[Federal Register: May 29, 2003 (Volume 68, Number 103)]
[Proposed Rules]
[Page 32231-32287]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29my03-35]
[[Page 32231]]
-----------------------------------------------------------------------
Part III
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
-----------------------------------------------------------------------
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
[[Page 32232]]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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,
[[Page 32234]]
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
------------------------------------------------------------------------
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.
------------------------------------------------------------------------
Angus Chemical Co., Northbrook, IL Hexetidine solution.
60062
------------------------------------------------------------------------
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
------------------------------------------------------------------------
Clinical Product Research, Inc., Prozyme Toothpaste, Anti-Plaquer
Shreveport, LA 71109 Oral Rinse, Anti-Plaquer
Toothpaste.
------------------------------------------------------------------------
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
------------------------------------------------------------------------
Madaus Medtech, Inc., (ACC Parodontax Toothpaste.
Consulting Group, Inc.) Washington
DC 20036
------------------------------------------------------------------------
Pfizer Inc, New York, NY 10017 Plax Pre-Brushing Dental Rinse.
------------------------------------------------------------------------
Pierre Fabre, S.A., 81106 Castres Eligydium Toothpaste, Eludil
Cedex, France Mouthwash.
------------------------------------------------------------------------
Prevention Laboratories (formerly 7- Prevention Mouth Rinse.
L Corp.), Harrisburg, IL 62947
------------------------------------------------------------------------
Procter & Gamble Co., Cincinnati, Crest Gum Care Toothpaste.
OH 45242
------------------------------------------------------------------------
[[Page 32235]]
SmithKline Beecham Consumer Brands Cepacol Gold and Mint Mouthwashes,
(Marion Merrell Dow, Inc.), Gly-oxide Liquid.
Parsippany, NJ 07054
------------------------------------------------------------------------
Vipont Pharmaceuticals, Fort Viadent Toothpaste and Oral Rinses.
Collins, CO 80522
------------------------------------------------------------------------
Warner-Lambert Co., Morris Plains, Listerine Antiseptic Mouthwash.
NJ 07950
------------------------------------------------------------------------
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.
1. Fitzgerald, R. J., and E. G. McDaniel, ``Dental Calculus in
the Germ-Free Rat,'' Archives of Oral Biology, 2:239-240, 1960.
2. Axelsson, P., and J. Lindhe, ``Effect of Controlled Oral
Hygiene Procedures on Caries and Periodontal Disease in Adults;
Results After 6 Years,'' Journal of Clinical Periodontology, 8:239-
248, 1981.
3. Grossi, S. G. et al., ``Assessment of Risk for Periodontal
Disease: I. Risk Indicators for Attachment Loss,'' Journal of
Periodontology, 65(3):260-267, 1994.
4. Emrich, L. J., M. Shlossman, and R. J. Genco, ``Periodontal
Disease in Non-Insulin-Dependent Diabetes Mellitus,'' Journal of
Periodontology, 62:123-131, 1991.
5. OTC Vol. 210642.
6. OTC Vol. 210464.
7. Boring, C. C., T. S. Squires, and T. Tong, ``Cancer
Statistics 1993,'' California Journal of Clinical Cancer, 43:7-26,
1993.
8. Vincent, R. G., and F. Marchetta, ``The Relationship of the
Use of Tobacco and Alcohol to Cancer of the Oral Cavity, Pharynx or
Larynx,'' American Journal of Surgery, 106:501-505, 1963.
9. Keller, A. Z., and M. Terris, ``The Association of Alcohol
and Tobacco with Cancer of the Mouth and Pharynx,'' American Journal
of Public Health, 55:1578-1588, 1964.
10. Tuyns, A. J., ``Oesophageal Cancer in Non-Smoking Drinkers
and in Non-Drinking Smokers,'' International Journal of Cancer,
32:443-444, 1983.
11. Smith, E. M., ``Epidemiology of Oral and Pharyngeal Cancers
in the United States: Review of Recent Literature,'' Journal of the
National Cancer Institute, 63(5):1189-1198, 1979.
12. Wynder, E. L. et al., ``Oral Cancer and Mouthwash Use,''
Journal of the National Cancer Institute, 70:255-260, 1983.
13. Blot, W. J., ``Smoking and Drinking in Relation to Oral and
Pharyngeal Cancer,'' Cancer Research, 48:3282-3287, 1988.
14. Graham, S. et al., ``Dentition, Diet, Tobacco, and Alcohol
in the Epidemiology of Oral Cancer,'' Journal of the National Cancer
Institute, 59:1611-1615, 1977.
15. Decker, J., and J. C. Goldstein, ``Risk Factors in Head and
Neck Cancer,'' New England Journal of Medicine, 306:1151-1155, 1982.
16. Elwood, J. M. et al., ``Alcohol, Smoking, Social and
Occupational Factors in the Aetiology of Cancer of the Oral Cavity,
Pharynx and Larynx,'' International Journal of Cancer, 34:603-612,
1984.
17. Gorsky, M., and S. Silverman, ``Denture Wearing and Oral
Cancer,'' Journal of Prosthetic Dentistry, 52:164-166, 1984.
18. Winn, D. M. et al., ``Diet in the Etiology of Oral and
Pharyngeal Cancer Among
[[Page 32277]]
Women from the Southern United States,'' Cancer Research, 44:1216-
1222, 1984.
19. McLaughlin, J. K. et al., ``Dietary Factors in Oral and
Pharyngeal Cancer,'' Journal of the National Cancer Institute,
80:1237-1243, 1988.
20. O'Reilly, P. et al., ``Alcohol Content of Proprietary
Mouthwashes,'' Irish Journal of Medical Science, 163:178-181, 1994.
21. Kowitz, G. M. et al., ``Effects of Mouthwashes on the Oral
Soft Tissues,'' Journal of Oral Medicine, 31:47-50, 1976.
22. Bernstein, M. L., ``Oral Mucosal White Lesions Associated
with Excessive Use of Listerine Mouthwash,'' Journal of Oral
Surgery, 46:781-785, 1978.
23. Weaver, A. et al., ``Mouthwash Use and Oral Cancer:
Carcinogen or Coincidence,'' Journal of Oral Surgery, 37:250-253,
1979.
24. Winn, D. M. et al., ``Mouthwash Use and Oral Conditions in
the Risk for Oral and Pharyngeal Cancer,'' Cancer Research, 51:3044-
3047, 1991.
25. Young, T. B., C. Ford, and J. Brandenburg, ``An
Epidemiologic Study of Oral Cancer in a Statewide Network,''
American Journal of Otolaryngology, 7:200-208, 1986.
26. Kabat, G. C., J. R. Herbert, and E. L. Wynder, ``Risk
Factors for Oral Cancer in Women,'' Cancer Research, 49:2803-2806,
1989.
27. Mashberg, A., P. Barsa, and M. L. Grossman, ``A Study of the
Relationship Between Mouthwash Use and Oral and Pharyngeal Cancer,''
Journal of the American Dental Association, 110:731-734, 1985.
28. Elzay, R. P., ``Local Effect of Alcohol in Combination with
DMBA on Hamster Cheek Pouch,'' Journal of Dental Research, 45:1788,
1966.
29. Henefer, E. P., ``Ethanol, 30 Percent, and Hamster Pouch
Carcinogenesis,'' Journal of Dental Research, 45:838-844, 1966.
30. Freedman, A., and G. Schklar, ``Alcohol and Hamster Buccal
Pouch Carcinogenesis,'' Oral Surgery, Oral Medicine, Oral Pathology,
46(6):794-804, 1978.
31. Tuyns, A. J., ``Association of Tobacco and Alcohol in
Cancer,'' Bul der Schweizerischen Akademie der Medizinischen
Wissenschaften, English abstract, 35:151-158, 1979.
32. Muller, P. et al., ``Tissue Damage in the Rabbit Oral Mucosa
by Acute and Chronic Direct Toxic Action of Different Alcohol
Concentrations,'' Experimental Pathology, 24:171-181, 1983.
33. Autrup, J. L., C. Hansen, and H. Autrup, ``Detection of
Tobacco Smoke Carcinogen-DNA Adducts in Cultured Rat Buccal Mucosa
Cells Following Exposure to Ethanol and Total Cigarette Smoke
Condensate or Chewing Tobacco,'' Chemico-Biological Interactions,
85:141-150, 1992.
34. Squier, C. A., P. Cox, and B. K. Hall, ``Enhanced
Penetration of Nitrosonornicotine Across Oral Mucosa in the Presence
of Ethanol,'' Journal of Oral Pathology, 15(5):276-279, 1986.
35. Ho, N. F. H., ``Biophysical Kinetic Modeling of Buccal
Absorption,'' Advanced Drug Delivery Reviews, 12:61-97, 1993.
36. Food and Drug Administration, Transcript of the June 6, 1996
Dental Plaque Subcommittee Meeting, OTC. Vol. 210480.
37. Cole, P. et al., ``Alcohol-Containing Mouthwash and
Oropharyngeal Cancer: An Epidemiologic Perspective,'' unpublished
study in OTC Vol. 210476.
38. Thomas, D. B. et al., ``Mouthwash and Oral Cancer: Results
from the L.E.O. Study in Western Washington State,'' submission to
the Dental Plaque Subcommittee, June 6, 1996, unpublished study in
OTC Vol. 210476.
39. Shapiro, S., J. V. Castellana, and J. M. Sprafka, ``Reviews
and Commentary: Alcohol-Containing Mouthwashes and Oropharyngeal
Cancer: A Spurious Association Due to Under Ascertainment of
Confounders?,'' American Journal of Epidemiology, 144(12):1091-1095,
1996.
40. Midanik, L., ``The Validity of Self-Reported Alcohol
Consumption and Alcohol Problems: A Literature Review,'' British
Journal of Addiction, 77:357-382, 1982.
41. Babor, T. F. et al., ``Verbal Report Methods in Clinical
Research on Alcoholism: Response Bias and Its Minimization,''
Journal of Studies on Alcohol, 48:410-424, 1987.
