Food and Drug Administration 21 CFR Part 356
[Docket No. 81 N-O33P]

RINOglO-AA01 Oral Health Care Drug Products AntigingivitisiAntiplaque

for Over-the-Counter Establishment HHS. rulemaking.

Human Use; of a Monograph

Drug Products;

Food and Drug Administration, Advance notice of proposed


The Food and Drug Administration that would

(FDA) is issuing an advance establish conditions under which of dental

notice of proposed rulemaking over-the-counter

(OTC) drug products are generally

for the reduction

or prevention

plaque and gingivitis misbranded. Subcommittee


as safe and effective and not of the Dental Plaque (NDAC) and

This notice is based on the recommendations of the Nonprescription Drugs Advisory


is part of FDA’ ongoing review of OTC drug products. s

Submit written

or electronic


by [insert date 90 days after

date ofpublication

in the Federal Register].

Submit reply comments by [insert

date 150 days after date of publication

in the Federal Register]. to the Dockets Management 5630 Fishers Lane, rm. to http://

Submit written

and reply comments

Branch (HFA-305),
1061, Rockville,

Food and Drug Administration,

MD 20852. Submit electronic




Robert L. Sherman, Center for Drug Food and Drug Administration, 5600


and Research (HFD-560),

Fishers Lane, Rockville,

MD 20857, 301-827-2222. In accordance with part 330 (21 CFR part 330),


FDA received on December 3, 3998, a report on OTC antigingivitis/antiplaque drug products regulations from the Dental Plaque Subcommittee (the Subcommittee). FDA

(§ 330.10(a)(6)) p rovide that the agency issue in the Federal (1) The monograph under which recommended by the

Register a proposed rule containing: Subcommittee, antiplaque which

establishes conditions are generally

OTC antigingivitis/

drug products


as safe and effective and excluded from the result in result

not misbranded; monograph

(2) a statement of the conditions determined

because the Subcommittee

that they would

the drugs not being generally recognized in misbranding;

as safe and effective or would excluded

(3) a statement of the conditions determined

from the monograph data are insufficient and (4)

because the Subcommittee to classify these conditions the conclusions

that the available

under either (1) or (2) of this paragraph; of the Subcommittee.

and recommendations conclusions discussioti,

The unaltered issued to stimulate the Subcommittee’ s

and recommendations evaluation,

of the Subcommittee


and comment

on the full sweep of independently


The report has been prepared

of FDA, and the agency has not yet fully evaluated Subcommittee’ s findings appear in this document

the report. The to obtain public comment

before the agency reaches any decision recommendations. the Subcommittee, any particular This document

on the Subcommittee’ s judgment of on

represents the best scientific

but does not necessarily in it.

reflect the agency’ position s

matter contained * % .


3 The Subcommittee combination combined was asked for its general recommendations antigingivitis/antiplaque ingredients on are

products in which

with other oral health care ingredients. the following as rational

The Subcommittee products:


oral health care combination combined

(1) An antigingivitis/antiplaque
active ingredient,

active ingredient

with an anticaries combined

(2) an antigingivitis/antiplaque active ingredient,

active ingredient

with a tooth desensitizer active ingredient desensitizer However, combination combinations dissenting

and (3) an antigingivitis/antiplaque active ingredient and a tooth


with an anticaries

active ingredient. the agency is not aware of any marketing products submitted history of such

eligible for the OTC drug review, nor were such to the Subcommittee. Therefore, the agency is

from these recommendations

at this time. Data are needed to of these combination products described products. above may be rulemaking. that these

establish the safety and effectiveness Accordingly, none of the combination

marketed OTC at this time under this advance notice of proposed The agency invites supporting combination use. Based on proposals from industry, recommendations considered interested the Subcommittee for final product products data and information recognized demonstrating

can be generally

as safe and effective for OTC

also made general formulations from to be

on testing requirements

effective. The agency is seeking specific information parties on testing protocols, effectiveness criteria,

and statistical

methods employed

to analyze the data from these tests. concluded that an active

The agency notes that the Subcommittee ingredient could be either an antigingivitis

agent or an antigingivitis/antiplaque

4 agent. While an ingredient Subcommittee may also be effective in reducing endpoint plaque, the and

stated that the therapeutic active ingredients

for both antigingivitis reduction in

antigingivitis/antiplaque gingivitis, which

is a significant

can be measured using gingival

index scores (see section 1I.C

of this document). The Subcommittee and gingivitis. concluded that there is an association between plaque

The Subcommittee

agreed, however, that the exact relationship Because the data in reducing plaque

between plaque and gingivitis submitted

cannot be quantified.

to support the effectiveness the Subcommittee However, includes

of stannous fluoride

were inconclusive, of identity indication

proposed an “antigingivitis” the Subcommittee’ s


for this ingredient. for this ingredient


a reference to plaque reduction. ingredients also be effective that work for

Although in reducing primarily

it did not require that antigingivitis plaque, the Subcommittee

agreed that ingredients

by means other than plaque reduction drug products

would be inappropriate

use in OTC antigingivitis symptoms

because these products

may mask the

of a more serious condition

and cause consumers to delay seeking believed that none of the plaque, this issue

the advice of a dentist. Because the Subcommittee submitted active ingredients discussed. the agency is seeking comment active ingredient

acted other than by reducing

was not further Therefore, antigingivitis reducing

on the basis for allowing effectiveness

an in More that

that has not demonstrated

plaque to bear labeling statements relating to plaque reduction. because of the safety concern that antigingivitis other than plaque reduction ingredients


work by a mechanism may give consumers

(e.g., anti-inflammatory) of a more

a false sense of security by masking symptoms

5 serious disease, the agency is also seeking comment on whether are solely antigingivitis plaque, constitute After reviewing agents, i.e., products products that

that do not significantly



OTC drug products. in response to this document, final monograph (TFM) for

all comments submitted

FDA will issue in the Federal Register a tentative OTC drug products gingivitis. proposal for the reduction or prevention

of dental plaque and the agency’ position s and

Under the OTC drug review procedures,

are first stated in the TFM, which has the status of a proposed rule. which has the status of

Final agency action occurs in the final monograph, a final rule.

In accordance with § 330.10(a)(2), the Subcommittee as confidential or prevention all information concerning

and FDA have held for the reduction by

OTC drug products submitted

of dental plaque and gingivitis All submitted information

for consideration

the Subcommittee.

will be put on public


in the Dockets Management after date of publication persons submitting provisions

Branch (see ADDRESSES) after [insert date 30 days

in the Federal Register], except to the extent that that it falls within the confidentially

it demonstrate

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 Evaluation should be submitted to Robert L. Sherman, Center for Drug

and Research (see FOR FURTHER INFORMATION CONTACT). under which the drug products be generally recognized conditions) as safe and 12

The agency advises that the conditions that are subject to this monograph effective and not misbranded would


will be effective

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

6 monograph would and that contain nonmonograph conditions, i.e., conditions that

cause the drug to be not generally may be initially


as safe and effective or delivered for

to be misbranded, introduction approved (ANDA).


or initially

into interstate

commerce unless they are the subject of an (NDA) or abbreviated new drug application that are

new drug application Further,

any OTC drug products after the effective

subject to this monograph date of the monograph

repackaged compliance introduced

or relabeled

must be in was initially

with the monograph or initially delivered

regardless of the date the product for introduction

into interstate commerce Manufacturers are urged to

unless they are the subject of an NDA or ANDA. comply voluntarily with the monograph

at the earliest possible date. and labeling of all OTC in the Federal providing for this

A proposed

review of the safety, effectiveness,

drugs by independent

advisory review panels was announced

Register of January 5, 1972 (37 FR 85). The final regulations OTC drug review under § 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 19,1990

claims was

issued in the Federal Register of September claims included the reduction or prevention gingivitis,

(55 FR 38560). These film,

of plaque, tartar, calculus, diseased, inflamed,

sticky deposits, bacterial buildup, gums, pyorrhea, acids. The Commissioner Vincent’ s

or swollen

disease, periodontal

disease, and tooth-destroying

of Food and Drugs appointed

the following

members submitted

of the Dental Products Panel (the Panel) to review the information

7 and to prepare a report under $5330.10(a)(l) effectiveness, and labeling of those products: and (a)(5) on the safety,

Paul B. Robertson, Chairperson Charles N. Bertolami William (resigned March 24, 1997)

H. Bowen (term ended October 31, 19%)

Carlos E. de1 Rio (resigned December 14, 1994) Julianne Glowacki Deborah Greenspan Richard D. Norman Burton Rosan Christine D. Wu comprised of two members from the Panel plus five formed to evaluate the of (term ended October 31,1994)

The Subcommittee, nonvoting submitted ingredients consultants

to the Panel, was subsequently

data and report its findings for the reduction

on the safety and effectiveness

or prevention

of dental plaque and gingivitis.

Each of the following William

was a voting member of the Subcommittee: [term ended April 1995)

H. Bowen, Chairperson

Robert J. Genco, Chairperson Ralph D’ Agostino Max A. Listgarten Shelia M. McGuire Eugene D. Savitt Stanley R. Saxe Jorgen Slots (resigned April Christine D. Wu

(from April

1995 to December 3, 1998)


Several nonvoting

liaison representatives

served on the Subcommittee. followed by


Jean Frazier, served as the consumer

liaison until June 6,1996,

Susan Cohen, until May 1997, and Donald S. Altman,

on May 27,1998.

8 Frederick followed (cosmetic) A. Curro, served as industry liaison (drug) until October 31, 1995, Jr., served as industry liaison

by Lewis P. Cancro. Gerald N. McEwen, until October 31, 1996.

On August 27, 1997, oversight

of the Subcommittee

was transferred


the Panel in the Center for Devices and Radiologic Nonprescription Drugs Advisory Committee

Health (CDRH) to the

in the Center for Drug Evaluation

and Research (CDER). The following FDA employees assisted the Subcommittee: Secretary to the Panel until Secretary to

Carolyn Tollendi June 7, 1996. Kennerly the Subcommittee May 9,1997, by Kathleen Subcommittee

served as CDRH Executive

K. Chapman served as CDER Executive followed

until December 17,1996,

by Andrea Neal until


by Rhonda Stover (interim)

until May 1998, followed

Reedy. Jeanne L. Rippere served as CDER liaison to the until June 7, 1996, followed by Robert L. Sherman. Stephanie until June 7, 1996.

A. Mason served as special assistant to the Subcommittee The Panel and the Subcommittee 3, 1993, for a joint organizational Subcommittee

were first convened on August 2 and meetings of the June 28 and 29,

meeting. Working

were held on December 16 and 17,1993;

October 11, and December 5, 6, and 7, 1994; April and 15, and December 4 and 5,1995;

10, 11, and 12, August 14

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 and December 6,1994. Minutes of most

were held on August 2 and 3,1993, Subcommittee

meetings are on public

display in the Dockets Management

Branch (see ADDRESSES).

9 The following Subcommittee individuals appeared before the Panel and/or the request to

at their own or at the Panel’ or Subcommittee’ s s for the reduction or prevention

discuss drug products Gariela Adam-Rodwell,

of plaque and gingivitis:

Sam Amer, Daniel M. Bagley, John E. Bailey, Michael Baumgartner, William J. Blot, Nancy Cole,

L. Barnett, Robert D. Bartizek, Kenneth L. But, Gregory A. Burkhart,

Lewis P. Cancro, James R. Cheever, Philip Catherine C. Davis, Phillip

W. Greg Collier, Mark M. Crisanti, M. DeSesso, Harvey L. Dickstein, Flamm, William E. Gilbertson,

Derfler, John J. Doyle, W. Gary

Jerry A. Douglass, Matthew Brian F. Gillespie,

David M. Graham, Robert N. Hyman, Eugene C. Lanzaiaco, A. Mason,

Heller, Jane E. Henney, Ira D. Hill, Peter B. Hutt, Frederick Kamper, Linda M. Katz, Bruce Kohut, Mark S. Leusch, Debbie L. Lumpkins, Stephen F. McClanahan, Morrisson, Surinder Milton

Kumar, Anthony V. Marshall,


Stephen H. McNamara,

Jerome A. Merski, David

Kevin P. Mulry,

Anne J. Mustafa, Paul J. Okarma, C. Lee Peeler, Jeanne L. Rippere, Norman A. See, James Siew, Gregory

Julie H. Rhee, David I. Richardson,

M. Serafino, Samuel Shapiro, Robert L. Sherman, Chakwan Singleton, Stellman, James Skiles, Thomas J. Slaga, R. William George K. Stookey, Howard

Soiler, Steven D.

Strassler, Stanley Tarka, Jr., John M. Weintraub, Clifford W. Whall, Gary M.

Treaty, Jack Vincent,

Frank A. Volpe, Michael

Jr., Donald J. White, Robert White, Charles Wiggins, David Williams, Williams, Deborah Winn, Roy Witkin,

and Patrice Wright. No person who so to appear before the Panel or

requested was denied an opportunity Subcommittee. The Subcommittee submissions, considered has thoroughly


the literature

and data persons, and

listened to additional all pertinent


from interested submitted

data and information

through December 3,

10 1998, in arriving at its conclusions and recommendations. The Subcommittee on and The ADA Products

wishes to thank the American Scientific testimony

Dental Association’ s

(ADA) Council

Affairs for its assistance in providing

data, information, deliberations.

during the course of the Subcommittee’ s its “Guidelines for Acceptance

also provided

of Chemotherapeutic

for the Control of Supragingival for consideration

Plaque and Gingivitis”

to the Subcommittee for safe

in making its recommendations

on the requirements

and effective OTC antigingivitis/antiplaque

ingredients. in 5 330.10, the or prevention three categories: or

In accordance with the OTC drug review regulations Subcommittee reviewed OTC drug products

for the reduction

of dental plaque and gingivitis Category I-Conditions prevention

with respect to the following

under which

OTC drugs for the reduction are generally recognized

of dental plaque and gingivitis

as safe and

effective and are not misbranded. Category II-Conditions prevention under which OTC drugs for the reduction are not generally recognized or as safe

of dental plaque and gingivitis

and effective or are misbranded. Category III-Conditions permit final classification I. Submission for which at this time. the available data are insufficient to

of Data and Information in the Federal Register of September 19,1990
(56 FR 9915), the following

Under the notices published
(55 FR 38650),

and March 8,199l

firms made

submissions determined

regarding contained

OTC drug products active ingredients or prevention

that the Panel/Subcommittee or labeling associated with claims

relating to the reduction

of dental plaque and gingivitis.

A. Submissions
by Firms
Firm Amencan Xyro!in (Morgan, Lew1.s 8 Bocfuus) Washmgton. DC 20036 Xyklol All Natural Toothpasle. I lnsadol Toothpaste, IL 60062 CT 06836 I Hexetldme soluhon CloseUp AntIplaque Toothpaste, Mentadent P Toothpaste.

SubmItted Products

Xyiol 32 Dental Cream.

Amer Co , Montecito,

CA 93150

Pyoralene Toothpaste

Angus Chemical Co., Northbrook, Chesebrough

Pond’ USA Co, Greenwich, s

Church 8 Dwight Co., Inc.. Pnnceton, CIBA-GEIGY Corp , Greensboro,

NJ 08543

Arm 8 Hammer Dental Tooth Powder, DenMrrce. and Gel lrgasan DP, lrgacare MP

NC 27419 LA 71109

Clintcal Product Research, Colgate-PalmolIve

Inc., Shreveport,

Prozyme Toothpaste,


Oral Rmse, AntI-Plaquer

Toothpaste. Tooth-

Co., Piscataway. Germany Associates,

NJ 08855

Colgate Tartar Control Toothpaste, paste I Thera-Med, Cholordont M.

Gelkam Oral Care Rinse, Dentaguard

E Merck, Frankfurter,

E. B Mlchaels Research Leaf, Inc., (Hyman, Lion Corp. (America), Madaus Medtech,

Inc., Mlllord, CT 06460 Washington DC 20005

Therasol Brush B Rtnse Anliplaque Oral Hygiene Solution, Therasol Rmse Llquld Dentltnce Oral Irngant. I 1 Xylitol I Check-Up DC 20036 Parodontax Gingival Toothpaste Toothpaste. Dental Rmse. Eludll Mouthwash.

Brush 8

Phelps B McNamara) Memphis, TN 38138

Inc., (ACC Consuiiing

Group, Inc.) WashIngton

Pfizer Inc, New York, NY 10017 Pierre Fabre, S.A., 81106 Castles Prevention Laboratories Cedex, France IL 62947

Plax Pre-Brushmg

Eligydium Toothpaste,

(formerly 7-L Carp ), Hamsburg,

PreventIon Mouth Rinse Crest Gum Care Toothpaste. Cepacol Gold and Mm1 Mouthwashes. Viadent Toothpaste and Oral Rinses. Glyaxide Liquid.

Procter & Gamble Co., Cmcinnati, OH 45242 SmithKline Beecham NJ 07054 Consumer Brands (Marion Merrell Dow, Inc.), Parsippany,

Vipont Pharmaceuticals, Warner-Lamberi

Forf Collms, CO 80522

Co.. Morris Plains, NJ 07950 Inc., Hazlet, NJ 07730

Llsterine Anttsephc Mouthwash. Omni-Med Brush-On Tooth Me&cation, Perio-Med Spray, Take-5 Plaque Fighter Brushless Dentifrice, Smokers Take-5 Plaque and Stain Fighter. Perimed Oral Hygiene Rmse.

WhIteHill Oral Technologies, Wilkins, Roy T., Westport,

CT 06880

In categorizing


as “active”

and “inactive,”

the advisory review

panels relied upon their expertise and understanding defined “active ingredient”

of these terms. FDA has practice

in its current good manufacturing


in § 210.3(b)(7) (21 CFR 210.3(b)(T)) as:
that is intended to furnish pharmacological activity or other

[Any] component

direct effect in the diagnosis, cure, mitigation, or to affect the structure term includes manufacture form intended or any function


or prevention

of disease,

of the body of man or other animals. The change in the in a modified

those components of the drug product to furnish

that may undergo chemical

and be present in the drug product activity or effect.

the specified

12 An “inactive ingredient ” is defined in 5 210.3(b)(8) as “any component

other than an active ingredient.”
B. Active Ingredients Submitted For Review

Labeled Ingredients Subcommittee: Alkyl Alkyl dimethyl dimethyl


in Marketed

Products Submitted

to the

amine oxide glycine

Aloe vera Bromchlorophene Carbamide peroxide chloride digluconate dihydrate

Cetylpyridinium Chlorhexidine Dicalcium Eucalyptol Hexetidine Hydrogen Menthol Methyl salicylate oil




Polydimethylsiloxane Poloxamer Povidone Sage oil Sanguinaria extract iodine

Sodium bicarbonate Sodium citrate Sodium lauryl sulfate Soluble pyrophosphate


Stannous fluoride Stannous pyrophosphate Thymol Triclosan Unsaponifiable Xylitol Zinc chloride Zinc citrate Some of these ingredients hexetidine, (bromchlorophene, triclosan, chlorhexidine digluconate, of corn fraction of corn oil

soluble pyrophosphate, for a material


fraction extent for

oil) were not marketed antigingivitis/antiplaque Although

time and to a material

use in the United reviewed

States. (See 21 U.S.C. 321(p)(2).)

the Subcommittee

data to support the safety and in the OTC and, xylitol was


of these ingredients,

they are not eligible for inclusion rulemaking although

drug review as part of this advance notice of proposed therefore, reviewed withdrew are not discussed in this document.

In addition,

by the Subcommittee, xylitol

the two firms that submitted by the Subcommittee.

data subsequently Therefore, xylitol

from consideration

is not discussed. The nomenclature in this document edition of “USAN used by the Subcommittee for the ingredients reviewed

was the currently

accepted terminology

stated in the 1996

and the USP Dictionary

of Drug Names.” Names which did not have

recommended USAN names.
C. Referenced

by FDA were used for any ingredients

OTC Volumes

All “OTC Volumes” made by interested

cited throughout

this document

refer to submissions in the

persons under the call-for-data

notices published

14 Federal Register of September included in these volumes, provisions 19, 1990, and March 8, 1991. The information made in accordance with

except for those deletions in 5 330.10(a)(Z),

the confidentiality

will be put on public


after [insert date 30 days after date of publication in the Dockets Management II. General Statements A. Definitions The Subcommittee adopted the following

in the Federal Register],

Branch (see ADDRRESSES).

and Recommendations


as its intended OTC drug The

meaning of terms specifically products for the reduction

used in this document


or prevention

of dental plaque and gingivitis.


was aware that some degree of variation

with other definitions

of the same term may exist.

Calculus. The hard concretions

(i.e., calcified

plaque) that form on teeth, classified

prostheses, and other hard surfaces. Calculus into supragingival calculus,

on teeth is clinically

which is located on surfaces not covered by the calculus, which is located apical (at the top) to

oral mucosa, and subgingival

the soft tissue margin of the gingiva.

Dental Plaque. Organized

coherent gel-like or mucoid derived

masses consisting

of microorganisms bacterial products

in an organic matrix

from saliva and extracellular

such as glucans, fructans,

enzymes, toxins, and acids. Plaque epithelial cells) and inorganic

also contains other cells (e.g., desquamated components such as calcium and phosphate.

It adheres to the teeth and other crevices and or

surfaces of the oral cavity. It occurs at the orifice of the gingival in the periodontal microbial pockets. Plaques may differ markedly and their localization.

in biochemical



Gingival Srrlcus. The shallow

groove between the tooth and the marginal



An inflammatory

lesion of the gingiva that is most frequently is characterized by tissue swelling the surface of healthy and

caused by dental plaque. Gingivitis redness, loss of stippling gingiva is comprised temperature. toothbrushing

(a normal state in which

of small lobes), glossy surface, and increased tissue such as

The gingiva also may bleed upon gentle provocation or may bleed spontaneously. Gingivitis

is usually not painful. microbial

Oral Hygiene. Self-administered

processes aimed at controlling

and other deposits in the oral cavity.

Pellicle. A thin, colorless, translucent and saliva, which forms rapidly

film derived from bacterial on tooth surfaces after natural oral bacteria begin to


cleansing or prophylaxis. adhere to the pellicle. formation.

