the study groups. Statistically significant differences in plaque 
scores among the groups were not detected.
    In five of the six studies reported, no significant differences in 
plaque scores were observed at the end of the evaluation period in 
subjects using stannous fluoride dentifrices compared with those using 
a control dentifrice. In 7 of 12 exams in two of the six studies, there 
was a reported statistically significant reduction in bleeding scores, 
and in five of the six studies there was a reduction in gingivitis 
scores associated with the use of stannous fluoride dentifrices.
    The Subcommittee evaluated additional information on the 
effectiveness of a 0.454 percent stannous fluoride dentifrice, 
including additional analyses it requested. The results of these 
analyses helped to establish that the study populations were 
appropriate for the OTC gingivitis indication recommended by the 
Subcommittee. Disease levels in the populations used in clinical 
studies supporting the stannous fluoride dentifrice were only slightly 
higher than disease levels established in published epidemiological 
studies and in surveys of oral health status conducted by the National 
Institute of Dental Research.
    Additional data were presented concerning the clinical relevance of 
the observed beneficial effects of the dentifrice on gingivitis. These 
data included site-specific analyses demonstrating that a 0.454 percent 
stannous fluoride dentifrice provided uniform efficacy in reducing 
gingivitis across the dentition and, in particular, in regions of 
significant disease. This site-based analysis was further expanded to 
compare treatment effects (e.g., causing a bleeding site to become a 
nonbleeding site) with benefits in preventing new disease (e.g., 
preventing a nonbleeding site from becoming a new bleeding site) during 
clinical studies. These analyses revealed that, compared to placebo, 
the stannous fluoride dentifrice was beneficial in preventing and 
reducing gingivitis and gingival bleeding.
    An analysis of the clinical benefits of stannous fluoride in 
reducing gingivitis compared to increased brushing, flossing, and 
frequent visits to a dentist indicated that a stannous fluoride 
dentifrice provides benefits comparable to the improvements observed 
from these established dental hygiene procedures.
    Finally, odds ratio analyses were used to determine the likelihood 
of an individual deriving a benefit from the use of a stannous fluoride 
dentifrice. Based on the benefits achieved from dental hygiene and 
benefits seen in studies CC-191 and CC-238 (Ref. 89), a meaningful 
benefit for a subject was defined as at least a 33-percent reduction in 
bleeding. Using this definition, the results of five long-term studies 
(Refs. 89 and 91) were pooled to estimate an overall odds ratio for 
improvement relative to a sodium fluoride control. After 3 months of 
use, the odds ratio was 1.57 with a 95-percent confidence interval of 
1.29 to 1.85.
    A review of the cited literature indicates that a number of studies 
examined the effects of stannous fluoride in gels, mouthrinses, and 
dentifrices. Many of these studies were of short duration, used few 
subjects, or used special groups of subjects. Thus, the quality and 
relevance of the data are, in some instances, questionable. The results 
are far from uniform in showing benefits from the use of stannous 
fluoride.
    With the exception of the studies submitted by the sponsor, there 
appear to be few studies involving the use of dentifrices containing 
stannous fluoride. Ogaard et al. (Ref. 92) studied the effect of a 
stannous fluoride dentifrice on plaque regrowth in 15 subjects for 24 
hours and 21 subjects for 3 weeks using a crossover design. Stannous 
fluoride was compared to a sodium monofluorophosphate dentifrice and a 
dentifrice without fluoride. Stannous fluoride gave significantly lower 
regrowth values than monofluorophosphate or placebo.
    In the 3-week crossover study (Ref. 92), 21 orthodontic subjects 
brushed twice daily for 1 minute with a stannous fluoride dentifrice or 
placebo paste. Less plaque was observed in the stannous fluoride group 
when the orthodontic brackets were 1 to 5 millimeters (mm) from the 
gingiva; if the brackets were closer, there was no difference in the 
effects of the stannous fluoride and the placebo dentifrice. No 
significant improvement was observed in gingival health regardless of 
treatment group.
    Bay and Rolla (Ref. 93) conducted a double-blind, crossover study 
in 40 pupils aged 15 years to compare the effects of a stannous 
fluoride dentifrice and a placebo dentifrice without stannous fluoride. 
The number of times the dentifrice was used was not stated, and the 
gender of the pupils was not disclosed. The study continued for 4 
weeks. There was reduced plaque formation in the stannous fluoride 
group and a small reduction in gingival index.
    Svatun (Ref. 94) compared the effect of dentifrices containing: (1) 
0.4 percent stannous fluoride, (2) a similar dentifrice without 
stannous fluoride, (3) 0.4 percent stannous fluoride plus stannous 
pyrophosphate, and (4) 0.8 percent chlorhexidine gel. Twelve female 
dental students were included and tests lasted for 4 days. The test 
products were placed in cap splints that covered the teeth only and 
held in place for 2 minutes twice daily. Subjects rinsed with sucrose 
(15 percent) for 1 minute every other hour to enhance plaque formation. 
No mechanical oral hygiene was allowed during the study. The dentifrice 
containing 0.4 percent stannous fluoride plus stannous pyrophosphate 
gave significantly lower plaque scores than the dentifrice containing 
0.4 percent stannous fluoride alone, or a similar dentifrice without 
stannous fluoride. There was a wide

[[Page 32251]]

range in scores among subjects using the dentifrice containing 0.4 
percent stannous fluoride plus stannous pyrophosphate.
    In a second study in the same report (Ref. 94), Svatun examined the 
influence of polishing teeth with a stannous fluoride or sodium 
monofluorophosphate dentifrice on 24-hour plaque regrowth in 8 mentally 
retarded home care subjects. Oral hygiene was suspended for 24 hours. 
There was less plaque regrowth following the stannous fluoride 
treatment, confirming the results of previous studies showing the 
effectiveness of stannous fluoride as a plaque inhibiter. A cap splint 
pilot study comparing stannous fluoride and sodium monofluorophosphate 
dentifrices did not result in any improvement in the gingiva of these 
subjects.
    Several studies have been carried out using rinses or gels 
containing stannous fluoride. It is doubtful whether the results from 
these studies are strictly applicable to dentifrices containing 
stannous fluoride. Nevertheless, the data are worth exploring because 
they may help to clarify the therapeutic potential of stannous 
fluoride.
    Svatun (Ref. 95) compared the plaque-inhibiting effects of 
mouthrinses containing 0.2 and 0.3 percent stannous fluoride, 0.1 
percent chlorhexidine, and distilled water randomly distributed among 
12 dental hygienist students. Subjects rinsed with 10 mL for 1 minute 
twice a day for 4 days, with no other oral hygiene permitted. Plaque 
index scores were brought to 0 at the beginning of each test period. 
Mean plaque scores were 0.35 for 0.2-percent stannous fluoride, 0.20 
for 0.3-percent stannous fluoride, 0.12 for chlorhexidine, and 1.02 for 
the placebo. A long-term study (Ref. 95) in another group of 5 students 
showed that the effect of a 0.3-percent stannous fluoride mouthrinse 
could be maintained for 3 weeks.
    Klock et al. (Ref. 96) compared the effects of rinsing with 
stannous fluoride or sodium fluoride (200 ppm fluoride) twice daily for 
2 years on oral health in adults. Thirty-seven subjects started the 
study; 15 withdrew during the first year and 3 withdrew during the 
second year. After 2 years, there were 12 in the stannous fluoride 
group and 7 in the sodium fluoride group, a total of 19 subjects. The 
authors commented: ``The population of subjects was generally 
unreliable.'' Plaque scores were not compared among the groups because 
the values were skewed at the baseline. Both groups showed a reduction 
in plaque at 1 year and subsequent increase after 2 years. Bleeding 
sites were significantly reduced after 1 year in the stannous fluoride 
group. This trend continued into the second year, but the results at 2 
years were no longer statistically significant. The lack of statistical 
significance is probably due to the loss of subjects between the first 
and second years. Other possible factors are the inability of subjects 
to comply with the mouthrinsing regimen and the development of 
bacterial resistance to the stannous fluoride rinse. The stannous 
fluoride group harbored significantly fewer S. mutans than did the 
sodium fluoride group.
    Several studies examining the effects of 0.4-percent stannous 
fluoride gels have been carried out in persons wearing prosthetic or 
orthodontic appliances. The validity of extrapolating data from these 
studies to support clinical claims for 0.4-percent stannous fluoride 
dentifrice is open to question even though these studies may provide 
information on the potential therapeutic effect of stannous fluoride.
    Derkson and MacEntee (Ref. 97) examined the effects of a 0.4-
percent stannous fluoride gel in 17 subjects with overdentures using a 
double-blind, crossover design. A nonfluoridated gel was used as a 
control. Each gel was applied daily for 6 months. Gingival and plaque 
index scores were recorded. A total of 34 teeth in 12 subjects who 
completed the study were available for assessment. No difference 
between the effects of two gels was observed in Gingival Bleeding Index 
scores from subjects who used the stannous fluoride gel first. Subjects 
who used the placebo first showed a 19-percent reduction in gingival 
index scores following use of stannous fluoride gel. The plaque index 
scores did not show any significant difference.
    Tinanoff et al. (Ref. 98) conducted a double-blind study in 61 
adults with fixed or removable dental prostheses. Subjects were given a 
thorough prophylaxis, including scaling and root planing, and were 
instructed to brush once daily for 2 weeks with a regular dentifrice. 
After the 2-week washout period, subjects then brushed twice daily 
(without rinsing) with a 0.22 percent sodium fluoride gel or 0.4 
percent stannous fluoride gel. Subjects were not permitted to have a 
dental prophylaxis during the course of the study. At the end of 6 
months, gingival index scores in the stannous fluoride group, using all 
teeth (including abutment teeth), were 48 percent lower than in the 
control group. The authors noted ``increasing change between groups 
over time in the percent bleeding site scores appears to be due to rise 
in the number of bleeding sites in the sodium fluoride group during 
course of the study.'' (There was no reduction in the number of 
bleeding sites compared with baseline.) Differences in plaque scores 
were statistically significant only when computed for abutment teeth. 
The authors noted ``higher baseline plaque index scores in the sodium 
fluoride group as compared to the stannous fluoride group might in some 
way influence other clinical or microbial indices.'' The stannous 
fluoride group harbored 2.5 log fewer S. mutans than did the sodium 
fluoride group.
    Two relatively long-term studies of 0.4 percent stannous fluoride 
gel gave apparently contrasting results. However, the apparent 
disparity may be a reflection of the type of subjects and the 
hypothesis studied. Boyd, et al. (Ref. 87) monitored the gingival 
health of 81 adolescents undergoing orthodontic treatment with fixed 
appliances while investigating the effects of daily brush-on 0.4 
percent stannous fluoride gels. One gel contained 98 percent available 
tin (used twice daily), and the other gel contained 2 percent available 
tin (used once daily and later twice daily). The control group did not 
use any gel. Subjects were instructed not to rinse after using the gel. 
Subjects continued their normal oral hygiene practices. Sites were 
scored at baseline and at 1, 3, 6, and 9 months after appliances were 
applied. There was a gradual increase in plaque accumulation from 
baseline to 9 months in all groups and no statistically significant 
difference in plaque scores among the groups. The gingival and plaque 
indices showed similar patterns. However, the percentage of sites with 
an index greater than 1 was statistically significantly less than 
observed in other groups. The percentage of sites with a Bleeding 
Tendency score greater than 1 also followed a similar pattern. Thus, 
use of stannous fluoride gel was associated with a smaller increase in 
gingival index and percent Bleeding Tendency compared with controls. 
However, there was no reduction in the indices compared with baseline.
    In a second long-term study, Wolff et al. (Ref. 88) studied the 
effects of 0.4 percent stannous fluoride gel, 0.22 percent sodium 
fluoride gel, and a fluoride-free placebo gel in three groups of 281 
subjects over 18 months. All subjects brushed with a sodium 
monofluorophosphate dentifrice twice daily. Subjects then used either a 
stannous fluoride, sodium fluoride, or placebo gel twice daily 
immediately after brushing with no rinsing for 30 minutes after using 
gel. Plaque, bleeding, and gingival indices were assessed after 6, 12, 
and 18 months.

[[Page 32252]]

 There was no significant difference in the mean plaque index between 
any of the groups. The gingival index declined in all groups, with no 
differences detected between groups. No differences were observed among 
any groups at any time.
    Based on the analyses of effectiveness on a site and subject basis 
compared to other oral health care practices and on odds-ratio 
calculations conducted on the submitted data, the Subcommittee 
concludes that, although available clinical data do not show 
reproducible long-term effects in reducing dental plaque mass, stannous 
fluoride is safe and effective in a dentifrice at an appropriately 
formulated concentration of 0.454 percent as an OTC antigingivitis 
agent.
2. Category I Combinations of Active Ingredients (See General 
Combination Policy in section II.E of this document)
    Eucalyptol, menthol, methyl salicylate, and thymol. The 
Subcommittee concludes that a combination of essential oils consisting 
of eucalyptol (0.092 percent), menthol (0.042 percent), methyl 
salicylate (0.060 percent), and thymol (0.064 percent) in a 
hydroalcoholic vehicle containing 21.6 to 26.9 percent alcohol in a 
mouthrinse is safe and effective as an OTC antigingivitis/antiplaque 
agent.
    a. Safety. Eucalyptol is a volatile oil prepared by steam 
distillation of the fresh leaves of Eucalyptus globulus. Eucalyptol is 
colorless, or a pale yellow volatile liquid with a characteristic 
aromatic, somewhat camphoraceous odor, and a spicy and cooling taste. 
Eucalyptol is also known as cineol, cineolcayeptol, and cajuptol. It is 
insoluble in water, but it is miscible with alcohol, chloroform, and 
ether.
    The Dental Panel concluded that eucalyptol is safe as an OTC 
anesthetic/analgesic active ingredient for topical use on the mucous 
membranes of the mouth and throat when used at a concentration of 0.025 
to 0.1 percent in the form of a rinse, mouthwash, gargle, or spray (47 
FR 22712 at 22826, May 25, 1982). It was reviewed and found safe by the 
Flavor and Extract Manufacturer's Association of the United States 
(FEMA) (Ref. 99).
    Menthol is a secondary alcohol extract from peppermint oil or made 
synthetically. Chemically, it is also known as hexahydrothymol and 3-
paramenthanol. Menthol may be made synthetically by the hydrogenation 
(reduction) of thymol. The Dental Panel concluded that menthol is safe 
as an OTC active ingredient for topical use on the mucous membranes of 
the mouth and throat at a concentration of 0.04 to 2.0 percent in the 
form of a rinse (47 FR 22712 at 22813). Menthol was reviewed and found 
safe by FEMA (Ref. 100).
    Methyl salicylate is the methyl ester of salicylic acid. Prior to 
the discovery of a method for chemical synthesis of methyl salicylate, 
it was produced by steam distillation from natural sources. The 
natural-source products are known as gaultheria oils, betula oil, sweet 
birch oil, teaberry oil, and wintergreen oil. Today, these names are 
used synonymously with methyl salicylate. Methyl salicylate is prepared 
synthetically by esterifying salicylic acid with methanol. The Dental 
Panel concluded that methyl salicylate is safe for topical use on the 
mucous membranes of the mouth and throat when used within the proposed 
dosage limit up to a 0.4-percent concentration in the form of a rinse, 
mouthwash, gargle, or spray, not more than three to four times daily 
(47 FR 22712 at 22828). Methyl salicylate was reviewed and found safe 
by FEMA (Ref. 101).
    Thymol, also known as thyme camphor, is 5-methy-2-isopropyl-2-
phenol. It may be prepared synthetically or obtained from volatile oils 
distilled from Thymus vulgans and other related plant sources. Thymol 
is an alkyl derivative of phenol and has bactericidal and fungicidal 
properties. It was reviewed and found safe by the Advisory Review Panel 
on OTC Dentifrice and Dental Care Drug Products (the Dental Panel) (47 
FR 22712 at 22829, May 25, 1982) and by FEMA (Ref. 102).
    The safety of the combination of the four ingredients has been 
assessed in numerous long-term clinical studies. These studies showed 
no clinical pathologic change or adverse reactions (Refs. 103, 104, and 
105).
    Because OTC drug products are readily available, the determination 
of the safety of single ingredients and combinations of ingredients 
also requires consideration of possible abuse. Exaggerated use studies 
have been done. In one study (Ref. 106), 47 healthy adult subjects 
screened for sensitivity and allergy histories rinsed with 20 mL of the 
combination of essential oils for 30 seconds under supervision at 5 
hourly intervals each day for 5 days and repeated 18 days later for 1 
day. No subject developed any oral mucosal lesions attributable to the 
test product. A second study (Ref. 107) of 45 adult subjects followed a 
similar protocol. One subject had erythema (2-centimeter lesion) and 
epithelial sloughing on day 5 of the irritation phase of the study. In 
a third exaggerated use study involving 18 xerostomic (dryness of the 
mouth from salivary gland dysfunction) adults, 2 subjects experienced 
what was described as ``utransient mucosal sloughing'' and continued 
the regimen. The remaining xerostomic subjects did not develop mucosal 
lesions (Ref. 108). These studies showed that the potential for mucosal 
irritation is minimal when these ingredients are used according to 
label directions.
    Two studies evaluated possible shifts in oral microbial populations 
and the emergence of opportunistic organisms or potential pathogens. 
One study in 83 subjects (Ref. 109) showed analysis of plaque samples 
from active agent and control groups. There were no significant 
increase in presumptive oral pathogens, spirochetes, black-pigmented 
Bacteroides, S. mutans, or C. albicans. A second 6-month study (Ref. 
110) examined plaque at 3 and 6 months. Three microbiological 
approaches were used: (1) Microscopic enumeration of cocci, motile and 
nonmotile rods, and spirochetes, (2) recovery on selective and 
nonselective culture media, and (3) enumeration by colony morphology on 
a nonselective medium. No clinically significant shifts were found in 
the composition of the flora.
    Mutagenicity studies have been reported (Ref. 111). The fixed 
combination of essential oils did not show mutagenic potential in the 
Ames test, the Unscheduled DNA Synthesis test, and the Mouse 
Micronucleus test.
    Much of the evidence of the safety of the combination of these 
ingredients comes from their extensive history of use (well over 100 
years) and the low incidence of consumer complaints reported by the 
manufacturer. The data included an estimate of one adverse reaction 
report for every 38,700,000 doses of these ingredients sold, which is 
described as an extremely low rate. The four ingredients in this 
combination have had a long and safe marketing history which 
contributes to the Subcommittee's conclusion that the combination is 
safe when used according to label directions.
    b. Effectiveness. The Subcommittee evaluated seven 6-month, 
randomized, controlled trials of the effectiveness of a fixed 
combination of eucalyptol (0.092 percent), menthol (0.042 percent), 
methyl salicylate (0.060 percent), and thymol (0.064 percent) in a 
hydroalcoholic vehicle containing 21.6 to 26.9-percent ethyl alcohol. 
One study was a 6-month, randomized, controlled study (Ref. 103) 
involving 145 students and staff at an East Coast university, aged 18 
to 54 years, randomized into three groups using either the above fixed 
combination, a vehicle control (a 26.9-percent hydroalcoholic vehicle 
containing all the ingredients in the test

[[Page 32253]]

product except the essential oils), or a water control. Of the 145 
subjects who entered the study, approximately 62 percent were male and 
20 percent were smokers. Inclusion criteria were 20 natural teeth 
exclusive of large carious lesions, orthodontically banded, fully 
crowned, abutment, and third molar teeth, and a minimum score of 2.0 
using a modified Loe-Silness Gingival Index plus a minimum score of 1.8 
using the Turesky modification of the Quigley-Hein Plaque Index. Of 129 
subjects completing the study, 45 were in the essential oils group 
(mean age 26.1 years), 43 were in the vehicle control group (mean age 
27.9 years), and 41 were in the water control group (mean age 24.7 
years).
    Subjects were supervised as they rinsed twice daily from Monday to 
Friday with 20 mL for 30 seconds. Coded 3-ounce (oz) bottles and 
graduated plastic cups were distributed for twice daily unsupervised 
weekend use. Coded 16-oz bottles were distributed for holidays and 
recesses. Subjects were required to maintain a diary of unsupervised 
rinse use. Subjects followed their usual oral hygiene regimen, with no 
dental treatment, scaling, or polishing prior to the rinse regimen.
    All intraoral examinations were performed by the same examiner. 
Gingivitis was scored using the modified Loe and Silness Gingival Index 
which adds an additional score between the 1 and 2 of Loe and Silness, 
thus having two levels of ``Mild Inflammation,'' and eliminates the 
bleeding component from the original criteria for ``Moderate 
Inflammation.'' This index was later published by Lobene (Ref. 112) and 
is used in five of the eight ``definitive'' studies. Results (see Table 
4 below) showed a continuous decline in adjusted mean gingivitis scores 
for each of three groups from baseline through 6 months.

                                                      Table 4.--Results of the Lamster Study Group
--------------------------------------------------------------------------------------------------------------------------------------------------------
                        Group                                 Baseline                 1 month                  3 months                 6 months
--------------------------------------------------------------------------------------------------------------------------------------------------------
Essential Oils                                                        2.62                     2.08                     1.57                     1.20
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vehicle Control                                                       2.67                     2.20                     1.94                     1.66
--------------------------------------------------------------------------------------------------------------------------------------------------------
Water Control                                                         2.66                     2.32                     1.93                     1.67
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Mean scores for the fixed combination of essential oils were 
statistically significantly less than controls at 3 and 6 months and 28 
percent less than either control group mean score at 6 months. Control 
groups of this monitored, supervised, mostly young, dental school 
population continued to show a decrease in mean gingival index scores 
over time. No bleeding assessments were made.
    A second study (Ref. 104) involved mostly dental students and staff 
of the same university, with the same inclusion criteria. Subjects were 
randomized into three groups, with 44 in the essential oils group (mean 
age 25 years), 38 in the vehicle control (a 26.9-percent hydroalcoholic 
vehicle containing all the ingredients in the test product except the 
essential oils) group (mean age 29 years), and 45 in the water control 
group (mean age 27 years). Upon entering the study, all subjects had a 
dental prophylaxis (defined as a scaling and rubber cup polishing), 
followed in 3 weeks by a baseline 1 examination. Two additional 
prophylaxes were done for each subject 4 to 7 days apart, followed in 3 
to 4 days by a baseline 2 assessment. Prior to the first rinse, another 
(fourth) polishing was done. Subjects were randomly assigned to either 
the fixed combination of essential oils, a vehicle control, or a 
colored water control.
    Supervision of rinsing and monitoring was the same as in the first 
study and gingivitis was scored as before. No bleeding assessment was 
done. Results (see Table 5 below) were recorded at 1, 3, and 6 months, 
with all assessments performed by one examiner. No intra-examiner 
variability testing is noted. Eighty-five subjects completed an 
additional 3 months of unsupervised rinsing. Most of the subjects who 
did not participate for the additional 3 months of the study were 
recently graduated dental students who were not available for the 9-
month examination. The 6-month mean gingival index score for the 
essential oils was 10.4 percent less than the water control and 6.5 
percent less than the vehicle control, but no statistically significant 
differences existed between groups for any interval.

                                               Table 5.--Mean Gingival Index Scores From the Gordon Study
--------------------------------------------------------------------------------------------------------------------------------------------------------
                     Group                            Baseline 1           Baseline 2            1 month              3 months             6 months
--------------------------------------------------------------------------------------------------------------------------------------------------------
Mean Gingival Index Score
--------------------------------------------------------------------------------------------------------------------------------------------------------
  Essential Oils                                              1.60                 1.39                 1.54                 1.27                 1.31
--------------------------------------------------------------------------------------------------------------------------------------------------------
  Water                                                       1.60                 1.38                 1.55                 1.38                 1.46
--------------------------------------------------------------------------------------------------------------------------------------------------------
  Vehicle                                                     1.59                 1.33                 1.49                 1.25                 1.37
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Mean gingival index scores for the 127 subjects who completed 6 
months of the study were as follows: 1.23 for the essential oil group, 
1.42 for the vehicle control group, and 1.57 for the water control 
group. Results for the 85 subjects who completed 9 months showed a 
statistically significant difference in mean gingival index scores, as 
follows: 1.12 for the essential oils, 1.43 for the vehicle control, and 
1.52 for the water control.
    The investigators stated that the lack of difference for gingivitis 
observed between groups for 6 months was probably due to improvement in 
gingival health resulting from four prophylaxes initially, followed by 
continuation of usual oral hygiene.
    A third study involving 115 subjects in two study groups (essential 
oils and

[[Page 32254]]

5-percent hydroalcohol) was conducted at the University of Maryland 
using the same protocol (Ref. 105). Of the 115 subjects, 107 completed 
the study; 60 percent were male, 40 percent were female; 17 percent 
were smokers and 83 percent were nonsmokers. Each subject received a 
dental prophylaxis on the day the first rinse was given. Baseline 
gingival index scores were recorded prior to the prophylaxis and after 
7 days of treatment. Fifty-four subjects (mean age 28.5 years) were in 
the essential oils group and 53 subjects (mean age 27.6 years) were in 
the 5-percent hydroalcohol control group. The analysis (see Table 6 
below) was based on adjusted mean gingival index scores at 3 and 6 
months.