42. Czarnecki, D. M. et al., ``Five-Year Reliability of Self-
Reported Alcohol Consumption,'' Journal of Studies on Alcohol,
51:68-76, 1990.
43. Liu, S. et al., ``Reliability of Alcohol Intake as Recalled
from 10 Years in the Past,'' American Journal of Epidemiology,
143:177-186, 1996.
44. Van de Mheen, P. J., and L. J. Gunning-Schepers, ``Reported
Prevalences of Former Smokers in Survey Data: The Importance of
Differential Mortality and Misclassification,'' American Journal of
Epidemiology, 140:52-57, 1994.
45. Williams, G. M., ``Mechanisms of Alcohol Beverage
Consumption in Oral Cancer Risk: Lack of Relevance to Mouthwash
Use,'' unpublished article in OTC Vol. 210476.
46. Organization of Economic Cooperation and Development,
Guidelines for Testing of Chemicals, ISBN 92-64-12900-6, adopted
February 24, 1987.
47. Food and Drug Administration, ``Toxicological Principles for
the Safety Assessment of Direct Food Additives and Color Additives
in Food,'' Redbook I, 1982.
48. Food and Drug Administration, ``Toxicological Principles for
the Safety Assessment of Direct Food Additives and Color Additives
in Food,'' Redbook II (draft), 1993.
49. Yuen, G. J., ``Altered Pharmacokinetics in the Elderly,''
Clinical Geriatric Medicine, 6:257-267, 1990.
50. Russell, R. M., ``Changes in Gastrointestinal Function
Attributed to Aging,'' The American Journal of Clinical Nutrition,
Supplement 6, 55:1203S-1207S, 1992.
51. Holt, P. R., and J. A. Balint, ``Effects of Aging on
Intestinal Lipid Absorption,'' American Journal of the Physiological
Society, 264:G1-G6, 1993.
52. Atillasoy, E., and P. R. Holt, ``Gastrointestinal
Proliferation and Aging,'' Journal of Gerontology -- Biological
Sciences, 48:B43-B49, 1993.
53. Yamada, H., B. Sacktor, and J. Kinsella, ``Age-Associated
Changes in Ammoniagenesis in Isolated Rat Renal Tubule Segments,''
American Journal of Physiology, 262:F600-F605, 1992.
54. Ahronheim, J. C., Handbook of Prescribing Medications for
Geriatric Patients, Little, Brown and Co., Boston, MA, pp. 1-12,
1992.
55. Draize, J. H., ``Dermal Toxicity,'' in Appraisal of Safety
of Chemicals in Foods, Drugs and Cosmetics, The Association of Food
and Drug Officials of the United States, Austin, TX, pp. 46-59,
1959.
56. Shelanski, H. A., and M. V. Shelanski, ``A New Technique of
Human Patch Tests,'' in Proceedings of Scientific Section, The
Toilet Goods Association, 19:46-49, 1953.
57. Kligman, A. M., ``The Identification of Contact Allergens by
Human Assay; III. The Maximization Test: A Procedure for Screening
and Rating Contact Sensitizers,'' Journal of Investigative
Dermatology, 47:393-409, 1966.
58. The United States Pharmacopeia--23, The National Formulary--
18, United States Pharmacopeial Convention, Inc., Rockville, MD, p.
329, 1995.
59. Scheie, A. A., ``Modes of Action of Currently Known Chemical
Antiplaque Agents Other Than Chlorhexidine,'' Journal of Dental
Research, 68:1609-1616, 1989.
60. Smith, R. N., R. N. Anderson, and P. E. Kolenbrander,
``Inhibition of Intergeneric Coaggregation Among Oral Bacteria by
Cetylpyridinium Chloride, Chlorhexidine Digluconate and Octenidine
Dihydrochloride,'' Journal of Periodontal Research, 26:422-428,
1991.
61. Merianos, J. J., ``Quaternary Ammonium Antimicrobial
Compounds,'' in Disinfection, Sterilization and Preservation, edited
by S. S. Block, 4th ed., Lea & Febiger Co., Philadelphia, PA, pp.
225-255, 1991.
62. OTC Vol. 210421.
63. Nelson, J. W., and S. C. Lyster, ``The Toxicity of Myristyl-
gamma-Picolinium Chloride,'' Journal of the American Pharmaceutical
Association (Science Edition), 35:89-94, 1946.
64. OTC Vol. 210013.
65. ``Chronic Toxicity,'' unpublished studies C.1 and C.2, in
OTC Vol. 210421.
66. Lin, G. H. Y., K. A. Voss, and T. J. Davidson, ``Acute
Inhalation Toxicity of Cetylpyridinium Chloride,'' Food and Chemical
Toxicology, 29:851-854, 1991.
67. Margarone, J. et al., ``The Effects of Alcohol and
Cetylpyridinium Chloride on the Buccal Mucosa of the Hamster,''
Journal of Oral Maxillofacial Surgery, 42:111-113, 1984.
68. Segreto, V. A., ``A Clinical Investigation to Assess the
Effects on Plaque, Gingivitis, and Staining Potential of an
Experimental Mouthrinse--Study 002393,'' unpublished study in OTC
Vol. 210421.
69. Stookey, G. K., ``A Clinical Study Assessing the Safety and
Efficacy of Two Mouthrinses with Differing Concentrations of An
Active Ingredient in Commercially-Available Mouthrinses--Study
005293,'' unpublished study in OTC Vol. 210421.
70. OTC Vol. 210014.
71. Lobene, R. R. et al., ``The Effect of Cetylpyridinium
Chloride on Human Plaque Bacteria and Gingivitis,'' Pharmacology
Therapeutics in Dentistry, 4:33-47, 1979.
[[Page 32278]]
72. Cassidy, J., ``HPT Chlorhexidine Study (CC-105),''
unpublished study in OTC Vol. 210421.
73. OTC Vol. 210015.
74. Ciancio, S. G. et al., ``Clinical Evaluation of a Quaternary
Ammonium-Containing Mouthrinse,'' Journal of Periodontology, 46:397-
401, 1975.
75. Norris, P. E., and B. W. Bollmer, ``Gingivitis Effectiveness
Compared to CPC and a Placebo Mouthrinse (CC-125),'' unpublished
study in OTC Vol. 210421.
76. Sturzenberger, O. P., and B. W. Bollmer, ``Clinical
Evaluation of Concentrations of CPC (CC-121): Four-Month Results,
Terminal Report,'' unpublished report in OTC Vol. 210421.
77. Ciancio, S. G., ``Effect of Cepacol on Gingivitis and
Supragingival Plaque, Study 012-SC-026,'' unpublished study in OTC
Vol. 210015.
78. Lobene, R. R., ``An Evaluation of the Effect of Cepacol
Mouthwash on Gingivitis and Supragingival Plaque, Study 012-RL-
028,'' unpublished study in OTC Vol. 210015.
79. Ackerman, P. B., and J. DiGennaro, ``An Evaluation of the
Effect of Cepacol Mint Mouthwash on Gingivitis and Supragingival
Plaque, Study 012-035 and Study 012-037),'' unpublished studies in
OTC Vol. 210015.
80. Moran, J., and M. Addy, ``The Effects of Cetylpyridinium
Chloride Prebrushing Rinse as an Adjunct to Oral Hygiene and
Gingival Health,'' Journal of Periodontology, 62:562-564, 1991.
81. Hunter, L. et al., ``A Study of a Pre-Brushing Mouthrinse as
an Adjunct to Oral Hygiene,'' Journal of Periodontology, 65(8):762-
765, 1994.
82. Hunter-Rinderle, S. J. et al., ``Evaluation of
Cetylpyridinium Chloride-Containing Mouthwashes Using In Vitro Disk
Retention and Ex Vivo Plaque Glycolysis Methods,'' Journal of
Clinical Dentistry, 8:107-113, 1997.
83. ``Health Effects of Ingested Fluoride Executive Summary,''
in National Research Council Report, pp. 3-11, 15-17, 1994.
84. ``Fluorides and Oral Health Report of World Health
Organization Expert Committee on Oral Health Status and Fluoride
Use,'' in World Health Organization Technical Report Series 846, pp.
26-29, 1994.
85. OTC Vol. 210263.
86. Whitford, G. M., ``Acute Fluoride Toxicity,'' in The
Metabolism and Toxicity of Fluoride, Karger AG, New York, NY, pp.
124-149, 1989.
87. Boyd, R. L. et al., ``Effects on Gingivitis of Two Different
0.4% Stannous Fluoride Gels,'' Journal of Dental Research, 67:503-
507, 1988.
88. Wolff, L. F. et al., ``Effect of Toothbrushing With 0.4%
Stannous Fluoride and 0.22% Sodium Fluoride Gel on Gingivitis for 18
Months,'' Journal of the American Dental Association, 119:283-289,
1989.
89. OTC Vol. 210380.
90. Murray, J. J., and A. J. Rugg-Gunn, ``Fluoride Toothpastes
and Dental Caries, Fluoride Prophylactic Pastes and Dental Caries,
and Topical Fluorides and Dental Caries,'' in Fluorides in Caries
Prevention, 2d ed., Wright-PSG, Boston, MA, pp. 100-153, 1982.
91. OTC Vol. 210380A.
92. Ogaard, B. et al., ``Plaque-Inhibiting Effect in Orthodontic
Patients of a Dentifrice Containing Stannous Fluoride,'' American
Journal of Orthodontics, 78:266-271, 1980.
93. Bay, I., and G. Rolla, ``Plaque Inhibition and Improved
Gingival Condition by Use of a Stannous Fluoride Toothpaste,''
Scandinavian Journal of Dental Research, 88:313-315, 1980.
94. Svatun, B., ``Plaque-Inhibition Effect of Dentifrices
Containing Stannous Fluoride,'' Acta Odontology Scandanavia, 36:205-
210, 1978.
95. Svatun, B. et al., ``A Comparison of the Plaque-Inhibiting
Effect of Stannous Fluoride and Chlorhexidine,'' Acta Odontology
Scandinavia, 35:247-250, 1977.