A few hours after deposition,

These processes represent the earliest stages of plaque


A disease condition

of the periodontium probing



inflammation periodontal

of the gingiva, increasing

depth, and destruction alveolar bone.

of the

ligament and the adjacent supporting term for calculus.
of Terms

Tartar. A synonymous

B. Background

and General Discussion

1. Background
The Subcommittee effectiveness or prevention products was charged with the evaluation or combinations of ingredients of the safety and for the reduction

of ingredients

of plaque and gingivitis

as claimed in the labeling of OTC drug and standards used in and toxicology.

in light of present-day





In making its evaluation, the Subcommittee relied upon factual data found by independent journals. Manufacturers to FDA to of

in standard textbooks and scientific investigators included provide

articles published

in medical, dental, and other scientific

some of these scientific a scientific

articles in their submissions

basis for claims made for the safety and effectiveness Data supplied by manufacturers in unpublished

their ingredients. studies performed

reports of

by private laboratories laboratories

under contract to the manufacturer in

or in manufacturers’ making judgments. marketing

were also used by the Subcommittee also gave due consideration clinical

The Subcommittee and widespread

to data from


usage when in agreement with facts.

basic data from controlled
2. Plaque

studies and scientific

Plaque, also known examined

as dental plaque and/or microbial

plaque, has been explained in the of dental

for several decades with most of the information

past 25 years. Plaque has a critical etiological caries, gingivitis, and periodontal community

role in the development

disease. It is now clear that dental plaque made up of bacteria and a bacterially with other materials of these

is a variable biologic synthesized

matrix. While dental plaque may be combined

such as food particles and sloughed epithelial components

cells, the combination plaque.

is called materia alba and is no longer considered

The precise genera and species of microorganisms may differ from individual and within within to individual,

in each dental plaque

site to site in the same individual, health

a specific site over time. Plaque from sites of similar clinical subjects tends to be more similar in composition


than plaque variation

from sites in different within

subjects. Even though there is considerable of plaque is influenced

dental plaques, the composition

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). is also affected by its location above or below the plaque and

Plaque composition

gingiva. Dental plaques are subdivided subgingival plaque. The distinction

into supragingival

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 locations. The extracellular component matrix synthesized by the bacteria is a significant populations may differ in plaque from the two

of plaque. Because the matrix provides plaque organisms with plaque is not easily removed. The can be used to the

strong adhesive and cohesive properties,

tenacity of plaque to adhere to the surfaces of oral structures distinguish

plaque from debris, in that plaque is not removed by flushing

mouth with water. Plaques differ not only quantitatively composition. Acfinomyces Streptococcus forsythus, For example, microorganisms species, Sfrepfococcus species, Spirochetes, but qualitatively in their bacterial

found in dental plaque include

sanguis, S. mutans, and other Porphyromonas gingivalis, recta, Bacteroides

and other Bacteroides

species, Campylobacter


micros, Eikenella Eubacterium

corrodens, Actinobacillus species, Fusobacterium species, in bacterial

actinomycetemcomitans, Capnocytophaga composition

species, and Prevotella species. This difference potential

has a major effect on its pathogenic

both for periodontal or associated with diseases.

diseases and caries. Some dental plaques are not pathogenic disease, whereas others are etiologic

factors for caries and periodontal

38 However, pathogenic the two types of plaque cannot be distinguished potential is dependent of microbes, upon the microbial visually. The including


the metabolic


dietary patterns, and the intrinsic to treat all plaques as having

resistance of the host. It may be prudent pathogenic 3. Calculus Calculus is a hard concretion through deposition of mineral potential.

that forms on the teeth or dental prostheses

salts in dental plaques. Human calculus is



dental plaque, which is almost always covered on its adherent, nonmineralized soft plaque. There

external surface by vital, tightly

may also be loosely held materials alba, shed bacteria, desquamated animals, calcified (Ref. 1). However,

associated with calculus such as materia epithelial cells, and blood cells. In germ-free accumulation likely

deposits may occur in the absence of bacterial in humans, virtually of calcium all calculus seen clinically and phosphates within

results from the deposition plaques. Calculus formation 2 weeks of plaque formation

bacterial after 1 or

occurs in an orderly fashion, beginning and resulting in full calcification

of plaque after

2 to 4 weeks. The process occurs more rapidly Calculus may form subgingivally

in some persons than in others.

and is often stained and tenaciously

attached to the crown and/or root of the tooth. Calculus may also form supragingivally, Supragingival coronal (toward the crown) to the gingival margin. calculus is found in greater amounts on tooth surfaces adjacent and

to the openings of the ducts of the major salivary glands. Both subgingival supragingival unsightly, calculus are often stained; supragingival when formed in abundance calculus can be


on labial (facing the lips) factor in the

surfaces. Although


calculus is a contributing

development gingivitis, of gingivitis, and can also be associated with the progression and periodontal of


abscesses, the exact nature of the role is not clear. Supragingival calculus can which can

of supragingival accumulate

calculus in gingivitis

plaque and act as a nidus (nest) for plaque formation,

lead to gingivitis. Calculus facilitates the periodontal the retention of dental plaque in close proximity to

tissues. It reduces the effectiveness Subgingival

of overall hygiene methods calculus interferes with the

to control dental plaque accumulation. regeneration of lost periodontal

attachment. a basic step in the prevention and

The removal of calculus is considered treatment of inflammatory periodontal

diseases. The formation

of supragingival

calculus can be limited subgingival gingivitis,

through mechanical

or chemical methods. Preventing

calculus formation,

if possible, would not necessarily reduce free of calculus can still harbor plaque. prevention of subgingival

because a surface currently

Present methods calculus. 4. Gingivitis Gingivitis,

do not allow for the predictable

an inflammation

of the gingiva, affects most of the population are tissue swelling and redness, The gingiva or may bleed

at one time or another. The signs of gingivitis loss of stippling,

glossy surface, and increased tissue temperature. such as toothbrushing, such as bleeding,

may also bleed upon gentle provocation, spontaneously. by lay persons. Gingivitis is a response to injury, Some signs of gingivitis,

can be identified

often resulting

in localization

of tissue

damage and neutralization agents cannot be adequately

of the effects of injurious neutralized or eliminated,

agents. If the injurious they may lead to




of the soft tissue and periodontitis. to start with gingivitis, Histologically,

While most cases

of periodontitis

are believed

most cases of gingivitis is characterized by

do not progress to periodontitis. inflammatory exudate or infiltrate,


loss of collagen of the gingival into the infiltrated


tissue, and proliferation the epithelium lining

of the epithelium

tissue. Sometimes

the sulcus (crevice bounded

by the tooth and free the junctional epithelium

gingiva) may develop microulcerations. usually is at or near the cementoenamel and root). Gingivitis, especially

In gingivitis, junction


of the tooth crown

when severe, may be self-diagnosable such as bleeding,

because people gingival (pocket-like

can recognize some of the signs of gingivitis, discoloration, structure and swelling, which

gives rise to pseudopockets of the gingiva without

caused by inflammation

effecting the sulcus

base). In the early stages of gingivitis formation, only noncalcified

when there is little or no pseudopocket thorough daily

plaque, and little or no calculus,

oral hygiene may resolve the disease. Under these conditions, of gingivitis is appropriate. When OTC drug products gingivitis

self-treatment and

for the prevention

control of plaque-associated oral hygiene, including maintain their gingival

are used as part of a program of good they can help consumers

regular dental checkups, health. form of gingivitis

The most common occurs in all individuals

is termed marginal



at some time. It is limited

to the gingivae around

the collar of the tooth. However, with mild gingivitis associated gingivitis, can be controlled

people are seldom easily able to detect sites Plaquegingiva, plaque

because there may be no pain or bleeding. an inflammation of the interdental or inhibition

and marginal of microbial

or prevented

by removal

accumulation. Chemotherapeutic agents can enhance the benefits of traditional with a dentifrice and regular use

methods of oral cleansing by toothbrushing of dental floss and other cleaning aids. Readily available OTC drug products plaque-associated role. However, determined gingivitis are intended

for the prevention to play a significant in periodontitis

and control of public health have not been

the effects of these products

in large scale studies. OTC drug products care.

are useful adjuncts to,

but do not replace, regular professional In the later stages of gingivitis calculus, it becomes more difficult Therefore, gingivitis, self-treatment which has limited

with the formation

of pseudopockets


for people to resolve the gingivitis. potential for resolution of severe care of

should be treated as part of a regular professional can progressively

program. Gingivitis

worsen and lead to the deveIopment

pockets that can be difficult 5. The Interrelationship

for people to clean.

Between Plaque and Gingivitis A critical plaque mass change.

Dental plaque can be causally related to gingivitis. at the gingival However, margin for a particular

length of time can initiate

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


plaque levels and levels of gingivitis. plaque accumulation,

For example, with little health,

or no supragingival

most often there is gingival especially

whereas heavy levels of plaque accumulation, are often associated with gingivitis. Plaque forms readily

at the gingival margin,

on tooth surfaces in individuals

with poor oral

hygiene. It takes, histologically,

about 3 to 4 days with no oral hygiene in

22 periodontally healthy subjects to develop microscopic of the gingival evidence of gingivitis. epithelium, especially the

This evidence consists of infiltration junctional infiltration epithelium,

with inflammatory connective

cells (including

neutrophils), and beginning

of the gingival

tissue with lymphocytes,

loss of collagen. The Subcommittee gingivitis induced spontaneously gingivitis does not know how long plaque must be present before appears. When distinguishing gingivitis between experimentally under conditions of

and spontaneous


normal oral hygiene) the following

are found: (I) Most subjects over a period gingivitis measurable

of 1 to 3 weeks of cessation of oral hygiene developed with clinical before clinical complex indices, and (2) subjects must accumulate signs of gingivitis are apparent.

a certain level of plaque mature plaque with mature flora with

In addition,

flora appears to be correlated

with gingivitis.


plaque, comprised

of a complex gram-positive

and gram-negative gingivitis.

motile organisms, is often associated with spontaneous The Subcommittee accumulation accepts that gingivitis

is associated with an of any

of plaque along the gingival

margin but is unaware

evidence that shows that there is a close correlation plaque and the induction of gingivitis,

between the amount of

as can be assessed using present day between the quantity complex of

methods. It should be noted that the relationship plaque present and the degree of gingivitis reductions

is sufficiently

such that

in plaque mass alone are inadequate could be expected. Therefore,

to conclude gingivitis

that a therapeutic reductions must

effect on gingivitis

be measured directly.

23 6. Periodontitis Most cases of periodontitis not all cases of gingivitis clinically by gingivitis are believed to start with gingivitis, Periodontitis although

lead to periodontitis.

is characterized attachment,

of varying severity, loss of periodontal

increased probing depth, and radiographically supporting bone. In advanced of gingivitis

detectable loss of alveolar and

disease, the teeth may become increasingly and the relationship However, of gingivitis to the onset

mobile. Progression of periodontitis this relationship

are not well understood.

one approach to addressing oral hygiene

comes from human studies in which meticulous plaque control and control of gingivitis (Ref. 2). It is not clear whether

leading to excellent

appears to prevent was

the onset of periodontitis due to reduction meticulous

this prevention or to

of supragingival

plaque associated with gingivitis, also prevents colonization

oral hygiene, which

of the subgingival

area by periodontal periodontitis.

pathogens that are responsible

for the onset of

What is clear, however,

is that in most instances meticulous of gingivitis and suppression of

plaque control appears to lead to reduction the onset or rate of progression loss of periodontal attachment

of periodontitis.

Despite periodontal


and loss of bone often persists. Moreover, may suffer from recurrent gingivitis, root appears to

people treated for periodontitis sensitivity,

and increased susceptibility

to root caries. Periodontitis which

progress in alternating and localized, followed

cycles of exacerbation,

are often asymptomatic studies indicate disorders, (Refs. 3 and

by periods of remission. such as diabetes mellitus


that systemic conditions as well as smoking,

and neutrophil periodontitis

increase the risk for developing

24 Histologically, the gingiva becomes inflamed, is lined with a pathologically The junctional epithelium and the sulcus is deepened altered epithelial is displaced apically. lining, The

to form a pocket which the pocket epithelium.

pocket is largely filled with a subgingival the adjacent denuded


that is in contact with calculus deposits.

root surface or adherent subgingival

The alveolar process (portion supports

of the upper and lower jaws that forms and in a “horizontal” tissue attachment

the tooth sockets) shows evidence of destruction pattern with concomitant

or “vertical” to the root.

loss of the connective

There are several variants of the disease, including early-onset periodontitis (which includes localized

adult periodontitis, periodontitis and


associated with systemic diseases, necrotizing refractory common planing, and recurrent periodontitis.



Of these, adult periodontitis

is the most

form of the disease, and it responds most predictably and plaque control.

to scaling, root

7. Oral Hygiene The Subcommittee’ s the self-administered definition of oral hygiene in this document microbial represents

processes aimed at controlling

and other with plaque

deposits in the oral cavity. Regular oral hygiene, by interfering accumulation without and maturation, favors facultative or living

(able to grow or live with or in the absence of oxygen) clean dentition inflammatory and changes

oxygen) over anaerobic (growing

bacteria. In the process, regular oral hygiene promotes fresh breath, and decreases the risk of plaque-mediated in the oral cavity. Today, mechanical is the primary control method for maintaining or surfactant

plaque removal with assorted devices good oral hygiene. Chemical mouthrinses) is used primarily plaque as an

(e.g., antiseptic

25 adjunct to mechanical treatment methods and may be particularly useful for the cleansing, persons.

of surfaces that are not readily plaque control,

accessible to mechanical

for postsurgical Antibiotics

and for oral care of handicapped

may be used as adjuncts

to oral hygiene to suppress or eliminate not readily accessible to

specific segments of the bacterial mechanical cleansing. Status


,C. Drug/Cosmetic

The current statutory consideration


of “drug”

and “cosmetic” for the reduction includes

require some or prevention any article or prevention

when applying

them to products

of plaque and gingivitis. “intended


to the act, a “drug” cure, mitigation,

for use in the diagnosis,


of disease,” or any article “intended

to affect the structure

or any function

of the body * * * .” (See 21 U.S.C. 321(g).) According includes sprinkled, an article or component thereof “intended

to the act, a “cosmetic” to be rubbed, poured, applied to the human attractiveness,

or sprayed on, introduced

into, or otherwise beautifying,

body or any part thereof for cleansing, or altering the appearance Some products Therefore,
* * *.”


(See 21 U.S.C. 321(i).) or the other. use”

may not clearly fall under one definition in classifying a product

another consideration

is the “intended

of the product,

which is largely dependent labeling.*

on the claims made for the product to accurately describe a

and the accompanying product’ s the public products,

In attempting principles

benefits, one of the guiding with ambiguous

should be to avoid misleading in the case of mouthrinse benefit, while

claims. Unfortunately,

it is easy to make claims that suggest a drug-like the guidelines for cosmetic products.

staying within

Much of the controversy

‘ The legal opinions reflect FDA’ position. s

of this scientific

panel in this area may not and do not necessarily

26 regarding the “drug” versus “cosmetic” around the use of the word “dental deposits, etc.). 1. Antiplaque Products of the ADA and the American Academy of Periodontology basic to the the issue for these products revolves

plaque” or its synonyms

(plaque, bacterial

It is the position that the control prevention

of dental plaque is a therapeutic of caries and periodontal association between control


and treatment

diseases, particularly

latter. The well-established and gingivitis

dental plaque accumulation be accompanied by

demands that effective

of gingivitis

effective control of dental plaque. “Nonspecific” decreasing the entire microbial attempt at differentially species, although

plaque control involves manner, i.e., without bacterial any

mass in a nonspecific or suppressing composition periodontal


any particular

shifts in bacterial and controlling lesions.

may occur. It is the primary infections that may lead to

therapy for preventing periodontal



plaque control implies

the control of specific pathogens, using

strategies that will preferentially microorganisms. agents, typically the microbial after treatment This approach antibiotics,

suppress certain species or categories of generally requires the use of antimicrobial spectrum. Ideally,

with a specific antimicrobial


of the dental plaque should be assessed before and agents used are appropriate and

to insure that the antimicrobial

that the therapy has the desired effect. The nonspecific to achieve clinically health care products a statistically control of dental plaque needs to be thorough significant therapeutic in order

benefits. While some OTC oral to

may be able to reduce the rate of plaque formation degree, the inhibitory effect on plaque is often


27 insufficient to be considered of therapeutic benefit. It is also highly unlikely relationship

that the marginal

control of bacterial

deposits has a significant

to most, if not all, of the cosmetic claims. Outcome variables such as taste and “feel” are more likely to be affected by flavoring reduce surface tension than by minor variations The claim that a product significantly agents and products that

in plaque accumulation.

reduces dental plaque (statistically that the reduction is with the

speaking) may mislead people into thinking therapeutically significant.

Thus, people may purchase a product

mistaken notion that a therapeutic of seeking effective care for potential Therefore, the Subcommittee

benefit may be derived from its use, instead signs and symptoms of disease.

proposes that any reference to the control with or without qualifications, should be

of dental plaque or its equivalents, interpreted

as a drug claim. In addition,

the Subcommittee

proposes that an or prevention of

OTC drug product

making any reference to the reduction a clinically significant

dental plaque also must demonstrate Thus, antiplaque 2. Tartar Products The Subcommittee (calculus) be interpreted

effect on gingivitis.

claims should not stand alone.

proposes that any reference to supragingival as a cosmetic claim. The Subcommittee tartar. Drug Products labels of antigingivitis/antiplaque that labeling include


did not make

any reference to subgingival D. Labeling

of Antigingivitis/Antiplaque

Having reviewed products,

the submitted


the Subcommittee


the following:

28 1. Ingredients

Antigingivitis/antiplaque plus such inactive ingredients

agents should contain

only active ingredients The label

as may be necessary for formulation. of each active ingredient

should state the name and quantity units as specified

in appropriate

later in this document. allergic reactions, safety concerns, and

For various reasons, including personal preference, ingredients. components Subcommittee individuals

may wish to avoid using certain inactive

It is impossible of drug products

to make a free choice in this regard unless all the are listed on the labels. Therefore, that all inactive However, ingredients the product the be listed on should not benefit. and The

strongly recommends

the label in descending

order of quantity. ingredients

imply or claim that its inactive Subcommittee coloring

have a therapeutic

recognizes that although

full disclosure

of flavoring


is desirable, this may be impractical

and confusing Thus, with present
(21 CFR 701.3).

because of the large number of ingredients flavoring regulations and coloring ingredients

that may be involved.

may be listed in accordance in cosmetic products

for labeling such ingredients

2. Statement of Identity The labeling must indicate ingredient recommends demonstrate recommended an antiplaque the principal intended action of the active The Subcommittee that The

as well as the indication

for use of the product.

that the statement of identity an antigingivitis

for active ingredients

effect should be “antigingivitis.” for active ingredients

statement of identity

that also demonstrate

effect should be,“antigingivitis/antiplaque.”

29 3. Indications The indications simply for antigingivitis/antiplaque drug products should be

and clearly stated, inform the user of the general pharmacological and provide a reasonable expectation The indications of results to be

action of the product, anticipated confined

from use of the product. to the conditions

should be specific and The no claim

for which the product

is recommended. for which

labeling for any product

that contains an active ingredient

is made would be misleading. a. For all antigingivitis indication products. The Subcommittee’ s antigingivitis recommended active ingredients (select

for OTC drug products


is: “helps (select one of the following: one or more of the following: disease,’ or ‘ bleeding gums’ ).” b. For antigingivitis Subcommittee’ s containing following: gingivitis.” c. For all antigingivitis/antiplaque recommended antiplaque indication products

‘ control,’ ‘ reduce,’ or ‘ prevent’ ) ‘ gingivitis,

‘ gingivitis,’

an early form of gum


stannous fluoride.

The drug products



for OTC antigingivitis

stannous fluoride

is the statement in paragraph

a. above and/or the

“helps interfere with harmful

effects of plaque associated with


The Subcommittee’ s containing antigingiviti.4 ‘ control,’

for OTC drug products is: “helps

active ingredients

(select one of the following:

‘ reduce,’ ‘ prevent,’ or ‘ remove’ plaque that leads to (select one or more of the ) following: gums’ ).” d. For antigingivitis/antiplaque of eucalyptol, menthol, products containing the fixed combination ‘ gingivitis,’ ‘ gingivitis, an early form of gum disease,’ or ‘ bleeding

methyl salycilate,

and thymol. The Subcommittee’ s

30 recommended combination indication of eucalyptol, for OTC drug products menthol, containing the fixed is the

methyl salycilate,

and thymol

statement in paragraph the following:

c. above and/or the following:

“helps (select one of to

inhibit,’ or ‘ ) plaque bacteria that contribute kill’ ‘ control, ’ ‘ of (select one or more of the following: ‘ gingivitis,’

the development

‘ gingivitis,

an early form of gum disease,’ or ‘ bleeding gums’ ).” 4. Directions for Use for use should be clear, direct, and provide sufficient

The directions information labeling

to permit safe and effective use of the product.