                      Table 6.--Adjusted Mean Gingival Index Scores From the DePaola Study
----------------------------------------------------------------------------------------------------------------
                Group                         Baseline 1                3 months                 6 months
----------------------------------------------------------------------------------------------------------------
Essential Oils                                         2.288                    1.522                    0.918
----------------------------------------------------------------------------------------------------------------
5% hydroalcohol                                        2.200                    1.576                    1.385
----------------------------------------------------------------------------------------------------------------

    Results included the distribution of gingival index scores in 
percentage at both baselines and at 6 months. No zero scores were 
recorded at baselines 1 and 2, but zero scores accounted for 38 percent 
of all scores in the essential oil group and 19 percent of all scores 
in the control group at 6 months.
    The fourth study (Ref. 113), conducted at the University of 
Maryland, included a bleeding index (Ref. 114) in addition to the 
established inclusion criteria, assessments, and regimen of supervised 
rinsing twice a day on weekdays. This study compared the fixed 
combination of essential oils to 0.12 percent chlorhexidine gluconate 
and a control solution of flavored, colored 5 percent alcohol. There 
were 41 subjects in the essential oils group (mean age 29.2 years), 41 
subjects in the chlorhexidine gluconate group (mean age 29.2 years), 
and 42 subjects in the control group (mean age 28.6 years). Following 
baseline examination, all subjects were given a dental prophylaxis. 
Assessments were made at 3 and 6 months. Two examiners were used, but 
only one examiner recorded gingivitis, plaque, and bleeding indices. 
Teeth used for a plaque collection at time of assessment were 
eliminated from statistical analysis for gingival, bleeding, and plaque 
indices. The specific teeth used were not cited in this report. 
Adjusted mean gingival scores (see Table 7 below) were presented for 3 
and 6 months.

                        Table 7.--Adjusted Mean Gingival Scores From the Overholser Study
----------------------------------------------------------------------------------------------------------------
                Group                          Baseline                 3 months                 6 months
----------------------------------------------------------------------------------------------------------------
Essential Oils                                         2.234                    1.328                    0.748
----------------------------------------------------------------------------------------------------------------
Chlorhexedine Gluconate                                2.281                    1.032                    0.810
----------------------------------------------------------------------------------------------------------------
5% Hydroalcohol Control                                2.221                    1.409                    1.166
----------------------------------------------------------------------------------------------------------------

    At 6 months, both active mouthrinses were statistically 
significantly different than the control in gingival index scores; the 
mean value of the essential oils score was 35.9 percent less than the 
mean value of the control score.
    The distribution of gingival index scores at baseline and at 6 
months for scores 0, 1, 2, and 3 were also presented in percentages. No 
zero scores were recorded at baseline. At 6 months, the percentage of 
gingival units with zero scores was 26 percent for control, 46 percent 
for the essential oils and 43 percent for chlorhexidine gluconate. 
Scores 1 and 3 were comparable for the three study groups but score 2 
differed, decreasing from baseline to 6 months from 74 to 17 percent 
for the essential oils, 70 to 23 percent for chlorhexidine gluconate, 
and 74 to 34 percent for the control.
    Bleeding index scores (see Table 8 below) declined for all groups 
and were not statistically significantly different at 6 months.

                            Table 8.--Bleeding Index Scores From the Overholser Study
----------------------------------------------------------------------------------------------------------------
                Group                          Baseline                 3 months                 6 months
----------------------------------------------------------------------------------------------------------------
Essential Oils                                          .71                      .40                      .29
----------------------------------------------------------------------------------------------------------------
Chlorhexedine Gluconate                                 .72                      .28                      .25
----------------------------------------------------------------------------------------------------------------
5% Hydroalcohol Control                                 .66                      .37                      .33
----------------------------------------------------------------------------------------------------------------

    Mankodi (Ref. 115) conducted a similar study using the Loe-Silness 
Gingival Index, thus adding a bleeding component. This study compared 
the combination of essential oils to the same formulation with the 
addition of mint flavor and a 5-percent water-alcohol control. Each 
subject was given a prophylaxis on the day rinsing began. There were 42 
subjects in the essential oils group (mean age 31.1 years), 44 subjects 
in the essential oils plus mint group (mean age 30.6 years), and 38 
subjects in the control group (mean age 33.1 years). The percentage 
difference between mean gingival index scores (see Table 9 below) at 6 
months showed a score for the essential oils (0.90) that was 22.4 
percent less than the control score (1.16).

[[Page 32255]]



                           Table 9.--Mean Gingival Index Scores From the Mankodi Study
----------------------------------------------------------------------------------------------------------------
                  Group                          Baseline                3 months                6 months
----------------------------------------------------------------------------------------------------------------
Mean Gingival Index Score (adjusted for 3 and 6 months)
----------------------------------------------------------------------------------------------------------------
Essential Oils                            1.19                    0.93                    0.87
----------------------------------------------------------------------------------------------------------------
Essential Oils plus Mint                  1.22                    1.00                    0.91
----------------------------------------------------------------------------------------------------------------
Control                                   1.23                    1.10                    1.18
----------------------------------------------------------------------------------------------------------------

    A second study by Mankodi et al. (Ref. 116) compared the effects of 
the combination of essential oils, chlorhexidine gluconate, and a 5-
percent water-alcohol control. There were 34 subjects (mean age 32 
years) in the essential oils group, 36 subjects (mean age 31.4 years) 
in the chlorhexidine gluconate group, and 38 subjects (mean age 32.2 
years) in the water-alcohol control group. The protocol was similar to 
the earlier studies with the exception of the use of the Russell 
Periodontal Index ``to further describe the study population,'' and the 
use of the Loe and Silness Gingival Index for assessment. The results 
(see Table 10 below) showed a statistically significant difference 
between the essential oil and control groups at 6 months, with the mean 
gingival index score for the essential oils group being 14.0 percent 
less than the mean score for the control group.

                          Table 10.--Mean Gingival Index Scores From the Mankodi Study
----------------------------------------------------------------------------------------------------------------
                  Group                          Baseline                3 months                6 months
----------------------------------------------------------------------------------------------------------------
Mean Gingival Index Scores
----------------------------------------------------------------------------------------------------------------
Essential Oils                            1.31                    1.22                    1.04
----------------------------------------------------------------------------------------------------------------
Essential Oils Plus Mint                  1.35                    1.04                    0.99
----------------------------------------------------------------------------------------------------------------
Control                                   1.27                    1.18                    1.21
----------------------------------------------------------------------------------------------------------------

    A third study by Mankodi (Ref. 117) compared the effects of the 
combination of essential oils, the same combination plus flavor, and a 
5-percent water-alcohol control. There were 48 subjects in the 
essential oils group (mean age 32 years), 43 subjects in the essential 
oils plus mint group (mean age 32 years), and 50 subjects in the water-
alcohol control group (mean age 34 years). The protocol was similar to 
previous studies, but supervision on weekdays was limited to one of the 
two daily rinses, and this study used the Lobene modification of the 
Loe-Silness Gingival Index. Subjects received a prophylaxis following 
their baseline examination. Gingivitis was scored at baseline, 3 
months, and 6 months. All intraoral examinations were performed by a 
single qualified dental examiner. Units of statistical analysis were 
the respective mean index scores determined for each subject. Gingival 
indices were analyzed by the analysis of variance, using baseline 
scores as the covariant. Results of gingival index scoring (see Table 
11 below) are adjusted means for 3 and 6 months. Mean score percent 
reduction from control at 6 months for the combination of essential 
oils plus flavor was 10.8 percent and 10.2 percent for the combination 
without flavor. Both active groups are statistically significantly 
different at 6 months.

                          Table 11.--Mean Gingival Index Scores From the Mankodi Study
----------------------------------------------------------------------------------------------------------------
                  Group                          Baseline                3 months                6 months
----------------------------------------------------------------------------------------------------------------
Essential Oils Plus Mint                  2.16                    1.68                    1.66
----------------------------------------------------------------------------------------------------------------
Essential Oils                            2.20                    1.63                    1.67
----------------------------------------------------------------------------------------------------------------
Control                                   2.19                    1.82                    1.86
----------------------------------------------------------------------------------------------------------------

    An eighth 6-month controlled trial (Ref. 118) used the fixed 
combination of essential oils and a ``flavor variant'' control. The 
results showed the mean gingival scores significantly lower than the 
control group at 6 months.
    These studies demonstrated that the fixed combination of essential 
oils has some effectiveness in preventing inflammation of the gingiva. 
The initial analyses relied solely on statistical hypothesis testing 
(the use of p values), which does not convey important quantitative 
information. However, a number of concerns (strength of the effect and 
its statistical significance, the generalizibility of the studies to 
the population which can most benefit, and the unit of analysis 
(subject versus site)) were resolved to make a valid determination as 
to the strength of antigingivitis efficacy for these ingredients.
    Generalizibility of randomized, controlled trials to the population 
who will use the product is a concern. These studies use young 
populations, weighted with dental students, where supervision and 
timing of use is present. Much of the population that will benefit from 
an antigingivitis agent is middle-aged and older, having fully crowned

[[Page 32256]]

and restored teeth, and abutment teeth, which have been omitted from 
scoring in these trials. These teeth are among the ones most in need of 
combating gingivitis.
    Because it is the individual who is at risk, it is important to 
know if each subject has changed. Use of mean gingival index scores for 
each individual subject is the correct way to calculate the mean score 
for each trial group at various intervals. However, analysis of each 
site infers that all sites provide independent observations. This 
assumes that 100 sites in one subject provide the same outcome 
information as one site in each of 100 subjects. Differences between 
subjects are greater than variations within subjects (Ref. 119). The 
principle noted is ``In investigations where experimental units on 
different levels are employed, use the highest level unit as 
computational unit'' (Ref. 120). All sites within one subject are not 
at equal risk for gingivitis. Inflammation tends to be more overt at 
interdental areas than at lingual or facial sites. To quantify the 
findings (i.e., who and how many in the study groups are affected, and 
by how much) and to present the findings with appropriate indicators of 
measurement error or uncertainty (such as confidence intervals), 
further analyses were completed.
    Data from pooled analyses of the eight 6-month studies were 
presented to the Subcommittee. Results showed that mean index values 
for men differed between the control and essential oils regimen and 
were similar to differences seen in women for gingival bleeding, 
gingival index, and plaque index. Differences in mean values between 
the control and active agent were presented for subjects aged 18 to 39 
years and were similar to differences seen in subjects 40 years old and 
older. The percent of subjects who improved in bleeding, gingival 
index, and plaque scores from the initial exam to 6 months was greater 
in the essential oil group than the control group.
    Pooled data from the eight studies were used to compute the odds 
ratio for reduction in gingival index score. The odds ratio was 4.21 
with a 95-percent confidence interval (CI) of 2.79 to 6.36 to achieve a 
goal of 33 percent reduction in score. The bleeding score odds ratio 
for all studies where bleeding was assessed was 5.12 (CI 3.29 to 7.97). 
Again, the target goal was a 33-percent reduction in score. For the 
reported plaque index score reduction of 33 percent, the pooled (eight 
studies) odds ratio was calculated at 10.53 (CI 7.06 to 15.71).
    The Subcommittee concludes that a combination containing eucalyptol 
(0.092 percent), menthol (0.042 percent), methyl salicylate (0.060 
percent), and thymol (0.064 percent) in a hydroalcoholic vehicle 
containing 21.6 to 26.9 percent alcohol in a mouthrinse meets the 
requirements of FDA's policy regarding fixed combinations of OTC active 
ingredients with the same pharmacological action. The Subcommittee 
concludes that each of these ingredients contributes to the 
antibacterial activity of the combination, and that each is safe 
individually and in combination.
    Based on the data submitted, the Subcommittee concludes that the 
combination of eucalyptol (0.092 percent), menthol (0.042 percent), 
methyl salicylate (0.060 percent), and thymol (0.064 percent) in a 
hydroalcoholic vehicle containing 21.6 to 26.9 percent alcohol in a 
mouthrinse is safe and effective as an OTC antigingivitis/antiplaque 
agent.

B. Category II Conditions

    None.

C. Category III Conditions

    The available data are insufficient to permit final classification 
at this time. Data to demonstrate safety and effectiveness as an 
antigingivitis/antiplaque agent will be required in accordance with the 
guidelines set forth above (see general guidelines on safety and 
effectiveness in section II.H of this document.)
1. Category III Single Active Ingredients
    Aloe vera
    Dicalcium phosphate dihydrate
    Hydrogen peroxide
    Sanguinaria extract
    Sodium bicarbonate
    Sodium lauryl sulfate
    Zinc citrate
    a. Aloe vera. The Subcommittee concludes that there are 
insufficient data to permit final classification of the safety and 
effectiveness of aloe vera as an OTC antigingivitis/antiplaque 
ingredient. Aloe vera (known in commerce as Curacao Aloe) is a brownish 
black, opaque mass with a fractured surface that is uneven, waxy, and 
somewhat resinous (Ref. 121). Aloe vera is obtained from the parenchyma 
tissue in the center of the leaf by mechanical or chemical means and is 
highly variable in its properties. The main constituents are 
polysaccharides, mainly glucomannans, anthraquinone glycosides, and 
glycoproteins. Other constituents may include sterols, saponins, and 
organic acids. Aloe vera is topically applied as an emollient, to aid 
in wound healing, and relieve burns (including sunburn), and is used 
for colonic irrigation. Extracts of aloe vera have been shown to 
enhance phagocytosis (ingestion by a cell of particulate material, such 
as microorganisms) in adult bronchial asthma. It is also used as an 
ingredient in many cosmetic preparations (Ref. 122). Aloe vera is 
produced by boiling Aloe juice down and pouring the viscous residue 
into empty spirit cases, in which it is allowed to solidify. Aloe vera 
possesses a nauseating and bitter taste and a disagreeable, penetrating 
odor. It is almost entirely soluble in 60 percent alcohol and contains 
not more than 30 percent of substances insoluble in water. Solutions of 
aloes gradually undergo change and, after a month, may no longer react 
normally and may lose the bitterness natural to aloes (Ref. 123).
    i. Safety. The safety of aloe vera is difficult to discern from the 
data. However, there are studies in which the toxicity of components of 
aloe vera are discussed, e.g., the component, acemannan (Ref. 124). 
Also, there is evidence that application of aloe vera to wounds will 
delay healing (Refs. 125 and 126). The Subcommittee concludes that the 
data are insufficient to permit final classification of the safety of 
aloe vera.
    ii. Effectiveness. The Subcommittee concludes that there are 
insufficient data to permit final classification of the effectiveness 
of aloe vera as an OTC antigingivitis/antiplaque ingredient.
    Aloe vera, a plant extract, has been claimed to have 
antiinflammatory and antiprostaglandin effects, as well as cathartic 
effects (Ref. 127). There are also claims that aloe vera extract is 
effective against several gram-positive and gram-negative organisms as 
well as C. albicans. However, the Subcommittee finds that the studies 
are conflicting and that the concentrations required appear to be 20 
percent to 90 percent.
    The enzyme blend of protease, lipase, and amylase is described as 
contributing to 3 percent of the formulation reviewed. There is only a 
general rationale for use in periodontal disease for debridement 
resulting in reduction of deposits of hard and soft excretions. 
However, no valid scientific evaluation of this proposed activity is 
apparent from the submitted data or from the literature (Ref. 128). In 
addition, no specific testing of the formulation has been presented or 
was located in the literature (Ref. 128). Therefore, the Subcommittee 
concludes that there are insufficient data to permit final 
classification of the effectiveness of aloe vera as an OTC 
antigingivitis/antiplaque ingredient.

[[Page 32257]]

    b. Dicalcium phosphate dihydrate. Dicalcium phosphate dihydrate is 
one of several phosphate preparations that have been used as buffers, 
fillers, and abrasives in OTC dentifrices and as inactive ingredients 
in numerous drug products. The Subcommittee concludes that dicalcium 
phosphate dihydrate is safe when used as a buffer, filler, or abrasive 
in a dentifrice, but not generally recognized as effective for OTC use 
as an antigingivitis agent.
    i. Safety. The safety of dicalcium phosphate dihydrate has been 
established on the basis of animal experiments and consumer use as a 
primary component of oral care products. It is included in the list of 
inactive ingredients in OTC anticaries formulations (45 FR 20666 at 
20670), and is also approved by FDA as an optional food additive 
ingredient in the manufacture of flour (21 CFR 137.105 and 137.185). 
Dicalcium phosphate dihydrate has a reported oral LD50 value 
of greater than 10 g/kg for rats, and a dermal LD50 value of 
greater than 7 g/kg for rabbits. It is nonirritating or slightly 
irritating on rabbit skin and in eye irritation tests, respectively. 
Rodent oral limit tests, dermal irritation tests, and human irritation 
tests using various dentifrice formulations containing 5 percent to 88 
percent dicalcium phosphate dihydrate were submitted (Ref. 129). These 
studies were carried out using toothpaste containing from 5 percent to 
88 percent dicalcium phosphate dihydrate. The LD50 in rats 
is greater than 16 g/kg for a toothpaste containing 60:40 weight to 
volume (w/v) suspension of dicalcium phosphate dihydrate. Oral tissue 
irritation or sensitization potential of toothpaste containing 
dicalcium phosphate dihydrate was also evaluated in a series of studies 
(Ref. 129). The tests were carried out by having the subject brush 7 
days, 5 times a day to provide an exaggerated test for oral tissue 
irritation. In no instances were any of the dentifrices containing 
dicalcium phosphate dihydrate either irritating or sensitizing under 
conditions of the test.
    No reports were available regarding the toxicity of ingested 
dicalcium phosphate dihydrate in humans. It is estimated that the 
average adult might consume 2 to 3 g of phosphorous per day and, with 
an extreme diet containing maximum quantities of additives and 
naturally occurring phosphorous, could consume 6 to 7 g per day. 
Ingestion of an entire medium-size tube of toothpaste would increase 
the phosphorous consumption by several g, an amount unlikely to be 
significantly toxic. The saline cathartic effect of large doses of 
phosphate-containing materials would tend to limit their absorption to 
nontoxic levels. The Subcommittee concludes that, in general, dicalcium 
phosphate dihydrate can be regarded as safe.
    ii. Effectiveness. Studies of the short-term use of dicalcium 
phosphate dihydrate-containing dentifrices in man have shown reduction 
of supragingival plaque to be greater than toothbrushing with water 
(Ref. 129). These studies do not implicate dicalcium phosphate 
dihydrate as an active ingredient but rather might be explained by the 
abrasive effect of dicalcium phosphate dihydrate in assisting plaque 
removal by toothbrushing. Gingivitis reduction is also seen in such 
experiments, but this could also be related to the abrasive effects of 
dicalcium phosphate dihydrate and removing plaque. The Subcommittee 
believes there is no evidence for chemical interference with plaque 
formation or plaque removal and no evidence of dicalcium phosphate 
dihydrate as an antigingivitis agent. The Subcommittee concludes that, 
based on the available data, it would be inappropriate to claim that 
the plaque reduction associated with the use of this abrasive qualifies 
it as an antigingivitis/antiplaque agent.
    c. Hydrogen peroxide. The Subcommittee concludes that hydrogen 
peroxide is safe at concentrations of up to 3 percent, but there are 
insufficient data available to permit final classification of its 
effectiveness at 1.5 to 3 percent concentrations for long-term OTC use 
as an antigingivitis/antiplaque agent.
    Hydrogen peroxide was isolated by Thenard in 1818 and has been of 
commercial interest since the mid-nineteenth century. Hydrogen peroxide 
has been a component of OTC drugs such as topical antiinfectants, 
canker sore treatments, and earwax softeners. A 3-percent solution of 
hydrogen peroxide has been widely used as a topical antiseptic agent 
for suppurative (producing pus) wounds, inflammation of the skin and 
mucous membranes, by dentists for irrigation during root-canal therapy, 
and as a mouthrinse for acute necrotizing ulcerative gingivitis. 
Decomposition of hydrogen peroxide releases large volumes of oxygen, 
approximately ten times the volume of the solution. A 30-percent 
solution has been used for bleaching nonvital pulpless teeth.
    The Advisory Review Panel on OTC Oral Cavity Drug Products 
classified hydrogen peroxide as a Category I ingredient for short-term 
use in oral wound cleansing and debriding in concentrations from 1.5 to 
3 percent in aqueous solution (47 FR 22760 at 22906, May 25, 1982). Ten 
percent carbamide peroxide in anhydrous glycerin, which releases 3 
percent hydrogen peroxide, is also classified in Category I. Hydrogen 
peroxide is listed in the USP (Ref. 130).
    i. Safety. The Subcommittee evaluated the toxicity and mutagenicity 
of hydrogen peroxide. The toxicity data suggested that 1.5 to 3 percent 
hydrogen peroxide in aqueous solution has a low toxicity. When ingested 
in large doses, hydrogen peroxide produces esophagitis and gastritis 
(Ref. 131). Few primary systemic toxic effects are expected at low 
concentrations because hydrogen peroxide decomposes in the oral cavity 
(Ref. 132) and bowel before absorption can occur.
    The acute toxicity of hydrogen peroxide depends on the 
concentration tested, with more concentrated solutions being relatively 
more toxic than dilute solutions. In rats, concentrations of 0.25 
percent to 0.5 percent hydrogen peroxide added to drinking water 
decreased growth and increased mortality within 6 weeks (Ref. 133). 
Decreased body weight was seen in Osborne-Mendel rats given 0.45 
percent hydrogen peroxide in drinking water for 5 months, but this 
decreased body weight was regained within 2 weeks after replacing the 
hydrogen peroxide-containing drinking water with tap water (Ref. 134). 
The decreased body weight was possibly attributed to decreased liquid 
intake when hydrogen peroxide was provided in the drinking water. In 
case studies, fatal poisoning (Refs. 135 and 136) has been reported for 
ingestion of hydrogen peroxide at concentrations exceeding 3 percent or 
excessive ingestion of 3 percent hydrogen peroxide. Generally, 
ingestion of household peroxide (3 to 9 percent) causes no significant 
toxic effects (Refs. 137, 138, and 139).
    The LD50 of hydrogen peroxide has been established by 
Ito et al. (Ref. 140) as 1,567 mg/kg body weight in rats dosed with a 
5-percent solution. The low acute toxicity of hydrogen peroxide is 
confirmed by unpublished data indicating an LD50 of 5,000 
mg/kg body weight for 6 percent hydrogen peroxide in rats (Ref. 141).
    Teratogenic activity has not been demonstrated for hydrogen 
peroxide (Ref. 142). Hydrogen peroxide can be absorbed through the oral 
mucosa (Ref. 143) and epidermis (Ref. 144), but the exposure of the 
oral cavity to hydrogen peroxide is generally limited since it 
undergoes rapid decomposition. After 1 minute of brushing, less than 20 
percent of the hydrogen peroxide introduced into the oral cavity can be 
recovered (Ref 145).