96. Klock, B. et al., ``Comparison of Effect of SnF2
and NaF Mouthrinses on Caries Incidence, Salivary S. mutans, and
Gingivitis in High Caries Prevalent Adults,'' Scandinavian Journal
of Dental Research, 93:213-217, 1985.
97. Derkson, G. D., and M. M. MacEntee, ``Effect of 0.4%
Stannous Fluoride Gel on the Gingival Health of Overdenture
Abutments,'' Journal of Prosthetic Dentistry, 48:23-26, 1982.
98. Tinanoff, N. et al., ``Clinical and Microbiological Effects
of Daily Brushing with Either NaF or SnF2 Gels in
Subjects with Fixed or Removable Dental Prostheses,'' Journal of
Clinical Periodontology, 16:284-290, 1989.
99. ``Scientific Literature Review of Aliphatic Ethers in Flavor
Usage,'' Vol. 1 (Revised September 1985), in OTC Vol. 210297.
100. ``Scientific Literature Review of Alicyclic Compounds of
Carbon, Hydrogen and Oxygen in Flavor Usage,'' Vol. 1 (Revised
September 1985), in OTC Vol. 210299.
101. ``Scientific Literature Review of Salicylate and
Salicylaldehyde in Flavor Usage,'' Vol. 1 (Revised January 1984), in
OTC Vol. 210298.
102. ``Scientific Literature Review of Phenols in Flavor
Usage,'' Vol. 1 (Revised September 1985), in OTC Vol. 210296.
103. Lamster, I. et al., ``The Effect of Listerine
Antiseptic[reg] on Reduction of Existing Plaque and Gingivitis,''
(Study [numsign]931-0170 in Warner-Lambert Research Report),
Clinical Prevention Dentistry, 5:12-18, 1983.
104. Gordon, J. M., I. B. Lamster, and M. C. Seiger, ``Efficacy
of Listerine Antiseptic in Inhibiting the Development of Plaque and
Gingivitis,'' (Study [numsign]931-342 in Warner-Lambert Research
Report), Journal of Clinical Periodontology, 12:697-704, 1985.
105. DePaola, L. G. et al., ``Chemotherapeutic Inhibition of
Supragingival Dental Plaque and Gingivitis Development,'' (Study
[numsign]931-0647 in Warner-Lambert Research Report), Journal of
Clinical Periodontology, 16:311-315, 1989.
106. ``Oral Irritation/Sensitization Potential of Fresh Burst
Listerine Antiseptic,'' (Study [numsign]931-0977 in Warner-Lambert
Research Report), unpublished study [numsign]931-1089 in OTC Vol.
210458.
107. ``Oral Irritation/Sensitization Potential of an
Experimental Mouthrinse Formulation,'' [Study [numsign]931-1012 in
Warner-Lambert Research Report], unpublished study [numsign]931-1163
in OTC Vol. 210458.
108. ``The Irritation Potential of Listerine Antiseptic in
Xerostomic Subjects,'' (Study [numsign]931-1044 in Warner-Lambert
Research Report),'' unpublished study [numsign]931-1163 in OTC Vol.
210458.
109. Minah, G. E. et al., ``Effects of 6 Months Use of an
Antiseptic Mouthrinse on Supragingival Dental Plaque Microflora,
Journal of Clinical Periodontology,'' 16:347-352, 1989.
110. Walker, C., ``Long-Term Effect of Listerine Antiseptic on
Dental Plaque Microbial Composition,'' (Study [numsign]931-0654 in
Warner-Lambert Research Report), unpublished study in OTC Vol.
210292.
111. OTC Vol. 210291.
112. Lobene, R. R. et al., ``A Modified Gingival Index for Use
in Clinical Trials,'' Clinical Preventative Dentistry, 8:3-6, 1986.
113. Overholzer, C. D. et al., ``Comparative Effects of Two
Chemotherapeutic Mouthrinses on the Development of Supragingival
Dental Plaque and Gingivitis,'' (Study [numsign]931-0730 in Warner-
Lambert Research Report), Journal of Clinical Periodontology,
17:575-579, 1990.
114. Caton, J. G., and A. M. Polson, ``The Interdental Bleeding
Index: A Simplified Procedure for Monitoring Gingival Health,'' The
Compendium of Continuing Education in Dentistry, Article [numsign]1,
88:89-92, 1985.
115. Mankodi, S., ``Efficacy of Listerine and Listerine Plus
Mint in Inhibiting the Development of Dental Plaque and
Gingivitis,'' (Study [numsign]931-780 in Warner-Lambert Research
Report), unpublished study in OTC Vol. 210292.
116. Mankodi, S. et al., ``Comparative Antiplaque/Antigingivitis
Efficacies of Two Antiseptic Mouthrinses,'' (Study [numsign]931-792
in Warner-Lambert Research Report), Abstract [numsign]1099, Journal
of Dental Research, 69:246, 1990.
117. Mankodi, S., ``Efficacy of Cool Mint Listerine and
Listerine Antiseptic Compared to a Hydroalcohol Control in
Inhibiting the Development of Supragingival Dental Plaque and
Gingivitis,'' (Study [numsign]931-0866 in Warner-Lambert Research
Report), unpublished study in OTC Vol. 210391.
118. ``Efficacy of a Reduced Alcohol Listerine Mouthrinse in
Inhibiting the Development of Supragingival Dental Plaque and
Gingivitis When Used as an Adjunct to Usual Oral Hygiene for 6
Months,'' (Study [numsign]931-1176 in Warner-Lambert Research
Report), unpublished study in OTC Vol. 210458.
119. Osborn, J., ``The Choice of Computational Unit in the
Statistical Analysis of Unbalanced Clinical Trials,'' Journal of
Clinical Periodontology, 14:519-523, 1987.
120. Blomqvist, N., ``On the Choice of Computational Unit in
Statistical Analysis,'' Journal of Clinical Periodontology, 12:873-
876, 1985.
121. The United States Pharmacopeia--23, National Formulary--18,
United States Pharmacopeial Convention, Inc., Rockville, MD, pp. 46-
47, 1995.
122. Wren, R. C., Potter's New Cyclopaedia of Botanical Drugs
and Preparations, The C. W. Daniel Co., LTD., Cambridge, England,
pp. 8-9, 1994.
[[Page 32279]]
123. Grieve, M., A Modern Herbal: The Medicinal, Culinary,
Cosmetic and Economic Properties, Cultivation and Folklore of Herbs,
Grasses, Fungi, Shrubs and Trees with All Their Modern Scientific
Uses, Dover Publications, Inc., New York, NY, pp. 26-29, 1982.
124. Fogleman, R. W. et al., ``Toxicologic Evaluation of
Injectable Acemannan in the Mouse, Rat, and Dog,'' Veterinary and
Human Toxicology, 34:201-205, 1992.
125. Schmidt, J. M., and J. S. Greenspoon, ``Aloe Vera Dermal
Wound Gel is Associated With a Delay in Wound Healing,'' Obstetrics
and Gynecology, 78:115-117, 1991.
126. Hunter, D., and A. Frumkin, ``Adverse Reactions to Vitamin
E and Aloe Vera Preparations After Dermabrasion and Chemical Peel,''
Cutis, 47:193-196, 1991.
127. Davis, R. H. et al., ``Aloe Vera, Hydrocortisone, and
Sterol Influence on Wound Tensile Strength and Anti-Inflammation,''
Journal of the American Podiatric Medical Association, 84:614-621,
1994.
128. OTC Vols. 210084, 210084A and 210084B.
129. OTC Vol. 210081.
130. The United States Pharmacopeia--23, The National
Formulary--18, United States Pharmacopeial Convention, Inc.,
Rockville, MD, p. 767, 1995.
131. ``Hydrogen Peroxide: Use or Abuse,'' Approved by the
Executive Council of the American Academy of Periodontology, pp. 1-
2, October 1988.
132. Marshall, M. V., L. P. Cancro, and S. L. Fischman,
``Hydrogen Peroxide: A Review of Its Use in Dentistry,'' Journal of
Periodontology, 66:786-796, 1995.
133. Romanowski, A., J. R. Murray, and M. J. Huston, ``Effects
of Hydrogen Peroxide on Normal and Hypertensive Rats,''
Pharmaceutica Acta Helvetiae, 35:354-357, 1960.
134. Hankin, L., ``Hydrogen Peroxide Ingestion and the Growth of
Rats,'' Nature, 4647:1453, 1958.
135. Giusti, G. V., ``Case Report: Fatal Poisoning with Hydrogen
Peroxide,'' Forensic Science, 2:99-100, 1973.
136. Humbertson, C. L., B. S. Dean, and E. P. Krenzelok,
``Ingestion of 35% Hydrogen Peroxide,'' Journal of Toxicology--
Clinical Toxicology, 28:95-100, 1990.
137. Dickson, K. F., and E. M. Caravati, ``Hydrogen Peroxide
Exposure: 325 Exposures Reported to a Regional Poison Control
Center,'' Journal of Toxicology--Clinical Toxicology, 32:705-714,
1994.
138. Henry, M. C. et al., ``Hydrogen Peroxide 3% Exposures,''
Journal of Toxicology--Clinical Toxicology, 34:323-327, 1996.
139. Rackoff, W. R., and D. F. Merton, ``Gas Embolism After
Ingestion of Hydrogen Peroxide,'' Pediatrics, 85:593-594, 1990.
140. Ito, R. et al., ``Safety Study of Hydrogen Peroxide on
Acute and Subacute Toxicity,'' English abstract, Journal of The
Medical Society of Toho University, 23(5-6):531-537, 1976.
141. OTC Vol. 210326.
142. Korhonen, A., K. Hemminki, and H. Vainin, ``Embryotoxic
Effects of Eight Organic Peroxides and Hydrogen Peroxide on Three-
Day Chicken Embryos,'' Environmental Research, 33:54-61, 1984.
143. Ludwig, R., ``Intra-Oral Use of Hydrogen Peroxide,''
Zeitschrift fur die Gesamte Experimentelle Medizin, 131:452-465,
1959.