The product effective dose

should include

a clear statement of the smallest usually maximum doses (or concentration

and, where applicable, per time interval.

if more appropriate) should be broken down clinical

If dosage varies by age, the directions used directions directions

by age groups. The Subcommittee

from the supportive for use. dentifrice products. dentifrice

trials as the basis for its recommended a. For an tigingivitis directions products monograph

or an tigingivitis/an


The drug

for use for antigingivitis should be consistent for OTC anticaries

or antigingivitis/antiplaque

with the directions drug products

required in the final

in 21 CFR 355.50(d)(l). “Adults and children

b. For antigingivitis/antiplaque 12 years of age and older: Vigorously

oral rinse products. swish 20 milliliters

of rinse between your the rinse. under 6

teeth twice a day for 30 seconds and then spit out. Do not swallow Children 6 years to under 12 years of age: supervise use. Children

years of age: do not use.” 5. Warnings Labeling of antigingivitis include warnings and antigingivitis/antiplaque products should

against unsafe use, side effects, and adverse reactions.

a. For all antigingivitis than used for brushing and antigingivitis/antiplaque swallowed, products. “If more

(rinsing) is accidentally

get medical help bleeding, or redness

or contact a Poison Control Center right away. If gingivitis,

persists for more than 2 weeks, see your dentist. See your dentist immediately if you have painful increasing periodontitis, or swollen gums, pus from the gum line, loose teeth, or of

spacing between the teeth. These may be signs or symptoms a serious form of gum disease.” products containing stannous fluoride.

b. For an tigingivitis the reach of children 6. Additional Labeling

“Keep out of

under age 6.” Statements dentifrice drug products. In addition to warning

For stannous fluoride statements, the following antigingivitis product dentifrice

statements should appear on the label of drug products containing stannous fluoride: “This

may produce surface staining of the teeth. Adequate tooth brushing or permanent and may be

may prevent these stains which are not harmful removed by a dentist.” E. Combination Drug Products Policy

1. General Combination The Subcommittee active ingredients

recognizes that there may be a reason for combining However, such combinations rationale. The Subcommittee a

in certain OTC drug products.

must be based on a sound and logical scientific applied the OTC drug review regulation

in 5 330.10(a)(G)(iv) in developing drug products. The

combination Subcommittee ingredients

policy for antigingivitis/antiplaque believes that it is rational

to combine oral health care as well as the criteria

that meet the regulatory


32 adopted by the Subcommittee, provided together with suitable inactive ingredients, makes a contribution to the claimed the

that: (a) Each active ingredient

effect, (b) the active ingredients ingredients (c) combining compared

are safe and effective and combining of any individual

does not decrease the effectiveness the ingredients


does not decrease the safety of the combination (d) the inactive inhibit ingredients are safe and do

to a single ingredient,

not interact with or otherwise (e) there is asignificant combination,

the effectiveness

of the active ingredients,

target population

that can benefit from the use of the for use and

and (f) the combination

contains adequate directions

is labeled with adequate warnings The Subcommittee an active ingredient concludes

against unsafe use. that the same general principles pharmacological class reviewed apply when by

from a different

another OTC drug advisory reviewed

panel is combined The rationale

with an active ingredient for such combinations should

by this Subcommittee.

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 The Subcommittee combination product recommends Products that each claimed active ingredient contribution to the claimed from different in a

must make a significant Further,

effects of the product. pharmacological concurrently established

two Category I active ingredients to treat different

groups may be combined

symptoms its

if each Category I active ingredient dosage range, the combination

is present within

is rational,

there is a significant and the

target population

that suffers from the concurrent


33 combination used alone. 3. Category 1 Combination The Subcommittee antiplaque Antigingivitis/Antiplague considers it rational Drug Products antigingivitis/ is as safe and as effective as each individual active ingredient

to combine

agents with an anticaries

agent. It is also rational to combine agent. In addition,

antigingivitis/antiplaque the Subcommittee

agents with a tooth desensitizing it rational to combine


an antigingivitis/antiplaque in a single drug product.

agent with an anticaries Further,

agent and a tooth desensitizer believes that although the combination

the Subcommittee

it has been presented with of two or more antigingivitis ingredients, or combinations

no scientific ingredients,

basis to recommend

two or more antigingivitis/antiplaque and antigingivitis/antiplaque

of antigingivitis

ingredients, provided

it is theoretically that each

reasonable to combine such ingredients, ingredient contributes

it is demonstrated

to the claimed effect and does not decrease the safety

or effectiveness

of another active ingredient. Drug Products that the single active ingredients menthol, methyl salicylate, and the

F. Testing of An tigingivitis/Antiplaque The Subcommittee fixed combination concludes

of eucalyptol,

and thymol

placed in Category I have been shown through effective for OTC use in the control of gingivitis product formulation can have a significant the Subcommittee demonstrate


trials to be safe and

and plaque. However, because of these

impact on the effectiveness

active ingredients, antiplaque


that OTC antigingivitis/ through the testing

drug products

their effectiveness

described below. Based on the varying mechanisms I active ingredients, the Subcommittee recommends

of action of the Category testing specific to each of


the Category I active ingredients traditional

to demonstrate

their effectiveness


dosage forms (dentifrice,

gel, paste, or rinse).

1. Changes in Traditional The Subcommittee I active ingredients the Subcommittee effectiveness

Dosage Forms recommends that drug products containing Category by

formulated be required

in dosage forms other than those reviewed to demonstrate randomized, antigingivitis/antiplaque controlled, clinical trial.

by a single 6-month, Testing

2. Final Formulation

The following a standard

testing should be conducted with effectiveness

on the product

formulation, trials, and it must



by clinical

a negative control. demonstrate formulation reasonable

In general, for a product

to be considered equivalent


that it is statistically and statistically statistical


to the standard


to the negative control as assessed by of the study, the standard must However, during the

analyses. For validation

be statistically rulemaking

superior to the negative control. process, the criteria manufacturers.
Chloride Rinse.


for these tests should be provided

by the product

a. Cetylpyridinium


the in vitro antimicrobial plaque organisms organisms include, commonly


of the product


representative Representative
Actinomyces Bacteroides

associated with gingivitis. to, typed stains of:

but are not limited
P. gingjvalis,

vjscosus, forsythus,

F. nucleatum, Candida


species, S. mutans,

and gram negative enteric activity should

rods. Testing to determine include minimal inhibitory

a product’ s

in vitro antimicrobial


(MIC) assays, or 30-second kill-time

studies, as appropriate.



the availability

of the active ingredient

using a Disk in a

Retention submission

Assay (DRA). A suggested method to the Subcommittee the biological and Regrowth in a submission

for this assay is included

(Ref. 5). activity of the formulation using an ex vivo for this


Plaque Glycolysis assay is included b. Stannous

Model (PGRM). A suggested protocol to the Subcommittee (Ref. 5).

An in vitro determination commonly

of antimicrobial


against representative (described in paragraph in

plaque organisms

associated with gingivitis

F.2.a. of this document) vitro antimicrobial

is recommended. should include

Testing to determine

a product’ s


MIC assays, %&second kill-time

studies, or plaque biofilm

assays, as appropriate. activity of the formulation using ex vivo


the biological for assay, Ref. 5).

PGRM (protocol
c. Fixed

Combination Salicylate

of Eucalyptol(O.092 (0.060






and Thymol(O.064




the in vitro antimicrobial


using 3O-second kill-time organisms obtained F.2.a

studies with both standard laboratory from saliva sampling. of this document. Representative

strains and wild-type organisms

are listed in paragraph

Conduct kill-time

testing using an exposure time of 30 protein. Use an initial inoculum of I-

seconds in the presence of exogenous percent transmission.


the in vivo activity

of the formulation


a short-term

experimental protocol,


study of at least 2 weeks duration. a clinically

A representative and a (Ref. 6).


the test product,

tested standard,

negative control,

is included

in a submission

to the Subcommittee


The criterion

for study validation

is statistically




plaque and gingivitis negative control.

scores between the clinically

tested standard

and the in this the

To establish comparability accepted statistical

to the standard mouthrinse test of clinical comparability),

test (or another generally new mouthrinse


must satisfy the “at least as good as” statistical scores, i.e., at least statistically to the clinically tested standard.

criteria for both plaque and gingivitis significantly
G. Inactive


or equivalent

1. Alcohol

in Oral Health Care Drug Products contain alcohol (up to 26 percent or more). appeared

Many OTC mouthrinses

Concerns were raised when published to show a possible risk of developing of mouthrinses available containing

reports and other information oropharyngeal

cancers from daily use After reviewing concerning the high

high concentrations

of alcohol.

data, the Subcommittee mouthrinses

has the following


alcohol-content (oral).

and cancer of the buccal cavity and pharynx

a. Oral cancer.

Based on the 2993 statistics

for oral cancer in the United are the eighth most common

States (Ref. i’ the buccal cavity and pharynx ), site of cancer, representing Approximately approximately

3 percent of all cancers reported. oral cancer. The ratio of men rate for and 50

30,000 people per year develop

to women developing

oral cancer is about 2 to 1. The s-year survival

persons with oral cancer is about 33 percent for African-Americans percent for Caucasians. Alcohol approximately through consumption three-fourths and tobacco smoking/chewing of oral cancers in the United

account for States (Refs. 8 poor dental

13). Other less clearly established

causal factors include

37 conditions, oral infections, nutritional deficiencies,

and possibly

high alcohol-

content mouthrinses

(Refs. 14 through associated

b. Adverse reactions

with mouthrinses.

A drug that ordinarily

causes no adverse effects with short-term

exposure may produce pathologic usage of a drug and/or its in the mouth may result in should be evaluated (Ref. 20). ingredients, describes for chronic,

tissue changes after chronic usage. Prolonged metabolites cumulative long-term combined with various compounds

effects in oral tissues. Mouthrinses usage and resulting manifestations

Mucous membranes

of the mouth can absorb mouthrinse into the bloodstream.

which may pass systemically local adverse reactions irritancy

The literature

from mouthrinse

usage, ranging in severity from

and sensitization

to cancer (Refs. 21, 22, and 23).

Some case-control

studies suggest a causal association between mouthrinse in the largest study to date by the

use and oral cancer risk, most recently National Cancer Institute

(Ref. 24). The cancer risk seems to be greater in to

females (60 percent) than in males (40 percent) and varies in proportion dose, tending to increase with increasing the alcohol concentration duration and frequency

of use and

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 alcoholalso

contents of 25 percent or higher. However, contain other active ingredients, membranotropic

since these mouthrinses

such as essential oils with lipophilic, mouthrinses may affect

effects, some high alcohol-content

tissues by a variety of mechanisms.

38 Studies that have evaluated cause cancer have a number subject accounts without documentation, the potential for alcohol in mouthrinses (I) Investigations based on to

of shortcomings:

benefit of medical classification

records or other written of exposure to known risk factors doseuse,

(2) unreliable

such as alcohol and tobacco in study subjects, (3) lack of consistent response relationships and (4) combining based on frequency and/or duration

of mouthrinse despite

cases of cancer of the buccal cavity and pharynx

the fact that mouthrinses buccal cavity.
c. Alcohol

are in direct contact only with the mucosa of the

and oral cancer.



of alcoholic


is a known risk factor for oral cancer, pure alcohol does not show a direct carcinogenic with alcoholic These include action in laboratory animals or humans. The cancer associated related to contaminating carcinogens.

beverages is probably urethane produced

from urea reacting with ethyl alcohol during compounds catalyzed agents.

yeast fermentation from precursor Commercial carcinogens. conversion acetaldehyde cells. Animal cocarcinogen,

of fruit juices, and n-nitrosamine


and amines, amides, or other nitrosatable contain distilled


ethanol free of these contaminating of ethanol to enhance the

Other findings of procarcinogens to produce

suggest an ability to mitogens,

and of ethanol’ metabolite s acid (DNA) abnormalities in human


studies have indicated in association

that ethanol may also function

as a

with other substances that are true carcinogens the penetration of carcinogens into

(Ref. 28). Alcohol

may act by facilitating

the mucosa (Refs. 29 through compounds

33). Weak carcinogenic


and other in the presence

have been shown to have enhanced


39 of alcohol (Ref. 33). Alcohol intracellular (Ref. 28). Based on these studies, the Subcommittee recommends that further studies metabolism may act directly on epithelial cells by altering to carcinogens

and rendering

cells more susceptible

on the possible cancer risk associated with high alcohol-content be conducted. mouthrinse These studies should include and pertinent dietary ingredients. Although

mouthrinses of the

testing various components

d. Abuse and misuse of mouthrinses. contain alcohol, the potential due to use of these products mouthrinse security, product

some OTC mouthrinses

for development seems negligible.

of drug tolerance and addiction However, misuse of any

may occur if the product

gives the user a false sense of advice. This


the users’ desire to seek professional s acute for mouthrinses without resolving

problem may be particularly symptoms periodontitis danger. e. Alcohol combination the incidence concludes QS a facilitator. of a gingivitis infection.

that may subdue signs and a more severe, underlying


A label warning

should alert the consumer to this

While the Subcommittee

recognizes that the

of alcohol and tobacco is associated with a marked increase in of oral cancer as compared to exposure to tobacco alone, it is unknown. potentiating Animal studies

that the mechanism

of this synergism

(Ref. 28) have shown that alcohol has a topical production of squamous cell carcinoma

effect in the

in animal cheek pouches treated with Decreased latency and larger

7,1%dimethylbenz(a)-anthracene tumors were observed as compared


to controls. similar

Other animal studies (Refs. 29, 30, 32, and 33) have demonstrated effects. These studies were older and implied

a model that is not comparable

40 to what happens in humans. Moreover, species-specific, performed and limited information some carcinogens is available are extremely

on direct experiments

on the human mucosa. effect of alcohol in causing an increased risk of oral to a topical effect, as noted in the animal studies, then a high concentration this may be as significant continued of alcohol may have as alcoholism in

If the synergistic cancer is attributed

daily use of oral rinses containing a tissue altering effect. Whether the epidemiology

of oral cancer warrants


One of the few mechanistic demonstrated by permeability

evidences for a local alcohol effect has been studies. In the presence of nicotine, of carcinogens alcohol had

a greater relative effect on penetration

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 taken up and held in the oral

reservoir effect, so that compounds epithelium, extending the duration

are rapidly

of their effect (Ref. 35). This mechanism using alcohol to increase of proprietary drugs after

has recently been utilized permeability,

in a formulation

thereby obtaining

systemic delivery

only a mucosa exposure. It is clear that further research is needed to investigate as an enhancer of the penetration addition, the threshold of carcinogens the role of alcohol

through the oral mucosa. In necessary to achieve this

of alcohol concentration


needs to be investigated. Conclusions and Recommendations Regarding Alcohol

2. The Subcommittee’ s Content in Mouthrinses

On June 6, 1996, the Subcommittee, (e.g., epidemiologists and statisticians)

along with other scientific held a workshop


(Ref. 36) to further

consider whether Although alcohol-containing mouthrinses contributed to oral cancers. mouthrinses between high as

some studies have implicated

high alcohol-content

a possible cause of oral/pharyngeal alcohol-content findings mouthrinses

cancer, the relationship

and oral/pharyngeal

cancer is not clear. The

of various studies are contradictory relationship. A major difficulty of confounding

and do not show a consistent in deciding by known cause and effect in risk factors, such as


these studies is the possibility high alcoholic

beverage consumption reviewed

and tobacco use. of a specificity analysis

The Subcommittee

new data consisting

(Ref. 37) using data from the W inn et al. study (Ref. 24) and a preliminary analysis from an unpublished (Ref. 38). In addition, published study of laryngeal, reviewed esophageal, and oral cancer seven case-control studies,

the Subcommittee

between 1979 and 1991 (Refs. 12,13, and 23 through

27), of the

association between mouthrinse described below.

use and oral cancer. These studies are

Weaver et al. (Ref. 23) reported the use of alcohol-containing among 11 subjects with oropharyngeal smoke or drink alcoholic study regarding oropharyngeal hypothesis cancer who indicated


that they did not

beverages. These cases became part of a case-control mouthrinses and

an association between alcohol-containing cancer. Although the study was unevaluable,

it generated the

that led to subsequent studies. study by Wynder et al. (Ref. 12) evaluated the

A 1983 case-control relationship findings

between mouthrinses

and oropharyngeal

cancer. No positive for for for

were reported for men. In women, the relative risk, unadjusted beverage consumption, However, was statistically significant

smoking and alcoholic daily use of mouthrinses.

there was no consistent


42 duration or frequency of use. Further, a refined analysis using a multiple use and

logistic model indicated oropharyngeal a dose-response alcoholic

no association between mouthrinse concluded

cancer. The investigators

that, due to the absence of by tobacco and between

relationship / and the possibility

of confounding

beverage use, it was not possible to attribute use and oral cancer in women.

an association

daily mouthrinse

A 1983 case-control from a previous

study by Blot et al. (Ref. 13) included

female subjects for

study of snuff use. A relative risk of 2.94 was reported but did not use tobacco products. (confidence relationships interval

women who used a mouthrinse this was not statistically were no consistent



= 0.8 to 4.7), and there of


for years of use, frequency (i.e., diluted

use, time retained in the mouth, or concentration Because dose-response relationships are important

vs. full strength). whether

in considering

there is an association between mouthrinse Subcommittee between

use and oral cancer, the

concludes that this study does not support a causal association mouthrinses and oropharyngeal case-control cancer. studies


The Subcommittee published


three additional

between 1985 and 1989 (Refs. 25,26, and 27). One study by Kabat interest because, although mouthrinses were not

et al. (Ref. 26) is of particular

associated with increased oral cancer risk in terms of frequency of use, cases were significantly mouthrinses

or duration

more likely than controls to state that beverages using

were used to disguise breath odors caused by alcoholic

or tobacco. In contrast, similar proportions a mouthrinse

of cases and controls reported

to conceal food odors or for mouth infections concludes that these findings indicate drinking

or dental problems. that mouthrinse and/or smoking. use

The Subcommittee

may be serving as a surrogate for underreported

43 A 1991 study by Winn et al. (Ref. 24) was the largest case-control among the seven published 1,249 controls). Odds-ratios studies evaluating for oropharyngeal mouthrinses study

(866 cases and for

cancer risk after adjusting interval

tobacco and alcoholic

beverage use were 1.4 (confidence interval

1.0 to 1.8)

in men and 1.6 (confidence relationships,

1.1 to 2.3) in women. Dose-response of use, and age when use

such as duration

of use, frequency

started, were questionable, reported.

with no trend analysis of these relationships for dental X-rays.

This study also showed a decreased odds-ratio plausible

There is no biologically

reason to expect X-rays to be protective is likely a reflection of less

against oral cancer, and the negative association

frequent visits for dental care by cases versus controls. However, association to quality could not be eliminated by adjustment

the negative

for factors that are relevant

of dental care (e.g., education). a statistically significant of the data. due to

Thus, this study was capable of producing noncausal association

that could not be eliminated

by adjustment

Further, regarding underreported

the odds ratio for mouthrinse

use, confounding

use of tobacco and alcoholic

beverages, both strong risk factors elevated odds ratio.

for oropharyngeal

cancer, could result in an artificially can be produced

Such a false association underreporting Information

even though the extent of

is the same in both the case and control groups (Ref. 39). in the published literature indicates that especially (Refs. 40 through 44). The drinking and

sometimes smoking are underreported Subcommittee relationship oropharyngeal concludes

that these studies do not support a causal mouthrinses and

between the use of alcohol-containing cancer.

44 The Subcommittee specificity reviewed unpublished new data that included a

analysis (Ref. 37) of the data from the Winn et al. study (Ref. 24). 75 cases (38 men and 37 women) who did not have cell cancer of the mouth) based on of Diseases codes. The excluded

This analysis excluded oropharyngeal evaluation

cancer (i.e., epithelial

of the International primarily


cases consisted and Iymphomas

of tumors of the minor salivary glands and sarcomas to occur within the oral cavity. Excluding cancer in men and women, beverage use indicated that cases these

that happened

cases left 535 and 256 cases of oropharyngeal respectively. Evaluation

of smoking and alcoholic

both of these risk factors were more strongly associated with the included than with the total number of cases (included nor alcoholic plus excluded).

Neither smoking cases. This

beverage use were associated with the excluded that the excluded

analysis indicated the included original

cases may not have the same etiology as in the

cases and, therefore,

should not have been included

analysis conducted use.

by Winn et al. (Ref. 24) to evaluate risk associated

with mouthrinse

When odds ratios for mouthrinse included originally

use in women were calculated

for the

cases, they were decreased relative to the odds ratios for total cases reported by Winn et al. (Ref. 24). This was true for a number of duration of use, frequency of use, age when use began, use among the



and alcohol concentration. excluded

Higher odds ratios for mouthrinse

cases suggested that mouthrinse cases than with included explanation

use was more strongly associated cases. However, there is no cases explained

with excluded biologically


for this finding

since the excluded

represent a variety of tumor types whose origins cannot be presently by topical exposure to ethanol via mouthrinse use. In addition,

the data were

45 inconsistent with a dose-response with respect to duration of use, frequency

of use and age when mouthrinse may be related to information specificity

use started, which suggests that this finding The

bias rather than a causal association.

analysis among male cases was less informative nor information

than for females bias as the

and supports neither a causal hypothesis explanation originally for the weak association

with mouthrinse

use (odds ratio 1.4) value of the specificity male cases

reported by Winn et al. (Ref. 24). The limited

analysis in males is likely related to the fact that: (1) The excluded represented

a smaller percentage of the total male cases and (2) the odds ratio use in males is smaller than it is in females. Both of these to detect any shifts in odds ratios. The Subcommittee analysis of the Winn et al. study (Ref.

for mouthrinse

factors make it difficult concludes

that, overall, the specificity

24) indicates that this study does not support a causal association between
mouthrinse use and oropharyngeal cancer (Ref. 37). case-control study of laryngeal,


analyses from an unpublished

esophageal, and oral cancer (Ref. 38) showed that the odds ratio for mouthrinse use in males and females combined beverage use) was 1.4 (confidence of frequency, question duration, (adjusted for cigarette and alcoholic interval

1.0 to 2.0). However, the analyses

and age when use started showed inconsistencies In addition,

a causal relationship.

when the data were evaluated with for smoking and containing no

respect to alcohol content, the highest odds ratio (unadjusted alcoholic beverage use) was found among users of mouthrinses

alcohol (e.g., salt water, vinegar, baking soda in water). The Subcommittee concludes showing that this finding differs from the Winn et al. study (Ref. 24) results having the highest

that odds ratios were elevated only for mouthrinses

46 alcohol content and is inconsistent between alcohol-containing An unpublished of alcoholic Subcommittee with the hypothesis of a causal association


and oral cancer. concerning possible mechanisms to the

review of the literature

beverage consumption (Ref. 45). Although

and oral cancer risk was submitted alcoholic beverage consumption on experimental

is a known

risk factor for oral cancer and the literature

mechanistic concerning how

studies (e.g., in vitro and animal studies) raises speculations the biological concludes effects of alcohol may modulate

cancer risk, the Subcommittee use in humans

that the relevance of these studies to mouthrinse

has not been established. Based on the studies reviewed, available containing Chairman the Subcommittee concludes that the

data do not support a causal relationship mouthrinses abstaining.

between the use of alcoholwith the

and oral cancer. The vote was unanimous The Subcommittee acknowledges

that epidemiologic

research on oropharyngeal

cancer will continue,

and that the conclusion

reached by the Subcommittee deliberations. However,

is based on the data available at the time of its

because some studies did report a relationship mouthrinses and pharyngeal cancer,

between the use of high alcohol-content the Subcommittee the relationship pharyngeal mouthrinses concentration panel. agrees that further

studies should be conducted mouthrinses

to determine

between high alcohol-content

and oral/ that all

cancers. In addition,

the Subcommittee


should be labeled in a readily in percent, e.g., “Contains

readable manner with the alcohol display

- % alcohol” on the principal

47 IJ. General Guidelines on Safety and Effectiveness

1. General Statement The Subcommittee regarding arrived at its conclusions and recommendations after considering adopted the to restrict as desirable

the safety and effectiveness data and information

of all active ingredients

all pertinent following


The Subcommittee

general “points

to consider. ” These are not intended for studies recognized

investigators, approaches antiplaque applicable,

but are recommendations to determine

the safety and effectiveness

of OTC antigingivitis/

active ingredients.