[[Page 32258]]

    In the oral cavity, toxic effects of hydrogen peroxide vary from 
pulpal alterations (Ref. 146) to gingival lesions (Refs. 147 and 148) 
and oral irritation in rats (Ref. 149) under certain conditions. Adding 
a 1- to 1.5-percent solution to drinking water resulted in apparent 
enamel demineralization in rats over an 8-week period (Ref. 149). This 
effect on enamel was possibly due to the hydrogen-ion (pH) 
concentration of the solution used rather than true carious lesions. In 
addition, no enamel solubility was found from an in-vitro experiment 
using a 1.5-percent aqueous solution on human enamel (Ref. 141).
    The Subcommittee's discussion of mutagenicity is not intended to be 
a complete review of the literature concerning the mutagenic nature of 
hydrogen peroxide, but is intended to point out the apparent mutagenic 
safety concerns associated with hydrogen peroxide. Any mutagenic role 
of hydrogen peroxide will be further discussed with sodium bicarbonate 
and hydrogen peroxide in combination.
    Numerous reports indicate a mutagenic role for hydrogen peroxide 
(Refs. 150, 151, and 152). Reviews on the genotoxicity of hydrogen 
peroxide can be found in reports by the European Centre for 
Ecotoxicology and Toxicology of Chemicals (ECETOC) (Refs. 153 and 154) 
and in an overview of hydrogen peroxide genotoxicity presented at the 
Subcommittee meeting on December 4, 1995 (Ref. 155).
    Hydrogen peroxide can produce hydroxyl radicals which are reactive 
but short-lived (Refs. 155 and 156). In vitro superoxide and hydroxyl 
radicals caused chromatic exchanges in mammalian cells and 
preneoplastic changes (Refs. 153 and 154). Although hydroxyl radicals 
and singlet oxygen can damage DNA in vitro, the genotoxic potential of 
hydrogen peroxide depends on the proximity of unprotected DNA. In vitro 
genotoxicity tests enhance the opportunity for DNA damage and are 
conducted in cells with defective DNA repair systems. Genotoxic effects 
are not seen with hydrogen peroxide in the presence of protective 
enzyme systems that are normally present intracellularly, in the 
presence of iron chelating agents, and in the presence of hydroxyl 
radical scavengers.
    The mechanism of mutagenesis through superoxide radical production 
was also suggested by MacRae et al. (Ref. 157). In contrast to most of 
the references available, Taylor et al. (Ref. 158) suggested that 
hydrogen peroxide itself and not hydroxyl radicals was responsible for 
DNA strand breaks in epithelial and fibroblast cultures. Most carefully 
controlled in vitro studies have shown that the participation of 
transition metal ions, such as iron or copper, is required for DNA 
damage to occur (Ref. 159).
    In some bacterial mutagenesis studies, hydrogen peroxide was found 
to be a weak mutagenic agent (Refs. 160 through 167). Many strains are 
not sensitive to hydrogen peroxide and hydroxyl radicals and mutations 
are only seen in certain bacterial strains that are sensitive to 
oxidative damage (Ref. 168). The addition of an external enzymatic 
metabolic source resulted in abolition of the weak genotoxic effects 
seen in sensitive bacterial strains. These enzyme sources are normally 
present throughout the body, and the presence of detoxifying enzymes 
may explain the lack of genotoxicity seen in whole animals that have 
been administered hydrogen peroxide. In the oral cavity, salivary 
peroxidase serves as the initial line of defense against hydrogen 
peroxide (Ref. 169).
    Additional studies were conducted to evaluate systemic effects of 
long-term administration of hydrogen peroxide, and the endpoint 
measured was sister chromatic exchange (SCE), a very sensitive assay 
for genotoxic damage. Hydrogen peroxide was administered to hamsters 
for 6 months at 70 mg/kg (Ref. 170) and to mice for 3 months (Ref. 
171). In both studies, there was no increase in SCE formation following 
long term ingestion of hydrogen peroxide. A single administration of a 
carbamide peroxide-containing dentifrice to rats at 1,000 mg/kg daily 
for 5 days did not increase the incidence of SCE (Ref. 172). Woolverton 
also examined two commercial carbamide peroxide-containing dental 
products for micronucleus formation. After two exposures, these 
products did not increase the incidence of micronucleated erythrocytes 
(Ref. 173).
    Similar results were seen in a micronucleus assay for chromosomal 
damage in mice that were given hydrogen peroxide intraperitoneally or 
in drinking water at 0.6 percent for 2 weeks (Refs. 174 and 175). The 
SCE and micronucleus studies consistently demonstrated a lack of 
genotoxicity following hydrogen peroxide ingestion or intraperitoneal 
injection.
    Hydrogen peroxide was reported to promote carcinomas in rodents 
following intraperitoneal injections (Ref. 176) and through its 
addition to drinking water (Refs. 177, 178, and 179). Duodenal 
hyperplasia has been found in the rat model following the addition of 
1.5 to 3 percent hydrogen peroxide to drinking water (Ref. 176). Ito et 
al. (Ref. 140) observed similar toxicity with higher doses of hydrogen 
peroxide. In mice with reduced catalase activity, hyperplastic and 
neoplastic duodenal nodules were found (Ref. 179). Ito's report of the 
carcinogenicity of hydrogen peroxide has been evaluated by FDA 
toxicologists who concluded that the results of the study did not 
provide sufficient evidence to designate hydrogen peroxide as a 
carcinogen (53 FR 53176, December 30, 1988). Similar conclusions were 
drawn by a panel of toxicologists who reviewed the potential 
carcinogenicity of hydrogen peroxide for the International Agency for 
Research on Cancer (IARC) (Refs. 180 and 181).
    A long-term study was conducted in F344 rats in which hydrogen 
peroxide was administered in drinking water for 18 months at 
concentrations of up to 0.6 percent, the maximal tolerated dose in F344 
rats (Ref. 182). All surviving animals were sacrificed at 24 months of 
age. Hydrogen peroxide ingestion in the 0.6-percent hydrogen peroxide 
group was 677 mg/kg/day for females and 433 mg/kg/day for males, with a 
total ingestion of 72.7 g hydrogen peroxide in females and 81.4 g 
hydrogen peroxide in males during the course of the study. There was no 
evidence of carcinogenicity at any organ site in this study following 
hydrogen peroxide ingestion.
    In Syrian hamsters, applications of 3 percent and 30 percent 
hydrogen peroxide produced pathogenic changes associated with 
preneoplastic lesions. Preneoplastic lesions are reversible following 
cessation of exposure (Ref. 178). When combined with DMBA, a known 
carcinogen, hydrogen peroxide, at a concentration of 30 percent, 
appeared to augment the carcinogenic effects associated with DMBA (Ref. 
183). No carcinogenicity was seen in this study resulting from hydrogen 
peroxide alone at concentrations of 3 or 30 percent.
    Marshall et al. (Ref. 184) conducted two carcinogenesis studies of 
16 weeks and 20 weeks in hamsters to compare the effects of similar 
dentifrices with and without the combination of hydrogen peroxide and 
sodium bicarbonate in the presence of DMBA. The authors reported that 
the results demonstrated that an oral product containing hydrogen 
peroxide and sodium bicarbonate was not carcinogenic and that the 
combination did not enhance the tumorigenicity of DMBA. In summary, 
these robust animal studies (Refs. 183 and 184) indicate that hydrogen 
peroxide does not increase the incidence of oral cavity tumors in 
combination with a known carcinogen.

[[Page 32259]]

    Several studies challenge the carcinogenesis of hydrogen peroxide. 
Cell culture experiments rich in catalase show a marked decrease in the 
mutagenic effects of hydrogen peroxide (Refs. 185 and 186). Further, 
variations exist between species in their ability to control the 
destructive effects by the release of catalase and reduced glutathione 
(Ref. 187). The mutagenic potential of hydrogen peroxide as measured by 
production of hydroxyl radicals in the presence of Fe2+ has also been 
shown to be concentration dependent in a Chinese hamster cell line 
(Ref. 188). Additional mechanistic studies (Refs. 189 and 190) also 
suggested that the gel and paste phases of a toothpaste reduce the 
formation of free radicals. A generous supply of catalase in the oral 
cavity and studies demonstrating that hydrogen peroxide is rapidly 
degraded in the oral cavity indicate that hydrogen peroxide is unlikely 
to have a mutagenic potential at concentrations up to 3 percent (Ref. 
191).
    The ECETOC 1992 Joint Assessment of the toxic effects of hydrogen 
peroxide (Refs. 153 and 154) had the following conclusions: (1) 
Hydrogen peroxide concentrations of less than 1 percent do not appear 
to have gastrointestinal (GI) tumor-promoting potential; (2) chronic 
ingestion of 0.1 to 0.15 percent hydrogen peroxide causes an 
inflammatory response in gastroduodenal tissue of mice; (3) the 
mutagenicity of hydrogen peroxide in bacteria is a function of the 
genotype of the strain; (4) hydrogen peroxide has genotoxic potential 
only through the direct exposure of hydroxyl radicals on target DNA; 
(5) catalase reduces or abolishes the mutagenic response to hydrogen 
peroxide; (6) in vivo, many factors may contribute to the reduction of 
bioavailable hydrogen peroxide for systemic genotoxic action; (7) the 
possibility of genotoxic effect on cells that directly contact hydrogen 
peroxide at the site of application cannot be ruled out; and (8) no 
data are available to fully evaluate chronic toxicity and resulting 
carcinogenic potential of hydrogen peroxide.
    The rate of decomposition of hydrogen peroxide in the oral cavity 
was determined in adults, children, and xerostomics. Hydrogen peroxide 
decomposition was so rapid that it was difficult to establish a rate of 
decomposition. In all cases, less than 27 percent of the hydrogen 
peroxide introduced into the oral cavity was present after 1 minute of 
brushing with dentifrices containing up to 3 percent hydrogen peroxide 
(Ref. 145). Most residual hydrogen peroxide would be expectorated with 
the dentifrice after brushing, leaving very little for ingestion. Based 
on clinical studies and adverse event reporting, the lack of irritation 
to soft tissues of the oral mucosa following use of hydrogen peroxide-
containing dentifrices provides further evidence of the safety of long-
term use of hydrogen peroxide-containing dental products.
    Hydrogen peroxide presents safety concerns at concentrations above 
3 percent because of the lack of controlled studies conducted with 
concentrations between 3 percent and 30 percent hydrogen peroxide. 
Available evidence indicates that acute toxic effects encountered with 
high concentrations of hydrogen peroxide (i.e., 30 percent) are rapidly 
repaired, leaving no deleterious effects. The discussion above mentions 
only some of the many published articles detailing the mutagenic 
potential of this ingredient. Despite some safety concerns, the 
gathering of appropriate clinical data outweighs the currently 
documented risks, which are inconclusive. While the experimental data 
suggest a mutagenic effect of hydrogen peroxide, the Subcommittee's 
review of current data indicates that, at concentrations of up to 3 
percent in oral care products, the risk appears to be especially 
minimal and hydrogen peroxide is safe for its intended use.
    ii. Effectiveness. Because of the preponderance of anaerobic and 
microaerophilic microorganisms associated with most forms of 
periodontal disease, the testing of oxygenating agents to inhibit or 
kill these microorganisms is understandable. The primary killing 
mechanism for hydrogen peroxide is through the release of oxygen. 
Unfortunately, the action is short-lived and inhibited by organic 
matter.
    Hydrogen peroxide added to a mouthrinse has been shown to increase 
the release of hypothiocyanate into saliva. Hypothiocyanate has been 
reported to be a bacteriostatic agent against some microbial species 
(Refs. 192 and 193) through the activation of the lactoperoxidase 
system (Ref. 194). The addition of hydrogen peroxide to human whole 
saliva resulted in increased amounts of hypothiocyanate and this effect 
was concentration dependent (Ref. 195). This study also showed that the 
concentration of hydrogen peroxide was critical to obtain optimum 
bacteriocidal effect. Incubation time for inhibitory effects required 
several minutes, which may be a significant stumbling block in 
utilizing exogenous hydrogen peroxide through this mechanism of action. 
Another study of the lactoperoxidase/hypothiocyanate antimicrobial 
mechanism found that rinsing with a solution containing hydrogen 
peroxide can readily produce hypothiocyanate, although the amount was 
dependent on the volume and pH of the rinse and the concentration and 
pH of the hydrogen peroxide (Ref. 196).
    In a 2-week, crossover study, Wennstrom and Lindhe (Ref. 197) found 
that a hydrogen peroxide-containing mouthrinse effectively prevented 
the colonization of several morphological groups of microorganisms, 
e.g., fusiforms, filaments, motile and curved rods, and spirochetes. 
These groups have been repeatedly associated with several forms of 
periodontal diseases. Plaque and gingivitis scores were also markedly 
reduced. The concentration of hydrogen peroxide released was not 
determined. In another short-term study, a 1.5-percent hydrogen 
peroxide rinse significantly reduced both plaque and gingivitis scores 
over the 7-day test period (Ref. 198). In a study using a rat model in 
which test animals on a high cariogenic diet were inoculated with 
plaqueforming microbial species, a 10-percent urea (carbamide) peroxide 
gel and 1 percent hydrogen peroxide solution significantly reduced the 
accumulation of plaque (Ref. 199). A 3-week study using 10 percent urea 
(carbamide) peroxide gel compared with a placebo showed a significant 
decrease in gingivitis but no comparable reduction in plaque scores 
(Ref. 200). The authors suggested that the oxygenating effects of the 
test solution produced an environment unsuitable for the microbial 
species responsible for the development of gingivitis. Similar results 
were found in another 3-week study using 10 percent urea peroxide gel 
(Ref. 201).
    In contrast, a 3-week study comparing 1 percent hydrogen peroxide, 
0.12 percent chlorhexidine, and a placebo rinse found little effect of 
the hydrogen peroxide on gingivitis scores and no demonstrable effects 
on plaque scores (Ref. 202). A 2-week study using a 1.5-percent 
hydrogen peroxide rinse compared to a placebo showed no benefit from 
the hydrogen peroxide either as a rinse or when delivered by an 
irrigation system (Ref. 203).
    Testing of an 11-percent urea (carbamide) peroxide gel in a 3-month 
study (Ref. 204) and a 6-month study (Ref. 205) showed that plaque 
scores were significantly reduced when compared to conventional oral 
hygiene toothpaste controls. However, no effect on gingivitis could be 
determined in either study. In an 18-month study comparing a 1.5-
percent hydrogen peroxide rinse with a fluoridated rinse

[[Page 32260]]

in conjunction with toothbrushing in subjects undergoing orthodontic 
treatment, a clear benefit was found for the hydrogen peroxide rinse 
group (Ref. 206). The rinse appeared to prevent the accumulation of 
plaque and the subsequent development of gingivitis. However, once 
plaque formed, the experimental rinse did not reduce the established 
plaque and gingivitis. In contrast, a 24-week study comparing a 1.5-
percent hydrogen peroxide rinse with water rinses did not find a 
significant reduction in either plaque scores or in papillary bleeding 
scores (Ref. 207). A 2-year study comparing a 1.5-percent hydrogen 
peroxide rinse with a 0.1-percent chlorhexidine rinse, but without a 
placebo control, found a reduction in sulcus bleeding but not plaque 
scores for the hydrogen peroxide group (Ref. 208).
    The Subcommittee concludes that there is a lack of well-controlled 
studies of sufficient length to draw firm conclusions regarding the 
effectiveness of hydrogen peroxide. The clinical data suggest that 
hydrogen peroxide may positively effect plaque and gingivitis scores, 
but the data are contradictory, lacking well-controlled clinical 
studies of adequate length. Further studies are needed to determine the 
value of this ingredient as an antiplaque agent. Optimizing the 
concentration, required exposure time, and best delivery vehicle would 
be major steps forward. The potential positive effect as an active 
ingredient is suggested by the current data. However, long-term 
efficacy is unknown.
    d. Sanguinaria extract. The Subcommittee concludes that sanguinaria 
extract at 0.03 to 0.075 percent concentration is safe, but there are 
insufficient data available to permit final classification of its 
effectiveness in an oral rinse or dentifrice dosage form as an OTC 
antigingivitis/antiplaque active ingredient.
    Sanguinaria extract is prepared by warm acidulated alcoholic 
extraction of the rhizome of Sanguinaria canadensis (more commonly 
known as blood root or puccoon), followed by precipitation with a metal 
salt. Six principal benzophenanthridine alkaloids are present in the 
extract with sanguinarine (50 percent) and chelerythrine (25 percent) 
being the major ones. Sanguinaria extract is a bright orange, free-
flowing, amorphous powder that is hygroscopic and electrostatic. It is 
soluble at 25[deg] C in methanol to 1 percent weight per weight (w/w), 
in chloroform to 0.75 percent w/w, in water or water buffered with one 
percent citric acid to 2 percent w/w. Sanguinaria extract exhibits a pH 
dependent lipophilicity and partitions to a significant extent into the 
lipid phase of a lipid/water mixture above pH 6.5. Sanguinaria extract 
has been described in several pharmacopeia (Refs. 209 and 210) and 
textbooks (Ref. 211). Uses include relief of spongy and red gums and in 
OTC cough syrups as an expectorant. Sanguinaria extract was introduced 
into homeopathic practice in 1837.
    i. Safety. Safety studies addressing acute toxicity, irritation 
potential, sensitization potential, reproductive toxicity, birth defect 
potential, chronic organ toxicity, and carcinogenic potential were 
conducted in animals using sanguinaria extract and sanguinarine 
chloride.
    The acute toxicity of sanguinaria extract was determined by oral 
gavage to Sprague-Dawley rats with doses from 500 to 3,000 mg/kg. In 
one study (Ref. 212), the oral LD50 of sanguinaria extract 
was 1,440 mg/kg. This suggests that sanguinaria extract is probably 
poorly absorbed orally. The lethal dose of sanguinaria extract in two 
Cynomolgus monkeys was above 50 mg/kg. The acute dermal LD50 
in a limited study using 10 adult New Zealand rabbits was greater than 
200 mg/kg body weight. Acute inhalation toxicity of sanguinaria extract 
(2.2 mg/liter) in 10 rats resulted in mortality in 3 of 5 males and no 
females. Gross pathology examination revealed no lesions or 
abnormalities. The LD50 from two studies of sanguinarine 
chloride determined by oral gavage in rats was 1,525 and 1,663 mg/kg. 
The intravenous LD50 in rats was 28.7 mg/kg, and the 
intraperitoneal LD50 in mice was 17.7 mg/kg.
    Studies concerning the multidose subchronic toxicity of sanguinaria 
extract (Refs. 213, 214, and 215) and sanguinarine chloride (Refs. 216, 
217, and 218) were conducted in rats and monkeys at doses ranging from 
5 to 405 mg/kg for 2 to 13 weeks. In a 4-week oral gavage study in 
monkeys (Ref. 215), 100 mg/kg of sanguinaria extract was determined to 
be the appropriate high-dose for a subsequent 13-week toxicity study in 
monkeys. A 13-week gavage study in monkeys (Ref. 216) with 0 to 60 mg/
kg showed no treatment-related toxicity except minor GI irritation of 
limited duration. The study suggested a NOAEL of 30 mg/kg per day once 
tolerance is achieved. A 13-week oral gavage study in rats (50 to 400 
mg/kg per day) (Ref. 214) showed evidence of dose-related toxicity, 
principally involving GI irritation and body weight loss at all dosage 
levels. Mortality was observed at doses of 100 mg/kg per day and above, 
with a NOAEL of less than 50 mg/kg per day. Administration in the diet 
appears to protect against GI irritation. A 4-week dietary toxicity 
study in rats (5 to 405 mg/kg per day) (Ref. 213) showed a group mean 
body weight loss at 405 mg/kg. Based on these studies, evidence of 
minor treatment-related toxicity associated with sanguinaria extract 
and sanguinarine chloride is limited to GI irritation.
    Pharmacokinetic studies assessing metabolism, disposition, 
distribution, and elimination of sanguinaria extract and sanguinarine 
chloride were conducted in rats and mice (Refs. 219, 220, and 221). The 
metabolism of sanguinaria extract was tested in vitro in rat and rabbit 
liver homogenates and in vivo in 10 human subjects for at least 6 
months (Ref. 219). Results indicated that no benz[c]acridine (50 parts 
per billion (ppb) detection limit) was formed in the rat or rabbit 
liver homogenates. Neither benz[c]acridine (1 ppb detection limit) nor 
sanguinarine chloride (25 ppb detection limit) was found in the urine 
of the human subjects.
    Studies evaluating the biological disposition of radiolabeled 
sanguinarine chloride in rats (Ref. 220) and mice (Ref. 221) suggested 
low absorption, with excretion of over 50 percent (mice) and 88 percent 
(rats) of the total dose in feces. Less than 1.0 percent (rats) and 0.9 
percent (mice) was excreted in the urine.
    Analysis of rat tissues collected 96 hours following oral 
administration of 5 mg/kg indicated a total recovery of approximately 
6.1 percent of the administered radioactivity. Excretion via urine, 
feces, and expired air accounted for 95.1 percent of the administered 
dose in the 96-hour post-administration period. Blood levels in the rat 
achieved less than 1.5 percent of the net dose administered orally, 
peaking around 8 hours and declining to near 1 hour levels by 96 hours.
    Expired air accounted for an average of 18.3 percent (mice) and 6.0 
percent (rats) of the dose administered. The nature of the blood 
radioactive residues and excreted \14\C-carbon was not determined. An 
overall mean recovery in mice of 97.89 percent of the \14\C-carbon 
during the 96 hours following oral administration of sanguinarine 
chloride labeled at one and/or both methylene-dioxy groups suggests 
that a substantial portion of the radiolabeled test product may be 
transformed into nonlabeled benzophenanthridine metabolites. These 
results suggested that sanguinarine chloride is satisfactorily 
recovered after oral or intravenous administration.
    A cardiovascular study in dogs treated intravenously with 
sanguinarine

[[Page 32261]]