144. Ludwig, R., ``Distribution of Skin Hydroperoxidase and
Trans-epidermal Penetration of Hydrogen Peroxide Following its
Epicutaneous Application,'' English abstract, p. 312, Acta
Histochem, 19:303-315, 1964.
145. Marshall, M. W., and P. P. Gragg, ``The Effect of Fluoride
Salts on Hydrogen Peroxide Decomposition in the Oral Cavity,'' AADR
Abstracts, Abstract [numsign]301, Journal of Dental Research,
77:143, 1998.
146. Gaengler, P., ``The Response of the Pulp-Dentine System to
Drugs,'' English abstract, p. 330, Stomatology, DDR, 26(5):327-330,
1976.
147. Herrin, J. R., C. A. Squier, and W. C. Rubright,
``Development of Erosive Gingival Lesions After Use of a Home Care
Technique,'' Journal of Periodontology, 58:785-788, 1987.
148. Rees, T., and C. F. Orth, ``Oral Ulcerations with Use of
Hydrogen Peroxide,'' Journal of Periodontology, 57:689-692, 1986.
149. Shapiro, M., V. Brat, and B. H. Ershoff, ``Induction of
Dental Caries and Pathological Changes in Periodontium of Rat with
Hydrogen Peroxide and Other Oxidizing Agents,'' Journal of Dental
Research, 39:332-343, 1960.
150. Sasaki, M. et al., ``Cytogenetic Effects of 60 Chemicals on
Cultured Human and Chinese Hamster Cells,'' La Kromosomo II, 20:574-
584, 1980.
151. Schmidt, F., ``Experiments on the Carcinogenic Effect of
Hydrogen Peroxide and on the Mechanism of Ray Cancerogenesis,''
English abstract, p. 84, Acta Biological Medicine of Germany, 13:74-
85, 1964.
152. Simon, R. H., C. H. Scoggin, and D. Patterson, ``Hydrogen
Peroxide Causes the Fatal Injury to Human Fibroblasts Exposed to
Oxygen Radicals,'' Journal of Biological Chemistry, 256:7181-7186,
1981.
153. ``The ECETOC [European Centre for Ecotoxicology and
Toxicology of Chemicals]: Joint Assessment of Commodity Chemicals
No. 22: Hydrogen Peroxide,'' CAS No. 7722-84-1, 141, January 1993.
154. ``The ECETOC [European Centre for Ecotoxicology and
Toxicology of Chemicals]: Special Report No. 10: Hydrogen Peroxide
OEL Criteria Document,'' CAS No. 7722-84-1, 1996.
155. Food and Drug Administration, ``Hydrogen Peroxide: An
Overview on Genotoxicity of Hydrogen Peroxide,'' Transcript of the
Advisory Dental Plaque Subcommittee Meeting, December 4, 1995.
156. Pryor, W. A., ``Oxy-Radicals and Related Species: Their
Formation, Lifetimes, and Reactions,'' Annual Review of Physiology,
48:657-667, 1986.
157. MacRae, W. D., and H. F. Stich, ``Induction of Sister-
Chromatid Exchanges in Chinese Hamster Ovary Cells by Thiol and
Hydrazine Compounds,'' Mutation Research, 68:351-365, 1979.
158. Taylor, W. G. et al., ``Type-Specific Cell Killing and DNA
Strand Breaks After Exposure to Visible Light or Hydrogen
Peroxide,'' abstract, Journal of Cell Biology, 83:111a, 1979.
159. Gutteridge, J. M. C., ``Biological Origin of Free Radicals
and Mechanisms of Antioxidant Protection,'' Chemico-Biological
Interactions, 91:133-140, 1994.
160. Thacker, J., ``Radiomimetic Effects of Hydrogen Peroxide in
the Inactivation and Mutation of Yeast,'' Radiation Research,
68(2):371-380, 1976.
161. Hoffman, M. E., and R. Meneghini, ``Action of Hydrogen
Peroxide on Human Fibroblast in Culture,'' Photochemistry and
Photobiology, 30:151-155, 1979.
162. Lesko, S. A., R. J. Lorentzen, and P. O. Ts'o, ``Role of
Superoxide in Deoxyribonucleic Acid Strand Scission,'' Biochemistry,
19:3023-3028, 1980.
163. Levin, D. E. et al., ``A New Salmonella Tester Strain
(TA102) with A-T Base Pairs at the Site of Mutation Detects
Oxidative Mutagens,'' Proceedings of the National Academy of
Science, USA, 79:7445-7449, 1982.
164. Hamelin, C., L. Poliquin, and Y. S. Chung, ``Mutagenicity
of Ozone Relative to Other Chemical and Physical Agents in
Escherichia coli K12,'' Review of Canadian Biology, 40:305-307,
1981.
165. Hanham, A. F., B. P. Dunn, and H. F. Stich, ``Clastogenic
Activity of Caffeic Acid and Its Relationship to Hydrogen Peroxide
Generated During Auto-Oxidation,'' Mutation Research, 116:333-339,
1983.
166. Freese, E. B. et al., ``Inactivating DNA Alterations
Induced by Peroxide and Peroxide-Producing Agents,'' Mutation
Research, 4:517-531, 1967.
167. Thacker, J., and W. F. Parker, ``The Induction of Mutation
in Yeast by Hydrogen Peroxide,'' Mutation Research, 38:43-52, 1976.
168. Ames, B. N., M. C. Hollstein, and R. Cathcart, ``Lipid
Peroxidation and Oxidative Damage to DNA: Lipid Peroxides'' in
Biology and Medicine, Academic Press, Inc., New York, NY, pp. 339-
351, 1982.
169. Carlsson, J., ``Salivary Peroxidase: An Important Part of
Our Defense Against Oxygen Toxicity,'' Journal of Oral Pathology,
16:412-416, 1987.
170. Li, Y. et al., ``Effect of Long-Term Exposure to a Tooth
Whitener,'' Abstract [numsign]1162, Journal of Dental Research,
72:248, 1993.
171. Li, Y. et al., ``Safety Evaluation of Opalescence Sustained
Release Whitening Gel,'' Abstract [numsign]3304, Journal of Dental
Research, 75:430, 1996.
172. Adam-Rodwell, G. et al., ``Safety Profile of Colgate
Platinum Professional Tooth Whitening System,'' The Compendium of
Continuing Education in Dentistry, Supplement 17:S622-S630, 1994.
173. Woolverton, C. J., V. B. Haywood, and H. O. Heymann,
``Toxicity of Two Carbamide Peroxide Products Used in Nightguard
Vital Bleaching,'' American Journal of Dentistry, 6:310-314, 1993.
174. Regnier, J. F. et al., ``Micronucleus Tests in Mice with
Hydrogen Peroxide,'' Abstract [numsign]193, Fundamental and Applied
Toxicology, 30:233, 1996.
175. Bentley, K. S. et al., ``Evaluation of Micronuclei in Mouse
Bone Marrow
[[Page 32280]]
Following Administration of Hydrogen Peroxide
(H2O2) in Drinking Water or by Intraperitoneal
Injection,'' Environmental and Molecular Mutagenesis, EMS Abstracts,
Supplement 27:7, 1996.
176. Hirota, N., and T. Yokoyama, ``Enhancing Effect of Hydrogen
Peroxide Upon Duodenal and Upper Jejunal Carcinogenesis in Rats,''
Gann, 72(5):811-812, 1981.
177. Ito, A. et al., ``Induction of Duodenal Tumors in Mice by
Oral Administration of Hydrogen Peroxide,'' Gann, 72:174-175, 1981.
178. Ito, A. et al., ``Induction and Characterization of Gastro-
Duodenal Lesions in Mice Given Continuous Oral Administration of
Hydrogen Peroxide,'' Gann, 73(2):315-322, 1982.
179. Ito, A. et al., ``Correlation Between Induction of Duodenal
Tumor by Hydrogen Peroxide and Catalase Activity in Mice,'' Gann,
75(1):17-21, 1984.
180. ``Hydrogen Peroxide in Allyl Compounds, Aldehyes, Epoxides,
and Peroxides,'' in IARC Monographs on the Evaluation of
Carcinogenic Risks of Chemicals to Humans, Vol. 36, pp. 85-314,
1985.
181. ``Alcohol Drinking,'' in IARC Monographs on the Evaluation
of Carcinogenic Risks of Chemicals to Humans, Vol. 44, pp. 101-151,
251-261, 1988.
182. Food and Drug Administration, Takayama, S., ``The Toxicity
and Carcinogenic Potential of H2O2,'' in
Japanese National Institute of Health Sciences Report JCT 77-02, p.
121, Transcript of the December 1995 Dental Plaque Subcommittee
Meeting, OTC Vol. 210479.
183. Weitzman, S. A. et al., ``Effects of Hydrogen Peroxide on
Oral Carcinogenesis in Hamsters,'' Journal of Periodontology,
57(11):685-688, 1985.
184. Marshall, M. V. et al., ``Hamster Cheek Pouch Bioassay of
Dentifrices Containing Hydrogen Peroxide and Baking Soda,'' Journal
of the American College of Toxicology, 15:45-61, 1996.
185. Carlsson, J., and V. Carpenter, ``The RecA+ Gene Product is
More Important Than Catalase and Superoxide Dismutase in Protecting
Escherichia coli Against Hydrogen Peroxide Toxicity,'' Journal of
Bacteriology, 142:319-321, 1980.
186. Oya, Y., K. Yamamoto, and A. Tonomura, ``The Biological
Activity of Hydrogen Peroxide: I. Induction of Chromosome-Type
Aberrations Susceptible to Inhibition by Scavengers of Hydroxyl
Radicals in Human Embryonic Fibroblasts,'' Mutation Research,
172:245-253, 1986.
187. Higgins, C. P. et al., ``Polymorphonuclear Leukocyte
Species Differences in the Disposal of Hydrogen Peroxide
(H2O2),'' Proceedings of the Society of
Experimental Biology And Medicine, 158:478-481, 1978.