In some cases, other methods may be equally Also, these recommended that an

or newer methods may be preferable. all information

studies may not produce ingredient is generally

necessary to determine


as safe and effective.

2. Guidelines
An OTC drug included

in a monograph

is described in 5 330.10 as for use and consists of



among qualified

experts as safe and effective

as not misbranded.

Proof of the safety of an OTC drug ingredient applicable

adequate tests by methods reasonably the prescribed, include recommended,

to show the drug is safe under of use. This proof shall General

or suggested conditions human experience

results of significant

during marketing.


of safety shall ordinarily by unpublished

be based upon published

studies which

may be corroborated effectiveness investigations

studies and other data. Proof of consists of controlled
(21 CFR 314.126b))

of an OTC drug ingredient as defined in 5 314.126(b)

clinical by qualified relief of the type

experts to show that the drug provides claimed in its labeling. reasonably applicable



The latter requirement to the drug in question

may be waived if it is not or essential to the validity of

48 the investigation substantiate controlled and an alternative method of investigation is adequate to by partially human experience be based

effectiveness. or uncontrolled


may be corroborated

studies, and reports of significant of effectiveness

during marketing. upon published other data.

General recognition

shall ordinarily

studies that may be corroborated

by unpublished

studies and

The characteristics developed supporting sufficient evaluation

of adequate and well-controlled

studies have been Studies should provide

over a period of years and are described the safety and effectiveness

in § 314.126.

of OTC drug ingredients

details of study design, conduct, of the data in relationship

and analysis to allow a critical

to the above characteristics. the agency has stated that, in it

In several proposed and final monographs, order for an active ingredient is necessary that the ingredient standards be published Pharmacopeia to be included be adequately

in an OTC drug monograph, characterized

and that these States

in an official

compendium Formulary

such as the United

(USP) or the National

(NF) (58 FR 28194 at 28284). strength, quality, recommends and chemical contact and and that

Such specifications purity

are necessary to assure the identity, Therefore,

of the active ingredient.

the Subcommittee its physical

a full description characteristics

of the ingredient, and stability,


be provided,

and that manufacturers for ingredients

work with the USP to develop monographs currently included included in that compendium. compendium,

that are not that are currently of the

For ingredients

in an official

reference to the current edition

USP or the NF may satisfy this requirement. a. Safety. The Subcommittee’ s ingredients and ingredient determination of the safety of single criteria: (I)


is based on the following

49 The incidence the ingredient and risk of adverse reactions and significant was used according to adequate directions side effects when in the labeling, (2)

the margin of safety under conditions

of normal use and the potential of widespread

for harm OTC

that might result from abuse or misuse under conditions availability, including (3) the potential irritation, ulceration, for inducing untoward

effects on the oral tissues,


erosion, and minor effects such

as discoloration

of the teeth, restorations,

and prostheses, etc., and (4) states that microbial of changes in

assessment of the benefit-to-risk safety should be determined representative opportunistic oral microbial

ratio. The Panel further clinical evaluation



(e.g., the possible emergence of in order to assure that there under conditions

organisms or potential


is no adverse change in the balance of the oral microflora of expected OTC use. i. Toxicological to demonstrate recommends studies. A variety of toxicological

data can be obtained

that an active ingredient that manufacturers

is safe. The Subcommittee studies discussed the use

conduct the applicable

below and emphasizes that these recommendations of alternative methods comparable methods that are currently

do not preclude

available or better recommends intended for

that may be developed

in the future. The Subcommittee

that the following

data be available for the active ingredient(s) of the mouth and throat.

use on the mucous membranes

Testing the effects of various ingredients can reflect human subpopulations studies in nonsalivating

on animal subpopulations


should be considered acceptable,

(e.g., hyposalivation controlled in vivo

animals). Adequate, toxicity

studies of acute and chronic available.

in several species of animals should be single-dose gavage studies, repeat-dose

Such studies may include

50 gavage studies, oral irritation and dermal sensitization reproductive ingredients toxicologic, studies, pharmacokinetic/biodistribution regarding the genetic, potential should be considered basis. It is not for studies,

studies. Information and carcinogenic

that are going to be used daily on a long-term

necessary to determine of the ingredient. be useful.

the LDso (lethal dose for 50 percent of the test animals) information about the minimal lethal dose would


All or some of the recommended necessary for all active ingredients. an ingredient


studies may not be that might preclude

Some circumstances

from the above testing are: (1) It is already generally recognized (3) it has been used previously in

as safe, (2) it is a direct food additive, approved monograph dental drug products, with a different

or (4) it is the subject of an OTC drug

but similar or related use at a similar concentration Published above. primary concerns regarding antigingivitis/ the active ingredient that gavage unless using a can articles may be considered in lieu

and for a similar time period. of the testing recommended

One of the Subcommittee’ s antiplaque ingredients is whether

or not swallowing

presents a threat to the user. The Subcommittee


studies be used to address concerns about potential applicable published or unpublished

systemic toxicity

studies have been conducted and comparable

dietary admixture

mode of administration

toxicokinetics Single

be shown between gavage and dietary modes of administration. administration gavage studies are typically performed

using a limit-value potential


in the rat at a specified
46, 47,

high dose to evaluate acute toxicity


and 48). In the absence of adequate dietary admixture

studies, repeat from

dose gavage studies may be employed

to evaluate systemic toxicity

multiple exposures. The test article is administered days. active ingredients to rats on a number of


Where there is a concern that antigingivitis/antiplaque may induce untoward

effects on the oral mucosa, the dosage to be used for based on the concentration of human exposure

these studies should be justified levels. An appropriate comparable remaining

dosage range may extend, for example, from a low dose a single dose of mouthrinse of a mouthrinse or the amount

to swallowing following

expectoration toxicity

to a high dose that either greater than the per day

causes dose-limiting clinical

or is several orders of magnitude

exposure levels. Such studies usually use four applications days. The oral irritation

for a period of 28 consecutive a negative and a positive an identical

should include both in

control group. All test articles should be applied

manner. A negative control group may consist of animals that are control is a group of to cause a minimal

treated with either water or saline, and the positive animals that are treated with the solution degree of irritation solution without

that is known

being inhumane

to the animals (e.g., s-percent

of sodium lauryl sulfate). recommends whether that the study include abraded mucosa

The Subcommittee in order to determine

the test ingredient

delays or prevents the healing of changes the

of oral lesions. The parameters to include in the oral tissue, such as sloughing,

are any gross observations or bleeding. Following


sacrifice of each animal, the histopathology ii. Studies
in older adults.

of oral tissues should be examined. is concerned that older

The Subcommittee

adults might be at greater risk for potential antigingivitis/antiplaque because of the continually active ingredients. increasing

systemic toxicity

from the use of concern who

This is of particular

size of the older adult population,

52 are retaining more natural teeth and becoming products. in drug responses in the elderly. (Ref. 49). Absorption function, can but the a significant population for

of antiplaque/antigingivitis Publications

have described differences

Changes in pharmacokinetics theoretically majority

have been reviewed

be altered by noted changes in gastrointestinal

of studies have shown no difference Distribution

in rate or extent of absorption the body is affected water decreases.

of the drug examined.

of a drug within

because fat content of body weight increases and intracellular For example, albumin albumin concentration

is reduced and drugs which bind to to the rest of the body. Hepatic metabolism

are more free to distribute

may be altered. Reduction

of blood flow to the liver will decrease clearance is affected in some older adults by loss of renal

of some drugs. Renal excretion mass and functional nephrons.

Russell (Ref. 50) noted that despite numerous impaired GI function with aging, most functions

reports in the literature remain relatively intact


because of the large reserve capacity of the intestine, a review critically analyzing available information GI physiology of lipids,

pancreas, and liver. In on age-related changes in data suggested lipid intercurrent

the digestive and absorptive digestion and absorption

are well-preserved stress may produce

in the aging. However, impairment (Ref. 51).

illness or experimental

in aging animals and

humans that is not seen in younger controls Atillasoy

and Holt (Ref. 52) noted that the GI tract represents an organ by rapid proliferation. Contrary to generally not held

system characterized prejudices,

the authors write, a state of hyperproliferation, occurs in the epithelial


cells of the stomach, small intestine,

53 and large intestine rodents. In a gavage study (Ref. 53) Yamada et al. investigated ammoniagenesis (exhibiting significant in isolated nephron renal acidotic senescent of stable-fed, aged rodents when compared to young adult

segments from control,

deteriorating difference

teeth due to aging), and young adult rats. No ammonia production

was seen in glutamine-dependent ammonia production

in the segments. However, significantly

in glomeruli

from old rats was

greater than in young rats. consistent findings to warrant that in

There appear to be no available additional

gavage studies of antigingivitis/antipIaque findings

active ingredients

older animals will produce more meaningful

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. Subcommittee
Although disposition,


considers a comment by Ahronheim
much has been written about age-related

(Ref. 54) appropriate:
alterations in drug of these changes. Cross-sectional

there is disagreement on aged individuals

as to the extent and inevitability suffer from several problems.

Studies focusing studies comparing individuals

young and old subjects sometimes

compare young, healthy or nursing homes. If the aged can alter

with aged subjects gathered from hospitals they may nonetheless

subjects are “healthy”

have subclinical a drug’ disposition s

disease, which

outcomes in studies that seek to determine

and effects. However, so that the study’ s studies

aged subjects that are truly healthy may represent results may not be applicable are almost impossible that the geriatric In addition physiology, to the general elderly

an elite minority population.


to complete

and data is sparse, but recent findings



is, indeed, heterogeneous. it is not known how generalizations to drug disposition, about aging since most drugs

to these pitfalls,

even if they are true, can be applied

have not been subjected to exhaustive be reached based on pharmacokinetic pharmacodynamic activity, age-specific testing and few conclusions about density, can

data. Even less is known

changes because the study of age-related tissue receptor is in its infancy. We must therefore rely on clinical conclusions about efficacy

and sensitivity

observations toxicity

to a large extent when drawing

and potential

of various agents in use. The Subcommittee


that the results of

the usual gavage studies are adequate. iii. Irritation Observations

and delayed contact sensitization
adequate clinical

studies in humans. to demonstrate the


studies are sufficient of an ingredient


and sensitization However,


or ingredient the use


if necessary, a number of methods embodying skin irritancy and

of patch testing have proven of value in determining systemic sensitization. The Subcommittee


one of the following and sensitivity: tests

three methods of patch testing to address concerns of irritancy


testing. In the Draize human skin irritancy

and sensitization

or one of its various modifications

(Ref. 55), the testing should be performed

on the skin of the subject’ back or arm. s

Method of Shelanski

and Shelanski.

In this method (Ref. 56), the active at frequent intervals


or the formulation

under study are applied

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 in susceptible are made to detect primary individuals. skin irritants and provoke sensitization or not the

The challenging

dose detects whether

drug is a skin sensitizer.


procedure uses an irritant

of K&man.

This procedure over a desquamated

(Ref. 57) or one of test site.

its modifications Desquamation

is performed

by using a rubbing technique

that facilitates

55 penetration, thereby hastening and accentuating the skin-sensitizing potential

of the substance. Other validated iv. Microbiologic potential evaluafion.

human models may be used. The Subcommittee ingredients pathogens, is concerned about the effects to

of antigingivitis/antiplaque

with antimicrobial

allow emergence of opportunistic microorganisms,

induce resistance in oral of inherently resistant potential to

or allow an oral overgrowth microbial

pathogens. Representative the total cultivable monitored product

species and their relative proportion


in supragingival

plaque and saliva should be use of the antiplaque

over at least a 6-month period of continuous to determine

if a shift in the oral flora has occurred that might result of pathogenic microorganisms, which may include

in the proliferation


species and other yeast, Staphylococcus aureus and other Staphylococcus species, beta-hemolytic Additionally, mechanism

Streptococci, and enteric gram-negative


for those antigingivitis/antiplaque

where the

of action is suspected to be antimicrobial, associated with gingival

an assessment of changes

in microorganisms determination

disease should be carried out. One

should be made prior to the start of use, one at the conclusion time. In vitro minimum inhibitory the

of the study, and one at an intermediate concentrations development

should be assessed for representative of increased resistance after prolonged

species to determine antimicrobial therapy.

b. Efiectiveness. The Subcommittee’ s effectiveness antiplaque of ingredients


of the therapeutic for antigingivitisl

and combinations

of ingredients

use is based on published

and unpublished

studies containing to be scientifically valid

pharmacological and pertinent. or combination

data considered by the Subcommittee Clinical criteria for proof of effectiveness were determined

of a single ingredient data from valid

of ingredients

by evaluating

56 controlled studies and by calling on the clinical expertise of the Subcommittee or combination of

members. Proof of effectiveness ingredients was determined

of a single ingredient

by evaluating

data from valid, well-controlled of the symptoms or a therapeutic

studies demonstrating

a significant


benefit for the stated indication Although product

in the labeling. review, not a must be

the OTC drug review is an active ingredient

review, the Subcommittee properly, according

recognizes that a final product


to accepted pharmaceutical properly,

manufacturing may be

practices. If a product

is not formulated

active ingredients

present in less than the minimum not exert the intended Therefore, ingredients therapeutic

effective dose, may be in a form that does effect(s), or may not be bioavailable. it important whether or not inert

the Subcommittee


or other active ingredients principal

in a formulation

might alter the effect of a mean

of the product’ s pharmaceutical

active ingredient.

The designation

necessity as an inactive is pharmacologically

ingredient inactive.

does not necessarily

that the ingredient

The Subcommittee

considers its recommended


to consider” concerning These “points the to

acceptable current approaches for arriving effectiveness consider” techniques of OTC antigingivitis/antiplaque

at valid conclusions drug products.

do not preclude

the use of newer, more refined laboratory

or clinical

to establish effectiveness.

c. Clinical

trials. Acceptable

studies should state the specific objectives literature, and present the scientific and duration rationale

of the study, a review of pertinent for the use of the ingredient. should be thoroughly measuring

The mode, frequency,

of application

described. The indices and variables selected for the methods of measurement, and the rationale for


57 such choices should be characterized. effectiveness ingredient, a clinically gingivitis. of an OTC antigingivitis or ingredient significant combination endpoint, The Subcommittee ingredient, believes that the

antigingivitis/antiplaque by evidence of of

should be demonstrated a reduction


and/or prevention of as

In general, the Subcommittee


also expect a reduction

dental plaque mass and/or plaque virulence indicated

(degree of pathogenicity

by the severity of the disease produced). can reduce gingivitis

However, the Subcommittee without a demonstrated

also believes that an ingredient reduction

of plaque. Where possible, additional by demonstrating

evidence for the effectiveness a shift in the plaque flora. between reduction or

of the agent should be provided

i. Design. Studies should measure the difference prevention as compared include of dental plaque and gingivitis resulting

from the test ingredient designs and therapeutic studies

to a placebo. Examples of acceptable experimental factorial, sequential, single-blind,

crossover, parallel,


studies. Preference should be given to using double-blind The placebo is the formulation or some other suitable placebo.

with a placebo control. the active ingredient,

of the test agent without

ii. Subjects. A sufficient statistical

number of subjects should be used to permit The number of subjects tested should by the placebo

analysis for the data obtained. to eliminate

be sufficient

examiner bias and bias introduced

effect, if applicable, variability

and to allow for anticipated

dropouts and estimated the

of effect. The subjects should be of both genders and within is intended.

age groups for which the active ingredient criteria should be given. iii. Conduct demonstrate

Specific exclusionary

of the study. The study should be of sufficient The duration




will depend upon the actual use,

58 anticipated effect, potential sustained benefits, and any safety considerations.

The Subcommittee duration antiplaque to provide

believes that such studies should be at least 6 months in sufficient time for an ingredient to exert an antigingivitis/ Six months

effect and for adverse events to manifest themselves. time to investigate the possibility

will also provide

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 and oral health evaluations appropriate historical, intervals of pathogenic microorganisms. Scoring and at

should be done at baseline, at completion, medical,

during the study. Baseline demographic,

and physical

data for each subject should be obtained and recorded. a medical history, a complete oral examination, data.

Such data should include laboratory

studies, if indicated,

and other pertinent

The treatments randomization controlled preparation indication

should be performed

on a random basis. The


should be used so that variables not otherwise of applications of the

balance out. The number and frequency

should be in accordance with the method outlined for use and directions in the labeling. The clinical

in the investigative team

should monitor appropriate

subjects during the study to detect any adverse events and take of dose response and possible mechanism

action. An evaluation

of action would iv. Appropriate

enhance any submission. assessments. Appropriate must be used. of data. Investigative methods should be described in assessments using validated or

accepted techniques
v. Interprefation


detail so that experiments

can be repeated by another investigator of statistical analysis should be

to verify and confirm determined

results. Methods

before starting the study.

59 Positive evidence of effectiveness two studies, each conducted addition to statistical should be obtained from a minimum investigative group. In of

by an independent clinical



should be addressed. changes not being controlled trials of

Strength of effect and concern about statistically clinically significant reflect the importance if individuals


of randomized

longer duration interventions. (categorical)

to determine Statistical

benefit from proposed agents and using a nominal


can be easily calculated

scale such as gingival normal distribution

index scores. A large “N” offers scores with so that parametric statistics can be used,

an approximately

as if using exact measures such as in an interval index, however, is a nominal

or ratio scale. The gingival between 0 and 2 is not exist in mean

scale and the difference

the same as the difference gingival discerned


1 and 3. Slight differences

index scores which

are not clinically can produce

obvious and cannot be easily a change in the response significance

in a subject. A product

variable that is statistically remains unanswered. III. Classification In addition considered conclusions following


yet the question of clinical

of Active Ingredients to carefully reviewing the submitted data, the Subcommittee at its The

all pertinent

data and information regarding

available in arriving the active ingredients. recommended

and recommendations tables summarize

the Subcommittee’ s


of active ingredients:
Active Ingredients Aloe vera Cetylpyrfdinium chloride dihydrate


INGREDIENTS Safety Ill I I I I Efficacy III I Ill Ill Ill

Dicalcium phosphate Hydrogen Sanguinaria peroxide extract

Actwe lngredtents Sodturn btcarbonate Sodwm lauryl sulfate Stannous Zmc citrate lluonde (for gmgwtls)

Safety I I I I Efficacy Ill III I Ill

Active lngredlenl Alkyf dImethyl amlne oxide and alkyl dlmethyl glyone Eucalyptol, Hydrogen Hydrogen Hydrogen Peppermtnt menthol, methyl sallcylale, peroxide and powdone and thymol Combmahon

Safety III I Ill I I I I I Efficacy III I Ill Ill II1 Ill Ill Ill


peroxlde and sodwm btcarbonate peroxlde, sodwm citrate, sodium lauryl sulfate, and .zmc chloride

011and sage oil and poloxamer and zinc citrate

Polydimethylsiloxane Stannous


A. Category

I Conditions

The Subcommittee antigingivitis/antiplaque ingredients


Category I labeling

for all Category I single of active

active ingredients

and combinations

(see section 1I.D of this document).

1. Category I Single Active Ingredients
Cetylpyridinium Stannous fluoride a. Cetylpyridinium cetylpyridinium chloride chloride (rinse)

chloride (rinse).

The Subcommittee



at concentrations available

of 0.045 to 0.1 percent with at least chloride is safe and

72 to 77 percent chemically effective antiplaque the United for use in mouthrinse



as an OTC antigingivitis/ mouthrinses chloride have been used in

agent. Cetylpyridinium-containing States since 1940. Cetylpyridinium

0.025 percent to 0.1 Products containing The more

percent has been marketed nationally cetylpyridinium chloride

in several products.

have also been marketed


than 55-year U.S. marketing ingredient’ s safety. chloride chloride including is a quaternary nitrogenous activity compound I-hexahistory is significant with respect to the

Cetylpyridinium decyl pyridinium microorganisms, well described

with antimicrobial viruses. Its chemical

against many properties are

and physical as a cationic

in the USP (Ref. 58). It is classified a cetyl radical substituted acid it forms a chloride contributing


agent and contains 1. In hydrochloric molecule lipophilic,

for hydrogen

atom on position

salt. The cetyl radical renders the balance which nitrogenous of

to the lipophilic/hydrophilic activity activity of such quaternary is dependent

is necessary for the antimicrobial compounds. The antimicrobial

upon the positioning

the charged molecule positioning

with bacterial

cells that carry a net negative portion of the cetylpyridinium in leakage of cellular of cell growth,

charge. This chloride components, to

allows the hydrophilic

interact with the cell membrane, disruption of cellular metabolism,

resulting inhibition

and cell death region is the activity the chloride claim.