chloride (0.075 mg/kg) demonstrated no treatment-related effect on 
heart function or cardiovascular health (Ref. 222) at a dose 30 times 
the maximum daily absorbed dose expected from brushing and rinsing.
    Sanguinaria extract was tested in a fertility/reproduction study in 
rats (Ref. 223), in developmental toxicity studies in rats and rabbits 
(5 to 400 mg/kg per day) (Refs. 224, 225, and 226), and in a perinatal/
postnatal study in rats (5 to 60 mg/kg per day) (Ref. 227). The NOAEL 
level of sanguinaria extract was 25 mg/kg per day for development 
toxicity in rabbits, and 15 mg/kg per day for maternal toxicity. 
Sanguinaria extract had no effect on fertility, reproduction, or fetal 
and neonatal development in rats and rabbits at doses below those 
resulting in general toxicity in the adult animals.
    Mutagenicity studies were conducted with both sanguinaria extract 
and sanguinarine chloride with in vitro methods using microorganisms 
and mammalian cells in culture and in vivo in mice. Weak positive 
responses were elicited only in the bacterial assay using Salmonella 
typhimurium (Ames assay) in the presence of metabolic activation (Ref. 
228). Studies of sanguinaria extract were negative in the bacterial 
assay with Escherichia coli (Ref. 229), in an unscheduled DNA synthesis 
assay in rat primary hepatocytes (Ref. 230), and in a micronucleus 
cytogenetic assay in mice (Ref. 231). An Ames test for metabolites of 
sanguinaria extract in rat urine using S. typhimurium was negative. 
Studies of sanguinaria chloride were negative in other Ames assays with 
S. typhimurium (Ref. 232), and Saccharomyces cerevisiae (Ref. 233) with 
and without metabolic activation. Two mammalian cell assays (Ref. 234) 
with sanguinarine chloride, including a Chinese hamster ovary (CHO)-
hypoxanthine-guanine phosphoribosyltransferase (HGPRT) forward gene 
mutation assay and unscheduled DNA synthesis assay in rat primary 
hepatocytes (Ref. 235) provided results that were equivocal or 
uninterpretable. Neither study, however, gave a positive mutagenic 
response. The CHO assay is historically difficult to conduct and 
interpret.
    Long-term (90 to 98 weeks) carcinogenicity studies (Ref. 236) by 
gavage at dosages of 0 to 60 mg/kg per day sanguinaria extract in rats 
did not produce treatment-related preneoplastic or neoplastic lesions 
to suggest a carcinogenic effect. Dosage at 40 mg/kg per day did not 
produce toxicity and is considered the NOAEL dosage. A lifetime diet 
carcinogenicity study of sanguinaria extract was evaluated in rats (8 
to 200 mg/kg per day) (Ref. 237). No test related hematological, 
biochemical, or urological changes were observed at any dosage level. 
No test article related macro- or microscopic pathology changes were 
observed. A 200 mg/kg per day dosage level can be considered the NOAEL 
level.
    Two controlled 13-week subchronic studies done in monkeys and dogs 
(Ref. 238) examining ocular toxicity provided no evidence that 
sanguinaria extract or sanguinarine chloride affected intraocular 
pressure or produced any other ophthalmologic changes.
    Human exposure to sanguinarine with twice daily use of toothpaste 
and oral rinse has been estimated to be 0.056 mg/kg per day (Ref. 238). 
Comparison of doses tested in animal studies with human doses expected 
from use of toothpaste or oral rinse appears to support the use of 
sanguinaria extract at a significantly higher concentration than 
contained in currently marketed products.
    Ten animal safety studies conducted between 1982 and 1984 were 
submitted for dentifrice formulas containing 300 to 2,000 [mu]g/mL of 
sanguinaria extract. None of the studies tested the currently marketed 
toothpaste formula containing 750 [mu]g/mL of sanguinaria extract. 
Acute oral toxicity was greater than 20 g/kg in rats for a toothpaste 
formula containing 300 [mu]g/mL of sanguinaria extract, and 5 g/kg in 
rats for a formula containing 500 [mu]g/mL of sanguinaria extract 
(Refs. 239, 240, and 241). Primary skin and eye irritation studies 
carried out in rabbits (Refs. 242 and 243) demonstrated mild irritation 
reaction when a toothpaste formula containing less than 750 [mu]g/mL 
was tested. Mild mucosal irritation was observed when a toothpaste 
formula containing 300 [mu]g/mL of sanguinaria extract was tested in 
cheek pouches of hamsters (Refs. 244 through 248).
    Two clinical studies (Refs. 249 and 250) demonstrated only mild 
mucosal irritation in test subjects. No differences were noted in the 
severity of lesions between the test and control groups.
    Eleven clinical studies of animal safety conducted between 1983 and 
1987 (Ref. 251) were submitted. Because modification of the oral rinse 
formulation from pH 3.2 to pH 4.5 began in 1989, none of these studies 
provided animal safety data on the currently marketed oral rinse (pH 
4.5).
    Based on data on the oral rinse formula containing 450 to 1,000 
[mu]g/mL sanguinaria extract at a pH of 3.2, no mucosal irritation was 
noted in the hamster cheek pouch (Refs. 252 and 253) or albino guinea 
pig studies (Ref. 254). No signs of toxicity or pharmacological effects 
were observed in test animals when a rinse formula of 450 [mu]g/mL 
sanguinaria extract at pH 3.2 was tested (Ref. 255).
    Four human studies conducted between 1982 and 1985 evaluated the 
irritation and sensitization potential of dentifrice formulas 
containing sanguinaria extract using a repeated insult patch test 
design involving a 2-percent aqueous slurry (Refs. 256 through 259). 
These studies demonstrated no induction of irritation or allergic 
contact dermatitis. An exaggerated use study (Ref. 260) using an 
earlier formula (300 [mu]g/g sanguinaria extract) demonstrated no 
irritation or sensitization in soft oral cavity tissues. Two 6-month 
studies on a toothpaste containing sanguinaria and sodium 
monofluorophosphate (Refs. 261 and 262) showed no adverse effects on 
oral hard or soft tissues. Soft tissue examinations included inspection 
of the lips, tongue, hard and soft palate, gingiva, mucobuccal fold 
areas, inner surface of the cheeks, and sublingual areas. Although 
testing of the microbial flora was inconclusive in one study (Ref. 
261), sanguinaria did not promote overgrowth through the development of 
resistant microbial strains.
    A 6-month, double-blind, randomized study using a dentifrice 
containing 0.075 percent sanguinaria extract (Ref. 263) showed no 
significant oral irritation or adverse reactions. A 1-week exaggerated 
use study showed that 18 of the 28 subjects experienced mucosal 
sloughing (Ref. 264).
    Although nine human safety studies were presented, only one study 
(Ref. 265) tested the currently marketed oral rinse containing 300 
[mu]g/mL of sanguinaria extract at pH 4.5. However, this study tested 
the efficacy of the formula and was not designed to test the safety of 
the oral rinse. Three of the remaining eight studies showed that 
repeated application of the earlier oral rinse formula at pH 3.2 under 
a semiocclusive patch test did not induce clinically significant 
irritation or evidence of induced contact dermatitis in humans (Refs. 
266, 267, and 268). This earlier rinse formula gave no evidence of 
localized or generalized clinical manifestations in test subjects in 
two of the 7-day exaggerated use studies (Refs. 269 and 270). The 
Subcommittee concludes that sanguinaria extract at 0.03 to 0.075 
percent concentration in an oral rinse or dentifrice dosage form is 
safe.
    ii. Effectiveness. The Subcommittee reviewed controlled clinical 
studies ranging from 1 week to 6 months in duration. Three short-term 
studies (two 1 week and one 1 month) had equivocal results between the 
active and placebo toothpaste preparations. Of the three

[[Page 32262]]

studies that tested the currently marketed toothpaste containing 750 
[mu]g/g of sanguinaria extract, only one 6-month, double-blind study 
(Ref. 271) demonstrated a significant decrease in plaque at 3 months. 
Results from this study also showed that gingival index scores in the 
active group were significantly lower than the placebo group at 28 
weeks. The other two studies were short-term studies of 1 and 4 weeks 
(Refs. 272 and 273) in which no differences were detected between the 
active and placebo groups. A 10-week study (Ref. 274) showed that the 
toothpaste formulation containing 300 [mu]g/g of sanguinaria extract 
reduced plaque and gingival bleeding, but the zinc chloride in the 
formulation diminished the plaque-reducing effect. It was not clearly 
documented whether zinc chloride affects the effectiveness of the 
currently marketed toothpaste. Based on the short-term clinical 
studies, the effectiveness of the toothpaste containing 750 [mu]g/g 
sanguinaria extract in plaque and gingivitis reduction cannot be 
determined. The effect of zinc chloride on the effectiveness of the 
toothpaste also needs further study.
    Five studies used a toothpaste formula containing 750 [mu]g/g 
sanguinaria extract and 0.8 percent sodium monofluorophosphate (Refs. 
263, 264, 273, 275, and 276). Equivocal results were noted in two 6-
month studies (Refs. 263 and 276) and in a 1-week study (Ref. 264). One 
toothbrushing study (Ref. 273) compared the effect of eight toothpaste 
formulations on plaque and gingivitis in school children. Because the 
study design concerning the control product and subject selection was 
inadequate, this study did not support effectiveness. One-way analysis 
of variance (ANOVA) showed that the differences between groups were not 
statistically significant. In addition, no significant differences in 
plaque or gingivitis reduction were noted between groups using a 
fluoride toothpaste containing zinc chloride plus sanguinaria extract 
and a dentifrice containing zinc chloride without sanguinaria extract.
    A 1-week, exaggerated use effectiveness study (Ref. 275) tested 
three regimens of the toothpaste and oral rinse on plaque reduction. 
The study design and protocol employed did not allow accurate testing 
of the effectiveness of the toothpaste. Based on all of the data 
submitted, none of the studies provided evidence of effectiveness.
    The Subcommittee evaluated 26 additional controlled clinical 
studies (Ref. 277). Seven of the 26 studies (Refs. 265 and 278 through 
283) provided equivocal results. The remaining 19 studies (ranging from 
1 to 8 weeks), conducted for various reasons, evaluated proper dosage, 
clinical study designs, optimal plaque and gingival indices to be 
employed, product safety, effectiveness of the regimen (toothpaste and 
oral rinse combination use), and the role of zinc chloride in plaque 
reduction.
    Among the 19 studies, 9 tested the effectiveness of an oral rinse 
with a final pH of 4.5. Some short-term clinical trials, employing the 
7-day exaggerated use study design, demonstrated statistically 
significant differences between an earlier rinse product (pH 3.2) and 
the placebo control in plaque reduction only. However, the only two 
long-term, 6-month studies testing the effectiveness of this earlier 
rinse product (pH 3.2) did not demonstrate any effectiveness in plaque 
or gingivitis reduction when compared to a placebo. The 7-day 
exaggerated use study design was validated as a screening test for 
formulation development (Ref. 284). In addition, studies investigating 
the role of zinc chloride in the effectiveness of the oral rinse 
provided confusing and controversial results. Two 1-week studies (Refs. 
285 and 286) demonstrated that no significant difference in plaque 
reduction was observed between a sanguinaria extract and zinc chloride 
rinse and a rinse without sanguinaria extract. The effect of zinc 
chloride alone was only mildly less than that obtained with the 
combination of sanguinaria extract and zinc chloride. However, a 2-
week, experimental gingivitis, crossover study (Ref. 287) demonstrated 
that the oral rinse with sanguinaria extract and zinc chloride 
performed significantly better than the placebo in plaque reduction. 
The effect on gingivitis was equivocal.
    One study trial (Ref. 288) evaluated the effect of the oral rinse 
on viable microorganisms after a single 60-second rinse. The rinse 
exhibited a selective effect on anaerobic organisms without adversely 
affecting aerobes or alpha-hemolytic streptococci. No long-term studies 
were available.
    While some data exist on the short-term effectiveness of the 
sanguinaria extract oral rinse or dentifrice, the Subcommittee 
evaluated selected studies that supported the effectiveness of the oral 
rinse used in combination with one of the sanguinaria toothpaste 
products. Five short-term (1 to 9 weeks) studies (Refs. 265 and 289 
through 292) demonstrated reductions in plaque or gingivitis. Four 6-
month studies also produced significant differences for the active 
regimen compared to placebo (Refs. 293 through 296). However, these 
nine studies varied substantially in design and formulation of the test 
dentifrice and oral rinse combinations. In studies prior to 1984, low 
dose toothpaste (300 microg/mL sanguinaria extract) and pH 3.2 oral 
rinse were used, whereas studies conducted since 1988 have included the 
750 microg/g sanguinaria extract toothpaste and a pH 4.5 oral rinse. 
Even if effectiveness were demonstrated for the combined regimen, the 
contribution of sanguinaria extract alone is not clear.
    The in vitro efficacy of the individual active components was also 
investigated. In vitro MICs of sanguinaria chloride and sanguinaria 
extract were tested against 176 clinical isolates and 43 reference 
strains of oral bacteria (Ref. 297). MIC's for sanguinaria chloride 
ranged from 16 to 32 microg/mL for all but 7 reference isolates. MICs 
for sanguinaria extract ranged from 16 to 24 [mu]g/mL for all strains 
except Wolinella succinogenes and one strain of Wolinella curva. For 
fresh isolates, MIC's for sanguinaria chloride and sanguinaria extract 
ranged from 16 to 32 microg/mL. Laboratory tests were also conducted on 
sanguinaria and fluoride-containing toothpaste to evaluate the 
bioequivalence of the product to positive controls. Tests included 
bioavailability, rat caries fluoride stability (Ref. 298), 
remineralization/demineralization, and in vivo bovine enamel fluoride 
uptake (Ref. 299). These tests are consistent with the required 
biological testing procedures for fluoride dentifrices (October 6, 
1995, 60 FR 52474 at 52510). Results obtained from these studies 
indicated that the sanguinaria/fluoride toothpaste formula was 
biologically equivalent to the clinically-tested control in promoting 
remineralization, promoting fluoride uptake into artificial enamel 
lesions, reducing the effects of acid challenge on enamel, and reducing 
caries in the rat caries model. Sanguinaria extract and zinc chloride 
were also shown not to interfere with fluoride bioavailability uptake 
profiles with decalcified enamel qualitatively comparable to profiles 
obtained from sound enamel.
    The Subcommittee concludes that, although mild staining and oral 
irritation may occur, sanguinaria extract at 0.03 to 0.075 percent 
concentration is safe. However, given the wide variations in study 
designs, test product concentrations and formulations, placebo 
controls, and statistical analyses, conclusions cannot be drawn 
regarding the effectiveness of sanguinaria extract as an OTC 
antigingivitis/antiplaque agent.
    e. Sodium bicarbonate. The Subcommittee concludes that sodium

[[Page 32263]]

bicarbonate is safe, but appears to have relatively poor efficacy as an 
OTC antigingivitis/antiplaque agent, requiring high dosages and 
extended exposure time to have a reasonable chance at affecting the 
oral flora and clinical parameters.
    Sodium bicarbonate has been used as an antacid as well as advocated 
as an ingredient in both toothpastes and mouthrinses. It has been 
generally regarded as a bactericidal agent that generates a hypertonic 
(causing water to flow out of the cell) environment, leading to 
disruption of the fluid equilibrium of the cell and dehydration, 
plasmolysis (cell shrinkage due to loss of water by osmosis), and 
eventual cell death.
    i. Safety. Sodium bicarbonate is GRAS for use in foods (21 CFR 
184.1736). Sodium bicarbonate is listed as an OTC antacid up to a 
maximum daily dose of 200 milliequivalent (mEq) bicarbonate ion (21 CFR 
331.11(k)(1)). The usual dose is 1 to 5 g, providing up to 60 mEq. In 
OTC mouthrinse applications, sodium bicarbonate has been determined to 
be safe and effective for use as a debriding ingredient (47 FR 22712 at 
22907, May 25, 1982). Ingestion of large amounts of sodium bicarbonate 
causes several blood chemistry changes, including increased sodium 
levels, resulting in toxic effects that produce hypernatremia 
(excessive amount of sodium in the blood) (Refs. 300, 301, and 302). 
The LD50 is 7.57 to 8.9 g/kg body weight for the rat.
    Sodium bicarbonate does not appear to be teratogenic or mutagenic 
using conventional testing, with no discernable effects on fetal 
survival in several species. It does not produce photosensitization, 
acute ocular irritation, or skin irritation by standard methods.
    ii. Effectiveness. Few studies examine the effectiveness of sodium 
bicarbonate as a single active ingredient. Sodium bicarbonate has been 
found to be bactericidal to several oral microorganisms (Ref. 303). The 
authors suggest that the killing effect might be more than an osmotic 
imbalance created within the cells. This study showed several 
disturbing aspects about the effectiveness of this ingredient. For 
killing to be effective, relatively long periods of exposure were 
required, ranging from several minutes to hours. While a comparison to 
other antimicrobial agents is not intended as a criteria for 
effectiveness, sodium bicarbonate had a 10-fold poorer MIC range 
compared to sodium fluoride and a 1,000-fold poorer MIC range compared 
to sodium lauryl sulfate. In a study examining the effects of sodium 
bicarbonate on S. mutans, osmotic disruption occurred through salt 
concentration dependent cell lysis (Ref. 304).
    In a 20-day experiment on rats, sodium bicarbonate applications 
were ineffective at reducing plaque accumulations (Ref. 305). In a 6-
week study comparing the effects of a toothpaste containing sodium 
bicarbonate with a standard fluoride toothpaste, no increase in 
effectiveness was observed (Ref. 306). In a similar 8-week study, no 
difference was observed in either plaque or gingivitis scores between 
the control and sodium bicarbonate test toothpaste (Ref. 307).
    The Subcommittee concludes that sodium bicarbonate is safe, but 
there are insufficient data available to determine its effectiveness as 
an OTC antigingivitis/antiplaque agent.
    f. Sodium lauryl sulfate. The Subcommittee concludes that sodium 
lauryl sulfate is safe at concentrations of 0.1 to 5 percent, but there 
is insufficient evidence to support its effectiveness as an 
antigingivitis/antiplaque active ingredient. The Subcommittee notes, 
however, that sodium lauryl sulfate is a safe and effective foaming 
ingredient in toothpaste.
    Sodium lauryl sulfate is a synthetic detergent that acts as an 
anionic surfactant to lower surface tension. Sodium lauryl sulfate is 
available commercially as a viscous liquid, paste, or powder. It may 
contain small amounts of other sodium alkyl sulfates, although it 
consists mostly of sodium lauryl sulfate with a molecular weight of 
288.4 and the formula 
CH3(CH2)10CH2OSO3
Na. It is soluble in water and alcohols. It binds to positively charged 
tooth surfaces and positively charged side groups of proteins. Protein 
binding may lead to denaturation (loss of biological activity) through 
conformational changes in the molecule. It is stable in alkaline 
solutions and will hydrolyze (split into fragments by addition of 
water) at room temperature below a pH of 5 (Ref. 308).
    Sodium lauryl sulfate is used in cosmetics such as shampoos, 
deodorants, facial makeup, shaving preparations, and bath products, and 
in various oral care products. It is approved as a multipurpose food 
additive (21 CFR 172.822). Its ubiquity in personal care products can 
be estimated by a 1981 FDA Cosmetic Product Formulation List that shows 
it as an ingredient in 703 products (Ref. 308). In oral care products, 
sodium lauryl sulfate is used as a foaming agent and is frequently 
combined with other ingredients. It is found in mouthrinses and 
dentifrices, usually in concentrations of 5 percent or less (Refs. 308 
and 309). In most mouthrinses, it is found in concentrations of less 
than 1 percent. In skin care products, concentrations of sodium lauryl 
sulfate may range up to 50 percent. In the last two decades, sodium 
lauryl sulfate has replaced most other surfactants previously used for 
oral care drug products. It is estimated that 4 to 5 million pounds of 
sodium lauryl sulfate are used annually in the United States for oral 
health care products alone (Ref. 309).
    The estimated daily intake of sodium lauryl sulfate of about 1 to 
10 mg originates, in part, from personal products (including oral 
hygiene products), foods, and drinking water. Personal products account 
for about one-half or less of this intake (Ref. 310).
    i. Safety. Extensive safety data, both in animals and humans, show 
that sodium lauryl sulfate has a very low level of toxicity at doses 
used in oral health care products, is rapidly metabolized through the 
liver, and has no genotoxic or teratogenic effects (Ref. 311).
    1. Absorption and excretion. Sodium lauryl sulfate is poorly 
absorbed through the epithelial lining of the skin and mucosal 
surfaces. Aqueous radio-labeled sodium lauryl sulfate was applied to 
guinea pig skin in vivo by rubbing for 10 minutes, followed by washing 
and application of a nonocclusive dressing for 24 hours (Ref. 308). 
Most of the radioactivity was recovered on the skin at the experimental 
site, in the washing fluid, and in the dressing. Radioactivity of 0.1 
percent was recovered from exhaled air and urine. No radioactivity was 
found in the internal organs, feces, or carcass. The studies concluded 
that the presence of a strong anionic terminal group impaired sodium 
lauryl sulfate penetration through the skin.
    Rat skin was exposed for 15 minutes to radio-labeled (25 millimolar 
(mM)) sodium lauryl sulfate. Expired carbon dioxide, urine, feces, and 
skin were monitored for 24 hours. Autoradiography showed heavy 
concentrations of sodium lauryl sulfate on the skin surface and in the 
hair follicles. Quantifiable levels of sodium lauryl sulfate were also 
recovered in the urine (Ref. 308).
    If linear alkyl sulfates, including sodium lauryl sulfate, are 
deposited on the skin after a wash and rinse application, only a small 
amount actually penetrates the skin (Refs. 312 and 313). Sodium lauryl 
sulfate is rapidly absorbed through the intestine of mammals, rapidly 
metabolized through the liver, and is excreted in the

[[Page 32264]]

urine. Sodium lauryl sulfate is oxidized to carboxylic acid with 
butyric acid-4-sulfate as the major metabolite (Ref. 314).
    2. Acute toxicity. Sodium lauryl sulfate has an LD50 in 
rats ranging from 0.9 to 1.6 g/kg with a mean of around 1.3 g/kg (Refs. 
315 and 316). Studies (Ref. 308) indicated that sodium lauryl sulfate 
is slightly toxic. Signs of toxicity included diuresis, diarrhea, 
lacrimation, salivation, tremors, convulsions, sedation, anaesthesia, 
and death.
    Intraperitoneal administration of sodium lauryl sulfate (25 or 50 
mg/kg body weight per day for 3 days) decreased the level of some 
cytochrome P450 species (Ref. 317), stimulated haem-oxygenase activity 
(Ref. 318), and affected serum lipids (Ref. 317). The concentrations of 
sodium lauryl sulfate and the routes of administration in these studies 
were specifically designed to induce toxic effects, including death, 
and have little in common with human exposure to this ingredient with 
normal use of mouthrinses and dentifrices.
    3. Chronic toxicity studies. Rats fed a diet containing up to 2.25 
percent sodium lauryl sulfate for 13 weeks demonstrated enlarged liver 
cells and increased liver weight, as well as elevated levels of 
alkaline phosphatase and glutamic pyruvic transaminase. These changes 
were considered to represent accommodations to the increased work load 
required for the metabolism of sodium lauryl sulfate. Other changes 
noted included nonspecific enlargement of the kidneys, increased water 
consumption, and enlarged intestinal lymphatics. The sodium lauryl 
sulfate level below which no changes could be detected was 0.14 percent 
of the dietary intake, or 116 mg/kg body weight (Ref. 319). Another 
study found the ``no change'' level to be 0.1 percent (Ref. 316).
    In a 16-week feeding study in rats, daily doses of different 
percents of sodium lauryl sulfate in the diet had different results: 8 
percent resulted in death, 4 percent in significant growth retardation, 
and 2 percent in some growth retardation that was not statistically 
significant (Ref. 320). In a 1-year study in dogs, a 2-percent dietary 
intake of sodium lauryl sulfate caused some weight loss. The ``no 
change'' level was 1 percent (Ref. 308).
    The toxicology of alkyl sulfates has been extensively reviewed 
(Refs. 321 and 322). The Subcommittee notes several hypothetical 
examples (Ref. 313) that place the above findings in the context of 
human subject users. In the unlikely event of a 20-kg child ingesting 
10 mL of a mouthrinse containing 0.3 percent sodium lauryl sulfate 
daily, over a 13-week period, the daily dose ingested would be 1.5 mg/
kg body weight. Based on a ``no change'' level of 116 mg/kg in the rat 
feeding study, the safety factor is 77-fold (Ref. 319). The safety 
factor in a 50-kg adult ingesting 1 mL of the mouthwash daily would be 
over 1,900. Based on the 1-year study in dogs (Ref. 308), the safety 
factors for the child and adult would be greater than 500 and 13,000, 
respectively.
    4. Reproduction toxicity. Teratogenic studies in rats (Refs. 323 
through 326) revealed no evidence of teratogenicity. Some 
embryotoxicity was noted at high doses that were severely toxic to the 
dams.
    5. Mutagenic potential. Neither in vivo (Refs. 327 and 328) nor in 
vitro (Refs. 329 and 330) assays resulted in any increase in chromosome 
aberrations. There is no evidence that sodium lauryl sulfate 
incorporated in oral health care products is a teratogenic or mutagenic 
risk in humans.
    6. Skin irritation. At concentrations of 2, 10, and 20 percent, 
sodium lauryl sulfate produces a Draize skin irritancy test score 
compatible with that of a primary skin irritant (Ref. 308). The 1 to 6 
percent concentrations of sodium lauryl sulfate applied to human skin 
under an occlusive patch for 21 days were irritating to the skin. 
However, no irritancy potential could be detected in the absence of the 
occlusive patch (Ref. 331). Therefore, open application of sodium 
lauryl sulfate produces little, if any, irritation at these 
concentrations.
    7. Ocular irritation. The 10 percent sodium lauryl sulfate applied 
to the rabbit eye caused corneal damage if washing was delayed or 
withheld. A 1-percent sodium lauryl sulfate application caused little 
irritation and no corneal damage (Refs. 309, 321, and 322).
    8. Oral irritation potential. Sodium lauryl sulfate solutions in 
concentrations of 0.1 to 1 percent in 12 percent ethanol were swabbed 
for 30 seconds 4 times daily for 4 days on the oral mucosa of rats. 
Only mild cheilitis (inflammation of the lips) and sloughing were 
observed (Ref. 332). A single application of 0.2 percent sodium lauryl 
sulfate to the oral mucosa of rats did not produce any detectable 
changes, whereas increased cellularity was observed with a 2-percent 
application in half of the animals. After 3 weekly applications, the 
cellular reaction decreased (Ref. 333).
    The Subcommittee concludes that, based upon the results of the 
extensive toxicity tests (only some of which are referenced above), 
sodium lauryl sulfate does not constitute a risk to consumers in the 
concentrations found in oral health care products. The widespread use 
of sodium lauryl sulfate in numerous oral health care products, as well 
as in foods and other personal products, without any reported side 
effects attributable to normal use, further supports the safety of this 
ingredient.
    ii. Effectiveness. The Subcommittee concludes that there are 
insufficient data available to permit final classification of the 
effectiveness of sodium lauryl sulfate as an antigingivitis/antiplaque 
agent.
    Sodium lauryl sulfate is used in oral health care products because 
of certain desirable properties, which include: (1) Decreasing surface 
tension (Refs. 334 and 335), (2) affinity for enamel surfaces, leading 
to masking of receptor sites for bacterial proteins (Ref. 336), (3) 
emulsification of food and bacterial components (Refs. 334 and 337), 
(4) inhibition of selective enzymes that help form dental plaque (Refs. 
337, 338, and 339), (5) affinity for bacterial proteins and ability to 
denature them (Ref. 337), (6) disruption of cell membranes (Ref. 340), 
(7) inhibition of plaque formation through decreased surface tension 
and competition with negatively charged bacterial cells for binding 
sites on the tooth surface (Ref. 341), and (8) optimization of 
antibacterial properties of certain zinc salts (Ref. 340).
    These properties of sodium lauryl sulfate contribute to its 
usefulness to loosen and remove food particles (Refs. 342 through 349). 
Some of these properties also allow sodium lauryl sulfate to inhibit 
the formation of dental plaque (Ref. 350), exert a mild antibacterial 
effect (Ref. 351), and provide consumers with the feeling that tooth 
surfaces are smooth and clean and their breath is fresher (Ref. 352).
    In examining the results of clinical trials involving sodium lauryl 
sulfate, the types of products containing this ingredient and the 
characteristics that make it desirable for a particular product should 
be considered. Because of differences in formulations and the presence 
of other ingredients, it may be difficult to determine to what extent 
sodium lauryl sulfate contributes to some of the beneficial effects 
claimed for marketed products. For example, a major objective for 
mouthrinse users is to reduce oral malodor. However, it is difficult to 
compare the effect of rinses containing sodium lauryl sulfate to those 
that do not, since flavoring agents are obvious confounding factors 
(Refs. 352 through 357). The most common oral health care products that 
contain sodium lauryl sulfate include