188. Marshall, M. V., L. P. Cancro, and R. A. Floyd, ``Lack of
Mutagenicity and Free Radical Inhibition by a
H2O2-Containing Dentifrice,'' Abstract
[numsign]506, Journal of Dental Research, 73:168, 1994.
189. Marshall, M. V., R. A. Floyd, and L. P. Cancro, ``Hydrogen
Peroxide-Mediated Free Radical Formation,'' Abstract [numsign]383,
The Toxicologist, 13:119, 1993.
190. Marshall, M. V., L. P. Cancro, and R. A. Floyd,
``Inhibition of Hydroxyl Free Radical Formation by H2O2-Containing
Dentifrice,'' Abstract 602, The Toxicologist, 14:168, 1994.
191. Food and Drug Administration, Transcript of the December
17, 1996 Advisory Dental Plaque Subcommittee Meeting, pp. 13-20, OTC
Vol. 210481.
192. Thomas, E. L., K. P. Bates, and M. M. Jefferson,
``Hypothiocyanite Ion: Detection of the Antimicrobial Agent in Human
Saliva,'' Journal of Dental Research, 59(9):1466-1472, 1980.
193. Thomas, E. L., K. P. Bates, and M. M. Jefferson,
``Peroxidase Antimicrobial System of Human Saliva: Requirements for
Accumulation of Hypothiocynanite,'' Journal of Dental Research,
60(4):785-796, 1981.
194. Thomas, E. L. et al., ``Inhibition of Streptococcus mutans
by the Lactoperoxidase Antimicrobial System,'' Infection and
Immunity, 39(2):767-778, 1983.
195. Pruitt, K. M. et al., ``Limiting Factors for the Generation
of Hypothiocyanite Ion, an Antimicrobial Agent, in Human Saliva,''
Caries Research, 16:315-323, 1982.
196. Mansson-Rahemtulla, B. et al., ``A Mouthrinse which
Optimizes In Vivo Generation of Hypothiocyanite,'' Journal of Dental
Research, 62(10):1062-1066, 1983.
197. Wennstrom, J., and J. Lindhe, ``Effect of Hydrogen Peroxide
on Developing Plaque and Gingivitis in Man,'' Journal of Clinical
Periodontology, 6:115-130, 1979.
198. Gomes, B. C., M. L. Shakun, and L. W. Ripa, ``Effect of
Rinsing with a 1.5% Hydrogen Peroxide Solution (Peroxyl[reg]) on
Gingivitis and Plaque in Handicapped and Nonhandicapped Subjects,''
Clinical Preventive Dentistry, 6(3):21-25, 1984.
199. Firestone, A. R., R. Schmid, and H. F. Muhlemann, ``Effect
of Topical Application of Urea Peroxide on Caries Incidence and
Plaque Accumulation in Rats,'' Caries Research, 16:112-117, 1982.
200. Reddy, J., and L. M. Salkin, ``The Effect of a Urea
Peroxide Rinse on Dental Plaque and Gingivitis,'' Journal of
Periodontology, 47(10):607-10, 1976.
201. Zinner, D. D., L. F. Duany, and M. Llorente, ``Effects of
Urea Peroxide in Anhydrous Glycerol on Gingivitis and Dental
Plaque,'' Journal of Preventive Dentistry, 5(1):38-40, 1978.
202. Gusberti, F. A. et al., ``Microbiological and Clinical
Effects of Chlorhexidine Digluconate and Hydrogen Peroxide
Mouthrinses on Developing Plaque and Gingivitis,'' Journal of
Clinical Periodontology, 15:60-67, 1988.
203. Jones, C. M., A. S. Blinkhorn, and E. White, ``Hydrogen
Peroxide: The Effect on Plaque and Gingivitis When Used in an Oral
Irrigator,'' Clinical Preventive Dentistry, 12:15-18, 1990.
204. Kaslick, R. S., W. B. Shapiro, and A. I. Chasens, ``Studies
on the Effects of a Urea Peroxide Gel on Plaque Formation and
Gingivitis,'' Journal of Periodontology, 46:230-232, 1975.
205. Shapiro, W. et al., ``The Influence of Urea Peroxide Gel on
Plaque, Calculus, and Chronic Gingival Inflammation,'' Journal of
Periodontology, 44:636-639, 1973.
206. Boyd, R. L., ``Effects on Gingivitis of Daily Rinsing with
1.5% H2O2,'' Journal of Clinical
Periodontology, 16(9):557-562, 1989.
207. Clark, W. B. et al, ``Efficacy of Perimed[reg]
Antibacterial System on Established Gingivitis: 1. Clinical
Results,'' Journal of Clinical Periodontology, 16:630-635, 1989.
208. Gangler, von P., and W. Staab, ``Klinisch Kontrollierte
Zweijahresstudie zur Plaquekontrolle mit Chlorhexidindiglukonat und
Wasserstoffperoxid bei Periodontitis Marginalis,'' English abstract,
Zahn, Mund und Kieferheilkunde Mit Zentralblatt, 73(3):253-261,
1985.
209. Tyler, V. E., L. R. Brady, and J. E. Robbers,
Pharmacognosy, 9th ed., Lea & Febiger, Philadelphia, PA, p. 212,
1988.
210. National Formulary, 11th ed., American Pharmaceutical
Association, Washington, DC, p. 319, 1960.
211. ``Introduction to the Homeopathic Pharmacopeia of the
United States,'' Revision Service and HPUS Abstracts, abstract, in
Homeopathic Pharmacopeia Convention of the United States,
Washington, DC, 1993.
212. ``Acute Oral LD50 Assay in Rats,'' unpublished
study VS-14 in OTC Vol. 210303.
213. ``Four-Week Exploratory Dietary Toxicity Study in Rats,''
unpublished study VS-139 in OTC Vol. 210304.
214. ``Thirteen-Week Oral Toxicity Study in Rats,'' unpublished
study VS-93 in OTC Vol. 210304.
215. ``Four-Week Oral Gavage Study in Monkeys,'' unpublished
study VS-141 in OTC Vol. 210304.
216. ``Thirteen-Week Oral Toxicity Study in Cynomolgus
Monkeys,'' unpublished study VS-143 in OTC Vol. 210306.
217. ``Fourteen-day Feeding Study in Rats,'' unpublished study
VS-07 in OTC Vol. 210305.
218. ``Thirty-day Oral Gavage Study in Rats,'' unpublished study
VS-62 in OTC Vol. 210305.
219. Lin, Y. et al, ``Investigation of Benz Acridine Formation
From Sanguinarine and Sanguinaria Extract,'' unpublished study VPTS-
59 in OTC Vol. 210308.
220. ``Biological Disposition of \14\C-Labeled Sanguinarine in
Rats,'' unpublished study VS-122 (558-016) in OTC Vol. 210308.
221. ``Biological Disposition of \14\C-Labeled Sanguinarine in
Mice,'' unpublished study VRTS-29(558-027) in OTC Vol. 210308.
222. ``Cardiovascular Study in Dogs,'' unpublished study VS-87
in OTC Vol. 210308.
223. ``Fertility and Reproductive Performance in Rats,''
unpublished study VS-120 in OTC Vol. 210309.
224. ``Range-Finding Developmental Toxicity Study in Rabbits,''
unpublished study VS-135 in OTC Vol. 210309.
225. ``Developmental Toxicity in Rats,'' unpublished study VS-
137 in OTC Vol. 210309.
226. ``Developmental Toxicity in Rabbits,'' unpublished study
VS-136 in OTC Vol. 210309.
227. ``Perinatal and Postnatal Effects of Sanguinaria Extract in
Rats,'' unpublished study VS-138 in OTC Vol. 210309.
228. ``Salmonella/Mammalian-Microsome Plate Incorporation
Mutagenicity Assay
[[Page 32281]]
(Ames Test), and Escherichia coli WP2uvr Reverse Mutation Assay,''
unpublished study VS-97a in OTC Vol. 210310.
229. ``Salmonella/Mammalian-Microsome Plate Incorporation
Mutagenicity Assay (Ames Test), and Escherichia coli WP2uvr Reverse
Mutation Assay,'' unpublished study VS-97b in OTC Vol. 210310.
230. Curren, R. D., ``Unscheduled DNA Synthesis in Rat Primary
Hepatocytes,'' unpublished study VS-110 in OTC Vol. 210310.
231. Putnam, D. L., ``Micronucleus Cytogenic Assay in Mice,''
unpublished study VS-106 in OTC Vol. 210310.
232. ``Ames Test for Mutagenic Metabolites in Rat Urine,''
unpublished study VS-101 in OTC Vol. 210310.
233. ``Ames Test,'' unpublished study VS-00 in OTC Vol. 210310.
234. ``CHO/HGPRT Mammalian Cell Forward Gene Mutation Assay,''
unpublished study VS-72 in OTC Vol. 210310.
235. ``Rat Hepatocyte Primary Culture/DNA Repair Test,''
unpublished study VS-84 in OTC Vol. 210310.
236. ``Two-Year Oral Oncogenicity Study in Rats,'' unpublished
study VS-108 in OTC Vol. 210311.
237. ``Two-Year Oral Dietary Toxicity and Oncogenicity Study in
Rats,'' unpublished study VS-142 in OTC Vol. 210311.
238. Lord, G., E. I. Goldenthal, and D. L. Meyer, ``Sanguinarine
and the Controversy Concerning its Relationship to Glaucoma in
Epidemic Dropsy,'' Journal of Clinical Dentistry, 1(4):110-115,
1989.
239. ``Acute Oral Toxicity in Rats,'' unpublished study VS-10 in
OTC Vol. 210312.
240. ``Acute Oral Toxicity Study in Rats,'' unpublished study
VS-81a in OTC Vol. 210312.
241. ``Acute Oral Toxicity Study in Rats,'' unpublished study
VS-61 in OTC Vol. 210312.
242. ``Primary Dermal Irritation Study in Rabbits,'' unpublished
study VS-65 in OTC Vol. 210312.
243. ``Primary Eye Irritation Study in Rabbits,'' unpublished
study VS-51 in OTC Vol. 210312.