(Refs. 59 through critical

62). Because the positively activity,

charged hydrophilic that diminishes

to antimicrobial

any formulation

of this cationic product.

group or that competes with this group may inactivate it is essential to establish that the cetylpyridinium biologically active to justify an antigingivitis


in products

is sufficiently

i. Safety. The Subcommittee permit final classification

believes there are sufficient

safety data to as an OTC the

of the safety of cetylpyridinium


antimicrobial proposed conclusions

agent for topical use in the oral cavity when used within The Subcommittee chloride bases its

dosage limits set forth below.

on the safety of cetylpyridinium


used in

animal and pharmacokinetic

studies, assessment of adverse events in

62 randomized, placebo-controlled clinical trials, and postmarket and FDA. per kilogram (mg/ spontaneous

adverse event data reported

to the manufacturer chloride

The LD50 of cetylpyridinium kg) given subcutaneously,

is 250 milligrams

6 mg/kg intraperitoneally,

30 mg/kg intravenously,

and 200 mg/kg given orally as a pure compound

(Ref. 63). The data (Ref. 64) containing 0.05

show that the oral LDse values in the rat from a mouthrinse percent cetylpyridinium chloride

were 34 mg/kg to 48 mg/kg of the mouthrinse as compared to of

alone. This lower LD50 with the rinse formulation cetylpyridinium the mouthrinse, Subchronic chloride in solution

is likely due to the other components

such as the alcohol. toxicity studies of cetylpyridinium chloride administered and death in

orally at dose levels ranging from 5 to 500 mg/kg showed morbidity at 125, 250, and 500 mg/kg. At lower doses, the only significant rats and dogs was gastric irritation


at doses of 50 mg/kg per day and higher prior to 1950.

(Ref. 65). These studies are similar to studies conducted Two chronic

exposure safety studies of 6 months and 1 year were reported daily by oral gavage ranged from 5 to 75 mgl

(Ref. 65). Doses administered kg. Significant

decreases in body weight and weight gain were noted in 40GI irritation was manifested

and 75-mg/kg animals of both sexes. At necropsy, as thickening

of the stomach mucosa observed at the 40- and 75-mg/kg level, 15 mg/kg. eye irritation tests and dermal but

and in some animals administered Local irritation exposure. Evidence

studies (Ref. 65) included of eye irritation

was observed at high concentrations using cetylpyridinium

no dermal lesions were observed. Local irritation chloride irritation mouthrinse formulations

was assessed in the canine oral mucosa

model (Ref. 65). A cotton plug saturated with cetylpyridinium

63 chloride mouthrinse was applied to the gingival mucosa three to five times up to 0.45 percent Lin signs

a day for 4 days. Mouthrinse cetylpyridinium chloride



did not induce irritation inhalation toxicity difficulty,

after 20 applications.

et al. (Ref. 66) evaluated of toxicity, including

in rats and found clinical eye irritation,


and nasal discharge chloride/liter and

at concentrations above. However,

of approximately these nonlethal

0.1 mg cetylpyridinium effects were reversible.

A study of the effects of alcohol and cetylpyridinium buccal mucosa of hamsters was reported applications of 0.05 percent cetylpyridinium (Ref. 67). Animals chloride


on the

received daily

for 21 days on the

everted hamster cheek pouch. Abrasion differences

was also carried out. No significant and study animals.

were found between the control potential

Contact sensitization concentration a lo-percent

was assessed using a 25-percent chloride in petrolatum for sensitization was and

of cetylpyridinium concentration

for challenge.

No evidence of sensitization

observed in any of the 24 participants Pharmacokinetic elimination

(Ref. 65). distribution, and

studies assessing absorption, chloride

of cetylpyridinium

were done in rats and dogs (Ref. 65).

In the rat study, approximately cetylpyridinium chloride

85 percent of a single dose of radiolabeled

was detected in the feces and about 10 percent in since only 56.5 percent of the was recovered from the

the urine. The dog study was inconclusive, radiolabeled cetylpyridinium chloride


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

64 cetylpyridinium approximately reported chloride. In contrast, Lobene et al. (Ref. 71) found that chloride study

a quarter of the subjects using cetylpyridinium irritation

a slight, transient

of the gingiva. In one short-term chloride

(Ref. 72), more subjects in the cetylpyridinium have aphthous

group were found to irritation clinical and aphthous trials of

ulcers than the placebo group. Gingival in other randomized controlled

ulcers were not reported cetylpyridinium mucosal irritancy with hyposalivation,

chloride-containing potential


Further studies of the especially in those

of cetylpyridinium


are warranted. changes in pathogens in the

Studies (Refs. 65 and 73) showed that there are no significant the balance of the human oral flora or in the overgrowth such as Can&da. It appears that cetylpyridinium per milliliter chloride of potential

has activity

range of 0.32 to 8 micrograms S. sang& nucleatum, E. corrodens, and Candida

(pg/mL) in vitro against S. aureus, par&a, P. gingivalis, F.

Neisseria, albicans.


Data on teratogenic

and mutagenic

effects are available from in vitro and long-term cumulative effects on human

in vivo animal studies (Ref. 65). However, metabolism and teratogenic

effects are not available from controlled

studies. The FDA spontaneous-adverse reports submitted of the ingredient summarized suggest that clinical

reaction reports and adverse events experience following long-term Although OTC use the

has not revealed overt toxic manifestations.

FDA spontaneous

adverse drug reaction report (Ref. 65) indicates after ingestion of cetylpyridinium

that three deaths and six comas occurred chloride-containing mouthrinses,

it is unclear to what extent the mouthrinses these severe adverse events. as well as oral

or other circumstances The Subcommittee

may have contributed,to

notes that tooth and tongue staining,

65 irritation, chloride. In summary, the safety of cetylpyridinium evaluated in a variety of controlled, this information, in addition clinical chloride has been extensively studies. Based on during more than chloride, may occur with the use of products containing cetylpyridinium

and nonclinical

to adverse event data collected of mouthrinses containing

55 years of U.S. marketing the Subcommittee at concentrations

cetylpyridinium chloride


that cetylpyridinium

is safe when used formulations.

of 0.045 percent to 0.1 percent in mouthrinse The Subcommittee concludes

ii. Effectiveness. chloride

that cetylpyridinium ingredient within the

is effective as an OTC antigingivitis/antiplaque

dosage limits proposed above. The Subcommittee evaluated six placebo-controlled, blinded, clinical reduction in

efficacy trials (Ref. 65). In five of the six studies, a l5- to 27-percent in supragingival concentrations plaque was obtained with cetylpyridinium chloride

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 supragingival cetylpyridinium short-term published a significant reduction of

dental plaque with the use of 0.045 to 0.1 percent chloride mouthrinse. This is a reproducible finding in both

and 6-month literature

studies based on the data submitted

and in the

(Ref. 74). studies (Refs. 68 and 69), a 2-month study (based

The results of two 6-month (Ref. 75), and a 4-month upon gingival

study (Ref. 76) showed reductions

in gingivitis

index) ranging from 15.7 to 41 percent. Although

trends were

noted, no clear-cut dose response in the antigingivitis in any one study in that range.

effect was documented

66 Data from four other 6-month out by different reduction significant Similarly, studies (Ref. 70) (three of which a statistically were carried significant

research groups) did not demonstrate

in gingivitis. reduction

In the Ciancio study (Ref. 77), there was no statistically in gingivitis, although there was a reduction in gingival in plaque. index were

in the Lobene study (Ref. 78), no differences

seen at 4, 20, or 26 weeks, although reduction

there was a statistically


in gingival index at 8 weeks. In two studies (012-035 and 012-037) and DeGenero (Ref. 79), a mouthrinse containing cetylpyridinium

by Ackerman chloride

showed no effect on gingivitis

at 6 months. In a 6-week study by in a mouthrinse had no effect on

Moran (Ref. 80), cetylpyridinium plaque or gingivitis. gingivitis Although


most of the formulations

reduced plaque, the

results in these studies are not consistent. believes that differences chloride in the results of studies on are likely explained

The Subcommittee the effectiveness

of cetylpyridinium formulations


by the use of different

(Refs. 65, 70, and 81). Based on the data and chemical availability of

presented, the biological cetylpyridinium particular chloride


in a mouthrinse

appear to be greatly affected by the chloride in mouthrinse formulations



all at approximately markedly

0.045 percent nominal


were shown to vary of

between 4 and 77 percent. Thus, it is clear that inactivation chloride is likely based upon formulation. chloride


It is recommended be due

that the bioavailability determined

of cetylpyridinium

in each formulation

to reduce the possibility

that the active ingredient micelle (a colloid particle

is removed formed by an

to chemical reaction, complexing, aggregation of small molecules) Assessment of mouthrinses


or other sources of deactivation. chloride in



67 formulations similar to those tested in the positive studies (Refs. 68, 69, 76, chloride is available

and 77) show that 72 to 76 percent of the cetylpyridinium (Ref. 82). Therefore,

it is reasonable to assume that formulations chloride


72 to 76 percent available cetylpyridinium gingivitis and plaque.

are active in reducing

At the request of the Subcommittee, additional chloride analyses demonstrating

the manufacturer


the effectiveness

of cetylpyridinium practices, 33

on a site and subject basis, relative to other oral healthcare calculations. Specifically,

and on the basis of odds-ratio percent reduction

using a minimum studies were

in bleeding criterion,

results of 4 long-term

pooled to estimate an 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 interval of 2.75 to 3.45. Based on the totality that cetylpyridinium chloride agent. that of 0.454

with a 95 percent confidence of the data, the Subcommittee mouthrinse


is safe and effective as an OTC antigingivitis/antiplaque (dentifrice). The Subcommittee concludes

b. Stannous fluoride stannous fluoride

in a compatible


base at a concentration

percent is safe and effective for OTC use as an antigingivitis i. Safefy. Stannous fluoride agent in toothpastes

active ingredient.

has been used as an OTC caries-preventive States since 1954. Since 1981, it has been or sodium monofluorophosphate.

in the United

largely replaced by sodium fluoride However,

during this 27-year period, it is estimated that at least 70 billion were sold in the United States. Thus, a long market

doses of stannous fluoride history

exists to support its safety.

68 The toxicity extensively of ingesting fluoride from’ toothpaste has been reviewed

(Ref. 83). Concern has been expressed over the need to supervise toothpaste by young children because of the potential of stannous fluoride in

the use of fluoridated risk of developing


(Ref. 84). Acute toxicity

the rat (LD5o) appears to range from 31 to 300 mg/kg. Thus, it appears to have an acute toxicity Toxicity fluoride comparable to that of sodium fluoride formulation (Refs. 85 and 86). stannous marketed

studies show that a dentifrice plus stannous chloride dentifrices. toxicity


was comparable

to other nationally


Several subchronic formulations

tests of stannous fluoride

dentifrice over 3

have been carried out (Ref. 85). In a study conducted

months, rats received either 3.3 grams (g) dentifrice/kg/daily stannous fluoride/kg/daily) fluoride/kg/daily) stannous fluoride. Dentifrice dentifrice or 8.4 g dentifrice/kg/daily

(= 13.2 mg of

(= 33.6 mg of stannous to

by gavage. Any observed effects were not attributed Two additional W-day studies were conducted

in rats.

slurries in distilled

water were administered alterations

by gavage. All such

groups revealed microscopic

in the stomach lining, and squamous

as eosinophilic vacualization.

gastritis, squamous epithelial No other abnormalities


were observed. No tumorigenic


have been reported Studies conducted

from studies conducted in human volunteers

in male or female rats or mice.

who received 50 mg a day of the

stannous ion as stannous chloride is absorbed.

revealed that about 3 percent of the dose

Based on results from a 13-week oral toxicity chloride conducted through the National

study in rats on stannous Program (NTP), a safety


factor of 5,000 exists for potential

exposure to stannous salts from use of a

69 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 The Subcommittee’ s examination

toothpaste. analyses of clinical studies, including detailed

of soft tissue and microbiological

assays, revealed no adverse studied, no overgrowth of

shifts among the oral microbiological opportunistic


pathogens, and no development Significant reductions

of oral microbial

resistance to

stannous fluoride. subjects exhibiting Subcommittee

in S. mutans were observed among

higher levels of this organism. Based on these data, the that a 0.454 percent stannous fluoride dentifrice is

concludes use.

safe for long-term

Stannous ion in stannous fluoride staining of tooth surfaces, which and 88). In studies CC-191, subjects discontinued desquamation dentifrice.


has been associated with

in some instances may be severe (Refs. 87 and CC-247 (Ref. 89), 2.1 percent of tooth staining. Oral


the trial due to self-perceived

was reported by five subjects using a stannous fluoride

This adverse effect does not appear to be an extensive problem have used stannous fluoride gels without

because persons with hyposalivation adverse effects.

Because staining is a common phenomenon fluoride, sensitivity removed. the Subcommittee evaluated

with the use of stannous the extent of consumer

data concerning

to dental staining and the ease with which these stains can be Studies demonstrated that dental staining with 0.454 percent of consumers and that staining during

stannous fluoride

was noticed by a minority

can be removed from enamel surfaces and dental restorations

70 conventional recommends prophylactic that product procedures. labeling However, the Subcommittee on use by children and


a restriction

a statement concerning ii. Effectiveness. dentifrice hydrated formulations

the likelihood Stannous fluoride

of tooth staining. has been incorporated into numerous

that contain a variety of abrasive substances, including pyrophosphate, and a variety of excipient agents

silica gels, calcium

(see the Federal

of March 28,1980,45 of stannous fluoride

FR 20666 at 20684 to 20688). dentifrices to prevent rapid

The careful formulation oxidation for clinical and hydrolysis, effectiveness

and thereby inactivation, of these dentifrices.

of stannous ions is critical can be prevented in


several ways. In one approach, Another approach involves

water is excluded

from the formulation.

use of chelating

agents such as pyrophosphate,

citrate, gluconate, phytate, which

gantrez (a copolymer

of maleic acid and methyl ether) or In addition, incorporation or stannous of

form soluble stannous complexes.

of another stannous compound, chloride, provides a steady-state

such as stannous pyrophosphate situation is relatively

in which the concentration

bioavailable the inclusion

stannous fluoride

stable. It is essential to note that without stabilization

of stannous fluoride to obtain optimum

alone in a dentifrice clinical

is not sufficient containing


Clearly, products

stannous fluoride

may have a defined shelf life. history as a cariesconcentration (Ref. 86). have given

Stannous fluoride preventive

has a long and well-established

agent (Ref. 90). Stannous fluoride

at a 0.4-percent

results in a concentration Effects of stannous fluoride mixed results which, concentration

of 970 parts per million on plaque formation

(ppm) fluoride and gingivitis

in part, reflect the duration

of the studies, the

used, and the type of subjects studied.

71 The Subcommittee supportive fluoride 6-month evaluated the results of three primary 0.454percent trials and three stannous

trials (Refs. 85 and 89) of a stabilized dentifrice for antiplaque and antigingivitis

claims. Two of the primary

trials (CC-191 and CC-238) carried out in Indiana had results that with each other (Ref. 89). The final assessments were consistent 3-month assessments. The third study (CC-247), conducted

are consistent

with the interim in Northfield,

lasted for 7 months and had results that appeared to differ in (Ref. 89). The Indiana studies had index, 30.5 percent reduction of 2.6

some measures from those in Indiana reductions

of 18.8 percent and 20.5 percent in gingival index, and a nonsignificant

and 33.4 percent in bleeding

percent and 3.1 percent compared with placebo in plaque. In contrast, the Northfield study (one evaluator) reported a 10.7-percent reduction in gingivitis

in the stannous fluoride increase in the bleeding Turesky modified

group and a statistically

not significant

6.6-percent in a

index. There was a 17.8-percent



Plaque Index and a l.l-percent


using the Silness & Loe Plaque Index system. Two graders were used in this study, and they obtained the 3-month significant of product large numerical differences in their assessments at

assessment period and the final 7-month assessment. No shifts in the microbial use. double-blind and independent studies (CC-l 74, CC-1 78, flora were reported after 3 and 6 months

Three supportive

and CC-205) have been reported continued for 6 months

(Ref. 91). Two studies (CC-174 and CC-178) Study CC-

and the third study (CC-205) for 2 months. significant differences

174 demonstrated stannous fluoride


in the indices from the

group compared

with the negative control at the 1.5- and

72 s-month grading periods. However, all indices were not significant at the 7-

month grading period. Study CC-178 (Ref. 91) revealed no significant bleeding, compared significant fluoride differences in the gingival, group,

and plaque indices after 2 months use in the stannous fluoride with the control. difference After 6 months use, there was a statistically index (9.3 percent) in the stannous were not detected in the bleeding

in the gingivitis differences

group. Significant


plaque indices among the two groups. Study CC-205 (Ref. 91), which was conducted a significant fluoride difference difference for 2 months only, revealed index of the stannous 23.9 percent

(15.4 percent) in the gingivitis with the control. index. However,

group compared in.the bleeding

There was a reported

the scores for both groups were

exceptionally significant

low compared with all of the study groups. Statistically differences in plaque scores among the groups were not detected. no significant differences in plaque

In five of the six studies reported,

scores were observed at the end of the evaluation stannous fluoride dentifrices compared

period in subjects using dentifrice.

with those using a control

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 fluoride

in gingivitis

scores associated with the use of stannous

dentifrices. evaluated additional dentifrice, information including on the effectiveness additional analyses

The Subcommittee

of a 0.454 percent stannous fluoride

it requested. The results of these analyses helped to establish that the study populations were appropriate for the OTC gingivitis indication recommended studies

by the Subcommittee.

Disease levels in the populations

used in clinical

73 supporting the stannous fluoride dentifrice were only slightly higher than

disease levels established

in published

epidemiological Institute

studies and in surveys of Dental Research. relevance of the

of oral health status conducted Additional

by the National concerning

data were presented

the clinical

observed beneficial site-specific dentifrice

effects of the dentifrice

on gingivitis.

These data included

analyses demonstrating provided uniform

that a 0.454 percent stannous fluoride gingivitis across the dentition

efficacy in reducing

and, in particular,

in regions of significant to compare treatment

disease. This site-based analysis effects (e.g., causing a bleeding new disease (e.g.,

was further expanded

site to become a nonbleeding preventing clinical a nonbleeding

site) with benefits in preventing

site from becoming

a new bleeding site) during

studies. These analyses revealed that, compared to placebo, the dentifrice was beneficial in preventing and reducing

stannous fluoride gingivitis

and gingival bleeding. benefits of stannous fluoride in reducing

An analysis of the clinical gingivitis

compared to increased brushing, that a stannous fluoride

flossing, and frequent visits to a dentifrice provides benefits dental

dentist indicated comparable

to the improvements

observed from these established

hygiene procedures. Finally, individual odds ratio analyses were used to determine deriving the likelihood of an

a benefit from the use of a stannous fluoride


Based on the benefits achieved from dental hygiene and benefits seen in studies CC-191 and CC-238 (Ref. 89), a meaningful reduction in bleeding. benefit for a subject was Using this definition,

defined as at least a X&percent the results of five long-term

studies (Refs. 89 and 91) were pooled to estimate relative to a sodium fluoride control.

an overall odds ratio for improvement

74 After 3 months of use, the odds ratio was 1.57 with a $&percent interval of 3.29 to 3.85. of the cited literature indicates that a number of studies and dentifrices. confidence

A review


the effects of stannous fluoride

in gels, mouthrinses,

Many of these studies were of short duration, groups of subjects. Thus, the quality instances, questionable.

used few subjects, or used special

and relevance of the data are, in some in showing benefits

The results are far from uniform

from the use of stannous fluoride. With the exception of the studies submitted the use of dentifrices by the sponsor, there appear containing stannous fluoride. dentifrice on

to be few studies involving

Ogaard et al. (Ref. 92) studied the effect of a stannous fluoride plaque regrowth

in 1.5 subjects for 24 hours and 21 subjects for 3 weeks using was compared to a sodium fluoride. Stannous

a crossover design. Stannous fluoride monofluorophosphate fluoride dentifrice

and a dentifrice


gave significantly

lower regrowth

values than monofluorophosphate

or placebo. In the %week crossover study (Ref. 92), 21 orthodontic twice daily for 1 minute with a stannous fluoride dentifrice subjects brushed or placebo paste.

Less plaque was observed in the stannous fluoride brackets were 1 to 5 millimeters closer, there was no difference placebo dentifrice. No significant group.

group when the orthodontic

(mm) from the gingiva; if the brackets were in the effects of the stannous fluoride improvement and the health

was observed in gingival

regardless of treatment

Bay and Rolla (Ref. 93) conducted pupils

a double-blind,

crossover study in 40 dentifrice

aged 15 years to compare the effects of a stannous fluoride without stannous fluoride.

and a’ placebo dentifrice

The number of times the

75 dentifrice disclosed. formation index. Svatun (Ref. 94) compared percent stannous fluoride, the effect of dentifrices dentifrice containing: (1) 0.4 was used was not stated, and the gender of the pupils was not The study continued for 4 weeks. There was reduced plaque group and a small reduction in gingival

in the stannous fluoride

(2) a similar


stannous fluoride, and (4) 0.8 and

(3) 0.4 percent stannous fluoride percent chlorhexidine

plus stannous pyrophosphate,

gel. Twelve female dental students were included were placed in cap splints that

tests lasted for 4 days. The test products

covered the teeth only and held in place for 2 minutes rinsed with sucrose (15 percent) for 1 minute plaque formation. The dentifrice pyrophosphate containing No mechanical

twice daily. Subjects

every other hour to enhance during the study.

oral hygiene was allowed


0.4 percent stannous fluoride

plus stannous

gave significantly

lower plaque scores than the dentifrice fluoride alone, or a similar dentifrice without

0.4 percent stannous

stannous fluoride. dentifrice

There was a wide range in scores among subjects using the
0.4 percent stannous fluoride


plus stannous

pyrophosphate. In a second study in the same report (Ref. 94), Svatun examined influence of polishing teeth with a stannous fluoride dentifrice on %-hour or sodium in 8 mentally the


plaque regrowth

retarded home care subjects. Oral hygiene was suspended was less plaque regrowth the results of previous as a plaque inhibiter. following the stannous fluoride

for 24 hours. There treatment, confirming

studies showing the effectiveness A cap splint pilot study comparing

of stannous fluoride stannous fluoride

76 and sodium monofluorophosphate improvement dentifrices
did not result in any

in the gingiva of these subjects.