[[Page 32265]]

mouthrinses, prebrushing rinses, and dentifrices.
    Mouthrinses are designed to provide cosmetic and/or therapeutic 
benefits. The major desirable characteristics of sodium lauryl sulfate 
are its affinity for enamel surfaces and its ability to reduce surface 
tension, which theoretically should interfere with dental plaque 
formation and provide a clean tooth feeling. Prebrushing rinses rely on 
these characteristics for additional emulsifying activity, thereby 
maximizing dental plaque removal that is largely the result of bristle 
action. Finally, because of its properties as a surfactant, sodium 
lauryl sulfate is frequently used in toothpastes as a foaming agent. 
Its superior cleansing properties compared to soap as a toothpaste 
ingredient were reported as early as 1937 (Ref. 358).
    In general, human mouthrinse studies have shown a moderate 
reduction in plaque formation in the test groups using sodium lauryl 
sulfate in various formulations, as compared to a control group using 
no sodium lauryl sulfate. No significant difference was observed 
between the test and control groups in gingivitis studies.
    Typical plaque and gingivitis scores from two representative 
studies are shown below. The scores at the end of these studies 
represent plaque and gingivitis score changes from a zero baseline, 
following an initial prophylaxis:

Table 12.--Plaque and Gingivitis Scores From the Barons Study (Ref. 359)
------------------------------------------------------------------------
       Study             Group (n)         Baseline            End
------------------------------------------------------------------------
                     ................            Plaque scores
------------------------------------------------------------------------
Test Product         Test (13)         0                 2.86
------------------------------------------------------------------------
(0.3% SLS)           Water (13)        0                 5.13
------------------------------------------------------------------------
  Net plaque reduction: 44%
------------------------------------------------------------------------
                     ................          Gingivitis scores
------------------------------------------------------------------------
                     Test (13)         0                 0.88
------------------------------------------------------------------------
                     Water (13)        0                 0.90
------------------------------------------------------------------------
  Net gingivitis reduction: 2% (not significant)
------------------------------------------------------------------------


 Table 13.--Plaque and Gingivitis Scores From the Pretara-Spanedda Study
                               (Ref. 348)
------------------------------------------------------------------------
       Study             Group (n)         Baseline            End
------------------------------------------------------------------------
                     ................            Plaque scores
------------------------------------------------------------------------
Test Product         Test (7)          0                 2.20
------------------------------------------------------------------------
(0.3% SLS)           0.1%              0                 2.43
                      chlorhexidine
                      (9)
------------------------------------------------------------------------
                     Water (9)         0                 4.78
------------------------------------------------------------------------
  Net plaque reduction: 54%
------------------------------------------------------------------------
                     ................          Gingivitis scores
------------------------------------------------------------------------
                     Test (7)          0                 0.93
------------------------------------------------------------------------
                     0.1%              0                 1.03
                      chlorhexidine
                      (9)
------------------------------------------------------------------------
                     Water (9)         0                 1.17
------------------------------------------------------------------------
  Net gingivitis reduction: 21% (not significant)
------------------------------------------------------------------------

    The statistically significant reductions in plaque scores in these 
studies, as compared to a water placebo, were not accompanied by a 
statistically significant reduction in gingivitis scores.
    No convincing evidence exists to support the effectiveness of 
prebrushing rinses, because the net beneficial effect of the rinses as 
compared to placebo is clinically insignificant. One of the products 
tested in the Truelove study (Ref. 349) (see Table 14 of this document) 
contains a number of ingredients other than sodium lauryl sulfate (Ref. 
360). However, sodium lauryl sulfate is listed as the only active 
component. The results of this study indicated that prebrushing rinsing 
with two rinses that contain sodium lauryl sulfate as the active 
ingredient is no more effective than rinsing with a suitable sodium 
lauryl sulfate-free placebo.

[[Page 32266]]



 Table 14.--Plaque/Gingivitis Scores From the Truelove Study (Ref. 349)
------------------------------------------------------------------------
               Agent                   Prebrush score    Postbrush score
------------------------------------------------------------------------
Test product (0.25% SLS)             2.56               1.11
------------------------------------------------------------------------
Other product (0.3% SLS)             2.94               1.23
------------------------------------------------------------------------
Placebo                              2.50               1.16
------------------------------------------------------------------------

    The results of the Emling study (Ref. 361) suggested a somewhat 
greater plaque score reduction with the test product containing 0.25 
percent sodium lauryl sulfate than the placebo (see Table 15 of this 
document). However, gingivitis scores were not measured in this study 
or in several other unpublished studies with the same experimental 
protocol that produced similar results (Refs. 362 and 363).

        Table 15.--Plaque Scores From the Emling Study (Ref. 361)
------------------------------------------------------------------------
               Agent                   Prebrush score    Postbrush score
------------------------------------------------------------------------
Test product (0.25% SLS)             3.12               2.05
------------------------------------------------------------------------
Placebo                              3.09               2.82
------------------------------------------------------------------------

    In addition, Beiswanger et al. (Ref. 364) were unable to detect a 
statistically significant difference in the degree of plaque reduction 
between active and placebo rinses.
    Van Dyke et al. (Ref. 365) also monitored gingival changes under 
conditions of prebrushing rinsing. They reported statistically 
significant reductions of plaque scores for both the placebo and the 
test rinse as compared to baseline scores. Although there was a 
statistically significant advantage of the test rinse over the placebo 
(1.61 versus 1.84 mean score) at interproximal surfaces for plaque 
scores, these differences were not clinically significant. Further, 
there were no differences in gingivitis scores before and after 
treatment, or between test and placebo scores.
    Kohut and Mankodi (Ref. 366) found no difference between test and 
placebo prebrushing rinses, either in the degree of plaque or 
gingivitis reduction. Similar results were reported by Singh (Ref. 367) 
and by Pontier et al. (Ref. 368) in children undergoing orthodontic 
treatment. In a 6-month clinical study, Lobene et al. (Ref. 369) failed 
to show that a test product containing 0.25 percent sodium lauryl 
sulfate was superior to a placebo in reducing plaque, gingivitis, or 
calculus.
    The Subcommittee concludes that sodium lauryl sulfate is effective 
to facilitate the removal of food and other particulate material and 
provide a clean tooth feeling, primarily through its surfactant 
properties and its affinity for binding to tooth surfaces. Sodium 
lauryl sulfate appears to have a minor inhibitory effect on plaque 
formation, following an initial dental prophylaxis. Although sodium 
lauryl sulfate has antibacterial properties in vitro, it is not clear 
to what extent this antibacterial effect is exerted in vivo. The 
antiplaque effect of sodium lauryl sulfate is at best moderate. Sodium 
lauryl sulfate does not have a significant effect on gingivitis. The 
role of sodium lauryl sulfate as a facilitator of plaque removal when 
used in a prebrushing rinse is marginal and does not result in any 
beneficial clinical improvement, such as gingivitis reduction or 
inhibition of calculus formation. Sodium lauryl sulfate is a safe and 
effective foaming ingredient when used in toothpaste.
    The Subcommittee concludes that sodium lauryl sulfate at 0.1 to 5 
percent concentration in an oral rinse or dentifrice dosage is safe, 
but that there are insufficient data available to permit final 
classification of its effectiveness as an antiplaque and antigingivitis 
agent.
    g. Zinc citrate. The Subcommittee concludes that zinc citrate is 
safe, but there is insufficient evidence to support its effectiveness 
as an OTC antigingivitis/antiplaque agent.
    Zinc citrate has a chemical formula of 
Zn3(C6H5O7)2 and 
is prepared from zinc carbonate and citric acid. It is described as a 
dihydrate, odorless powder, that is slightly soluble in water (Ref. 
370). Based on the known abilities of zinc to inhibit crystal formation 
and of citrate to inhibit crystal aggregation, zinc citrate replaced 
zinc chloride (highly effective but with a disagreeable taste) as a 
toothpaste ingredient to inhibit dental calculus formation (Ref. 371). 
Zinc citrate trihydrate 
(Zn3(C6H5O7)23H2
O) has been used to inhibit supragingival calculus formation.
    i. Safety. Zinc is ubiquitous in our environment and is an 
essential trace element in humans. Its role in humans continues to be 
the subject of investigation. The overall safety of zinc citrate has 
been well and extensively documented (Ref. 372). Acute toxicity studies 
in animals have shown zinc citrate to be only slightly toxic. Zinc 
citrate fed to rats for up to 13 weeks produced toxic effects only at 
high levels. No toxic effects were observed when toothpaste containing 
up to 10 percent zinc citrate was fed to rats and dogs for up to 18 
months. In humans, zinc salts are considered relatively nontoxic (Ref. 
372).
    Zinc citrate had no adverse effects on fertility, the fetus, or 
neonate in rats and rabbits (Ref. 372). This finding correlates with 
published findings on other zinc salts. No mutagenic effects have been 
reported from in vivo studies. Zinc does not have genotoxic effects or 
pose a carcinogenic hazard at levels normally found in the body (Ref. 
372). The oral irritation potential of toothpastes containing zinc 
citrate is no greater than that of other marketed toothpastes.
    ii. Effectiveness. The Subcommittee reviewed five short-term 
clinical studies, two 6-month studies, and a 3-year trial assessing the 
effect of zinc citrate on gingivitis (Ref. 373). The five studies had 
in common a 21-day experimental period in which subjects, following a 
4-week period of tooth cleaning and oral hygiene instruction, refrained 
from brushing one lower quadrant of teeth. An impression of each lower 
tooth arch was made and a plaster mold prepared. A plastic ``tooth 
shield'' was heated and vacuum fitted to

[[Page 32267]]

the plaster models. Subjects were instructed to place a measured 
quantity of dentifrice into the indentations in the tooth shield twice 
daily prior to its insertion in the mouth, and brush the remaining 
teeth. Plaque and gingivitis were assessed after 21 days. Various 
concentrations of zinc citrate in toothpaste or other ingredients alone 
or in combination with zinc citrate were used as well as placebos, 
which were not as effective as active ingredients. Because these 
studies were not randomized clinical trials, they cannot be considered 
as evidence of the effectiveness of zinc citrate.
    The first 6-month study by Hefti and Marks (Ref. 374) was conducted 
to evaluate the relative effectiveness of a hydrogen peroxide/baking 
soda/fluoride/zinc citrate dentifrice with a commercially available 
fluoride dentifrice and a commercially available fluoride antitartar 
dentifrice. This was essentially a supragingival calculus study where 
subjects were selected based on having a score of at least 6.0 on the 
Volpe-Manhold Calculus Index at the time of screening. Clinical exams 
during the trial period were done at 45, 90, and 180 days. The Modified 
Gingival Index by Lobene et al. (Ref. 112) was used for gingival 
assessment. Only simple means for the 6 months assessment were given 
for the 3 groups of 60 to 63 subjects. A simple p value was given, 
indicating the multiingredient product and the other antitartar 
toothpaste group had statistically lower scores than the fluoride-only 
commercially available toothpaste. Three means were given for 45 and 90 
days, plus one p value, showing similar results. No information was 
provided about subject characteristics, inclusion or exclusion criteria 
other than Volpe-Manhold Calculus Index scores, examiners, compliance, 
indicators of measurement error or uncertainty, or blinding. The 
conclusions concerning zinc citrate effectiveness were based on a 
multiagent product compared to other agents/ingredients.
    The second 6-month clinical study (Ref. 375) included 295 subjects 
selected from a population of 330 adults of which 311 fulfilled strict 
dental and medical health requirements. No further details on health 
requirements were given. No information was provided about the study 
population, e.g., age, sex, education, and socioeconomic status. 
Inclusion criteria included a gingival index score greater than 0.5 but 
less than 2.5 on a scale of 0 to 3. One-third of the qualifying 
subjects were selected for plaque collection, which was performed prior 
to disclosing for the plaque assessment. There was no information on 
how these subjects were selected.
    The products used were described as supplied by the sponsor in 
identical two-chamber, 5.2 oz pump dispensers, each with one of three 
three-letter codes. The report (Ref. 375) describes the three as 
``negative control dentifrice,'' ``experimental dentifrice,'' and 
``experimental dentifrice.'' An accompanying summary identified the 
products only as ``dual-phase dentifrices containing stannous salts 
and/or zinc citrate.'' One of the three-letter codes was identified 
only as ``the zinc citrate-containing dentifrice.'' Thus, there was no 
information about the composition and concentration of ingredients or 
details about differences in color, odor, and taste in the products 
tested. The Subcommittee does not believe this study adhered to strict 
criteria for a double-blind study because the following appeared in the 
report: ``Except for some complaints about the taste and staining 
associated with experimental dentifrice `ABC,' the products were 
favorably received.'' These complaints were associated with only one of 
the three tested products. This suggests that one product differed from 
the others in taste and staining and, therefore, the study was not a 
double-blind study.
    Examiners were described only as ``experimental examiners, who 
participated in a calibration exercise prior to initiating the 
investigation, performed the same assessments at each examination.'' 
The report did not discuss the number of examiners and their 
background, whether calibration was successful, or testing for intra-
examiner and inter-examiner reliability.
    Mean gingival index scores plus standard error were given for each 
of the three groups at baseline, 3 months, and 6 months (279 of 295 
subjects completed 6 months). All scores were reduced from baseline at 
3 and 6 months. The dentifrice containing zinc citrate was 
statistically significantly different (p<0.03) from the ``control'' 
group. Mean scores at 3 months were 0.87+/-.02 for the control 
dentifrice, 0.83+/-0.2 for the test dentifrice without zinc citrate, 
and 0.81+/-.02 for the test dentifrice containing zinc citrate. At 6 
months the scores were 0.92+/-0.2 for the control dentifrice, 0.86+/-
0.2 (p<0.04) for the test dentifrice without zinc citrate, and 0.85+/
-.02 (p<0.04) for the test dentifrice containing zinc citrate. The 
study does not provide evidence that a clinically significant 
improvement in gingival index scoring was due to zinc citrate.
    The 3-year trial (Ref. 376), of which results from the first 2 
years were submitted, was a caries study. The main objectives of the 
trial were to establish the reduction of caries increments caused by 
increasing the level of sodium monofluorophosphate and to investigate 
whether the inclusion of 0.5 percent zinc citrate affected caries 
increments. Three thousand children with a mean age of 12.5 years and 
all within a 1-year age range were recruited. Two clinicians assessed 
all subjects, who were then randomly assigned to one of six toothpaste 
groups. One-half of the subjects used a toothpaste containing zinc 
citrate. Plaque (using Greene and Vermillion's Simplified Oral Health 
Index (OHI-S)) and gingivitis (Loe and Silness Gingival Index) were 
assessed each year. Six teeth were assessed: One molar, premolar, and 
incisor in each arch, at four surfaces on each tooth.
    Differences between cumulative mean scores for groups using 
toothpastes with and without zinc citrate were calculated. One examiner 
showed nonstatistically significant differences for years 1 and 2 and a 
second examiner showed statistically significant differences. When 
pooled together, the small differences were statistically significant. 
There was no other information about examiner calibration or testing 
for intra and interexaminer reliability. Clinically significant effects 
due to zinc citrate could not be determined from this study.
    The Subcommittee's criteria for data submitted from randomized 
clinical trials include presenting information on all of the major 
study components, e.g., the protocol (study population, agents, 
outcomes, rationale for statistical analysis), methods of 
randomization, concealment of allocation to study group, and method of 
blinding. Results should be presented with appropriate indicators of 
measurement error or uncertainty, avoiding dependence solely on 
statistical hypothesis testing, such as the use of p values, which fail 
to convey important quantitative information. Based on these criteria, 
the Subcommittee concludes that the data submitted were insufficient to 
permit final classification of the effectiveness of zinc citrate as an 
OTC antigingivitis/antiplaque agent.
2. Category III Combinations of Active Ingredients
    Data to demonstrate safety and effectiveness as an antigingivitis/
antiplaque agent will be required in accordance with the general 
guidelines on safety and effectiveness in section II.H of this 
document.

[[Page 32268]]

    Alkyl dimethyl amine oxide and alkyl dimethyl glycine
    Hydrogen peroxide and povidone iodine
    Hydrogen peroxide and sodium bicarbonate
    Hydrogen peroxide, sodium citrate, sodium lauryl sulfate, and zinc 
chloride
    Peppermint oil and sage oil
    Polydimethylsiloxane and poloxamer
    Stannous pyrophosphate and zinc citrate
    a. Alkyl dimethyl amine oxide and alkyl dimethyl glycine. The 
Subcommittee concludes that there is insufficient evidence to support 
the safety and effectiveness of the combination of alkyl dimethyl amine 
oxide and alkyl dimethyl glycine as an OTC antigingivitis/antiplaque 
agent. This combination consists of two amphoteric (having both acidic 
and basic properties) quaternary ammonium inner salt surfactants said 
to have broad spectrum antimicrobial activity.
    i. Safety. An acute oral toxicity study (Ref. 377) of a 3-percent 
solution of alkyl dimethyl amine oxide and alkyl dimethyl glycine 
calculated that the LD50 in Sprague-Dawley rats was greater 
than 6,000 mg/kg. Necropsy observations included slight intestinal 
hemorrhage, slight liver discoloration, and slight to severe lung 
congestion.
    An additional acute toxicity study in beagle dogs (Ref. 378) was 
difficult to evaluate because the dosages were stated in mL/kg but the 
concentration of the solution was not stated. Although there did not 
appear to be a constant pattern at necropsy, all of the dogs displayed 
abnormal findings, such as cortical congestion of the mesenteric lymph 
nodes, white nodules on the gall bladder mucosa, and consolidation of 
the lungs with a yellow-colored mucoid material in the bronchi.
    A series of dermal toxicity studies was carried out. Again, because 
the concentration of the liquid used was not stated, these studies were 
difficult to evaluate. In one study (Ref. 379), the dermal toxicity of 
a 3-percent solution of the combination of alkyl dimethyl glycine and 
alkyl dimethyl amine oxide was evaluated on abraded skin of rabbits. 
Two of 20 animals displayed minimal reaction. An additional study (Ref. 
380) reported that 3.6 percent of an applied dose was absorbed through 
rabbit skin.
    Two dermal sensitization studies were carried out in guinea pigs 
(Refs. 381 and 382) and appeared to have diverse results. In one study 
(Ref. 381), the investigator concluded that there was no evidence 
suggesting the combination of these ingredients can act as a sensitizer 
in the guinea pig. However, it was unclear what concentration of the 
test material was used. In the second study (Ref. 382), it was 
concluded that repeated topical exposures of guinea pigs to a 3-percent 
solution of these ingredients has the potential to induce mild dermal 
sensitization.
    Based on the results of a Salmonella/microsome mutagenesis assay 
(Ref. 383), the authors concluded that the combination of alkyl 
dimethyl amine oxide and alkyl dimethyl glycine inhibits the growth of 
microorganisms at some concentrations. Although small increases were 
observed in several strains of S. typhimurium, the authors stated that 
these increases were not reproducible and were attributed to random 
fluctuations that do not represent a mutagenic response to the test 
product. The test, therefore, has some limitations.
    Eye and vagina1 irritant tests have also been conducted. A 3-
percent solution of alkyl dimethyl amine oxide and alkyl dimethyl 
glycine was judged to be a mild irritant in the eyes of dogs and a 
severe irritant in rabbits (Ref. 384). In an additional study conducted 
by a different institution, it was concluded that a 12.5-percent 
solution was not an irritant to rabbits. Results from vaginal 
irritation studies (Ref. 385) concluded that these ingredients produced 
an ``acceptable'' vaginal irritation score. However, it was unclear 
which concentrations were tested and what is an ``acceptable'' score. 
Six preparations appear to have been examined, but no information was 
presented on how they differed in composition.
    The data also included a series of studies (Refs. 386, 387, and 
388) evaluating a 10-percent solution of alkyl dimethyl amine oxide and 
alkyl dimethyl glycine as a body wash in nursing home patients. The 
evaluations appear to be largely subjective or gathered from 
interviews. Adverse effects were not observed.
    Dentists gave the combination of these ingredients to subjects to 
use as a mouthrinse (Refs. 389 and 390). Overall adverse effects, 
including tingling, mucosal irritation, stain, and a peppery sensation 
on the tongue, were reported by 0.5 to 0.8 percent of users. Other 
dentists (Ref. 391) reported adverse effects in 1.3 percent of 
subjects.
    The effects of the combination of these ingredients on mammalian 
cells were examined using a chromium release assay from human leukemic 
cells (H6-60). The release of chromium occurred at concentrations of 
0.025 to 0.005 percent. As the report notes, ``these findings are of 
some concern since the effective window approximates the MIC for 
several bacterial species'' (Ref. 392).
    ii. Effectiveness. A number of studies have been carried out to 
assess the effects of this combination on the growth of oral bacteria 
and on the ability of oral microorganisms to produce acid from glucose.
    The combination of alkyl dimethyl amine oxide and alkyl dimethyl 
glycine exhibits an antimicrobial effect against a wide range of 
microorganisms (Ref. 393). Lactobacillus casei is highly susceptible 
and is inhibited by as little as a 0.0004-percent solution. Several 
isolates of Pseudomonas are highly resistant to the combination. In 
general, the effect against gram-positive organisms was independent of 
pH. In contrast, the effect against gram-negative organisms was 
influenced by pH values. A 0.5-percent concentration of these 
ingredients completely inhibited bacterial glycolysis for 7 hours and 
inhibited the adherence of S. sobrinus to michrome wires. A lower 
concentration (0.05 percent) had less effect.
    Twelve subjects (Ref. 394) rinsed with various concentrations of 
alkyl dimethyl amine oxide and alkyl dimethyl glycine and other 
preparations with only 2 days allowed between testing each material. 
Concentrations of 0.1 percent or higher reduced the population of total 
cultivable flora and total Streptococcus populations for at least 1 
hour post rinse. Concentrations of 0.2 and 0.5 percent inhibited 
glycolysis in salivary sediment for several hours.
    A clinical study involving 84 females and 42 males (aged 20 to 49) 
used a 0.25-percent solution (pH 6.8) of this combination (Ref. 395). 
Subjects were divided into one of three groups using a placebo, the 
test ingredients, or a positive control. Gender distribution was not 
disclosed. Following a complete prophylaxis, subjects rinsed twice 
daily for 6 weeks with 20 mL of solution. Subjects were instructed to 
continue their normal oral hygiene throughout the study. Plaque was 
assessed using Turesky modification of the Quigley-Hein Index. Mean 
plaque scores at the end of the study were as follows: Placebo, 2.53 +/
- 0.56 (2.44 +/- 0.38), test ingredients, 2.05 +/- 0.58 (2.45 +/- 
0.36), and positive control, 1.96 +/- 0.33 (2.46 +/- 0.31). An F test 
(test for equality of variances) comparison of the final three numbers 
showed statistica1 differences. An F test between the test solution and 
the positive control showed no statistically significant difference. No 
other statistical tests were reported. Gingivitis was not assessed.
    A brief report (Ref. 396) claimed that a toothpaste containing 
these