244. ``Mucous Membrane Irritancy Assay: Hamster Cheek Pouch
Method,'' unpublished study VS-09 in OTC Vol. 210312.
245. ``Mucous Membrane Irritancy Study of a Dentifrice (Hamster
Cheek Pouch Method),'' unpublished study VS-23 in OTC Vol. 210312.
246. ``Mucous Membrane Irritancy Study of a Dentifrice (Hamster
Cheek Pouch Method),'' unpublished study VS-31 in OTC Vol. 210312.
247. ``Mucous Membrane Irritancy Study of Viadent 1500
Formulation (Hamster Cheek Pouch Method),'' unpublished study VS-33
in OTC Vol. 210312.
248. ``Twenty-One Day Mucous Membrane Irritancy Assay: Hamster
Cheek Pouch Method,'' unpublished study VS-50 in OTC Vol. 210312.
249. ``Acute Oral Toxicity Study in Rats,'' unpublished study
VS-95a in OTC Vol. 210313.
250. ``Mucous Membrane Irritancy Assay of a Formula and
Dentifrice (Hamster Cheek Pouch Method),'' unpublished study VS-95
in OTC Vol. 210313.
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-
81b, VS-112, and VS-131 in OTC Vol. 210313.
252. ``Mucous Membrane Irritancy Study of Oral Rinse,''
unpublished study VS-39 in OTC Vol. 210313.
253. ``Mucous Membrane Irritancy Assay: Hamster Cheek Pouch
Method,'' unpublished study VS-09 in OTC Vol. 210313.
254. ``Allergenicity Potential Study,'' unpublished study VS-53
in OTC Vol. 210313.
255. ``Acute Oral Toxicity in Rats,'' unpublished study VS-11 in
OTC Vol. 210313.
256. ``Repeated Insult Patch Test,'' unpublished study VS-13 in
OTC Vol. 210314.
257. ``Repeated Insult Patch Test,'' unpublished study VS-60b in
OTC Vol. 210314.
258. ``Repeated Insult Patch Test,'' unpublished study VS-82b in
OTC Vol. 210314.
259. ``Repeated Insult Patch Test,'' unpublished study VS-66 in
OTC Vol. 210314.
260. ``Irritation and Sensitization Potential of Exaggerated Use
of Product,'' unpublished study VS-17 in OTC Vol. 210314.
261. ``Six-Month Safety/Efficacy Study,'' unpublished study VS-
42 in OTC Vol. 210318.
262. ``Six-Month Safety/Efficacy Study,'' unpublished study VS-
56 in OTC Vol. 210314.
263. ``Six-Month Efficacy/Safety Study,'' unpublished study VS-
100 in OTC Vol. 210314.
264. ``Short-Term Evaluation of Dentifrice Efficacy In Vivo:
Evaluation of Four Different Slurry Formulations,'' unpublished
study RS-78 in OTC Vol. 210314.
265. Patel, A. R., ``The Effects of Chlorhexidine and
Sanguinarine on Gingivitis and Plaque in Orthodontic Patients,''
unpublished study CS-52 in OTC Vol. 210314.
266. ``Repeated Insult Patch Test,'' unpublished study VS-60a in
OTC Vol. 210314.
267. ``Repeated Insult Patch Test,'' unpublished study VS-82a in
OTC Vol. 210314.
268. ``Repeated Insult Patch Test,'' unpublished study VS-73 in
OTC Vol. 210314.
269. ``The Long-Term Safety and Efficacy Evaluation of an Oral
Rinse Containing Sanguinarine Chloride,'' unpublished study VS-41 in
OTC Vol. 210314.
270. ``The Long-Term Safety and Efficacy Evaluation of an Oral
Rinse Containing Sanguinarine Chloride,'' unpublished study VS-55 in
OTC Vol. 210314.
271. Lobene, R. R. et al., ``The Effects of a Sanguinaria
Dentifrice on Plaque and Gingivitis,'' Compendium Continuing
Education Dentistry, Supplement 7:S185-S188, 1986.
272. ``Short-Term Evaluation of Toothpastes In Vivo Exaggerated
Use Study,'' unpublished study RS-67 in OTC Vol. 210318.
273. ``The Effect of Dentifrice Formulations on Plaque and
Gingivitis in School Children,'' unpublished study VS-123 in OTC
Vol. 210318.
274. Klewansky, P., and D. Roth, ``Sanguinaria in the Control of
Bleeding in Periodontal Patients,'' Compendium Continuing Education
Dentistry, Supplement 7:S218-S220, 1986.
275. ``Short-Term Evaluation of Oral Hygiene Regimens In Vivo
Exaggerated Use Study,'' unpublished study RS-64 in OTC Vol. 210319.
276. Palcanis, K. G. et al., ``Longitudinal Evaluation of the
Effect of Sanguinarine on Plaque and Gingivitis,'' General
Dentistry, January-February:17-19, 1990.
277. A collection of 26 submitted studies in OTC Vols. 210300 to
210322.
278. ``Efficacy of Four Mouthrinses in Reducing Existing Plaque
and Inhibiting Further Plaque Growth,'' unpublished study VS-25 in
OTC Vol. 210320.
279. ``The Long-Term Safety and Efficacy Evaluation of An Oral
Rinse Containing Sanguinarine Chloride,'' unpublished study VS-41 in
OTC Vol. 210320.
280. ``The Long-Term (6-Months) Safety and Efficacy Evaluation
of An Oral Rinse Containing Sanguinarine Chloride,'' unpublished
study VS-55 in OTC Vol. 210320.
281. ``Sanguinarine and the Control of Plaque in Dental
Practice,'' unpublished study VS-43 in OTC Vol. 210318.
282. ``Short-Term Evaluation of Oral Rinses In Vivo: Effects of
Sanguinaria Concentration,'' unpublished study RS-43 in OTC Vol.
210320.
283. ``Short-Term Evaluation of Oral Rinses In Vivo: Effects of
Toothbrushing on Oral Rinse Efficacy,'' unpublished study RS-44 in
OTC Vol. 210320.
284. ``Short-Term Evaluation of Oral Rinse In Vivo Exaggerated
Use Study,'' unpublished study CS-51 in OTC Vol. 210319.
285. ``Short-Term Evaluation of Oral Rinse In Vivo Evaluation of
Zinc Chloride in the Oral Rinse Formula,'' unpublished study RS-77
in OTC Vol. 210319.
286. ``Short-Term Evaluation of Oral Rinse In Vivo Exaggerated
Use Study; Evaluation of Dose,'' unpublished study RS-66 in OTC Vol.
210319.
287. Southard, G. L. et al., ``The Relationship of Sanguinaria
Extract Concentration and Zinc Ion to Plaque and Gingivitis,''
Journal of Clinical Periodontology, 14:315-319, 1987.
288. ``Microbial Evaluation of Plaque,'' unpublished study RS-56
in OTC Vol. 210319.
289. ``Short-Term Evaluation of Oral Hygiene Regimens In Vivo
Exaggerated Use Study,'' unpublished study RS-63 in OTC Vol. 210319.
290. Greenfield, W., and S. J. Cuchel, ``The Use of an Oral
Rinse and Dentifrice as a System for Reducing Dental Plaque,''
Compendium Continuing Education Dentistry, Supplement 5:S82-S86,
1984.
291. Nygaard-Oestby, P., and I. Persson, ``Evaluation of
Sanguinarine Chloride in the
[[Page 32282]]
Control of Plaque in the Dental Practice,'' Compendium Continuing
Education Dentistry, Supplement 5:S90-S93, 1984.
292. Miller, R. A., J. E. McIver, and J. C. Gunsolley, ``The
Effects of Sanguinaria Extract on Plaque Retention and Gingival
Health,'' Journal of Clinical Orthodontics, 22(5):304-307, 1988.
293. Palcanis, K. G. et al., ``Longitudinal Evaluation of
Sanguinaria: Clinical and Microbiological Studies,'' Compendium
Continuing Education Dentistry, Supplement 7:S179-S184, 1986.
294. Hannah, J. J., J. D. Johnson, and M. M. Kuftinee, ``Long-
Term Clinical Evaluation of Toothpaste and Oral Rinse Containing
Sanguinaria Extract in Controlling Plaque, Gingival Inflammation,
and Sulcular Bleeding During Orthodontic Treatment,'' American
Journal of Orthodontics and Dentofacial Orthopedics, 96(3):199-207,
1989.
295. Harper, D. S. et al., ``Effect of 6 Months Use of a
Dentifrice and Oral Rinse Containing Sanguinaria Extract and Zinc
Chloride Upon the Microflora of the Dental Plaque and Oral Soft
Tissues,'' Journal of Periodontology, 61(6):359-363, 1990.
296. Kopczyk, R. A. et al., ``Clinical and Microbiological
Effects of a Sanguinaria-Containing Mouthrinse and Dentifrice With
and Without Fluoride During 6 Months of Use,'' Journal of
Periodontology, 62(10):617-622, 1991.
297. ``Minimum Inhibitory Concentration Testing of
Sanguinarine,'' unpublished study VPMS-01 in OTC Vol. 210321.
298. ``Fluoride Bioavailability, Enhanced Remineralization and
Demineralization Reduction Study,'' unpublished study VPTS-56a in
OTC Vol. 210321.
299. ``In Vivo Evaluation of Fluoride Uptake by Bovine Enamel
from Sanguinaria Dentifrice,'' unpublished study CS-54 in OTC Vol.
210321.
300. Puczynski, M. S., D. G. Cunningham, and J. C. Mortimer,
``Clinical Observations: Sodium Intoxication Caused by Use of Baking
Soda as a Home Remedy,'' Canadian Medical Association Journal,
128(7):821-822, 1983.
301. Mishra, S. K., U. K. Sharma, and N. P. Singh, ``Biochemical
Observations in Poultry Fed Diets Containing Sodium Bicarbonate,''
Indian Journal of Poultry Science, 16:201-205, 1981.
302. Robertson, W. O., ``Baking Soda (NaHC03)
Poisoning,'' Veterinary/Human Toxicology, 30:(2):164-165, 1988.