Several studies have been carried out using rinses or gels containing stannous fluoride. strictly applicable It is doubtful to dentifrices whether containing the results from these studies are stannous fluoride. Nevertheless, the

data are worth exploring potential

because they may help to clarify the therapeutic

of stannous fluoride. the plaque-inhibiting effects of mouthrinses

Svatun (Ref. 95) compared containing and distilled

0.2 and 0.3 percent stannous fluoride,
water randomly distributed

0.1 percent chlorhexidine,

among 12 dental hygienist

Subjects rinsed with 10 mL for 1 minute oral hygiene permitted.

twice a day for 4 days, with no other

Plaque index scores were brought to 0 at the beginning stannous and

of each test period. Mean plaque scores were 0.35 for O.&percent fluoride,

0.20 for 0.3-percent

stannous fluoride,

0.12 for chlorhexidine,

1.02 for the placebo. A long-term

study (Ref. 95) in another group of 5 students stannous fluoride mouthrinse could be

showed that the effect of a 0.3-percent maintained for 3 weeks.

Klock et al. (Ref. 96) compared or sodium fluoride

the effects of rinsing with stannous fluoride twice daily for 2 years on oral health during the first

(200 ppm fluoride)

in adults. Thirty-seven year and 3 withdrew the stannous fluoride

subjects started the study; 15 withdrew

during the second year. After 2 years, there were 12 in group and 7 in the sodium fluoride “The population group, a total of 19

subjects. The authors commented: unreliable.”

of subjects was generally

Plaque scores were not compared

among the groups because the in plaque

values were skewed at the baseline.

Both groups showed a reduction sites were

at 1 year and subsequent increase after 2 years. Bleeding

77 significantly continued statistically reduced after 1 year in the stannous fluoride group. This trend

into the second year, but the results at z years were no longer 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 development of subjects to comply with the mouthrinsing regimen and the rinse. The

of bacterial resistance to the stannous fluoride group harbored group. the effects of 0.4-percent significantly

stannous fluoride sodium fluoride

fewer S. mutans than did the

Several studies examining

stannous fluoride


have been carried out in persons wearing prosthetic The validity of extrapolating

or orthodontic

appliances. claims

data from these studies to support clinical dentifrice

for 9.4-percent

stannous fluoride

is open to question even though therapeutic effect of

these studies may provide stannous fluoride.


on the potential

Derkson and MacEntee (Ref. 97) examined stannous fluoride

the effects of a 0.4-percent using a double-blind,

gel in 17 subjects with overdentures

crossover design. A nonfluoridated applied daily for 6 months. Gingival

gel was used as a control. Each gel was and plaque index scores were recorded. the study were available for

A total of 34 teeth in 12 subjects who completed assessment. No difference Gingival Bleeding

between the effects of two gels was observed in

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 difference. study in 61 adults with gel. The plaque

index scores did not show any significant Tinanoff et al. (Ref. 98) conducted dental prostheses.

a double-blind

fixed or removable

Subjects were given a thorough

78 prophylaxis, including scaling and root planing, and were instructed to brush

once daily for 2 weeks with a regular dentifrice.

After the z-week washout rinsing) with a 0.22 percent

period, subjects then brushed twice daily (without sodium fluoride permitted gel or 0.4 percent stannous fluoride

gel. Subjects were not

to have a dental prophylaxis

during the course of the study. At the group, using

end of 6 months, gingival index scores in the stannous fluoride all teeth (including

abutment teeth), were 48 percent lower than in the control change between groups over time in the of bleeding

group. The authors noted “increasing percent bleeding

site scores appears to be due to rise in the number

sites in the sodium fluoride no reduction Differences

group during course of the study.” (There was sites compared significant with baseline.) only when computed

in the number of bleeding

in plaque scores were statistically

for abutment teeth. The authors noted “higher in the sodium fluoride in some way influence fluoride group. Two relatively apparently reflection long-term group as compared other clinical

baseline plaque index scores group might

to the stannous fluoride indices.”

or microbial

The stannous

group harbored 2.5 log fewer S. mutans than did the sodium fluoride

studies of 0.4 percent stannous fluoride the apparent disparity studied.

gel gave


results. However,

may be a

of the type of subjects and the hypothesis the gingival health of 81 adolescents while investigating

Boyd, et al. (Ref. orthodontic

87) monitored treatment


with fixed appliances

the effects of daily brush98 percent available tin (used

on 0.4 percent stannous fluoride

gels. One gel contained

tin (used twice daily), and the other gel contained

2 percent available

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

79 their normal oral hygiene practices. 3, 6, and 9 months after appliances in plaque accumulation statistically significant Sites were scored at baseline and at 1, were applied. There was a gradual increase

from baseline to 9 months in all groups and no difference in plaque scores among the groups. The patterns. However, significantly the percentage less than Tendency

gingival and plaque indices showed similar

of sites with an index greater than 1 was statistically

observed in other groups. The percentage of sites with a Bleeding score greater than 1 also followed fluoride a similar

pattern. Thus, use of stannous index and there was no

gel was associated with a smaller increase in gingival compared with controls. However,

percent Bleeding Tendency reduction

in the indices compared with baseline. study, Wolff et al. (Ref. 88) studied the effects of gel, 0.22 percent sodium fluoride gel, and a

In a second long-term

0.4 percent stannous fluoride fluoride-free

placebo gel in three groups of 281 subjects over 18 months. All dentifrice twice daily. or placebo gel after

subjects brushed with a sodium monofluorophosphate Subjects then used either a stannous fluoride, twice daily immediately after brushing and gingival

sodium fluoride,

with no rinsing for 30 minutes

using gel. Plaque, bleeding,

indices were assessed after 6,12, and in the mean plaque index in all groups, with were observed among

18 months. There was no significant


between any of the groups. The gingival no differences

index declined

detected between groups. No differences

any groups at any time. Based on the analyses of effectiveness on a site and subject basis compared calculations that, although conducted available dental

to other oral health care practices and on odds-ratio on the submitted clinical data, the Subcommittee concludes long-term

data do not show reproducible

effects in reducing

80 plaque mass, stannous fluoride appropriately antigingivitis formulated agent. of Active Ingredients (See General Combination is safe and effective in a dentifrice of 0.454 percent as an OTC at an


2. Category I Combinations

Policy in section 1I.E of this document) Eucalyptol, concludes menthol, methyl salicylate, and thymol. The Subcommittee of eucalyptol (0.092 and

that a combination

of essential oils consisting

percent), menthol thymol

(0.042 percent), methyl salicylate

(0.060 percent),

(0.064 percent) in a hydroalcoholic

vehicle containing

21.6 to 26.9

percent alcohol in a mouthrinse antiplaque agent.

is safe and effective as an OTC antigingivitisl

a. Safety. Eucalyptol fresh leaves of Eucalyptus volatile liquid

is a volatile globulus.

oil prepared by steam distillation Eucalyptol aromatic,

of the

is colorless, or a pale yellow somewhat camphoraceous odor,

with a characteristic

and a spicy and cooling taste. Eucalyptol cineolcayeptol, and cajuptol. It is insoluble

is also known as cineol, in water, but it is miscible with

alcohol, chloroform,

and ether. that eucalyptol is safe as an OTC anesthetic/ of the

The Dental Panel concluded analgesic active ingredient

for topical use on the mucous membranes

mouth and throat when used at a concentration form of a rinse, mouthwash, 1982). It was reviewed Association Menthol synthetically. paramenthanol.

of 0.025 to 0.1 percent in the

gargle, or spray (47 FR 22712 at 22826, May 25,

and found safe by the Flavor and Extract Manufacturer’ s States (FEMA) (Ref. 99). oil or made and 3--

of the United

is a secondary alcohol extract from peppermint Chemically, Menthol it is also known as hexahydrothymol

may be made synthetically

by the hydrogenation

(reduction) of thymol. The Dental Panel conclucied that menthol for topical use on the mucous membranes is safe as an of the mouth

OTC active ingredient

and throat at a concentration FR 22712 at 22813). Menthol Methyl salicylate

of 0.04 to 2.0 percent in the form of a rinse (47 was reviewed and found safe by FEMA (Ref. 100). acid. Prior to the discovery by

is the methyl ester of salicylic

of a method for chemical synthesis of methyl salicylate, it was produced steam distillation as gaultheria from natural sources. The natural-source products

are known oil.

oils, betula oil, sweet birch oil, teaberry oil, and wintergreen with methyl salicylate. salicylic Methyl

Today, these names are used synonymously salicylate is prepared synthetically

by esterifying

acid with methanol.

The Dental Panel concluded the mucous membranes proposed

that methyl salicylate is safe for topical use on the

of the mouth and throat when used within

dosage limit up to a O.&-percent concentration

in the form of a rinse,


gargle, or spray, not more than three to four times daily (47 FR salicylate was reviewed and found safe by FEMA (Ref.

22712 at 22828). Methyl 101). Thymol, also known

as thyme camphor, is 5-methy-2-isopropyl-z-phenol. or obtained from volatile oils distilled from

It may be prepared synthetically

Thymus vulgans and other related plant sources. Thymol is an alkyl derivative
of phenol and has bactericidal found safe by the Advisory and fungicidal properties. It was reviewed and

Review Panel on OTC Dentifrice

and Dental Care and

Drug Products (the Dental Panel) (47 FR 22712 at 22829, May 25,1982) by FEMA (Ref. 102). The safety of the combination in numerous pathologic long-term clinical of the four ingredients

has been assessed

studies. These studies showed no clinical and 105).

change or adverse reactions (Refs. 103,104,


Because OTC drug products safety of single ingredients consideration

are readily


the determination also requires

of the

and combinations

of ingredients

of possible abuse. Exaggerated use studies have been done. In adult subjects screened for sensitivity and

one study (Ref. 306), 47 healthy allergy histories

rinsed with 20 mL of the combination at 5 hourly intervals

of essential oils for 30

seconds under supervision

each day for 5 days and any oral mucosal lesions

repeated 18 days later for 1 day. No subject developed attributable followed to the test product. a similar protocol. sloughing

A second study (Ref. 107) of 45 adult subjects lesion)

One subject had erythema (Z-centimeter

and epithelial

on day 5 of the irritation

phase of the study. In a (dryness of the mouth what was

third exaggerated use study involving from salivary gland dysfunction) described remaining as “utransient xerostomic

18 xerostomic

adults, 2 subjects experienced and continued

mucosal sloughing”

the regimen. The

subjects did not develop mucosal lesions (Ref. 108). for mucosal irritation is minimal when

These studies showed that the potential these ingredients are used according

to label directions. populations and

Two studies evaluated

possible shifts in oral microbial organisms or potential

the emergence of opportunistic


One study

in 83 subjects (Ref. 109) showed analysis of plaque samples from active agent and control groups. There were no significant pathogens, spirochetes, black-pigmented increase in presumptive
S. mutans,



or C. albjcans.

A second 6-month microbiological

study (Ref. 110) examined

plaque at 3 and 6 months. Three enumeration of cocci,


were used: (1) Microscopic

motile and nonmotile nonselective

rods, and spirochetes,

(2) recovery on selective and by colony morphology on a

culture media, and (3) enumeration

83 nonselective composition medium. No clinically significant shifts were found in the

of the flora. studies have been reported (Ref. 111). The fixed combination in the Ames test, the test.


of essential oils did not show mutagenic Unscheduled


DNA Synthesis test, and the Mouse Micronucleus

Much of the evidence of the safety of the combination comes from their extensive history incidence included of consumer complaints

of these ingredients

of use (well over 100 years) and the low reported by the manufacturer. The data

an estimate of one adverse reaction report for every 38,700,OOO doses sold, which is described as an extremely low rate. The history is

of these ingredients four ingredients which contributes

in this combination

have had a long and safe marketing conclusion that the combination

to the Subcommittee’ s

safe when used according b. Effectiveness. controlled

to label directions. evaluated seven 6-month, randomized, of eucalyptol (0.092

The Subcommittee

trials of the effectiveness

of a fixed combination salicylate

percent), menthol thymol

(0.042 percent), methyl

(0.060 percent), and 21.6 to 26.9controlled study

(0.064 percent) in a hydroalcoholic

vehicle containing randomized,

percent ethyl alcohol. One study was a 6-month, (Ref. 103) involving

145 students and staff at an East Coast university,


18 to 54 years, randomized combination, containing

into three groups using either the above fixed (a 26.9-percent hydroalcoholic vehicle

a vehicle control all the ingredients

in the test product

except the essential oils), or 62

a water control.

Of the 145 subjects who entered the study, approximately

percent were male and 20 percent were smokers. Inclusion natural teeth exclusive crowned, abutment,

criteria were 20 banded, fully

of large carious lesions, orthodontically

and third molar teeth, and a minimum

score of 2.0 using


a modified Turesky

Loe-Silness modification


Index plus a minimum

score of 1.8 using the

the Quigley-Hein

Plaque Index. Of 129 subjects


the study, 45 were in the essential oils group (mean age 26.1 years), control group (mean age 27.9 years), and 41 were in

43 were in the vehicle the water control

group (mean age 24.7 years). as they rinsed twice daily from Monday to

Subjects were supervised

Friday with 20 mL for 30 seconds. Coded s-ounce (oz) bottles and graduated plastic cups were distributed 16-0~ bottles were distributed to maintain oral hygiene for twice daily unsupervised for holidays weekend use. Coded

and recesses. Subjects were required their usual prior to

a diary of unsupervised regimen,

rinse use. Subjects followed

with no dental treatment,

scaling, or polishing

the rinse regimen. All intraoral Gingivitis examinations were performed by the same examiner. Index which

was scored using the modified score between Inflammation,” criteria

Loe and Silness Gingival

adds an additional two levels of “Mild from the original published

the 1 and 2 of Loe and Silness, thus having and eliminates the bleeding component

for “Moderate


This index was later

by Lobene (Ref. 112) and is used in five of the eight “definitive” showed a continuous decline in adjusted 6 months.
6 months 1.57 1.94 1.93 1.20 1.66 1.67

studies. Results (see Table 4 below) mean gingivitis
Group Essential Oils

scores for each of three groups from baseline through
Baseline 2.62 2.67 2.66

1 month 2.08 2.20 2.32 3 months

Vehicle Control Water Control

Mean scores for the fixed combination significantly either control less than controls

of essential oils were statistically and 28 percent less than

at 3 and 6 months

group mean score at 6 months.


groups of this monitored,

85 supervised, mostly young, dental school population continued to show a assessments

decrease in mean gingival were made.

index scores over time. No bleeding

A second study (Ref. 104) involved the same university, randomized

mostly dental students and staff of criteria. Subjects were

with the same inclusion

into three groups, with 44 in the essential oils group (mean age (a 26.9-percent hydroalcoholic vehicle

25 years), 38 in the vehicle control 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 as a scaling and rubber cup polishing), examination. Two additional followed (defined

in 3 weeks by a baseline 1


were done for each subject 4 to 7

days apart, followed

in 3 to 4 days by a baseline 2 assessment. Prior to the was done. Subjects were randomly of essential oils, a vehicle control,

first rinse, another (fourth) polishing

assigned to either the fixed combination or a colored water control. Supervision and gingivitis of rinsing and monitoring

was the same as in the first study assessment was done. Results

was scored as before. No bleeding

(see Table 5 below) were recorded at I, 3, and 6 months, with all assessments performed Eighty-five by one examiner. No intra-examiner an additional variability 3 months testing is noted. rinsing.

subjects completed

of unsupervised

Most of the subjects who did not participate the study were recently graduated the g-month examination.

for the additional

3 months of

dental students who were not available for mean gingival index score for the and 6.5 percent less

The 6-month

essential oils was 10.4 percent less than the water control

86 than the vehicle control, but no statistically between groups for any interval.
TABLE Group Mean Glngwal Index Score Essential 011s Water Vehbcle I 1 60 1 60 1 59 I 1 39 1 38 1 33 I 1 54 1 55 1.49 I 1.27 i -38 1 25 I 1.31 1.46 1 37 5.-MEAN 1 GINGIVAL 1 INDEX SCORES FROM 1 THE GORDON 1 month STUDY 3 months 6 months Baseline 1 BaselIne 2




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 difference in mean gingival 9 months showed a statistically index scores, as follows: significant

1.12 for the essential oils,

1.43 for the vehicle control, The investigators

and 1.52 for the water control. for gingivitis observed

stated that the lack of difference

between groups for 6 months was probably health resulting from four prophylaxes

due to improvement followed

in gingival of


by continuation

usual oral hygiene. A third study involving and 5--percent hydroalcohol) using the same protocol 115 subjects in two study groups (essential oils was conducted at the University of Maryland the

(Ref. 105). Of the 115 subjects, 107 completed

study; 60 percent were male, 40 percent were female; 17 percent were smokers and 83 percent were nonsmokers. Each subject received a dental prophylaxis index scores were Fifty-four

on the day the first rinse was given. Baseline gingival recorded prior to the prophylaxis

and after 7 days of treatment.

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

87 analysis (see Table 6 below) was based on adjusted mean gingival at 3 and 6 months.
1 2.288 2200 3

index scores

1522 1576

6 months 0.918 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 included criteria, a bleeding at the University of Maryland, inclusion

index (Ref. 114) in addition

to the established

assessments, and regimen of supervised This study compared gluconate

rinsing twice a day on of essential oils to 0.12 of flavored, colored 5


the fixed combination and a control solution

percent chlorhexidine percent alcohol.

There were 41 subjects in the essential oils group (mean age gluconate group (mean age 29.2

29.2 years), 41 subjects in the chlorhexidine

years), and 42 subjects in the control group (mean age 28.6 years). Following baseline examination, all subjects were given a dental prophylaxis. were used, but indices. Teeth from

Assessments were made at 3 and 6 months. Two examiners only one examiner recorded gingivitis, plaque, and bleeding

used for a plaque collection statistical

at time of assessment were eliminated bleeding,

analysis for gingival,

and plaque indices. The specific teeth mean gingival scores (see Table

used were not cited in this report. Adjusted 7 below) were presented
Group Essential Oils Chlorhexedine Glwonate

for 3 and 6 months.
2.234 2.281



3 months 1.328 1.032







TABLE 7.-ADJUSTED --. -__5% Hydroalcohol ___. Control




At 6 months, both active monthrinses different than the control in gingival

were statistically


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 in percentages. No zero scores were units with zero

scores 0, 1, 2, and 3 were also presented recorded

at baseline. At 6 months, the percentage

of gingival

scores was 26 percent for control, percent for chlorhexidine

46 percent for the essential oils and 43 Scores 1 and 3 were comparable decreasing for the


three study groups but score 2 differed,

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. index scores (see Table 8 below) declined significantly
Group Essential Oils Gluconate Control

Bleeding not statistically

for all groups and were


at 6 months.
I Baseline .71 .72 .66 I 3 months .40 .26 .37 I 6 months 29 .25 .33



Chlorhexedine 5% Hydroalcchol

Mankodi Gingival

(Ref. 115) conducted

a similar

study using the Loe-Silness This study compared with the addition the of mint

Index, thus adding a bleeding



of essential oils to the same formulation water-alcohol control.

flavor and a s-percent prophylaxis

Each subject was given a

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

89 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
TABLE 9.-MEAN Group Mean Gingrval Index Score (adlusted for 3 and 6 months) Essential 011s Essential 011splus Mrnt Control 119 1 22 1 23 0.93 100 1 10 0.87 0 91 118

score (1.16).
Baseline 3 months I 6 months


A second study by Mankodi combination

et al. (Ref. 116) compared the effects of the gluconate, and a s-percent water-

of essential oils, chlorhexidine

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 group, and 38 subjects (mean age 32.2 years) in the water-alcohol group. The protocol gluconate control of

was similar to the earlier studies with the exception Index “to further describe the study

the use of the Russell Periodontal population,”

and the use of the Loe and Silness Gingival

Index for assessment. difference

The results (see Table 10 below) showed a statistically between the essential oil and control gingival


groups at 6 months, with the mean

index score for the essential oils group being 14.0 percent less than

the mean score for the control group.
TABLE 1 O.-MEAN Group Mean Gingival Index Scores Essential Oils Essential Oils Plus Mint Control 1.31 1.35 1.27 1.22 1.04 l.16 1.04 0.99 1.21 GINGIVAL INDEX SCORES FROM THE MANKODI STUDY Baseline I 3 months I 6 months

A third study by Mankodi combination

(Ref. 117) compared

the effects of the plus flavor, and a 5-

of essential oils, the same combination control.

percent water-alcohol

There were 48 subjects in the essential oils

90 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 age 34 years). The protocol on weekdays was limited the Lobene modification a prophylaxis following was similar to previous control group (mean

studies, but supervision

to one of the two daily rinses, and this study used of the Loe-Silness Gingival Index. Subjects received Gingivitis was scored at were performed

their baseline examination.

baseline, 3 months, and 6 months. All intraoral by a single qualified dental examiner.


Units of statistical

analysis were the indices

respective mean index scores determined

for each subject. Gingival

were analyzed by the analysis of variance, using baseline scores as the covariant. Results of gingival index scoring (see Table 11 below) are adjusted from control at 6

means for 3 and 6 months. Mean score percent reduction months for the combination

of essential oils plus flavor was 10.8 percent and without flavor. Both active groups are

10.2 percent for the combination statistically significantly
Essential Oils Plus Mint Essential Oils Control


at 6 months.
Baseline 2.16 2.20 2.19 1.68 1.63 I .a2 3 months 1.66 1.67 1.86 6 months


An eighth 6-month


trial (Ref. 118) used the fixed combination control. The results showed the mean

of essential oils and a “flavor gingival scores significantly


lower than the control group at 6 months. that the fixed combination inflammation hypothesis quantitative of essential oils

These studies demonstrated has some effectiveness

in preventing

of the gingiva. The initial

analyses relied solely on statistical which does not convey important

testing (the use of p values), information. However, the a number

of concerns (strength of the effect and its statistical


91 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 of randomized, controlled efficacy for these ingredients, 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. agent is middleteeth,

Much of the population

that will benefit from an antigingivitis

aged and older, having fully crowned

and restored teeth, and abutment

which have been omitted from scoring in these trials. These teeth are among the ones most in need of combating Because it is the individual gingivitis. to know if each

who is at risk, it is important

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. independent However, analysis of each site infers that all sites provide This assumes that 100 sites in one subject provide as one site in each of 100 subjects. Differences within subjects (Ref. 119). The units on different unit” (Ref.


the same outcome information

between subjects are greater than variations principle noted is “In investigations

where experimental

levels are employed, 120). All sites within Inflammation

use the highest level unit as computational

one subject are not at equal risk for gingivitis. areas than at lingual or

tends to be more overt at interdental the findings

facial sites. To quantify

(i.e., who and how many in the study with

groups are affected, and by how much) and to present the findings appropriate intervals), indicators of measurement error or uncertainty

(such as confidence

further analyses were completed.