[[Page 32269]]

ingredients reduced plaque formation by 43 percent in 15 subjects who 
used these ingredients for 7 days. Gingivitis apparently was not 
assessed. The report lacked essential information.
    In a combined animal and human study (Ref. 397) and a separate 
human study (Ref. 398), a toothpaste containing 1 percent of the 
combination of alkyl dimethyl amine oxide and alkyl dimethyl glycine 
applied topically three times weekly had no effect in preventing 
caries.
    In a more recent single-blind, randomized, crossover study in 20 
subjects (Ref. 399), the effects of four ingredients, including the 
combination of alkyl dimethyl amine oxide and alkyl dimethyl glycine, 
were compared with saline in preventing plaque regrowth. Subjects 
rinsed twice daily for 1 minute and suspended normal oral hygiene 
measures. Plaque was scored using a plaque index and plaque area 
assessment. The combination of alkyl dimethyl amine oxide and alkyl 
dimethyl glycine was significantly less effective than the other three 
agents tested, but was more effective than saline. Gingivitis was not 
assessed.
    Based on the data submitted, the Subcommittee concludes that there 
is insufficient evidence to support the safety and effectiveness of the 
combination of alkyl dimethyl amine oxide and alkyl dimethyl glycine as 
an OTC antigingivitis/antiplaque agent.
    b. Hydrogen peroxide and povidone iodine. The Subcommittee has 
determined that there is insufficient evidence to support the safety 
and effectiveness of the combination of hydrogen peroxide and povidine 
iodine as an OTC antigingivitis/antiplaque agent.
    i. Safety.
    The Subcommittee concludes that hydrogen peroxide is safe at 
concentrations of up to 3 percent. Because the final concentration of 
hydrogen peroxide in this combination is 1.5 percent when the 
separately packaged solutions are mixed, the Subcommittee considers 
this portion of the combination to be safe. The povidone iodine 
component of the combination (5 percent final concentration), however, 
raises several safety concerns, including acute and chronic toxicity.
    1. Acute toxicity study. An acute toxicity study (Ref. 400) was 
performed on rats to determine the LD50 iodine 
concentration. Ten animals were dosed with 5 g/kg with no fatalities 
occurring. The data established that povidone iodine is not considered 
toxic when the LD50 is greater than 5 g/kg. The only noted 
toxic effect at this level was hydronephrosis (distention with urine) 
of the kidneys of two male rats.
    2. Oral mucosal toxicity study. Oral mucosal toxicity was also 
examined in rats (Ref. 401). A solution containing 1.5 percent hydrogen 
peroxide and 5 percent povidone iodine was applied three times daily 
for 7 days to the oral mucosa of 12 albino rats. Two other groups of 12 
rats were exposed to the components individually. While there were 
animals in each group that did not gain weight normally, the 
differences between the groups were not significant. In the group that 
received the combination of ingredients, 5 of the 12 animals showed 
signs of acute iodine toxicity, including lethargy, diarrhea, and 
abnormalities in the GI tract. These signs suggest possible acute 
toxicity in humans due to iodine overdose. These abnormalities were not 
noted in the two groups exposed to hydrogen peroxide or povidone iodine 
solutions individually. No negative control group was included.
    3. Acute dermal toxicity study. In an acute dermal toxicity study, 
a 10-percent povidine iodine solution mixed with 3 percent hydrogen 
peroxide at 2 g/kg of body weight was applied to 10 albino rats (Ref. 
402). Skin reactions were recorded as slight, but 8 of 10 animals 
showed lethargy, nasal discharges, diarrhea, and other signs of GI 
disturbances. All 10 animals survived, showing only mild dermal 
irritation. The investigators defined the test mixture as nontoxic 
because the LD50 was greater than 2 g/kg of body weight.
    4. Eye irritation study. An eye irritation study was conducted on 
six albino rats by placing a standard mixture of 10 percent povidine 
iodine and 3 percent hydrogen peroxide (Ref. 403) into the conjunctival 
sac and scoring by the Draize technique at 1, 2, and 3 days after 
dosing. The test mixture was determined to be an irritant, causing 
iritis and moderate conjunctival irritation in five of six animals.
    5. Chronic toxicity study. Chronic toxicity is also of concern 
because of the activity of iodine on the thyroid. A 6-month prospective 
study in 50 subjects to assess thyroid function and iodine levels 
following prolonged exposure to the mouthrinse showed that iodine 
levels were significantly elevated in test subjects with increased 
protein bound iodine in blood and in urine samples (Ref. 404). In 
general, thyroid function tests remained within normal limits. These 
tests included serum thyroxine (T4), free T4, triiodiothyronine (T3), 
and free T4 index measurements. A small but significant rise in the 
serum thyroid stimulating hormone (TSH) was consistently noted. The 
investigators suggested that this small increase in serum TSH should be 
considered a normal physiological adaptive response to increased iodine 
intake and had no adverse effects on the subjects. While the study was 
a good first step in establishing the safety of chronic use of the test 
solution, there were several concerns. The total number of healthy 
subjects was relatively small and may not reveal possible side effects 
in a larger population. While the investigators considered increased 
TSH without concomitant serious side effects as a sign that subjects 
were able to tolerate increased iodine, an alternative interpretation 
is that the increased TSH was an early indication of a thyroid system 
that is not functioning properly. A larger and perhaps longer study is 
needed.
    6. Chronic use test in compromised thyroids. Although a second much 
smaller study examined the effects of chronic use of a mouthrinse 
containing hydrogen peroxide and povidone iodine in subjects with 
compromised thyroids, the number of subjects was completely inadequate 
to establish possible side effects.
    7. Mutagenicity tests. Tests to determine the mutagenicity of 
povidone iodine were carried out using the Salmonella/microsome 
mutagenesis assay, a micronucleus test in rats, and a rat hepatocyte 
DNA repair assay (Refs. 405, 406, and 407). While the tests indicated 
cell toxicity, they did not indicate a mutagenic effect. A cytotoxicity 
study examining the cytotoxic effects on Chinese hamster ovary cells 
was also reported (Ref. 408). The study concluded that the combination 
rinse is cytotoxic at a concentrations of 2,500 [mu]g/mL. The report 
indicated that when a metabolic activation mixture with the appropriate 
buffer and cofactors was added to the assay, the test rinse was no 
longer considered cytotoxic. The report did not elaborate on the 
possible ramifications of these results.
    In order to evaluate the acute toxicity studies submitted, the 
Subcommittee examined iodine toxicity in general. Acute toxicity of 
iodine tincture (2 percent iodine and 2.4 percent sodium iodine in a 50 
percent ethanol solution) has been recorded at levels relevant to the 
concentration of povidone iodine (5 percent) in this combination. Fatal 
events have occurred when as little as 30 mL of tincture of iodine have 
been ingested (Ref. 409). Acute toxic effects produce local actions in 
the GI tract. Iodine is corrosive, but is also readily inactivated by 
foodstuffs. When large concentrations of iodine are ingested,

[[Page 32270]]

resulting shock and tissue hypoxia have been noted (Ref. 409). 
Ingestion of lesser amounts can cause gastroenteritis, abdominal pain, 
and diarrhea that may be bloody. Nausea and vomiting are common with 
ingested iodine.
    The current product labeling recommends that children under 12 be 
supervised while using the product and warns against use by pregnant or 
nursing mothers, those with iodine sensitivity, and those with a 
history of thyroid disorder. Because of the potential toxic side 
effects, the labeling should include a warning that the product should 
not be used by children, women of child-bearing years, or anyone 
suffering from a thyroid disease, disorder, or ailment. Subjects 
considering long-term use of these ingredients should consult their 
physician to determine if any conditions exist that might 
contraindicate use.
    ii. Effectiveness.
    1. Six-month studies. Two 6-month studies (Refs. 410 and 411), a 3-
week study (Ref. 412), a 6-week study (Ref. 413), and a brief review of 
the antimicrobial effects of mouthrinses on dental plaque (Ref. 414) 
were submitted. The 6-month studies (Refs. 410 and 411) were designed 
similarly, using subjects admitted according to common exclusion 
criteria. Subjects received a thorough prophylaxis and were then 
assigned to one of four groups using a test rinse containing hydrogen 
peroxide and povidone iodine, a rinse containing only one of these 
ingredients in distilled water, or a distilled water placebo. Because 
the subject pool was divided into four groups, each group had a 
relatively limited number of subjects. Ninety total subjects completed 
one study (Ref. 410) with 23 in the test rinse group, and 96 subjects 
completed the other study (Ref. 411) with 23 in the test rinse group. 
Clinical assignments included measurements of plaque using the Turesky 
modification of the Quigley-Hein Plaque Index and the Papillary 
Bleeding Scoring, which attempts to quantitatively assess inflammation 
and bleeding at the interproxima1 sites.
    Several troubling aspects of the protocol jeopardized the value of 
the studies from the start. The overall sample size was immediately 
halved by including groups that used only hydrogen peroxide or only 
povidone iodine. The control rinse was substantially different from the 
test rinse and did not contain a placebo vehicle. The protocol for both 
studies included professional subgingival irrigation at 3-week 
intervals throughout the study. Further, subjects were instructed not 
to rinse, drink, or eat anything for 30 minutes following the rinsing 
procedure.
    Results from the two 6-month studies failed to provide convincing 
clinical data in support of the tested ingredients. For example, while 
one study showed borderline significant plaque index score differences, 
the other study did not. Neither study reported the overall gingival 
index (bleeding index) scores. It appears that there were no 
significant differences overall for the gingival index in either study. 
Instead, only scores for sites greater than or equal to three were 
chosen for analysis. While both studies suggested that significant 
differences could be determined in this limited and skewed selection of 
sites, p values for these comparisons were unclear or not reported. 
Because use of the test solution did not significantly affect plaque 
buildup in at least one of the studies, it is possible that the 
positive effect on the gingival condition was due to the subgingival 
irrigation professionally administered every 3 weeks during the test 
period. If the test solution altered the subgingival flora but did not 
significantly change the supragingival flora, the most likely 
contributing factor would be the professional irrigation.
    Further, the two studies were tabulated differently and the results 
were somewhat difficult to compare. One study compared sites while the 
other study examined differences between subjects. The number of sites 
used in these analyses was unclear or unstated. The investigators in 
one study chose sites over subjects for analysis because of the 
variation in the number of sites between subjects with a bleeding index 
greater than 3. Therefore, it is possible that one or only a few 
subjects had many sites and the remaining subjects had few sites that 
qualified. Such a distribution could produce results that realistically 
represent only a few subjects within the group rather than the group 
itself. As with several other important aspects of these studies, p 
values and standard errors for specific comparisons were often unclear 
or unstated.
    The studies included a limited number of samples for 
microbiological examination. The investigators in both studies utilized 
selective media along with other microbiological assays. Both study 
reports indicated that opportunistic pathogens (Candida and enteric 
bacteria) did not establish themselves in any of the test groups 
sampled. The test solution samples tended to show fewer presumed 
periodontal pathogens compared to control samples. However, the number 
of periodontal pathogens was generally quite low or absent depending on 
the species studied. While the microbiological data hold some interest, 
the use of professional subgingival irrigations throughout the studies 
made interpretation of the microbiology data difficult.
    The design of these studies made definitive conclusions very 
difficult, with no consistent or convincingly significant clinical 
effect on plaque or gingivitis. The toxicology data suggested that the 
combination is safe, but doubts linger. An appropriately sized study of 
healthy and thyroid-compromised subjects should be considered using a 
placebo that more closely resembles the test product. Subjects should 
not be instructed to refrain from eating, drinking, or rinsing and 
professional irrigation should not be included, as such procedures 
might significantly alter the results.
    2. Three and 6-week studies. Two short-term studies of 3 and 6 
weeks (Refs. 412 and 413) showed significant improvement in the 
clinical parameters reported. However, several ingredients reviewed by 
the Subcommittee, including some formulations of hydrogen peroxide, 
have shown positive short-term results only to fall short in long-term 
studies.
    Based on these studies, the Subcommittee finds that there is 
insufficient evidence to support the safety and effectiveness of the 
combination of hydrogen peroxide and povidone iodine as an OTC 
antigingivitis/antiplaque agent.
    c. Hydrogen peroxide and sodium bicarbonate. The Subcommittee 
concludes that the combination of sodium bicarbonate and hydrogen 
peroxide at concentrations up to and including 3 percent hydrogen 
peroxide is safe, but there are insufficient data available to permit 
final classification of the effectiveness of the combination as an 
antigingivitis/antiplaque agent.
    i. Safety. Hydrogen peroxide can produce hydroxyl radicals in the 
presence of iron (Fe+2) or copper (Cu+1) (Refs. 188 and 189) and in 
vitro studies have shown that sister chromatic exchanges can be 
produced by hydroxyl radicals. Experimental and clinical data are 
sparse demonstrating a significant mutagenic effect with the 
combination of hydrogen peroxide and sodium bicarbonate in oral health 
care products. Experimental and clinical data, however, do not 
demonstrate a significant mutagenic potential with the combination of 
hydrogen peroxide and sodium bicarbonate in oral health care products 
(Refs. 145, 188, and 189). The rapid decomposition of hydrogen peroxide 
in the presence of sodium

[[Page 32271]]

bicarbonate (Ref. 145) further reduces the likelihood of a mutagenic 
effect occurring with combination products.
    A 1989 mutagenicity study by Kuhn et al. (Ref. 415) tested varying 
concentrations of a gel containing levels of hydrogen peroxide up to 
100 [mu]g/plate in a bacteriological assay for toxicity and 
mutagenicity on several strains of S. typhimurium. The results showed 
no toxic or mutagenic effects on the strains tested, which was 
approximately 100 times greater than the optimal mutagenic response 
seen with aqueous hydrogen peroxide. This result is in contrast to 
other studies using strains of S. typhimurium that showed mutagenic 
action associated with hydrogen peroxide (Refs. 163, 168, and 416). 
This result is also in agreement with studies conducted with peroxide 
formulated in dental products that are uniformly not mutagenic in 
oxidant-sensitive bacterial strains (Refs. 172 and 417).
    After 1 minute of brushing, recovery of hydrogen peroxide in the 
presence of baking soda was less than 5 percent of the amount 
introduced into the oral cavity (Ref. 145). Identical results on 
hydrogen peroxide decomposition were seen in control subjects and 
subjects with impaired salivary flow.
    Using a rat animal model, a combination of sodium bicarbonate and 
hydrogen peroxide incorporated into a toothpaste vehicle was tested for 
oral mucosa irritancy by Meyers et al. (Ref. 418). The particular 
formulation was found to be a mild-to-moderate irritant. However, the 
test toothpaste was found to be less irritating compared to a common 
fluoridated toothpaste used as a control. Unfortunately, the 
concentrations of ingredients did not appear to be listed, including 
the concentration of sodium bicarbonate and hydrogen peroxide. These 
results do not agree with those reported by Marshall et al. (Ref. 184), 
in which no irritation was found to the oral mucosa of hamsters 
administered a dual phase hydrogen peroxide and sodium bicarbonate 
dentifrice containing 0.75 percent or 1.5 percent hydrogen peroxide and 
5 percent or 7.5 percent sodium bicarbonate once-daily, five times per 
week for up to 20 weeks.
    Two animal studies examined the potential for oral mucosal 
irritation by hydrogen peroxide in combination with sodium bicarbonate 
(Ref. 184). No mucosal irritation was observed after administration of 
a hydrogen peroxide and baking soda dentifrice once daily, five times a 
week for 20 weeks. These results support clinical and consumer studies 
that show no evidence of oral irritation following use of dentifrices 
containing a combination of these ingredients. A study by Kuhn et al. 
(Ref. 419) used a combination of 10 percent sodium bicarbonate and 1.5 
percent hydrogen peroxide. The study included exposure of the test 
animals to DMBA, a known carcinogen, and evaluated if any of the test 
compounds (including this combination) resulted in additional 
carcinomas. The test and control compounds were administered in a 20-
week cheek pouch mucosal irritation study and no additional 
carcinogenic effects from the test combination were found. These 
results and those seen in a second hamster bioassay (Ref. 184) are 
contrary to those of Weitzman et al. (Ref. 183) who found that, when 
combined with DMBA, hydrogen peroxide, only at a concentration of 30 
percent, appeared to augment the carcinogenic effects associated with 
DMBA. No augmentation of the carcinogenic effects of DMBA was seen with 
3 percent hydrogen peroxide in the Weitzman study (Ref. 183), whose 
results support the previous observations that concentrations of 
hydrogen peroxide of 3 percent or less are safe for use in the oral 
cavity.
    In a 9-month human trial with concentrations of 10 percent sodium 
bicarbonate and 1.5 percent hydrogen peroxide used as a dentifrice, 
Truelove (Ref. 420) found no increase in yeast concentrations in test 
subjects compared to subjects using a standard fluoridated dentifrice.
    There are reports in the literature of excessive use of these 
compounds producing marked gingival detrimental changes, although these 
lesions appear to be easily correctable (Refs. 421 and 422).
    ii. Effectiveness. The value of the combination of hydrogen 
peroxide and sodium bicarbonate has led to a continuing debate within 
the dental research and clinical communities. An in vitro MIC and 
minimal bactericidal concentration (MBC) study found that both 
ingredients were weak bacteriocidal agents, with sodium bicarbonate 
requiring extremely high dosages to cause bacterial cell death (Ref. 
423). Varying outcomes resulted from the concentration of ingredients, 
with some mixtures inhibiting/killing while other concentrations 
produced a synergistic effect. In one study, a combination of 3 percent 
hydrogen peroxide, 0.5 g of sodium bicarbonate, and 10 g sodium 
chloride was tested on 10 experimental and 10 control subjects who had 
moderate periodontitis and were carefully scaled and root planed at the 
beginning of the study (Ref. 424). The experimental subjects had the 
test ingredients administered at home with a toothbrush and at biweekly 
professional irrigations. Sites in the test group also received iodine 
applications. The results indicated that following scaling and root 
planing, and with a carefully monitored oral hygiene regimen including 
sodium chloride and iodine in addition to the hydrogen peroxide and 
sodium bicarbonate, a reduction of several clinical periodontal 
parameters occurred after 3 months of treatment. This study suggested a 
significant effect on the oral flora could be achieved by subgingival 
irrigation with these chemicals.
    In a 3-week study (Ref. 425), a 1.5-percent hydrogen peroxide and a 
2-percent sodium bicarbonate mouthrinse was tested in a positive and 
negative parallel-control study. The results indicated significant 
control of gingivitis and gingival bleeding compared to the negative 
control. The rinse compared favorably to the positive control 1.2 
percent chlorhexidine rinse. The Subcommittee found that the study only 
evaluated efficacy up to 3 weeks, and long-term results are unknown.
    Using a split-mouth design, Greenwell et al. (Ref. 426) tested the 
effect of this combination (hydrogen peroxide, sodium bicarbonate, and 
salt water) against standard oral hygiene methods. The effects on 
commonly monitored indices suggested no significant effect over the 
standard oral hygiene control except where initial therapy was not 
instituted. However, these subjects were diagnosed with treated or 
untreated periodontitis, and the study was limited to 8 weeks.
    In a similar study, four subjects with early periodontitis used 
either a fluoridated paste or an experimental paste containing 3 
percent hydrogen peroxide and sodium bicarbonate in a splitmouth study 
design. Over the 3-week test period, no discernible differences between 
the groups could be identified (Ref. 427). Similar results were found 
in a 3-month study in which the test ingredients (hydrogen peroxide and 
sodium bicarbonate) were applied with a toothpick (Ref. 428).
    In a 2-year study in which salts and hydrogen peroxide mixture was 
compared to conventional oral hygiene methods, no discernible 
differences could be found using phase contrast microbiological 
parameters (Ref. 429). In another 2-year study, no positive clinical 
effects were discernible from the use of the combination of test 
ingredients (hydrogen peroxide, sodium bicarbonate, and sodium 
chloride) compared to conventional oral hygiene methods (Ref. 430). The 
4-year data from the same subject group showed the same results as seen 
at 2 years (Ref. 431). As in the study noted above (Ref.

[[Page 32272]]

426), the subjects in this large-scale, long-term study had diagnosed 
early periodontitis. Keyes et al. (Refs. 432 and 433), in uncontrolled 
and poorly documented reports, indicated reductions in signs and 
symptoms associated with periodontal diseases when using a regimen 
consisting of a thick mix of sodium bicarbonate slightly moistened with 
a few drops of water and 3 percent hydrogen peroxide.
    Because of a lack of properly designed studies showing conclusively 
that the combination of hydrogen peroxide and sodium bicarbonate is 
effective, this combination of ingredients does not appear to present 
any added benefit to oral hygiene products. Further, most reports 
indicated that the two ingredients were no better at controlling plaque 
and gingivitis than products currently on the market which do not 
contain these ingredients. Moreover, many of the published references 
exploring the effects of these ingredients tested small numbers of 
subjects, did not employ controls, and/or used subjects with 
inappropriate disease entities, such as mild to moderate periodontitis. 
Many of the published references instituted a variety of professional 
cleanings, irrigations, instructional oral hygiene sessions, and 
additional possibly active ingredients during the test periods, thus 
further clouding the already contradictory results. Several studies did 
not disclose the concentrations of either ingredient, making it 
difficult to make conclusions.
    d. Hydrogen peroxide, sodium citrate, sodium lauryl sulfate, and 
zinc chloride. The Subcommittee concludes that the combination of these 
ingredients is safe, but there is insufficient evidence to permit final 
classification of its effectiveness as an OTC antigingivitis/antiplaque 
agent. The Subcommittee is aware of three formulations of a combination 
of hydrogen peroxide, sodium citrate, sodium lauryl sulfate, and zinc 
chloride. All of the active ingredients have potentially useful 
properties when included in a mouth rinse.
    Hydrogen peroxide (0.595 to 1.5 percent). Hydrogen peroxide is used 
for its antibacterial and foaming properties (see section III.C of this 
document).
    Sodium citrate (0.024 to 0.12 percent). Sodium citrate is used as 
an astringent and to enhance the antibacterial activity of zinc 
chloride.
    Sodium lauryl sulfate (0.06 to 0.15 percent). Sodium lauryl sulfate 
is used for its emulsifying and antiplaque formation properties (see 
section III.C of this document).
    Zinc chloride (0.016 to 0.08 percent). Zinc chloride is used for 
its antibacterial properties and its ability to reduce plaque 
accumulation and acid production by plaque bacteria. Zinc has also been 
shown to be effective in inhibiting calculus formation by interfering 
with the conversion of amorphous calcium phosphate to more crystalline 
calcium phosphate compounds and their growth (Ref. 434). The 
antibacterial effect of zinc salts may be enhanced in the presence of 
sodium lauryl sulfate.
    i. Safety. Because the above ingredients are used in combination, 
the safety and efficacy of these ingredients must be examined under 
conditions of combined use.
    Toxicity in animals. Acute oral toxicity tests in rats (Ref. 435) 
indicated that one of the three formulations (it is not clear from the 
protocol which one), is relatively nontoxic. The purpose of the study 
was to assess the toxicity of the combination of ingredients 
administered orally as a single dose to Sprague-Dawley rats, followed 
by a 14-day observation period. The combination was administered by 
oral gavage to five male and five female rats at a dose of 40 g/kg of 
body weight. Over the following 14 days all animals survived in 
apparent good health, although they exhibited hunched postures and 
loose stools for the first 2 days. No abnormal findings were observed 
at necropsy. This dose is considerably higher than the likely intake by 
subjects using these ingredients in a rinse.
    In another study on the effect of topical application of this 
formulation to hamster cheek pouches, 76 hamsters were divided into 3 
groups of 22 animals each, with equal numbers of males and females, and 
a fourth group of 10 animals. The test group received daily topical 
applications of the test formulation to their cheek pouches for a 30-
day period. The negative control group received comparable applications 
of water. The positive control group received 5 percent sodium lauryl 
sulfate. An additional group of 10 animals received a fixed combination 
of essential oils and water. At the end of the 30-day period, the cheek 
pouches were examined clinically and histologically. The results 
indicated no evidence of mucosal irritation in the form of epithelial 
damage, inflammation, hyperplasia, atrophy, or hyperkeratosis when 
compared to the water control (Ref. 436).
    Another hamster study of 30-days duration compared topical 
applications of the test formulation to abraded and non-abraded hamster 
cheek pouches with application of 0.12 percent chlorhexidine gluconate, 
1, 2, and 3 percent hydrogen peroxide, 5 percent sodium lauryl sulfate, 
and tap water. The animals on the test formulation gained weight 
normally and did not demonstrate any evidence of mucosal irritation in 
the form of inflammation, epithelial ulceration, hyperplasia (abnormal 
multiplication of cells in a tissue), atrophy, or hyperkeratosis 
(enlargement of the keratin layer due to increase in cell size), as 
compared to the water control. The test formulation did not interfere 
with the healing of abraded pouches (Ref. 436).
    ii. Effectiveness.
    1. Mechanism of action. It is not clear how this complex mixture 
behaves under conditions of normal use. One formulation contains 0.6 
percent hydrogen peroxide and is dispensed in a single bottle. In the 
other two formulations, the rinses are dispensed in two bottles, one of 
which contains hydrogen peroxide. The directions state that the 
contents of the two bottles should be mixed just prior to rinsing. 
According to the data, these latter two formulations have 2.5 to 3 
times the concentration of the active ingredients found in the first 
formulation and are combined with 1.5 percent hydrogen peroxide versus 
0.6 percent hydrogen peroxide used in the first formulation. One of the 
latter two rinses also has 5 times as much zinc chloride as the first 
rinse. The proportions of the ingredients vary among the three 
formulations, but are generally found in relatively low concentrations. 
The concentration ranges for the active ingredients are as follows: 
Hydrogen peroxide, 0.595 to 1.5 percent; sodium citrate, 0.024 to 0.12 
percent; sodium lauryl sulfate, 0.06 to 0.15 percent; and zinc 
chloride, 0.016 to 0.08 percent (Ref. 437).
    2. In vitro studies. Study 1 evaluated the effect of the 
combination formulation on acid production by S. mutans and included 
three experimental groups: (1) S. mutans in an enriched growth medium 
(control), (2) S. mutans in an enriched growth medium exposed for 
various durations to the combination formulation with a 1:4 dilution, 
(3) S. mutans in an enriched growth medium exposed for various 
durations to the combination formulation with a 1:8 dilution. After a 
5-minute exposure, the cells were centrifuged, washed, resuspended in 
combination formulation-free medium, and incubated. The viability of 
the bacterial cells was not affected by the exposure to the 
formulation, and the formulation did not kill the bacteria during a 5-
minute exposure. However, acid production by S. mutans was inhibited 
for 8 hours as a result of the

[[Page 32273]]

5-minute exposure, as compared to the control (Ref. 438).
    Study 2, carried out by Drake et al. (Ref. 439), was designed to 
determine the antimicrobial activity of the combination formulation. A 
spectrum of oral microorganisms was exposed to various dilutions of the 
combination formulation (1:2 and 1:128) for times varying from 5 
minutes to 2 hours. MIC's varied among the species tested. Periodontal 
pathogens, including P. gingivalis, F. mucleatum, E. corrodens, and A. 
actinomycetemcomitans, were among the more susceptible of the species 
tested, with MICs between dilutions of 1:64 and 1:28. Streptococci 
tended to be less susceptible. Under this protocol, S. mutans was 
inhibited by dilutions as low as 1:32, whereas in the previous study 
the combination formulation appeared to be ineffective even at 
dilutions as low as 1:4 (Ref. 438). This apparent discrepancy with 
study 1 is likely due to the longer exposure time of the bacteria in 
study 2 (up to 2 hours). Exposures of 15 minutes at a dilution of 1:4, 
or 5-minutes at a dilution of 1:2, were needed to kill all S. mutans 
cells in this study. Because mouthrinses are seldom used clinically for 
more than 30 to 60 seconds, it is doubtful that these results reflect 
the antibacterial effect of the mouthrinse in actual use.
    3. Human clinical trials. One 6-week, blinded, parallel clinical 
trial compared the relative efficacy of two of the three combination 
formulations on plaque and gingivitis in a human adult population (Ref. 
438). Subjects were divided into three groups, using either a 
commercial toothpaste and toothbrush (control), the ``regular 
strength'' (single-bottle) formulation and a commercial toothpaste and 
toothbrush, or the orthodontic strength'' (twin-bottle formulation not 
containing five times the concentration of zinc chloride) and a 
commercial toothpaste and toothbrush. Following the baseline 
examination, each subject was instructed to brush twice a day and, if 
assigned to a mouthrinse, to use the rinse after brushing. Baseline and 
6-week data included the Loe and Silness Gingival Index recorded on six 
surfaces per tooth, and Turesky's modification of the Quigley-Hein 
Plaque Index. A mean score per subject was calculated for each index. 
The results are in Table 16.