303. Newburn, E., C. I. Hoover, and M. I. Ryder, ``Bactericidal
Action of Bicarbonate Ion on Selected Periodontal Pathogenic
Microorganisms,'' Journal of Periodontology, 55:658-667, 1984.
304. Pollock, J. J. et al., ``Synergism of Lysozyme, Proteases
and Inorganic Monovalent Anions in the Bacteriolysis of Oral
Streptococcus mutans GS5,'' Archives of Oral Biology, 28(9):865-871,
1983.
305. Firestone, A. R., R. Schmid, and H. R. Muhlemann, ``Effect
of Topical Application of Urea Peroxide on Caries Incidence and
Plaque Accumulation in Rats,'' Caries Research, 16(2):112-117, 1982.
306. Goldberg, H. J. V., and K. Enslein, ``Effects of An
Experimental Sodium Bicarbonate Dentifrice on Gingivitis and Plaque
Formation: I. In Adults,'' Clinical Preventive Dentistry, 1(5):12-
16, 1979.
307. Winer, R. A., and A. Tsamtsouris, ``Effects of an
Experimental Sodium Bicarbonate Dentifrice on Gingivitis and Plaque
Formation: II. In Teenaged Students,'' Clinical Preventive
Dentistry, 1(5):17-18, 1979.
308. ``Final Report of the Safety Assessment for Sodium Lauryl
Sulfate and Ammonium Lauryl Sulfate,'' in Cosmetic Ingredient
Review, May 19, 1983, The Cosmetic, Toiletry, and Fragrance
Association, Inc., Washington, DC, pp. 1-59, 1983.
309. Pader, M., ``Surfactants in Oral Hygiene Products,'' in
Surfactant in Cosmetics, edited by M. M. Rieger, Marcel Dekker,
Inc., New York, NY, pp. 293-347, 1985.
310. OTC Vol. 210010.
311. OTC Vols. 210009 to 210012.
312. Howes, D., ``The Percutaneous Absorption of Some Anionic
Surfactants,'' Journal of the Society of Cosmetic Chemistry, 26:47-
63, 1975.
313. Howes, D. et al., ``Absorption Metabolism and Excretion of
Alternative Surfactants: Part 6. The Percutaneous Absorption and
Metabolic Fate in the Rat of Sodium Dodecyl (Lauryl) Sulphate and
Sodium Pentadecyl Sulphate,'' unpublished study in OTC Vol. 210011.
314. Black, J. G., and D. Howes, ``Chap. 2 Absorption,
Metabolism, and Excretion of Anionic Surfactants,'' in Anionic
Surfactants, edited by C. Gloxhuber, Marcel Dekker, Inc., New York,
NY, pp. 50-85, 1980.
315. Olson, K. J. et al., ``Toxicological Properties of Several
Commercially Available Surfactants,'' Journal of The Society of
Cosmetic Chemists, 32:469-476, 1962.
316. Walker, A. I. T. et al., ``Toxicity of Sodium Lauryl
Sulphate, Sodium Lauryl Ethoxysulphate and Corresponding Surfactants
Derived from Synthetic Alcohols,'' Food and Cosmetic Toxicology,
5:763-769, 1967.
317. Miura, Y., ``Effects of In Vivo Administration of
Detergents on the Hepatic Microsomal Cytochrome P-450 System in
Rats,'' Journal of Applied Toxicology, 7(3):213-217, 1987.
318. Ariyoshi, H. et al., ``Profile of Hemoproteins and Heme-
Metabolizing Enzymes in Rats Treated with Surfactants,'' Bulletin of
Environmental Contamination and Toxicology, 44:369-376, 1990.
319. Munday, R., ``Feeding Studies of Sodium Lauryl Sulphate
(13-week Test in Rats),'' unpublished study in OTC Vol. 210012.
320. Fitzhugh, O. G., and A. A. Nelson, ``Chronic Oral
Toxicities of Surface-Active Agents,'' Journal of the American
Pharmaceutical Association, 9:29-32, 1947.
321. Little, A. D., ``Alkyl Sulfates Human,'' in Human Safety
and Environmental Aspects of Major Surfactants: A Report to the Soap
and Detergent Association, May 31, 1977, Arthur D. Little, Inc.,
Cambridge, MA, pp. 165-232, 1977.
322. Goyer, M. M. et al., ``Alkyl Sulfates,'' in Human Safety
and Environmental Aspects of Major Surfactants, February 20, 1981,
Arthur D. Little, Inc., Cambridge, MA, Supplement pp. 85-125, 1981.
323. Ashmole, R. et al., ``Mutagenicity and Teratology of
Alternative Surfactants. IV. Teratology of Sodium Lauryl Sulphate:
Oral Administration in the Rat,'' unpublished study in OTC Vol.
210010.
324. Nomura, T. et al., ``The Synthetic Surfactants AS and LAS
Interrupt Pregnancy in Mice,'' Life Sciences, 26:49-54, 1980.
325. Palmer, A. K., M. A. Readshaw, and A. M. Neuff,
``Assessment of the Teratogenic Potential of Surfactants,''
Toxicology, 3:91-106, 1975.
326. Takahashi, A. et al., ``Effects of Dermal Application of
Sodium Dodecyl Sulfate (SDS) on Pregnant Mice and Their Fetuses,''
Japan, Annual Report Tokyo Metropolitan Research Laboratories of
Public Health, 27:113-118, 1976.
327. Hope, J., ``Cytogenetic Effects of Detergent Actives on
Bone Marrow: I. Acute Administration of Sodium Lauryl Sulphate to
Chinese Hamsters,'' unpublished study in OTC Vol. 210011.
328. Hope, J., ``Absence of Chromosome Damage in the Bone Marrow
of Rats Fed Detergent Actives for 90 Days,'' Mutation Research,
56:47-50, 1977.
329. Kawachi, T. et al., ``Results of Recent Studies on the
Relevance of Various Short-Term Screening Tests in Japan,''
Applicable Methods in Oncology, 3:253-267, 1980.
330. McGregor, D. B. et al., ``Responses of the L5178Y
tk+/tk- Mouse Lymphoma Cell Forward Mutation
Assay: III. 72 Coded Chemicals,'' Environmental and Molecular
Mutagenesis, 12:85-154, 1988.
331. Phillips, L. et al., ``A Comparison of Rabbit and Human
Skin Responses to Certain Irritants,'' Toxicology and Applied
Pharmacology, 21:369-382, 1972.
332. Pader, M. et al., ``Mouthwash: Background of Invention,''
United States Patent No. 4,150,151, April 17, 1979.
333. Ahlfors, E. E., and A. Larsson, ``Chemically Induced
Inflammation in Rat Oral Mucosa,'' Scandinavian Journal of Dental
Research, 96:428-434, 1988.
334. Helenius, A., and K. Simons, ``Solubilization of Membranes
by Detergents,'' Biochimica et Biophysica Acta, 415:29-79, 1975.
335. Miner, P., ``Signal Mouthwash and Close-Up Antiplaque
Rinse,'' unpublished study in OTC Vol. 210009.
336. Rykke, M., G. Rolla, and T. Sonju, ``Effect of Sodium
Lauryl Sulfate on Protein Adsorption to Hydroxyapatite In Vitro and
on Pellicle Formation In Vivo,'' Scandinavian Journal of Dental
Research, 98:135-143, 1990.
337. Jablonski, W. M., and J. A. Hayashi, ``Inhibition of
Extracellular Streptococcal Enzymes,'' Journal of Dental Research,
49(1):178, 1970.
338. Christenson, F., and M. Kilian, ``The Effect of
Chlorhexidine and Some Other Detergents on the Activity of
Dextransucrase from Streptococcus mutans,'' Acta Odontologica
Scandinavica, 35:119-123, 1977.
339. Ciardi, J. E., W. H. Bowen, and G. Rolla, ``The Effect of
Antibacterial Compounds on Glucosyltransferase Activity From
Streptococcus mutans,'' Archives of Oral Biology, 23:301-305, 1978.
[[Page 32283]]
340. Giertsen, E., A. A. Scheie, and G. Rolla, ``Plaque
Inhibition by a Combination of Zinc Citrate and Sodium Lauryl
Sulfate,'' Caries Research, 23:278-283, 1989.
341. Barkvoll, P., G. Embery, and G. Rolla, ``Studies on the
Interaction Between Sodium Lauryl Sulfate and Hydroxyapatite Using
Fourier Transformed Infrared Spectroscopy,'' Journal of Biological
Buccale, 16:75-79, 1988.
342. Gabrielli, E., and D. Consoli, ``Food Debris Removal Test:
Signal Versus Placebo,'' unpublished study in OTC Vol. 210009.
343. Manhold, B. S., and J. H. Manhold, ``A Study of Total Oral
Debris Clearance,'' Journal of the New Jersey State Dental Society,
39:64-77, 1967.
344. Payonk, G., and K. Snyder, ``Ability of Signal and Scope
Mouthwash to Remove Food Debris (Toasted Muffin) from the Oral
Cavity,'' unpublished study in OTC Vol. 210009.
345. Payonk, G., and K. Snyder, ``Ability of Signal and Scope
Mouthwash to Remove Party Snack Food Debris from the Oral Cavity,''
unpublished study in OTC Vol. 210009.
346. Payonk, G., and K. Snyder, ``Ability of Signal and
Listerine Mouthwash to Remove Food Debris (Egg/Toast) from the Oral
Cavity,'' unpublished study in OTC Vol. 210009.
347. Payonk, G., and K. Snyder, ``Ability of Signal and Scope
Mouthwash to Remove Food Debris (Egg/Toast) from the Oral Cavity,''
unpublished study in OTC Vol. 210009.
348. Pretara-Spanedda, P., and S. Birenz, ``A Clinical Trial to
Determine the Oral Hygiene Benefits of Signal Mouthwash,''
unpublished study in OTC Vol. 210009.
349. Truelove, R., ``Antiplaque Mouthrinse Study: Evaluation of
Signal VS Plax Versus Flavored Water--Three Day--No Brushing,''
unpublished study in OTC Vol. 210009.