92 Data from pooled analyses of the eight 6-month to the Subcommittee. studies were presented

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, Differences gingival index, and plaque index. and active agent were seen in

in mean values between the control

presented for subjects aged 18 to 39 years and were similar to differences in subjects 40 years old and older. The percent of subjects who improved 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 confidence in gingival index score. The odds ratio was 4.21 with a 95-percent interval (CI) of 2.79 to 6.36 to achieve a goal of 33 percent reduction was

in score. The bleeding score odds ratio for all studies where bleeding

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 The Subcommittee (0.092 percent), menthol thymol concludes that a combination

at 10.53 (CI 7.06 to 15.71). containing eucalyptol

(0.042 percent), methyl


(0.060 percent), and 21.6 to 26.9

(0.064 percent) in a hydroalcoholic

vehicle containing

percent alcohol in a mouthrinse regarding fixed combinations

meets the requirements of OTC active ingredients concludes activity

of FDA’ policy s with the same that each of these and that

pharmacological ingredients

action. The Subcommittee to the antibacterial and in combination.


of the combination,

each is safe individually

Based on the data submitted, combination of eucalyptol

the Subcommittee


that the

(0.092 percent), menthol

(0.042 percent), methyl

93 salicylate (0.060 percent), and thymol (0.064 percent) in a hydroalcoholic is safe and

vehicle containing

21.6 to 26.9 percent alcohol in a mouthrinse agent.

effective as an OTC antigingivitis/antiplaque B. Category II conditions None. C. Category III conditions The available Data to demonstrate agent will be required general guidelines data are insufficient

to permit final classification

at this time.

safety and effectiveness

as an antigingivitis/antiplaque set forth above (see

in accordance with the guidelines

on safety and effectiveness

in section 1I.H of this document.)

1. Category III Single Active Ingredients Aloe vera Dicalcium Hydrogen Sanguinaria phosphate peroxide extract dihydrate

Sodium bicarbonate Sodium lauryl sulfate Zinc citrate a. Aloe Vera. The Subcommittee to permit final classification OTC antigingivitis/antiplaque Curacao Aloe) is a brownish concludes that there are insufficient data

of the safety and effectiveness ingredient.

of aloe vera as an

Aloe vera (known in commerce as surface that from

black, opaque mass with a fractured

is uneven, waxy, and somewhat the parenchyma

resinous (Ref. 121). Aloe vera is obtained or chemical are and

tissue in the center of the leaf by mechanical

means and is highly variable in its properties. polysaccharides, mainly glucomannans,

The main constituents glycosides,


94 glycoproteins. Other constituents may include sterols, saponins, and organic to aid in wound healing,

acids. Aloe vera is topically and relieve burns (including


as an emollient,


and is used for colonic irrigation. (ingestion by

Extracts of aloe vera have been shown to enhance phagocytosis a cell of particulate material, such as microorganisms)

in adult bronchial (Ref. the Aloe

asthma. It is also used as an ingredient 122). Aloe vera is produced by boiling

in many cosmetic preparations Aloe juice down and pouring

viscous residue into empty spirit cases, in which it is allowed to solidify. vera possesses a nauseating odor. It is almost entirely and bitter taste and a disagreeable, penetrating

soluble in 60 percent alcohol and contains not more in water. Solutions of aloes gradually and may

than 30 percent of substances insoluble

undergo change and, after a month, may no longer react normally lose the bitterness natural to aloes (Ref. 123).

i. Safety. The safety of aloe vera is difficult However, there are studies in which the toxicity acemannan

to discern from the data. of components of aloe vera

are discussed, e.g., the component, evidence that application

(Ref. 124). Also, there is

of aloe vera to wounds will delay healing (Refs. 125 concludes that the data are insufficient to permit

and 126). The Subcommittee final classification ii. Effectiveness.

of the safety of aloe Vera. The Subcommittee concludes that there are insufficient of aloe vera as an OTC

data to permit final classification antigingivitis/antiplaque

of the effectiveness

ingredient. and

Aloe Vera, a plant extract, has been claimed to have antiinflammatory antiprostaglandin effects, as well as cathartic

effects (Ref. 127). There are also and gramfinds

claims that aloe vera extract is effective against several gram-positive negative organisms as well as C. albicans. However, the Subcommittee

95 that the studies are conflicting be 20 percent to 90 percent. The enzyme blend of protease, lipase, and amylase is described as contributing rationale to 3 percent of the formulation reviewed. There is only a general resulting in reduction evaluation and that the concentrations required appear to

for use in periodontal

disease for debridement However,

of deposits of hard and soft excretions. of this proposed literature activity

no valid scientific

is apparent from the submitted

data or from the has been

(Ref. 128). In addition,

no specific testing of the formulation (Ref. 128). Therefore, the

presented or was located in the literature Subcommittee classification antiplaque concludes

that there are insufficient

data to permit final

of the effectiveness ingredient. phosphate

of aloe vera as an OTC antigingivitis/

b. Dicalcjum





is one

of several phosphate


that have been used as buffers, fillers, and ingredients in numerous phosphate drug is

abrasives in OTC dentifrices products. The Subcommittee

and as inactive concludes

that dicalcium


safe when used as a buffer, filler, or abrasive in a dentifrice, recognized as effective for OTC use as an antigingivitis phosphate

but not generally

agent. has been established component in OTC

i. Safety. The safety of dicalcium on the basis of animal experiments of oral care products. anticaries formulations It is included


and consumer use as a primary in the list of inactive ingredients

(45 FR 20666 at 20670), and is also approved by FDA ingredient in the manufacture dihydrate of flour (21 CFR

as an optional

food additive

137.105 and 137.185). Dicalcium


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

96 in eye irritation tests, respectively. Rodent oral limit tests, dermal irritation formulations dihydrate were

tests, and human irritation containing submitted containing

tests using various dentifrice phosphate

pi percent to 88 percent dicalcium

(Ref. 129). These studies were carried out using toothpaste from 5 percent to 88 percent dicalcium phosphate containing dihydrate. dihydrate. The

LDsa in rats is greater than 16 g/kg for a toothpaste to volume irritation phosphate (w/v) suspension or sensitization dihydrate of dicalcium phosphate

60:40 weight Oral tissue


of toothpaste



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. containing dicalcium phosphate In no instances were any dihydrate either irritating

of the dentifrices or sensitizing

under conditions

of the test. the toxicity of ingested dicalcium

No reports were available regarding phosphate dihydrate

in humans. It is estimated that the average adult might per day and, with an extreme diet containing and naturally occurring phosphorous, could

consume 2 to 3 g of phosphorous maximum quantities of additives

consume 6 to 7 g per day. Ingestion would increase the phosphorous

of an entire medium-size

tube of toothpaste


by several g, an amount unlikely effect of large doses of phosphateto nontoxic phosphate levels. dihydrate

to be significantly containing

toxic. The saline cathartic would concludes


tend to limit their absorption that, in general, dicalcium

The Subcommittee

can be regarded as safe. ii. Efiectl’ veness. dihydrate-containing Studies of the short-term dentifrices use of dicalcium phosphate of supragingival

in man have shown reduction

plaque to be greater than toothbrushing

with water (Ref. 129). These studies

97 do not implicate dicalcium phosphate dihydrate as an active ingredient phosphate reduction but

rather might be explained dihydrate

by the abrasive effect of dicalcium

in assisting plaque removal by toothbrushing.


is also seen in such experiments, effects of dicalcium Subcommittee phosphate

but this could also be related to the abrasive dihydrate and removing plaque. The with

believes there is no evidence for chemical interference or plaque removal and no evidence of dicalcium agent. The Subcommittee be inappropriate concludes

plaque formation dihydrate

phosphate that, based

as an antigingivitis data, it would

on the available reduction

to claim that the plaque it as an

associated with the use of this abrasive qualifies agent. The Subcommittee

antigingivitis/antiplaque c. Hydrogen peroxide peroxide.

concludes that hydrogen

is safe at concentrations

of up to 3 percent, but there are insufficient of its effectiveness at 1.5 to 3

data available to permit percent concentrations agent. Hydrogen commercial peroxide

final classification for long-term

OTC use as an antigingivitis/antiplaque

was isolated by Thenard in 1818 and has been of century. Hydrogen peroxide canker sore peroxide (producing has

interest since the mid-nineteenth

been a component treatments,

of OTC drugs such as topical antiinfectants,

and earwax softeners. A 3-percent solution used as a topical antiseptic

of hydrogen

has been widely pus) wounds, for irrigation necrotizing

agent for suppurative


of the skin and mucous membranes, by dentists therapy, and as a mouthrinse of hydrogen for acute peroxide releases

during root-canal ulcerative gingivitis.


large volumes A 30-percent

of oxygen, approximately solution

ten times the volume of the solution. nonvital pulpless teeth.

has been used for bleaching

98 The Advisory hydrogen peroxide Review Panel on OTC Oral Cavity Drug Products classified as a Category I ingredient in concentrations for short-term use in oral wound

cleansing and debriding solution peroxide

from 3.5 to 3 percent in aqueous

(47 FR 22760 at 22906, May 25, 1982). Ten percent carbamide in anhydrous glycerin, which releases 3 percent hydrogen peroxide peroxide,

is also classified 130).

in Category I. Hydrogen

is listed in the USP (Ref.

i. Safety. The Subcommittee hydrogen peroxide hydrogen peroxide. The toxicity

evaluated the toxicity

and mutagenicity


data suggested that 1.5 to 3 percent hydrogen When ingested in large doses,

in aqueous solution peroxide

has a low toxicity.

produces esophagitis

and gastritis (Ref. 131). Few primary because hydrogen

systemic toxic effects are expected at low concentrations peroxide can occur. The acute toxicity of hydrogen peroxide decomposes

in the oral cavity (Ref. 132) and bowel before absorption

depends on the concentration more toxic than

tested, with more concentrated dilute solutions.


being relatively

In rats, concentrations

of 0.25 percent to 0.5 percent hydrogen

peroxide within

added to drinking

water decreased growth and increased mortality

6 weeks (Ref. 133). Decreased body weight was seen in Osborne-Mendel peroxide in drinking water for 5 months, but the

rats given 0.45 percent hydrogen

this decreased body weight was regained within hydrogen peroxide-containing drinking

2 weeks after replacing

water with tap water (Ref. 134). The to decreased liquid intake when

decreased body weight was possibly attributed hydrogen poisoning peroxide peroxide was provided in the drinking

water. In case studies, fatal for ingestion of hydrogen of 3

(Refs. 135 and 136) has been reported at concentrations

exceeding 3 percent or excessive ingestion

99 percent hydrogen peroxide. Generally, ingestion of household peroxide and 139). (3 to

9 percent) causes no significant The LDso of hydrogen

toxic effects (Refs. 137,138, has been established


by Ito et al. (Ref. 140) The low

as 1,567 mg/kg body weight in rats dosed with a 5-percent solution. acute toxicity indicating of hydrogen peroxide is confirmed by unpublished

data peroxide

an LD 50 of 5,000 mg/kg body weight for 6 percent hydrogen

in rats (Ref. 141). Teratogenic activity has not been demonstrated for hydrogen peroxide

(Ref. 142). Hydrogen 143) and epidermis peroxide minute is generally of brushing,


can be absorbed through

the oral mucosa (Ref.

(Ref. 144), but the exposure of the oral cavity to hydrogen limited since it undergoes rapid decomposition. peroxide After 1

less than 20 percent of the hydrogen (Ref 145). peroxide


into the oral cavity can be recovered

In the oral cavity, toxic effects of hydrogen alterations (Ref. 146) to gingival

vary from pulpal

lesions (Refs. 147 and 148) and oral irritation Adding a 1- to 1.5-percent solution

in rats (Ref. 149) under certain conditions. 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, experiment

no enamel solubility

was found from an in-vitro on human enamel (Ref. 141). is not intended to be a

using a 1.5-percent

aqueous solution

The Subcommittee’ s complete peroxide,


of mutagenicity

review of the literature but is intended


the mutagenic

nature of hydrogen safety concerns peroxide

to point out the apparent mutagenic peroxide. Any mutagenic

associated with hydrogen

role of hydrogen

will be further combination. Numerous 150,151, reports indicate a mutagenic role for hydrogen of hydrogen peroxide peroxide (Refs. can be of discussed with sodium bicarbonate and hydrogen peroxide in

and 152). Reviews on the genotoxicity

found in reports by the European Chemicals peroxide

Centre for Ecotoxicology

and Toxicology of hydrogen

(ECETOC) (Refs. 153 and 154) and in an overview genotoxicity presented at the Subcommittee

meeting on December 4,

1995 (Ref. 155). Hydrogen short-lived peroxide can produce hydroxyl radicals which are reactive but and hydroxyl radicals changes

(Refs. 155 and 156). In vitro superoxide exchanges in mammalian hydroxyl potential

caused chromatic

cells and preneoplastic

(Refs. 153 and 154). Although DNA in vitro, the genotoxic proximity opportunity of unprotected

radicals and singlet oxygen can damage of hydrogen peroxide depends on the

DNA. In vitro genotoxicity

tests enhance the

for DNA damage and are conducted

in cells with defective DNA peroxide in the

repair systems. Genotoxic presence of protective intracellularly, of hydroxyl

effects are not seen with hydrogen

enzyme systems that are normally


in the presence of iron chelating radical scavengers. of mutagenesis through

agents, and in the presence

The mechanism


radical production

was also suggested by MacRae et al. (Ref. 157). In contrast to most of the references available, itself and not hydroxyl epithelial and fibroblast Taylor et al. (Ref. 158) suggested that hydrogen radicals was responsible cultures. Most carefully of transition peroxide

for DNA strand breaks in controlled in vitro studies

have shown that the participation copper, is required

metal ions, such as iron or

for DNA damage to occur (Ref. 159).

In some bacterial mutagenesis be a weak mutagenic sensitive to hydrogen studies, hydrogen peroxide was found to

agent (Refs. 160 through peroxide and hydroxyl

167). Many strains are not radicals and mutations are only

seen in certain bacterial strains that are sensitive to oxidative 168). The addition abolition of an external enzymatic metabolic

damage (Ref.

source resulted in

of the weak genotoxic

effects seen in sensitive bacterial strains. These present throughout the body, and the presence seen in whole

enzyme sources are normally of detoxifying

enzymes may explain the lack of genotoxicity hydrogen peroxide.

animals that have been administered salivary peroxidase peroxide (Ref. 169).

In the oral cavity,

serves as the initial

line of defense against hydrogen


studies were conducted of hydrogen

to evaluate systemic effects of longand the endpoint measured was damage.

term administration sister chromatic Hydrogen


exchange (SCE), a very sensitive assay for genotoxic 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 A single administration following long term ingestion peroxide-containing of hydrogen dentifrice peroxide. to rats

of a carbamide

at 1,000 mg/kg daily for 5 days did not increase the incidence 172). Woolverton containing also examined two commercial

of SCE (Ref.

carbamide peroxideAfter two exposures, erythrocytes

dental products

for micronucleus


these products (Ref. 173).

did not increase the incidence

of micronucleated

Similar results were seen in a micronucleus damage in mice that were given hydrogen drinking

assay for chromosomal intraperitoneally or in


water at 0.6 percent for 2 weeks (Refs. 174 and 375). The SCE and

micronucleus following studies consistently peroxide demonstrated a lack of genotoxicity injection. in rodents its addition to



or intraperitoneal to promote

Hydrogen following drinking


was reported injections



(Ref. 176) and through

water (Refs. 177, 178, and 179). Duodenal the addition


has been found peroxide with

in the rat model following to drinking

of 1.5 to 3 percent hydrogen

water (Ref. 176). Ito et al. (Ref. 140) observed similar toxicity peroxide. In mice with reduced catalase activity,

higher doses of hydrogen hyperplastic

and neoplastic


nodules were found (Ref. 179). Ito’ s peroxide has been evaluated by FDA

report of the carcinogenicity toxicologists sufficient who concluded

of hydrogen

that the results of the study did not provide peroxide as a carcinogen (53 FR

evidence to designate hydrogen

53176, December 30, 1988). Similar conclusions toxicologists who reviewed the potential

were drawn by a panel of of hydrogen peroxide


for the International A long-term was administered

Agency for Research on Cancer (IARC) (Refs. 180 and 181). in F344 rats in which hydrogen peroxide of up to

study was conducted in drinking

water for 18 months at concentrations

0.6 percent, the maximal tolerated animals were sacrificed the 0.6-percent 433 mg/kg/day hydrogen

dose in F344 rats (Ref. 182). All surviving peroxide ingestion in

at 24 months of age. Hydrogen peroxide

group was 677 mg/kg/day

for females and peroxide

for males, with a total ingestion peroxide

of 72.7 g hydrogen

in females and 81.4 g hydrogen

in males during the course of the at any organ site in this study

study. There was no evidence of carcinogenicity following hydrogen peroxide ingestion.

In Syrian hamsters, applications peroxide produced pathogenic

of 3 percent and 30 percent hydrogen lesions.

changes associated with preneoplastic

Preneoplastic lesions are reversible following cessation of exposure (Ref. 178). hydrogen peroxide, at a

When combined concentration

with DMBA, a known


of 30 percent, appeared to augment the carcinogenic


associated with DMBA (Ref. 183). No carcinogenicity resulting from hydrogen peroxide

was seen in this study of 3 or 30 percent. studies of 16 weeks with

alone at concentrations two carcinogenesis


et al. (Ref. 184) conducted

and 20 weeks in hamsters to compare the effects of similar dentifrices and without the combination of hydrogen peroxide

and sodium bicarbonate

in the presence of DMBA. The authors reported that an oral product was not carcinogenic tumorigenicity containing hydrogen

that the results demonstrated and sodium bicarbonate


and that the combination

did not enhance the

of DMBA. In summary, that hydrogen

these robust animal studies (Refs. 183 does not increase the incidence carcinogen. of hydrogen peroxide. Cell of

and 184) indicate


oral cavity tumors in combination

with a known

Several studies challenge the carcinogenesis culture experiments effects of hydrogen

rich in catalase show a marked decrease in the mutagenic peroxide (Refs. 185 and 186). Further, variations exist

between species in their ability to control the destructive of catalase and reduced glutathione hydrogen peroxide

effects by the release potential of

(Ref. 187). The mutagenic of hydroxyl

as measured by production

radicals in the dependent in a

presence of FeZ+ has also been shown to be concentration Chinese hamster cell line (Ref. 188). Additional mechanistic

studies (Refs. 189 reduce

and 190) also suggested that the gel and paste phases of a toothpaste the formation

of free radicals. A generous supply of catalase in the oral cavity that hydrogen peroxide is rapidly degraded in the

and studies demonstrating

oral cavity indicate potential that hydrogen peroxide is unlikely to have a mutagenic

at concentrations

up to 3 percent (Ref. 191).

The ECETOC 1992 Joint Assessment of the toxic effects of hydrogen peroxide peroxide (Refs. 153 and 154) had the following concentrations conclusions: (1) Hydrogen

of less than 1 percent do not appear to have potential; (2) chronic ingestion of 0.1 to


(GI) tumor-promoting peroxide

0.15 percent hydrogen gastroduodenal

causes an inflammatory

response in peroxide peroxide in has

tissue of mice; (3) the mutagenicity of the genotype

of hydrogen

bacteria is a function genotoxic potential

of the strain; (4) hydrogen

only through the direct exposure of hydroxyl

radicals on

target DNA; (5) catalase reduces or abolishes the mutagenic hydrogen peroxide; (6) in vivo, many factors may contribute peroxide for systemic genotoxic

response to to the reduction

of bioavailable possibility


action; (7) the peroxide

of genotoxic

effect on cells that directly

contact hydrogen

at the site of application

cannot be ruled out; and (8) no data are available and resulting carcinogenic potential of

to fully evaluate chronic toxicity hydrogen peroxide.