                                  Table 16.--Gingival Index and Plaque Index Scores From the Grossman Study (Ref. 438)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                Baseline Gingival
                     Experimental Groups                              Index          6-week Gingival Index  Baseline Plaque Index   6-week Plaque Index
--------------------------------------------------------------------------------------------------------------------------------------------------------
Group 1 (control)                                                          1.52                   1.40                  20.76                  18.56
--------------------------------------------------------------------------------------------------------------------------------------------------------
Group 2 (1-bottle)                                                         1.48                   1.32                  19.91                  11.73
--------------------------------------------------------------------------------------------------------------------------------------------------------
Group 3 (2-bottle)                                                         1.47                   1.33                  19.15                  12.84
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Although the reduction in gingival index score was statistically 
significant for all three groups, the clinical significance of this 
reduction was marginal at best. There were no statistically significant 
differences among the three groups. The plaque index reduction was 
statistically significantly better for the mouthrinse groups than for 
the control group. However, the control group lacked a placebo rinse to 
determine whether the difference in plaque reduction was due to the 
rinsing effect or to some of the active ingredients in the test rinses. 
The degree of plaque reduction for any of the groups is of questionable 
clinical significance, because it did not result in any meaningful 
reduction of the gingivitis score.
    In another double-blind clinical study (Ref. 440), 119 adults were 
fitted with a toothshield (for either the right or left mandibular 
quadrant) that was designed to prevent toothbrushing from disturbing 
plaque accumulation. All subjects received an initial prophylaxis and 
were assigned to one of three experimental groups, each of which 
brushed their teeth (except for the shielded quadrant) once a day and 
used a different mouthrinse formulation twice a day for 1 minute. The 
final examination took place after 3 weeks, and 102 subjects completed 
the trial. Two rinses were variations of the two-phase system formula 
used in the 1-bottle and 2-bottle formulations. The third formulation 
was a control rinse dispensed as a two-phase system. The results show 
no statistically significant differences in gingival index scores or 
bleeding sites among the three experimental regimens, either on the 
shielded or nonshielded teeth.
    Plaque scores (Modified Turesky Plaque Index) were higher on 
shielded versus nonshielded teeth. The plaque scores after 3 weeks were 
lower for the two test rinses compared to the control rinse for both 
shielded and nonshielded teeth. However, the differences in plaque 
scores, while statistically significant, were not clinically 
significant.

 Table 17.--Data For Shielded Teeth From the Besselaar Labs Study (Ref.
                                  440)
------------------------------------------------------------------------
                                     Modified Plaque     Mean +/- Std.
        Experimental Groups           Index Baseline      Error 3-Week
------------------------------------------------------------------------
Data for Shielded Teeth
------------------------------------------------------------------------
  Group 1 (Test 1)                  2.21 +/- 0.08      2.73 +/- 0.08
------------------------------------------------------------------------
  Group 2 (Test 2)                  2.14 +/- 0.09      2.61 +/- 0.09
------------------------------------------------------------------------
  Group 3 (Control)                 2.15 +/- 0.09      3.03 +/- 0.09
------------------------------------------------------------------------
Data for Nonshielded Teeth
------------------------------------------------------------------------
  Group 1 (Test 1)                  1.95 +/- 0.07      1.76 +/- 0.07
------------------------------------------------------------------------
  Group 2 (Test 2)                  1.88 +/- 0.08      1.63 +/- 0.09
------------------------------------------------------------------------

[[Page 32274]]

 
  Group 3 (Control)                 1.91 +/- 0.07      2.24 +/- 0.06
------------------------------------------------------------------------

    The study results indicated that the test rinses had a marginal 
effect, at best, on plaque reduction, because plaque scores actually 
increased for all groups on shielded teeth, although less so, for the 
experimental rinses. None of the tested rinses had any effect to 
prevent development of gingivitis.
    Data collected in individual dental offices by dental practitioners 
(Ref. 437) had no protocols and lacked the basic requirements for 
controlled, randomized clinical trials. Therefore, these data were of 
questionable value.
    The Subcommittee concludes that this combination of ingredients is 
safe, but there are insufficient data to support its effectiveness as 
an OTC antigingivitis/antiplaque agent.
    e. Peppermint oil and sage oil. The Subcommittee concludes that 
peppermint oil and sage oil are safe, but there are insufficient data 
to classify the effectiveness of the combination as an OTC 
antigingivitis/antiplaque agent.
    Peppermint oil is described as the volatile oil distilled with 
steam from the fresh overground parts of the flowering plant Mentha 
piperita linne, rectified by distillation and neither partially nor 
wholly dementholized (Refs. 441 and 442).
    Sage oil is derived from the dried leaves of the plant Salvia 
officinalis, which contains the essential oil (Ref. 443). It is 
described as having carminative and astringent properties and is used 
as a flavoring agent. It is used with other volatile agents in 
preparations for respiratory-tract disorders, and in mouthwashes and 
gargles for disorders of the mouth and throat. It is also used in 
homeopathic medicine.
    Both peppermint oil and sage oil were reviewed by the Advisory 
Review Panel on OTC Oral Cavity Drug Products, which classified them as 
inactive ingredients (47 FR 22760 at 22764).
    i. Safety. Peppermint oil has been used as a food flavoring for 
many years (21 CFR 182.20). Safety studies on peppermint oil continue 
to the present. For example, Spindler and Madsen (Ref. 444) conducted a 
toxicity study in rats giving peppermint oil orally to groups of rats 
at dosage levels of 0, 10, 40, and 100 mg/kg body weight. Some 
encephalopathy and nephropathy were seen at the highest dose. The 
authors determined a NOAEL of 40 mg/kg body weight per day.
    Immunotoxicity testing of commonly used food flavoring ingredients 
including peppermint oil was reported (Ref. 445). Humoral and cell-
mediated immune responses in mice were evaluated. Only at very high 
dose levels did peppermint oil increase mortality rate and reduce 
survival time in the host resistance assay, but it did not 
significantly alter humoral immunity.
    Toothpaste and mouth rinse products containing both peppermint oil 
and sage oil were tested on the skin of rabbits with either no or 
slight-to-moderate irritant effects reported. Oral toxicity in rats 
showed no gross post mortem change. No untoward irritation or sensation 
relative to the oral mucosa was reported (Ref. 446).
    ii. Effectiveness. The Subcommittee concludes that there are 
insufficient data from controlled studies to permit final 
classification of the effectiveness of peppermint oil and sage oil as 
OTC active ingredients for the reduction of plaque and gingivitis.
    A single-blind study (Ref. 447) showed significantly less bleeding 
and less plaque in 25 dental students following 1 month use of the test 
toothpaste and oral rinse compared to 25 students using the placebo. 
However, all the relatively young dental students (age 25.5 +/- 2.1 
years) began with relatively low initial scores.
    Although several efficacy studies of a toothpaste and an oral rinse 
containing peppermint oil and sage oil have been conducted (Ref. 448), 
these studies lack various aspects of double-blind, well-controlled 
research.
    f. Polydimethylsiloxane and poloxamer. The Subcommittee concludes 
that these ingredients are safe, but there are insufficient data 
available to permit final classification of the effectiveness of the 
combination of polydimethylsiloxane and poloxamer as an OTC 
antigingivitis/antiplaque agent. The active ingredient is 
polydimethylsiloxane (dimethicone, simethicone), a fully methylated 
linear siloxane polymer used for its antifoaming properties in a number 
of marketed ingestible products such as antacids and certain foods (21 
CFR 176.200). In order to insure the emulsification of the active 
ingredient, poloxamer, a polymer of polyoxyethylene, is used as a 
nonionic surfactant.
    Polydimethylsiloxane combines readily with a number of other 
ingredients and has been packaged into different formulations 
(including sprays, mouthrinses, and dentifrices) and incorporated into 
oral hygiene devices (such as floss and interdental stimulators) and 
chewing gum. The ratio of the poloxamer to the polydimethylsiloxane 
varies from 100:1 in rinses to 1:1 in chewing gums. Concentrations 
range from 0.4 to 4 percent for liquid and gel emulsions, including 
toothpastes, and .01 to 0.2 g per use for interdental cleansing devices 
coated with solid emulsion, as well as chewing gum and mints.
    i. Safety.
    1. Toxicity in animals. Toxicity data in animals (Ref. 449) and 
humans (Ref. 450) indicate that polydimethylsiloxane has minimal 
toxicity. The biological safety of polydimethysiloxane has been tested 
by subdermal, intramuscular, and subcutaneous administration at greatly 
exaggerated dose levels in rats for periods of up to 26 weeks and 
further followups of up to 2 years. Monitoring included hematological 
and urinary chemistry, clinical parameters, and gross and microscopic 
anatomy. No effect was noted on the survival, body weights, clinical 
chemistry, hematology, urine chemistry, organ weights, or gross and 
microscopic anatomical features of the test animals that could be 
related to the tested product (Ref. 449). Acute toxicity testing of the 
poloxamer indicated minimal or no side effects from exaggerated doses 
via ingestion and intraocular administration of the tested products 
(Ref. 449).
    The combination of poloxamer and dimethicone, packaged as a gel, 
was tested for acute oral toxicity in rats and in a 20-day hamster 
cheek pouch application study. At a dose level of 10 g/kg of body 
weight no deaths were observed in the rat study. If this combination 
were toxic, at this dose level it would have been expected to kill one 
half or more of the animals. Additionally, no abnormal changes were 
observed in the cheek pouches after topical applications of 0.1 mL of 
the combination three times daily for 4 weeks.
    2. Toxicity in humans. No human toxicity data were submitted 
because poloxamer and dimethicone are categorized as safe (Ref. 450). 
The long-term use of the ingredients in antacids,

[[Page 32275]]

antiflatulents, and as an additive to certain foods without any report 
of harmful effects indicates that this combination is safe in the 
dosages and formulations in current use. The estimated daily intake 
varies from 0.2 g or less for sprays, gels, dentifrices, rinses, or 
dental floss to a high of 0.4 g per breath mint or candy (Ref. 451).
    ii. Effectiveness.
    1. Mechanisms of action. This combination acts by reducing the 
surface energy of the tooth (Ref. 452). Glantz (Ref. 453) showed a 
rapid increase in plaque formation with increasing surface energy in an 
in vitro assay. By reducing the surface energy with various 
surfactants, the rate of dental plaque build up can be theoretically 
reduced, particularly in the initial stages of dental plaque formation.
    2. Results from human clinical trials. In general, most of the 
human studies have shown a marginal reduction in plaque formation in 
the test groups, using assorted formulations, as compared to the 
placebo or control group. In those studies that monitored gingivitis, 
no detectable difference in gingivitis was observed between the test 
and control groups.

 Table 18.--Typical Plaque Scores From Representative Studies Measuring Changes From a Baseline With or Without
                                        an Initial Prophylaxis (Ref. 454)
----------------------------------------------------------------------------------------------------------------
               Study                      Groups(n)           Baseline              End          Mean Difference
----------------------------------------------------------------------------------------------------------------
Study 1986-01                        Test(10)            1.83                2.04               0.21
----------------------------------------------------------------------------------------------------------------
(OTC vol. 210259)                    Control(10)         1.78                2.10               0.31
----------------------------------------------------------------------------------------------------------------
Study 1986-02                        Test(13)            0                   1.62               T vs C\1\
----------------------------------------------------------------------------------------------------------------
(OTC vol. 210259)                    Control(13)         0                   1.78               0.16
----------------------------------------------------------------------------------------------------------------
Study WHOIT-1990                     Test(32)            0                   2.06-2.16          T vs C
----------------------------------------------------------------------------------------------------------------
(OTC vol. 210259)                    Control(32)         0                   2.30               0.14-0.24
----------------------------------------------------------------------------------------------------------------
Study WHD-001                        Test(30)            2.75                2.73               0.02
----------------------------------------------------------------------------------------------------------------
(OTC vol. 210259)                    Control(30)         2.62                2.69               0.06
----------------------------------------------------------------------------------------------------------------
Study 47-01                          Test(30)            0                   1.87               T vs C
----------------------------------------------------------------------------------------------------------------
(OTC vol. 210260)                    Control(30)         0                   2.11               0.24
----------------------------------------------------------------------------------------------------------------
(Gingival Index score)               Test(30)            0                   1.47               T vs C
----------------------------------------------------------------------------------------------------------------
                                     Control(30)         0                   1.56               0.09
----------------------------------------------------------------------------------------------------------------
\1\T vs C means Test versus Control.

    The protocols differed significantly from one another, as did the 
formulations of the test products. Nevertheless, it was clear that the 
differential effect on plaque scores between test and controls, while 
statistically significant, was not clinically relevant. Nor was it 
likely that the reduction in plaque scores is responsible for any 
potential cosmetic benefits that might be claimed. Therefore, it is 
misleading to claim that this combination has a plaque inhibitory 
effect. Such a claim might suggest a beneficial therapeutic or at least 
a cosmetic effect. While the plaque claim may be technically correct, 
the marginal nature of the effect is unlikely to have any clinically 
significant benefit, either therapeutic or cosmetic.
    g. Stannous pyrophosphate and zinc citrate. The Subcommittee 
concludes that this combination of ingredients is safe, but there is 
insufficient evidence of its effectiveness as an OTC antigingivitis/
antiplaque agent. Stannous pyrophosphate has the chemical formula 
Sn2P2O7 and is a free flowing, 
odorless white to offwhite powder (Ref. 455). The commercial form of 
stannous pyrophosphate is anhydrous stannous pyrophosphate. This 
ingredient has been used in a dentifrice based on prior demonstrated 
antibacterial effects, which have been ascribed to the soluble stannous 
ion.
    Because of reported antiplaque and anticalculus effectiveness, zinc 
citrate was combined in a dentifrice with stannous pyrophosphate (see 
discussion of zinc citrate chemistry in section III.C of this 
document).
    i. Safety. Based on animal studies and human use, the two 
ingredients used in the combination do not appear to present a risk in 
terms of acute toxicity, chronic toxicity, reproduction toxicity, 
genotoxicity, carcinogenicity, phototoxic sensitization, or oral 
irritation. Oral ecology studies were done to ensure that long-term use 
of antimicrobial agents does not result in a significant change in the 
balance of the normal flora. In a 21-day experimental gingivitis study 
by Watson, Jones, and Richie (Ref. 456) and a 6-month clinical trial by 
Jones et al. (Ref. 457), following use of a dentifrice containing 
stannous pyrophosphate (1 percent) and zinc citrate (0.5 percent), 
there were no significant changes in plaque flora, no increase in 
opportunistic organisms in saliva, and no development of resistance.
    ii. Effectiveness. Data on the clinical effectiveness of a fluoride 
toothpaste containing stannous pyrophosphate (1 percent) and zinc 
citrate (0.5 percent) included four studies: (1) An 18-hour plaque 
growth inhibition test, (2) a 21-day experimental gingivitis trial, (3) 
a 12-week motivational brushing trial, and (4) a 6-month normal use 
clinical trial.
    The plaque growth inhibition studies used an 18-hour protocol 
described by Harrap (Ref. 458) to test the effect of the combination 
dentifrice on plaque growth in vivo. Lloyd (Ref. 459) reported that the 
formulation reduced plaque significantly compared to a placebo 
toothpaste, showing the antimicrobial activity of the two

[[Page 32276]]

ingredients when formulated into a dentifrice.
    A 21-day experimental gingivitis study by Saxton and Cummins (Ref. 
460) enrolled 37 subjects who were brought to a state of no gingival 
inflammation following 4 weeks of repeated professional cleaning and 
oral hygiene instruction. One posterior lower segment of tooth was 
covered with a vacuum-formed tooth shield as described by Bosman and 
Powell (Ref. 461). Subjects were instructed not to brush that segment 
of the tooth, which was covered when the subjects cleaned the remainder 
of their dentition. The tooth shields also served as carriers for the 
daily application of the control and test toothpastes. Assessment of 
inflammation and bleeding was done at baseline and at 3 weeks. Mean 
scores were significantly lower for the test group at 3 weeks, which 
was interpreted as the test dentifrice being better in delaying 
development of gingivitis.
    A 12-week motivational brushing trial by Gaare et al. (Ref. 462) 
included 81 adult subjects described as receiving a prophylaxis and 
motivation at baseline and then using the combination dentifrice at 
least twice daily. Plaque index and GI scores improved at 6 weeks; 
plaque scores continued to improve at 12 weeks; and bleeding scores 
were maintained at 12 weeks.
    A 6-month normal use clinical study by Saxton et al. (Ref. 463) 
enrolled 268 subjects, with 251 completing the trial. Clinical 
assessments were made at baseline and at 1, 4, and 6 months. Tooth 
scaling and polishing were done after baseline assessments, which 
included plaque index by Loe (Ref. 464), modified gingival index by 
Lobene (Ref. 112), extrinsic stain indices by Lobene (Ref. 465), 
supragingival calculus by Volpe (Ref. 466), and gingival bleeding by 
Ainamo and Bay (Ref. 467). The results at 6 months showed no difference 
in mean plaque scores and no difference in mean modified gingival index 
scores. Gingival bleeding was statistically significantly lower for the 
test group (p<0.01) as was the mean calculus scores (p<0.01). Tooth 
staining area mean scores were statistically significantly higher 
(p<0.05) and the stain intensity mean score was also higher (p<0.00) 
for the test group. It was reported that 17 percent of the test group 
observed tooth staining for themselves. Tongue staining was clinically 
detectable in approximately 40 percent of test dentifrice subjects 
compared to approximately 10 percent of control dentifrice subjects (53 
versus 15 subjects at 6 months).
    The Subcommittee concludes that the combination of stannous 
pyrophosphate (1 percent) and zinc citrate (0.5 percent) in a 
dentifrice is safe. However, there are insufficient data to permit 
final classification of its effectiveness as an OTC antigingivitis/
antiplaque agent.

IV. Analysis of Impacts

    FDA seeks specific comment regarding any substantial or significant 
economic benefit or impact that this proposed rule would have on 
manufacturers or consumers of antigingivitis/antiplaque drug products. 
Comments regarding the benefit or impact of this proposed rule on such 
manufacturers or consumers should be accompanied by appropriate 
documentation. The agency will evaluate any comments and supporting 
data that are received and will assess the economic impact of this 
proposed rule in the preamble to the proposed rule.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements in this 
document are not subject to review by the Office of Management and 
Budget because they do not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the labeling statements are a ``public disclosure of 
information originally supplied by the Federal government to the 
recipient for the purpose of disclosure to the public'' (5 CFR 
1320.3(c)(2)).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Request for Comments

    The agency is providing interested persons a period of 90 days to 
submit written or electronic comments to the Dockets Management Branch 
(see ADDRESSES) regarding this advance notice of proposed rulemaking. 
Three copies of all written comments are to be submitted. Individuals 
submitting written comments or anyone submitting electronic comments 
may submit one copy. Comments are to be identified with the docket 
number found in brackets in the heading of this document and may be 
accompanied by a supporting memorandum or brief. The agency is also 
providing interested persons a period of 150 days to submit comments 
replying to comments regarding this advance notice of proposed 
rulemaking. Received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.