350. Lim, J. K. et al., ``Minimum Inhibitory Concentration of
Surfactants for Plaque Antiadherents (Short Communication),'' Caries
Research, 16:440-442, 1982.
351. Jenkins, S., M. Addy, and R. Newcombe, ``The Effect of
Triclosan, Stannous Fluoride, and Chlorhexidine Products on: (II)
Salivary Bacterial Counts,'' Journal of Clinical Periodontology,
17:698-701, 1990.
352. Gabrielli, E., and M. Carrabotta, ``Signal Versus Scope
Against a Garlic Insult,'' unpublished study in OTC Vol. 210009.
353. Gabrielli, E., and M. Carrabotta, ``Signal Versus Listerine
Against a Garlic Insult,'' unpublished study in OTC Vol. 210009.
354. Gabrielli, E., and M. Carrabotta, ``Signal Versus Listerine
Against Morning Mouth,'' unpublished study in OTC Vol. 210009.
355. Gabrielli, E., and M. Carrabotta, ``Signal Versus Scope
Against Morning Mouth,'' unpublished study in OTC Vol. 210009.
356. Gabrielli, E., and M. Carrabotta, ``In-Home Subjective
Assessment of Signal Versus Listerine for Clean and Refreshing Mouth
Feel,'' unpublished study in OTC Vol. 210009.
357. Gabrielli, E., and M. Carrabotta, ``A Subjective Mouthwash
Cleaning Test --Signal Versus Scope,'' unpublished study in OTC Vol.
210009.
358. Kitchin, P. C., and W. C. Graham, ``Sodium Alkyl Sulfate as
a Detergent in Toothpaste,'' Journal of the American Dental
Association and the Dental Cosmos, 24:736-755, 1937.
359. Birenz, S., and P. Pretara-Spanedda, ``Clinical Trial to
Determine the Oral Health Benefits of Signal Mouthwash: Trial II,''
unpublished study in OTC Vol. 210009.
360. OTC Vol. 210286.
361. Emiling, R. C., and S. L. Yankell, ``First Clinical Studies
of a New Prebrushing Mouthrinse,'' Compendium of Continuing
Education, Article [numsign]2, 5(9):637-640, 644-645, 1985.
362. Lobene, R. R., ``Plax Safety and Plaque Removal Study,''
unpublished study in OTC Vol. 210284.
363. Bailey, L., ``Direct Plaque Removal by a Pre-Brushing
Dental Rinse,'' Clinical Preventive Dentistry, 11(3):21-27, 1989.
364. Beiswanger, B. B. et al., ``The Relative Plaque Removal
Effect of a Prebrushing Mouthrinse,'' Journal of the American Dental
Association, 120:190-192, 1990.
365. Van Dyke, T. E. et al., ``Plaque and Gingivitis Reduction
by a Prebrushing Dental Rinse,'' unpublished study in OTC Vol.
210284.
366. Kohut, B. E., and S. Mankodi, ``The Effectiveness of a
Prebrushing Mouthrinse in Reducing Supragingival Plaque and
Gingivitis in Single-Use and Extended-Use Trials,'' American Journal
of Dentistry, 2:157-160, 1989.
367. Singh, S. M., ``Efficacy of a Prebrushing Rinse in Reducing
Dental Plaque,'' American Journal of Dentistry, 3:15-16, 1990.
368. Pontier, J. et al., ``Efficacy of a Prebrushing Rinse for
Orthodontic Patients,'' Clinical Preventive Dentistry, 12(3):12-17,
1990.
369. Lobene, R. R., P. M. Soparker, and M. B. Newman, ``Long-
Term Evaluation of a Prebrushing Dental Rinse for the Control of
Dental Plaque and Gingivitis,'' Clinical Preventive Dentistry,
12(2):26-30, 1990.
370. The Merck Index, edited by S. Burdaveri et al., 12th ed.,
Merck and Co., Rahway, NJ, p. 1734, 1996.
371. Mandel, I. D., ``Calculus Update: Prevalence, Pathogenicity
and Prevention,'' Journal of the American Dental Association,
126:573-580, 1995.
372. OTC Vols. 210192 through 210200.
373. OTC Vols. 210427, 210427A, 210427B.
374. Hefti, A., and R. Marks, ``A Clinical Investigation of an
Anti-Tartar Dentifrice,'' unpublished study in OTC Vol. 210427B.
375. Putt, M. S., ``A 6-Month Clinical Investigation of a Gum
Health Dentifrice,'' (Study [numsign]1094.3G), unpublished study in
OTC Vol. 210427B.
376. Burchell, C. K. et al., ``The Effect of 0.5% ZCT on Plaque
Gingivitis and Toothpaste Acceptability in the Lanarkshire Clinical
Trial After 1 and 2 Years of Use,'' unpublished study in OTC Vol.
210427B.
377. Shmidl, J. A., L. A. Hess, and M. L. Kohlenberg, ``Oral LD
50 Evaluation for C31G 3.0% Liquid,'' unpublished study in OTC Vol.
210272.
378. Dean, W., ``Acute Oral Toxicity Study in Beagle Dogs;
Antimicrobial Solution NPA-1-18A,'' International Research and
Development Corp., unpublished study in OTC Vol. 210272.
379. Shmidl, J. A., L. A. Hess, and M. L. Kohlenberg, ``Dermal
LD50 Evaluation for C31G 3.0% Liquid in Rabbits,''
unpublished study in OTC Vol. 210272.
380. Michaels, E. B., E. C. Hahn, and A. J. Kenyon, ``Mice and
Rabbit Models for Oral and Percutaneous Absorption and Disposition
of Amphoteric Surfactant C31G,'' American Journal of Veterinary
Research, 44:1977-1983, 1983.
381. ``Delayed Dermal Sensitization Study in the Guinea Pig;
C31G and B42 Concentrate,'' unpublished 1979 study in OTC Vol.
210272.
382. Shmidl, J. A., L. A. Hess, and M. L. Kohlenberg, ``Dermal
Sensitization Evaluation for C31G 3.0% Liquid in Guinea Pigs,''
unpublished 1983 study, in OTC Vol. 210272.
383. Munroe, J. S., ``Salmonella/Microsome Mutagenis Assay on
C31G Concentrate,'' unpublished study in OTC Vol. 210272.
384. Shmidl, J. A., L. A. Hess, and M. L. Kohlenberg, ``Eye
Irritation Evaluation for C31G 3.0% Liquid in Dogs,'' unpublished
1983 study in OTC Vol. 210272.
385. Reel, J. R., ``Drug Evaluation Report for Rabbit Vaginal
Irritation Assay,'' unpublished study in OTC Vol. 210272.
386. Munroe, J. S., ``Report on the Use of TopiCare[reg] at
Lincoln Park Nursing Home, NJ,'' unpublished study in OTC Vol.
210272.
387. Schroeter Research Services, ``Nurses' Interviews,''
Lincoln Park Intermediate Care Center, Weston, CT, unpublished study
in OTC Vol. 210272.
388. Haberman, J. V., ``North Jersey Nursing and Convalescent
Center Study,'' Wayne, NJ, unpublished study in OTC Vol. 210272.
389. Landers, W., ``Observations, Post-Questionnaire,'' OraTec
Corp., Herndon, VA, unpublished study, in OTC Vol. 210272.
390. Landers, W., ``Therasol Usage Report,'' OraTec Corp.,
Herndon, VA, unpublished study in OTC Vol. 210272.
391. Landers, W., ``Therasol Usage Report, 3rd Annual TheraSol
Survey,'' OraTec Corp., Herndon, VA, unpublished study in OTC Vol.
210273.
392. ``Determination of Antimicrobial Activity of Toothpastes by
Filter Paper Disk Method,'' Kema Nobel Consumer Goods, Sweden,
unpublished study in OTC Vol. 210273.
393. Corner, A. M. et al., ``C31G, a New Agent for Oral Use with
Potent Antimicrobial and Antiadherence Properties,'' Antimicrobial
Agents and Chemotherapy, University of Pennsylvania, School of
Dental Medicine, 12:350-353, 1988.
394. Corner, A. M. et al., ``Clinical Study of a C31G Containing
Mouthrinse: Effect on Salivary Microorganisms,'' Journal of Clinical
Dentistry, 2:34-38, 1988.
395. Huber, K. M., ``Clinical Summary: C31G, University of
Maryland Mouthrinse Study,'' University of Maryland, Baltimore, MD,
unpublished study in OTC Vol. 210273.
[[Page 32284]]
396. ``Panel Studies on the Comparison of Peridex[reg] to a C31G
Mouth Rinse,'' OraTec Corp., Herndon, VA, unpublished study in OTC
Vol. 210273.
397. Rotgans, J., and Stickforth, P., ``The Effect of Brushing
with an Amine-Containing Toothpaste (C31G) on Caries Incidence in
Rats and Plaque Accumulation and Gingivitis in Man,'' University of
Tubingen, Dental School, West Germany, unpublished study in OTC Vol.
210273.
398. Stickforth, P., and J. Rotgans, ``Die Wirkung einer
Chemotherapeutischen, Aminehaltigen Zahnpasta auf Plaquebildung,
Gingivitis und Karies im Klinischen und Tierexperimentellen
Versuch,'' German (English abstract), Deutsch Stomatologic 41:253-
257, 1991.
399. Renton-Harper, P. et al., ``A Comparison of Chlorhexidine,
Cetylpyridinium Chloride, Triclosan, and C31G Mouthrinse Products
for Plaque Inhibition,'' Journal of Periodontology, 67:486-489,
1996.
400. ``Oral LD50 Determination in Rats,'' Study
[numsign]4A-01, Olin Corp., New Haven, CT, unpublished study in OTC
Vol. 210007.
401. ``Oral Mucosal Irritation in Rats,'' Study [numsign]431,
Olin Corp., New Haven, CT, unpublished study in OTC Vol. 210007.
402. ``Acute Dermal Toxicity Study in Albino Rabbits,'' Study
[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