VIII. References

    The following references are on display in the Dockets Management 
Branch (see ADDRESSES) and may be seen by interested persons between 9 
a.m. and 4 p.m., Monday through Friday.
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    248. ``Twenty-One Day Mucous Membrane Irritancy Assay: Hamster 
Cheek Pouch Method,'' unpublished study VS-50 in OTC Vol. 210312.
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VS-95a in OTC Vol. 210313.
    250. ``Mucous Membrane Irritancy Assay of a Formula and 
Dentifrice (Hamster Cheek Pouch Method),'' unpublished study VS-95 
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    251. ``Acute Oral Toxicity Studies in Rats,'' unpublished 
studies VS-09, VS-11, VS-15, VS-16, VS-19, VS-20, VS-39, VS-53, VS-
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    252. ``Mucous Membrane Irritancy Study of Oral Rinse,'' 
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    255. ``Acute Oral Toxicity in Rats,'' unpublished study VS-11 in 
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    262. ``Six-Month Safety/Efficacy Study,'' unpublished study VS-
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[numsign]106A-01, Olin Corp., New Haven, CT, unpublished study in 
OTC Vol. 210007.
    403. ``Eye Irritation in Rabbits,'' Study [numsign]203-01, Olin 
Corp., New Haven, CT, unpublished study in OTC Vol. 210007.
    404. Ader, A. W. et al., ``Effect of Mouth Rinsing with Two 
Polyvinylpyrrolidone-Iodine Mixtures on Iodine Absorption and 
Thyroid Function,'' Journal of Clinical Endocrinology and 
Metabolism, 66:632-635, 1988.
    405. ``Salmonella/Microsome Mutagenesis Assay on a Mixture of 3% 
Aqueous Hydrogen Peroxide and 10% Aqueous Povidone Iodine,'' Olin 
Corp., New Haven, CT, unpublished study in OTC Vol. 210007.
    406. ``Micronucleus Test in Mice Perimed[reg] Oral Hygiene 
Rinse,'' Olin Corp., New Haven, CT, unpublished study in OTC Vol. 
210007.
    407. ``Rat Hepatocyte Primary Culture/DNA Repair Test,'' Olin 
Corp., New Haven, CT, unpublished study in OTC Vol. 210007.
    408. ``Chinese Hamster Ovary Mammalian Cell Cytotoxicity 
Assay,'' Olin Corp., New Haven, CT, unpublished study in OTC Vol. 
210007.
    409. Goodman, L. S., and G. Gilman, editors, 5th ed., The 
Pharmacological Basis of Therapeutics, Macmillan Publishing Co., 
Inc., Bailliere Tindall, London, England, pp. 995-996, 1975.
    410. Clark, W. B. et al., ``Efficacy of Perimed[reg] 
Antibacterial System on Established Gingivitis: Clinical Results,'' 
Journal of Clinical Periodontology, 16:630-635.
    411. Walker, C. B., ``Effect of Perimed[reg] Antibacterial 
System on the Subgingival Microbial Composition Associated with 
Established Gingivitis,'' unpublished study in OTC Vol. 210008.
    412. ``Statistical Report on the Clinical Evaluation of a 
Povidone-Iodine Hydrogen Peroxide Mixture in the Prevention and 
Treatment of Periodontal Disease,'' Olin Consumer Products Group, 
unpublished 3-week study in OTC Vol. 210008.
    413. Cutter, G. R., ``A Controlled Trial (6-week) of Povidone 
Iodine and Hydrogen Peroxide, Povidone Iodine and Distilled Water,'' 
unpublished study in OTC Vol. 210008.
    414. Walker, C. B., ``Microbiological Effects of Mouthrinses 
Containing Antimicrobials,'' Journal of Clinical Periodontology, 
15:499-505.
    415. Kuhn, J. et al., ``Salmonella/Microsome Assay for Bacterial 
Mutagenicity on Gel PCR-02-56/Paste PCR-02-122 (1:1),'' unpublished 
study in OTC Vol. 210185.
    416. Agnet, Y., J. L. Dorange, and P. Dupuy, ``Mutagenicity of 
Peracetic Acid on Salmonella typhimurium,'' Mutation Research, 
38:119, 1976.
    417. Li, I., ``Evaluation of Genotoxicity of a Tooth Whitener,'' 
AADR Abstracts, Abstract [numsign]413, Journal of Research 
Dentistry, 71:157, 1992.
    418. Meyers, D. et al., ``Four-Day Rat Oral Irritation Test on 
an Experimental Paste/Gel Dentifrice Formulation,'' unpublished 
study in OTC Vol. 210181.
    419. Kuhn, J. et al., ``Twenty-week Oral Mucosal Irritation 
(Hamster Cheek Pouch Method) with 6 and 12 Week Interim 
Sacrifices,'' unpublished study in OTC Vol. 210181.
    420. Truelove, R. B. et al., ``Evaluation of the Safety of a 
Hydrogen Peroxide-Baking Soda Dentifrice,'' unpublished study in OTC 
Vol. 210181.
    421. Austin, G., M. Mesa, and C. Lambert, ``The Keyes Technique 
and Self-Inflicted Injuries (Three Case Reports),'' Journal of 
Periodontology, 56(9):537-539, 1985.
    422. Levine, R. A., ``The Keyes Technique as Cofactor in Self-
Inflicted Gingival Lesions: A Case Report,'' Compendium Continuing 
Education Dentistry, 8:266-269, 1987.
    423. Miyaski, K. T., R. J. Genco, and M. E. Wilson, 
``Antimicrobial Properties of Hydrogen Peroxide and Sodium 
Bicarbonate Individually and in Combination Against Selected Oral, 
Gram-negative, Facultative Bacteria,'' Journal of Dental Research, 
65:1142-1148, 1986.
    424. Rosling, B. G. et al., ``Microbiological and Clinical 
Effects of Topical Subgingival Antimicrobial Treatment on Human 
Periodontal Disease,'' Journal of Clinical Periodontology, 10:487-
514, 1983.
    425. Putt, M. S., ``Human Clinical Study Final Report: Clinical 
Investigation of Plaque Inhibitory Mouthrinses,'' unpublished report 
in OTC Vol. 210189.
    426. Greenwell, H. et al., ``The Effect of Keyes Method of Oral 
Hygiene on the Subgingival Microflora Compared to the Effect of 
Scaling and/or Surgery,'' Journal of Clinical Periodontology, 
12:327-341, 1985.
    427. Cerra, M. B., and W. J. Killoy, ``The Effect of Sodium 
Bicarbonate and Hydrogen Peroxide on the Microbial Flora of 
Periodontal Pockets,'' Journal of Periodontology, 53:599-603, 1982.
    428. Walsh, M. M., and N. Kaufman, ``Subgingival Application of 
a Hydrogen Peroxide/Baking Soda Mixture with a Toothpick--
Periodontal Effects,'' Clinical Preventive Dentistry, 7(2):21-24, 
1985.
    429. Wolff, L. F. et al., ``Salt and Peroxide Compared with 
Conventional Oral Hygiene: II. Microbial Results,'' Journal of 
Periodontology, 58:301-307, 1987.
    430. Pihlstrom, B. L. et al., ``Salt and Peroxide Compared with 
Conventional Oral Hygiene: I. Clinical Results,'' Journal of 
Periodontology, 58(5):291-300, 1987.
    431. Wolff, L. F. et al., ``Four-Year Investigation of Salt and 
Peroxide Regimen Compared with Conventional Oral Hygiene,'' Journal 
of the American Dental Association, 118:67-72, 1989.
    432. Keyes, P. H., W. E. Wright, and S. A. Howard, ``V. 
Periodontics and Oral Hygiene, The Use of Phase-Contrast Microscopy 
and Chemotherapy in the Diagnosis and Treatment of Periodontal 
Lesions: An Initial Report (I),'' Quintessence International, 
9(1):51-56 and 69-76, 1978.
    433. Keyes, P. H., W. E. Wright, and S. A. Howard, ``V. 
Periodontics and Oral Hygiene, The Use of Phase-Contrast Microscopy 
and Chemotherapy in the Diagnosis and Treatment of Periodontal 
Lesions: An Initial Report (II),'' Quintessence International, 
9(1):69-76, 1978.
    434. OTC Vol. 210004.
    435. OTC Vol. 210207.
    436. OTC Vol. 210428.
    437. OTC Vol. 210001.
    438. Grossman, M. L., ``Clinical Comparison of Regular and 
Orthodontic Strength Prevention Mouth Rinse in Controlling Plaque 
and Gingivitis: A Pilot Study Conducted by New Institutional Service 
Company,'' unpublished study in OTC Vol. 210390.
    439. Drake, D. R. et al., ``The Antimicrobial Activity of 
Prevention Mouthrinse,'' American Journal of Dentistry, 6:239-242, 
1993.
    440. ``Clinical Investigation of a Plaque Inhibitory 
Mouthwash,'' [Product Literature Pamphlet], in OTC Vol. 210428.
    441. The United States Pharmacopeia--23, National Formulary--18, 
United States Pharmacopeial Convention, Inc., Rockville, MD, pp. 
2276-2277, 1995.
    442. The British Pharmacopoeia, Vol. 1, London, England, pp. 
442-443, 1988.
    443. Martingale, The Extra Pharmacopoeia, 30th ed., The 
Pharmaceutical Press, London, England, p. 1410, 1993.
    444. Spindler, P., and C. Madsen, ``Subchronic Toxicity Study of 
Peppermint Oil in Rats,'' Toxicology Letters, 62:215-220, 1992.
    445. Gaworski, C. L. et al., ``An Immunotoxicity Assessment of 
Food Flavoring Ingredients,'' Food Chemical Toxicology, 32:409-415, 
1994.
    446. Cuthbert, J. A., and S. M. A. Carr, ``Parodontax Toothpaste 
and Perodontax Mouthwash,'' unpublished study in OTC Vol. 210334.
    447. Willershausen, B., I. Guber, and G. Hamm, ``The Influence 
of Herbal Ingredients on the Plaque Index and Bleeding Tendency of 
the Gingiva,'' Journal of Clinical Dentistry, 2:77-80, 1991.
    448. OTC Vol. 210334.
    449. OTC Vol. 210257.
    450. OTC Vol. 210258.
    451. OTC Vol. 210256.
    452. OTC Vol. 210262.

[[Page 32285]]

    453. Glantz, P., ``On Wetability and Adhesiveness,'' 
Odontologisk Revy, Supplement 17, 20:84-132, 1969.
    454. OTC Vols. 210259 and 210260.
    455. The Merck Index, edited by S. Burdaveri et al., 12th ed., 
Merck and Co., Rahway, NJ, p. 1501, 1996.
    456. Watson, G. K., C. L. Jones, and J. A. Richie, ``The 
Microbiological Effects of Toothpastes Containing Stannous 
Pyrophosphate and Zinc Citrate on Developing Experimental 
Gingivitis,'' Unilever Technical Report [numsign]OLI2, unpublished 
study in OTC Vol. 210174.
    457. Jones, C. L. et al., ``The Effect of 6 Months Use of a 
Toothpaste Containing Stannous Pyrophosphate and Zinc Citrate on 
Oral Ecology,'' Unilever Technical Report, unpublished study in OTC 
Vol. 210173.
    458. Harrap, G. J., ``Assessment of the Effect of Dentifrices on 
the Growth of Dental Plaque,'' Journal of Clinical Periodontology, 
1:166-174, 1974.
    459. Lloyd, A. M., ``The Anti-Plaque Activity of Stannous 
Pyrophosphate/Zinc Citrate in an Eighteen Hour Plaque Growth 
Inhibition Test,'' Unilever Technical Report, unpublished study in 
OTC Vol. 210177.
    460. Saxton, O. A., and D. Cummins, ``The Effect of a Dentifrice 
Containing Stannous Pyrophosphate, Zinc Citrate and Sodium Fluoride 
on Developing Gingivitis,'' Unilever Technical Report, unpublished 
study in OTC Vol. 210178.
    461. Bosman, C. W., and R. N. Powell, ``The Reversal of 
Localized Experimental Gingivitis: A Comparison Between Mechanical 
Toothbrushing Procedures and a 0.2% Chlorhexidine Mouthrinse,'' 
Journal of Clinical Periodontology, 4:161-172, 1977.
    462. Gaare, D., G. Rolla, and J. I. Russel, ``Clinical Study 
into the Benefits of Regular Brushing with a Silica Based Dentifrice 
Containing Stannous Pyrophosphate and Zinc Citrate,'' Unilever 
Technical Report, unpublished study in OTC Vol. 210177.
    463. Saxton, C. A. et al., ``Six Month Study of the Effect of a 
Stannous Pyrophosphate/Zinc Citrate Dentifrice on Gingival Health 
and Calculus,'' Unilever Technical Report, unpublished study in OTC 
Vol. 210178.
    464. Loe, H., ``The Gingival Index, the Plaque Index and the 
Retention Index System,'' Journal of Peridontology, 38:610, 1967.
    465. Lobene, R. R. et al., ``Effects of Dentifrices on Tooth 
Stains with Controlled Brushing,'' Journal of the American Dental 
Association, 77:849-855, 1968.
    466. Volpe, A. R., J. H. Manhold, and S. P. Hazen, ``In Vivo 
Calculus Assessment: Part I, A Method and Its Examiner 
Reproducibility,'' Journal of Periodontology, 32:292, 1965.
    467. Ainamo, J., and I. Bay, ``Problems and Proposals for 
Recording Gingivitis and Plaque,'' Journal of International Dental, 
25(4):229-235, 1975.

List of Subjects in 21 CFR Part 356

    Over-the-counter drugs, Antigingivitis/antiplaque drug products.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 356 (as proposed in the Federal Register of 
May 25, 1982 (47 FR 22760), the Federal Register of January 27, 1988 
(53 FR 2436), the Federal Register of September 24, 1991 (56 FR 48302), 
and the Federal Register of February 9, 1994 (59 FR 6084)) be amended 
as follows:

PART 356--ORAL HEALTH CARE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE

    1. The authority citation for 21 CFR part 356 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. Section 356.3 is amended by adding paragraphs (o) and (p) to 
read as follows:


Sec.  356.3  Definitions.

* * * * *
    (o) Antigingivitis drug. A drug applied to the oral cavity to help 
reduce or prevent gingivitis.
    (p) Antigingivitis/antiplaque drug. A drug applied to the oral 
cavity to help reduce or prevent gingivitis and dental plaque.
    3. Section 356.13 is added to subpart B to read as follows:


Sec.  356.13  Antigingivitis active ingredients.

    The active ingredient of the product consists of stannous fluoride 
0.454 percent in a compatible dentifrice base.
    4. Section 356.15 is added to subpart B to read as follows:


Sec.  356.15  Antigingivitis/antiplaque active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits and in the dosage form 
established for each ingredient:
    (a) Cetylpyridinium chloride 0.045 to 0.1 percent in a mouthrinse 
with at least 72 to 77 percent available cetylpyridinium chloride.
    (b) Eucalyptol 0.092 percent in a mouthrinse when combined in 
accordance with Sec.  356.26(p).
    (c) Menthol 0.042 percent in a mouthrinse when combined in 
accordance with Sec.  356.26(p).
    (d) Methyl salicylate 0.060 percent in a mouthrinse when combined 
in accordance with Sec.  356.26(p).
    (e) Thymol 0.064 percent in a mouthrinse when combined in 
accordance with Sec.  356.26(p).
    5. Section 356.24 is amended by redesignating the text as paragraph 
(a) and by adding paragraph (b) to read as follows:


Sec.  356.24  Package-size limitations.

* * * * *
    (b) Due to the toxicity associated with fluoride active ingredients 
in Sec.  355.10 of this chapter, the following package-size limitations 
are required for antigingivitis drug products containing stannous 
fluoride:
    (1) Dentifrices. Dentifrice (toothpaste) packages shall not contain 
more than 276 milligrams (mg) total fluorine per package.
    (2) Exception. Package size limitations do not apply to 
antigingivitis/antiplaque drug products marketed for professional 
office use only and labeled in accordance with Sec.  355.60 of this 
chapter.
    6. Section 356.26 is amended by adding paragraphs (p), (q), (r), 
and (s) to read as follows:


Sec.  356.26  Permitted combinations of active ingredients.

* * * * *
    (p) The ingredients identified in Sec.  356.15(b), (c), (d), and 
(e) may be combined in a hydroalcoholic vehicle containing 21.6 to 26.9 
percent alcohol in a mouthrinse provided the product is labeled 
according to Sec.  356.65.
    (q) The antigingivitis/antiplaque active ingredient identified in 
Sec.  356.15(a) or the combination of ingredients identified in Sec.  
356.26(p) may be combined with any single anticaries active ingredient 
identified in Sec.  355.10 of this chapter.
    (r) The antigingivitis active ingredient identified in Sec.  
356.13(a) or the antigingivitis/antiplaque active ingredient identified 
in Sec.  356.15(a) or the combination of ingredients identified in 
Sec.  356.26(p) may be combined with any single tooth desensitizer 
active ingredient identified in Sec.  356.22.
    (s) The antigingivitis/antiplaque active ingredient identified in 
Sec.  356.15(a) or the combination of ingredients identified in Sec.  
356.26(p) may be combined with any single anticaries active ingredient 
identified in Sec.  355.10 of this chapter and any single tooth 
desensitizer active ingredient identified in Sec.  356.22.
    7. Section 356.65 is added to subpart C to read as follows:


Sec.  356.65   Labeling of antigingivitis/antiplaque drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as 
``antigingivitis'' or ``antigingivitis/antiplaque'' (optional: may 
include dosage form, e.g., dentifrice, toothpaste, mouthrinse).
    (b) Indications. The labeling of the product states, under the 
heading ``Uses,'' one or more of the phrases

[[Page 32286]]

listed in this paragraph (b), as appropriate. Other truthful and 
nonmisleading statements, describing only the indications for use that 
have been established and listed in this part, may also be used, as 
provided in Sec.  330.1(c)(2) of this chapter, subject to the 
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act 
(the act) relating to misbranding and the prohibition in section 301(d) 
of the act against the introduction or delivery for introduction into 
interstate commerce of unapproved new drugs in violation of section 
505(a) of the act.
    (1) For all antigingivitis products. The labeling states 
``[bullet]\1\ helps [select one of the following: `control,' `reduce,' 
or `prevent'] [select one or more of the following: `[bullet] 
gingivitis,' `[bullet] gingivitis, an early form of gum disease,' or 
`[bullet] bleeding gums'].''
---------------------------------------------------------------------------

    \1\See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    (2) For antigingivitis products containing stannous fluoride. The 
labeling states the indication in paragraph (b)(1) of this section and/
or the following: ``[bullet] helps interfere with harmful effects of 
plaque associated with gingivitis''.
    (3) For all antigingivitis/antiplaque products. The labeling states 
``[bullet] helps [select one of the following: `control,' `reduce,' 
`prevent,' or `remove'] plaque that leads to [select one or more of the 
following: `[bullet] gingivitis,' `[bullet] gingivitis, an early form 
of gum disease,' or `[bullet] bleeding gums'].''
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For all antigingivitis and antigingivitis/antiplaque products. 
(i) ``Stop use and ask a dentist\2\ if [in bold type] [bullet] 
gingivitis, bleeding, or redness persists for more than 2 weeks 
[bullet] you have painful or swollen gums, pus from the gum line, loose 
teeth, or increasing spacing between the teeth. These may be signs or 
symptoms of periodontitis, a serious form of gum disease.''
---------------------------------------------------------------------------

    \2\For these products, the word ``dentist'' should be 
substituted for ``doctor'' in the heading ``Stop use and ask a 
doctor if'' required by Sec.  201.66(c)(5)(vii) of this chapter.
---------------------------------------------------------------------------

    (ii) The following warnings shall be used in place of the general 
warning statements required by Sec.  330.1(g) of this chapter.
    (A) ``Keep out of reach of children under 6 years of age.'' 
[highlighted in bold type]
    (B) ``If more than used for [select appropriate word: `brushing' or 
`rinsing'] is accidentally swallowed, get medical help or contact a 
Poison Control Center right away.''
    (2) [Reserved]
    (d) Directions. The labeling of the product states, under the 
heading ``Directions,'' the following directions for use:
    (1) For antigingivitis dentifrice products containing 0.454 percent 
stannous fluoride in a paste dosage form with a theoretical total 
fluorine concentration of 850 to 1,150 parts per million identified in 
Sec.  355.10(c)(1) of this chapter. ``[bullet] adults and children 2 
years of age and older: brush teeth thoroughly, preferably after each 
meal or at least twice a day, or as directed by a dentist or doctor 
[bullet] instruct children under 6 years of age in good brushing and 
rinsing habits (to minimize swallowing) [bullet] supervise children as 
necessary until capable of using without supervision [bullet] children 
under 2 years of age: ask a dentist or doctor''.
    (2) For antigingivitis/antiplaque oral rinse products containing 
0.045 to 0.1 percent cetylpyridinium chloride. ``[bullet] adults and 
children 12 years of age and older: vigorously swish 20 milliliters of 
rinse between your teeth twice a day for 30 seconds and then spit out. 
Do not swallow the rinse. [bullet] children 6 years to under 12 years 
of age: supervise use [bullet] children under 6 years of age: do not 
use''.
    (3) For antigingivitis/antiplaque oral rinse products containing 
the combination of ingredients in Sec.  356.26(p). ``[bullet] adults 
and children 12 years of age and older: vigorously swish 20 milliliters 
of rinse between your teeth twice a day for 30 seconds and then spit 
out. Do not swallow the rinse. [bullet] children 6 years to under 12 
years of age: supervise use. [bullet] children under 6 years of age: do 
not use''.
    (e) Other information. The labeling of the product contains the 
following information under the heading ``Other information'':
    (1) For antigingivitis dentifrice products containing stannous 
fluoride. The labeling states ``[bullet] this product may produce 
surface staining of the teeth. Adequate tooth brushing may prevent 
these stains which are not harmful or permanent and may be removed by a 
dentist.''
    (2) For antigingivitis/antiplaque oral rinse products. The labeling 
states ``[bullet] this rinse is not intended to replace brushing or 
flossing''.
    8. Section 356.66 is amended by adding paragraphs (b)(10), (c)(5), 
and (d)(3) to read as follows:


Sec.  356.66  Labeling of combination drug products.

* * * * *
    (b) * * *
    (10) For permitted combinations identified in Sec.  356.26(p). The 
labeling of the product states, under the heading ``Uses,'' one or more 
of the indications for antigingivitis/antiplaque active ingredients in 
Sec.  356.65(b)(3), or the following: ``[bullet] helps [select one of 
the following: `control,' `inhibit,' or `kill'] plaque bacteria that 
contribute to the development of [select one or more of the following: 
`[bullet] gingivitis,' `[bullet] gingivitis, an early form of gum 
disease,' or `[bullet] bleeding gums'].''
    (c) * * *
    (5) For permitted combinations identified in Sec.  356.26. The 
warnings in Sec.  356.65(c) should be used.
    (d) * * *
    (3) For permitted combinations identified in Sec.  356.26. The 
directions in Sec.  356.65(d) should be used.
    9. Section 356.92 is added to subpart D to read as follows:


Sec.  356.92  Testing of antigingivitis/antiplaque drug products.

    The following testing should be conducted on the product 
formulation, a standard formulation with effectiveness documented by 
clinical trials, and a negative control.
    (a) Cetylpyridinium chloride rinse. One of the following tests 
should be conducted:
    (1) Determine the in vitro antimicrobial activity of the product 
against representative plaque organisms commonly associated with 
gingivitis. Representative organisms include, but are not limited to, 
typed stains of: Actinomyces viscosus, Fusobacterium nucleatum, 
Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, 
Candida species, Streptococcus mutans, and gram negative enteric rods. 
Testing to determine a product's in vitro antimicrobial activity should 
include minimal inhibitory concentration (MIC) assays, or 30-second 
kill-time studies, as appropriate.
    (2) Demonstrate the availability of the active ingredient using a 
Disk Retention Assay (DRA).
    (3) Demonstrate the biological activity of the product using an ex 
vivo Plaque Glycolysis and Regrowth Model (PGRM).
    (b) Combination of ingredients identified in Sec.  356.26(p). One 
of the following tests should be conducted:
    (1) Determine the in vitro antimicrobial activity of the product 
using 30-second kill-time studies with both standard laboratory strains 
and

[[Page 32287]]

wild-type organisms obtained from saliva sampling. Representative 
organisms include, but are not limited to, typed stains of: Actinomyces 
viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella 
intermedia, Bacteroides forsythus, Candida species, Streptococcus 
mutans, and gram negative enteric rods. Kill-time testing should be 
conducted using an exposure time of 30 seconds in the presence of 
exogenous protein. An initial inoculum of 1 percent transmission should 
be used.
    (2) Demonstrate the in vivo activity of the product in a short-term 
experimental gingivitis study of at least 2 weeks duration. Formulation 
comparability in this test is established if the new mouthrinse 
formulation satisfies the ``at least as good as'' statistical criteria 
for both plaque and gingivitis with respect to the clinically tested 
standard, or another generally accepted statistical test of clinical 
comparability. The criterion for study validation is statistically 
significant differences in plaque and gingivitis between the clinically 
tested standard and the negative control.
    (c) Stannous fluoride dentifrice.
    (1) In addition to tests required by Sec.  355.70 of this chapter, 
testing should include an in vitro determination of the antimicrobial 
activity against representative plaque organisms commonly associated 
with gingivitis. Representative organisms include, but are not limited 
to, typed stains of: Actinomyces viscosus, Fusobacterium nucleatum, 
Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, 
Candida species, Streptococcus mutans, and gram negative enteric rods. 
Testing to determine a product's in vitro antimicrobial activity should 
include MIC assays, 30-second kill-time studies, or plaque biofilm 
assays, as appropriate.
    (2) Demonstrate the biological activity of the product ex vivo 
using PGRM.
    (d) Test modifications. The formulation or mode of administration 
of certain products may require modification of the testing procedures 
in this section. In addition, alternative assay methods (including 
automated procedures) employing the same basic chemistry or 
microbiology as the methods described in this section may be used. Any 
proposed modification or alternative assay method shall be submitted as 
a petition in accordance with Sec.  10.30 of this chapter. The petition 
should contain data to support the modification or data demonstrating 
that an alternative assay method provides results of equivalent 
accuracy. All information submitted will be subject to the disclosure 
rules in part 20 of this chapter.

    Dated: May 12, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-12783 Filed 5-28-03; 8:45 am]
BILLING CODE 4160-01-S