The rate of decomposition determined in adults, children,

of hydrogen


in the oral cavity was peroxide

and xerostomics.


decomposition decomposition. introduced dentifrices

was so rapid that it was difficult

to establish a rate of peroxide with

In all cases, less than 27 percent of the hydrogen

into the oral cavity was present after 1 minute containing up to 3 percent hydrogen would peroxide

of brushing

(Ref. 145). Most after

residual hydrogen brushing,


be expectorated

with the dentifrice

leaving very little for ingestion. the lack of irritation

Based on clinical

studies and adverse

event reporting,

to soft tissues of the oral mucosa

105 following use of hydrogen peroxide-containing dentifrices provides further dental

evidence of the safety of long-term products. Hydrogen peroxide

use of hydrogen


presents safety concerns at concentrations studies conducted with

above 3

percent because of the lack of controlled concentrations

between 3 percent and 30 percent hydrogen that acute toxic effects encountered peroxide



evidence indicates concentrations

with high repaired,

of hydrogen

(i.e., 30 percent) are rapidly above mentions potential

leaving no deleterious the many published ingredient.

effects. The discussion articles detailing

only some of of this clinical While the of up

the mutagenic

Despite some safety concerns, the gathering of appropriate the currently documented risks, which are inconclusive. peroxide,

data outweighs the experimental Subcommittee’ s

data suggest a mutagenic

effect of hydrogen

review of current data indicates

that, at concentrations

to 3 percent in oral care products, and hydrogen peroxide

the risk appears to be especially use.


is safe for its intended

ii. Effecfiveness. microaerophilic

Because of the preponderance

of anaerobic and


associated with most forms of periodontal agents to inhibit The primary or kill these mechanism for the action

disease, the testing of oxygenating microorganisms hydrogen is understandable.



is through the release of oxygen. Unfortunately, by organic matter.

is short-lived Hydrogen

and inhibited peroxide

added to a mouthrinse

has been shown to increase the has been reported to

release of hypothiocyanate be a bacteriostatic through

into saliva. Hypothiocyanate

agent against some microbial of the lactoperoxidase

species (Refs. 192 and 193)

the activation

system (Ref. 194). The addition

of hydrogen peroxide to human whole saliva resulted in increased amounts and this effect was concentration dependent (Ref. 1%). was

of hypothiocyanate

This study also showed that the concentration critical to obtain optimum effects required in utilizing Another bacteriocidal

of hydrogen


effect. Incubation

time for inhibitory stumbling block

several minutes, which may be a significant peroxide

exogenous hydrogen

through this mechanism antimicrobial hydrogen

of action.

study of the lactoperoxidase/hypothiocyanate found that rinsing with a solution although containing


peroxide on

can readily produce hypothiocyanate,

the amount was dependent

the volume and pH of the rinse and the concentration peroxide (Ref. 196).

and pH of the hydrogen

In a z-week, crossover study, Wennstrom a hydrogen colonization fusiforms, peroxide-containing mouthrinse

and Lindhe effectively

(Ref. 197) found that the e.g., These groups diseases.


of several morphological filaments,

groups of microorganisms,

motile and curved rods, and spirochetes.

have been repeatedly Plaque and gingivitis of hydrogen peroxide

associated with several forms of periodontal scores were also markedly

reduced. The concentration In another short-term reduced both plaque

released was not determined. peroxide

study, a I.!%-percent hydrogen and gingivitis

rinse significantly

scores over the y-day test period (Ref. 198). In a study using diet were inoculated peroxide

a rat model in which test animals on a high cariogenic with plaqueforming microbial species, a lo-percent solution

urea (carbamide)

gel and 1 percent hydrogen accumulation (carbamide)



reduced the

of plaque (Ref. 199). A s-week study using 10 percent urea peroxide gel compared with a placebo showed a significant but no comparable reduction in plaque scores (Ref. 200).

decrease in gingivitis

The authors suggested that the oxygenating an environment development unsuitable of gingivitis. for the microbial effects of the test solution species responsible produced

for the

Similar results were found in another 3-week study gel (Ref. 201). 1 percent hydrogen peroxide, 0.12

using 10 percent urea peroxide

In contrast, a 3-week study comparing percent chlorhexidine, peroxide on gingivitis

and a placebo rinse found little effect of the hydrogen scores and no demonstrable effects on plaque scores rinse either

(Ref. 202). A 2-week study using a 1.5-percent

hydrogen peroxide

compared to a placebo showed no benefit from the hydrogen as a rinse or when delivered Testing of an ll-percent by an irrigation urea (carbamide)


system (Ref. 203). 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 no effect on gingivitis oral hygiene toothpaste in either study. rinse with

controls. However, In an 18-month a fluoridated orthodontic

could be determined hydrogen

study comparing

a 1.5-percent


rinse in conjunction treatment,

with toothbrushing

in subjects undergoing peroxide of

a clear benefit was found for the hydrogen

rinse group (Ref. 206). The rinse appeared to prevent the accumulation plaque and the subsequent development formed, the experimental gingivitis. peroxide of gingivitis. However,

once plaque

rinse did not reduce the established plaque and a 1.5-percent hydrogen in either

In contrast, a 24-week study comparing

rinse with water rinses did not find a significant bleeding


plaque scores or in papillary comparing chlorhexidine a 1.5-percent

scores (Ref. 207). A 2-year study rinse with a O.l-percent in sulcus



rinse, but without

a placebo control, found a reduction

bleeding but not plaque scores for the hydrogen

peroxide group (Ref. 208).


The Subcommittee of sufficient hydrogen positively


that there is a lack of well-controlled regarding the effectiveness peroxide

studies of

length to draw firm conclusions peroxide. The clinical

data suggest that hydrogen


effect plaque and gingivitis clinical

scores, but the data are contradictory,

lacking well-controlled needed to determine Optimizing

studies of adequate length. Further studies are as an antiplaque agent.

the value of this ingredient required

the concentration,

exposure time, and best delivery The potential positive effect as an active efficacy is

vehicle would ingredient unknown.

be major steps forward.

is suggested by the current data. However,


d. Sanguinaria


The Subcommittee


that sanguinaria

extract at 0.03 to 0.075 percent concentration data available or dentifrice to permit final classification

is safe, but there are insufficient of its effectiveness in an oral rinse active ingredient. alcoholic known extraction as blood

dosage form as an OTC antigingivitis/antiplaque extract is prepared by warm acidulated of Sanguinaria followed

Sanguinaria of the rhizome

(more commonly

root or puccoon), benzophenanthridine

by precipitation

with a metal salt. Six principal (50


are present in the extract with sanguinarine

percent) and chelerythrine

(25 percent) being the major ones. Sanguinaria amorphous powder that is hygroscopic

extract is a bright orange, free-flowing, and electrostatic. weight

It is soluble at 25’ C in methanol

to 1 percent weight per

(w/w), in chloroform

to 0.75 percent w/w, in water or water buffered Sanguinaria extract exhibits a

with one percent citric acid to z percent w/w. pH dependent lipophilicity and partitions

to a significant

extent into the lipid extract has been (Ref.

phase of a lipid/water described


above pH 6.5. Sanguinaria

in several pharmacopeia

(Refs. 209 and 210) and textbooks

23 1). Uses include as an expectorant. practice in 1837. i. Sufety. Safety studies addressing sensitization organ toxicity, sanguinaria potential, reproductive acute toxicity, irritation potential, chronic relief of spongy and red gums and in OTC cough syrups Sanguinaria extract was introduced into homeopathic


birth defect potential,

and carcinogenic


were conducted

in animals using

extract and sanguinarine of sanguinaria

chloride. extract was determined by oral gavage

The acute toxicity to Sprague-Dawley

rats with doses from 500 to 3,000 mg/kg. In one study (Ref. extract was 1,440 mg/kg. This suggests that

212), the oral LDso of sanguinaria sanguinaria sanguinaria extract is probably

poorly absorbed orally. The lethal dose of monkeys was above 50 mg/kg. The

extract in two Cynomolgus

acute dermal LD50 in a limited

study using 10 adult New Zealand rabbits was toxicity of sanguinaria

greater than 200 mg/kg body weight. Acute inhalation extract (2.2 mg/liter) in 10 rats resulted in mortality examination

in 3 of 5 males and no

females. Gross pathology

revealed no lesions or abnormalities. chloride determined by oral gavage

The LD50 from two studies of sanguinarine

in rats was 1,525 and 1,663 mg/kg. The intravenous kg, and the intraperitoneal Studies concerning

LDso in rats was 28.7 mg/

LD5a in mice was 17.7 mg/kg. the multidose subchronic toxicity chloride of sanguinaria (Refs. 216, 217,

extract (Refs. 213, 214, and 215) and sanguinarine and 218) were conducted

in rats and monkeys at doses ranging from 5 to 405

mg/kg for 2 to 13 weeks. In a B-week oral gavage study in monkeys (Ref. 215), 100 mg/kg of sanguinaria dose for a subsequent extract was determined toxicity to be the appropriate high-


study in monkeys. A 1%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 oral

a NOAEL of 30 mg/kg per day once tolerance is achieved. A Is-week

gavage study in rats (50 to 400 mg/kg per day) (Ref. 234) showed evidence of dose-related toxicity, principally involving GI irritation and body weight

loss at all dosage levels. Mortality

was observed at doses of 300 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 J-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 treatmentrelated toxicity is limited associated with sanguinaria extract and sanguinarine chloride

to GI irritation. studies assessing metabolism, disposition, chloride distribution, were of and

Pharmacokinetic and elimination conducted sanguinaria

of sanguinaria

extract and sanguinarine

in rats and mice (Refs. 219, 220, and 221). The metabolism

extract was tested in vitro in rat and rabbit liver homogenates

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 (1 ppb detection

in the rat or rabbit liver homogenates. limit) nor sanguinarine chloride

Neither benz[c]acridine

(25 ppb detection

limit) was found in the

urine of the human subjects. Studies evaluating chloride excretion the biological disposition of radiolabeled sanguinarine with

in rats (Ref. 220) and mice (Ref. 221) suggested low absorption,

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 administered accounted

a total recovery of approximately Excretion

6.1 percent of the


via urine, feces, and expired air dose in the 96-hour post-

for 95.1 percent of the administered


period. Blood levels in the rat achieved less than 1.5 percent orally, peaking around 8 hours and declining to

of the net dose administered

near 1 hour levels by 96 hours. Expired air accounted for an average of 18.3 percent (mice) and 6.0 percent The nature of the blood radioactive residues

(rats) of the dose administered.

and excreted ‘ 4C-carbon was not determined. mice of 97.89 percent of the *%-carbon administration of sanguinarine chloride

An overall mean recovery in oral

during the 96 hours following

labeled at one and/or both methyleneportion of the radiolabeled test product These

dioxy groups suggests that a substantial may be transformed into nonlabeled

benzophenanthridine chloride is satisfactorily


results suggested that sanguinarine or intravenous administration.

recovered after oral

A cardiovascular chloride function

study in dogs treated intravenously no treatment-related

with sanguinarine effect on heart

(0.075 mg/kg) demonstrated or cardiovascular

health (Ref. 222) at a dose 30 times the maximum and rinsing. study in rats (Ref.

daily absorbed dose expected from brushing Sanguinaria

extract was tested in a fertility/reproduction toxicity

223), in developmental

studies in rats and rabbits (5 to 400 mg/kg per study in rats (5 extract was

day) (Refs. 224, 225, and 226), and in a perinatal/postnatal

to 60 mg/kg per day) (Ref. 227). The NOAEL level of sanguinaria 25 mg/kg per day for development for maternal toxicity. Sanguinaria toxicity

in rabbits, and 15 mg/kg per day

extract had no effect on fertility,

reproduction, or fetal and neonatal development in rats and rabbits at doses

below those resulting Mutagenicity sanguinarine mammalian elicited

in general toxicity

in the adult animals. with both sanguinaria extract and and

studies were conducted


with in vitro methods using microorganisms

cells in culture and in vivo in mice. Weak positive assay using Salmonella activation typhimurium

responses were (Ames

only in the bacterial

assay) in the presence of metabolic extract were negative in the bacterial in an unscheduled

(Ref. 228). Studies of sanguinaria coli (Ref. 229), (Ref. 230),

assay with Escherichia

DNA synthesis assay in rat primary cytogenetic


and in a micronucleus metabolites

assay in mice (Ref. 231). An Ames test for was

of sanguinaria

extract in rat urine using S. fyphimurium chloride

negative. Studies of sanguinaria with S. typhimurium and without sanguinarine metabolic chloride,

were negative in other Ames assays

(Ref. 232), and Saccharomyces activation. including Two mammalian

(Ref. 233) with

cell assays (Ref. 234) with

a Chinese hamster ovary (CHO)(HGPRT) forward gene

hypoxanthine-guanine mutation


assay and unscheduled (Ref. 235) provided

DNA synthesis assay in rat primary results that were equivocal mutagenic or uninterpretable.

hepatocytes Neither

study, however, difficult

gave a positive to conduct

response. The CHO assay

is historically Long-term

and interpret. studies (Ref. 236) by gavage extract in rats did not produce lesions to suggest a carcinogenic toxicity and is considered extract

(90 to 98 weeks) carcinogenicity

at dosages of 0 to 60 mg/kg per day sanguinaria treatment-related preneoplastic or neoplastic

effect. Dosage at 40 mg/kg per day did not produce the NOAEL dosage. A lifetime was evaluated diet carcinogenicity

study of sanguinaria

in rats (8 to 200 mg/kg per day) (Ref. 237). No test related

hematological, biochemical, or urological changes were observed at any dosage pathology changes were the NOAEL

level. No test article related macro- or microscopic

observed. A 200 mg/kg per day dosage level can be considered level. Two controlled (Ref. 238) examining extract or sanguinarine other ophthalmologic 13-week subchronic ocular toxicity chloride changes.

studies done in monkeys and dogs no evidence that sanguinaria pressure or produced any


affected intraocular

Human exposure to sanguinarine

with twice daily use of toothpaste


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 higher concentration than contained in currently extract at marketed

a significantly products.

Ten animal safety studies conducted submitted for dentifrice


1982 and 1984 were

formulas containing

300 to 2,000 Fg/mL of sanguinaria marketed toothpaste formula

extract. None of the studies tested the currently containing 750 pg/mL of sanguinaria

extract. Acute oral toxicity formula containing

was greater

than 20 g/kg in rats for a toothpaste sanguinaria sanguinaria

300 pg/mL of 500 pg/mL of

extract, and 5 g/kg in rats for a formula


extract (Refs. 239, 240, and 241). Primary skin and eye irritation mild irritation

studies carried out in rabbits (Refs. 242 and 243) demonstrated reaction when a toothpaste Mild mucosal irritation 300 u.g/mL of sanguinaria [Refs. 244 through 248). formula containing

less than 750 pg/mL was tested. formula containing

was observed when a toothpaste

extract was tested in cheek pouches of hamsters

Two clinical irritation studies (Refs. 249 and 250) demonstrated only mild mucosal

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 Because modification between 1983 and 1987

(Ref. 251) were submitted.

of the oral rinse formulation animal

from pH 3.2 to pH 4.5 began in 1989, none of these studies provided safety data on the currently marketed oral rinse (pH 4.5). containing

Based on data on the oral rinse formula sanguinaria

450 to 1,000 pg/mL was noted in the

extract at a pH of 3.2, no mucosal irritation

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 extract at pH 3.2 was

animals when a rinse formula of 450 ug/mL sanguinaria tested (Ref. 255). Four human studies conducted irritation and sensitization potential between

1982 and 1985 evaluated the formulas containing a 2-

of dentifrice


extract using a repeated insult patch test design involving

percent aqueous slurry (Refs. 256 through no induction of irritation

259). These studies demonstrated An exaggerated use extract)

or allergic contact dermatitis.

study (Ref. 260) using an earlier formula demonstrated no irritation or sensitization containing

(300 ).rg/g sanguinaria

in soft oral cavity tissues. Two 6sanguinaria and sodium

month studies on a toothpaste monofluorophosphate

(Refs. 261 and 262) showed no adverse effects on oral included inspection of the lips,

hard or soft tissues. Soft tissue examinations

tongue, hard and soft palate, gingiva, mucobuccal the cheeks, and sublingual areas. Although

fold areas, inner surface of flora was

testing of the microbial

inconclusive through in one study (Ref. 261), sanguinaria of resistant microbial randomized did not promote strains. containing oral overgrowth

the development

A 6-month,


study using a dentifrice

0.075 percentsanguinaria irritation

extract (Ref. 263) showed no significant

or adverse reactions. A l-week

exaggerated use study showed that (Ref. 264). only one study (Ref. 300 pg/mL of

18 of the 28 subjects experienced Although

mucosal sloughing

nine human safety studies were presented, marketed oral rinse containing

265) tested the currently sanguinaria formula remaining

extract at pH 4.5. However,

this study tested the efficacy of the

and was not designed to test the safety of the oral rinse. Three of the eight studies showed that repeated application at pH 3.2 under a semiocclusive irritation of the earlier oral

rinse formula clinically

patch test did not induce contact dermatitis in


or evidence of induced

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 dosage form is safe. reviewed controlled clinical studies in

an oral rinse or dentifrice

ii. Effectiveness. The Subcommittee

ranging from 1 week to 6 months in duration. 1 week and one 1 month) had equivocal toothpaste toothpaste double-blind preparations. containing

Three short-term

studies (two

results between the active and placebo marketed

Of the three studies that tested the currently 750 pg/g of sanguinaria

extract, only one 6-month, a significant decrease in plaque index scores

study (Ref. 271) demonstrated

at 3 months. Results from this study also showed that gingival in the active group were significantly

lower than the placebo group at 28

weeks. The other two studies were short-term 272 and 273) in which no differences placebo groups. A lo-week formulation containing studies of 1 and 4 weeks (Refs.

were detected between the active and

study (Ref. 274) showed that the toothpaste extract reduced plaque and diminished the

300 ug/g of sanguinaria

gingival bleeding, plaque-reducing

but the zinc chloride

in the formulation

effect. It was not clearly documented of the currently


zinc chloride Based on the containing 750

affects the effectiveness short-term clinical

marketed toothpaste. of the toothpaste reduction

studies, the effectiveness

ug/g sanguinaria determined.

extract in plaque and gingivitis

cannot be of the toothpaste

The effect of zinc chloride study.

on the effectiveness

also needs further

Five studies used a toothpaste



750 pg/g sanguinaria (Refs. 263, 264, 273, 275, studies (Refs. 263 and study (Ref. 273)

extract and 0.8 percent sodium monofluorophosphate and 276). Equivocal 276) and in a l-week compared results were noted in two 6-month

study (Ref. 264). One toothbrushing formulations

the effect of eight toothpaste

on plaque and gingivitis the control product effectiveness. between differences

in school children.

Because the study design concerning

and subject selection was inadequate, One-way analysis of variance (ANOVA) groups were not statistically in plaque or gingivitis toothpaste containing containing significant.

this study did not support

showed that the differences In addition, no significant


were noted between groups using a fluoride plus sanguinaria extract. study (Ref. 275) tested three The study extract and a dentifrice

zinc chloride without

zinc chloride


A l-week,

exaggerated use effectiveness

regimens of the toothpaste design and protocol

and oral rinse on plaque reduction.


did not allow accurate testing of the

effectiveness of the toothpaste. evidence Based on all of the data submitted, of effectiveness. 26 additional controlled clinical studies (Ref. none of

the studies provided The Subcommittee


277). Seven of the 26 studies (Refs. 265 and 278 through equivocal conducted optimal results. The remaining

283) provided

19 studies (ranging from 1 to 8 weeks), proper dosage, clinical product study designs,

for various reasons, evaluated

plaque and gingival of the regimen

indices to be employed, (toothpaste

safety, use), and


and oral rinse combination

the role of zinc chloride

in plaque reduction. of an oral rinse with a the 7-day significant differences in plaque

Among the 19 studies, 9 tested the effectiveness final pH of 4.5. Some short-term exaggerated between reduction clinical

trials, employing statistically

use study design, demonstrated

an earlier rinse product only. However,

(pH 3.2) and the placebo control 6-month

the only two long-term,

studies testing the any

effectiveness effectiveness

of this earlier rinse product in plaque or gingivitis

(pH 3.2) did not demonstrate when compared


to a placebo. test for the role and

The 7-day exaggerated formulation

use study design was validated (Ref. 284). In addition,

as a screening


studies investigating confusing

of zinc chloride controversial

in the effectiveness

of the oral rinse provided

results. Two l-week difference

studies (Refs. 285 and 286) demonstrated was observed between a

that no significant sanguinaria

in plaque reduction

extract and zinc chloride

rinse and a rinse without


extract. The effect of zinc chloride obtained However, with the combination a 2-week, experimental

alone was only mildly

less than that

of sanguinaria gingivitis,

extract and zinc chloride. crossover study (Ref. 287) extract and zinc chloride


that the oral rinse with sanguinaria

performed on gingivitis significantly better than the placebo in plaque reduction. The effect

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 hemolytic streptococci. No long-term

adversely affecting aerobes or alphastudies were available. effectiveness evaluated of the sanguinaria selected studies with

While some data exist on the short-term extract oral rinse or dentifrice, that supported the effectiveness toothpaste

the Subcommittee

of the oral rinse used in combination products. Five short-term

one of the sanguinaria

(1 to 9 weeks) in plaque for

studies (Refs. 265 and 289 through or gingivitis.

292) demonstrated


Four 6-month studies also produced


differences 296). However,

the active regimen compared to placebo (Refs. 293 through these nine studies varied substantially dentifrice toothpaste and oral rinse combinations. (300 yg/mL sanguinaria

in design and formulation

of the test

In studies prior to 1984, low dose

extract) and pH 3.2 oral rinse were used, the 750 pg/g sanguinaria were extract

whereas studies conducted extract toothpaste demonstrated

since 1988 have included

and a pH 4.5 oral rinse. Even if effectiveness regimen, the contribution

for the combined

of sanguinaria

alone is not clear. The in vitro efficacy of the individual investigated. In vitro MICs of sanguinaria active components chloride was also extract were

and sanguinaria

tested against 176 clinical 297). MIC’ for sanguinaria s

isolates and 43 reference strains of oral bacteria (Ref. chloride ranged from 16 to 32 ug/mL for all but extract ranged from 16 to 24 pg/mL and one strain of Wolinella curva.

7 reference isolates. MICs for sanguinaria for all strains except Wolinella


For fresh isolates, MIC’ for sanguinaria s ranged from 16 to 32 ug/mL. Laboratory sanguinaria and fluoride-containing to positive controls. chloride and sanguinaria extract on

tests were also conducted


to evaluate the bioequivalence bioavailability, rat caries and in vivo with the

of the product fluoride

Tests included


(Ref. 298), remineralization/demineralization,

bovine enamel fluoride required biological

uptake (Ref. 299). These tests are consistent for fluoride dentifrices

testing procedures

(October 6, 1995, that the to the fluoride

60 FR 52474 at 52510). Results obtained sanguinaria/fluoride clinically-tested toothpaste

from these studies indicated equivalent promoting

formula was biologically remineralization,

control in promoting

uptake into artificial enamel, and reducing zinc chloride

enamel lesions, reducing

the effects of acid challenge on extract and

caries in the rat caries model. Sanguinaria with fluoride

were also shown not to interfere

bioavailability to profiles

uptake profiles with decalcified obtained from sound enamel. concludes

enamel qualitatively


The Subcommittee irritation

that, although

mild staining and oral

may occur, sanguinaria

extract at 0.03 to 0.075 percent concentration in study designs, test product and statistical analyses, extract

is safe. However, concentrations conclusions

given the wide variations and formulations,

placebo controls,

cannot be drawn regarding the effectiveness agent. concludes

of sanguinaria

as an OTC antigingivitis/antiplaque
e. Sodium bicarbonate.

The Subcommittee

that sodium


is safe, but appears to have relatively agent, requiring

poor efficacy as an OTC exposure


high dosages and extended

time to have a reasonable chance at affecting the oral flora and clinical parameters.

Sodium bicarbonate an ingredient has been used as an antacid as well as advocated and mouthrinses. It has been generally (causing water to as

in both toothpastes

regarded as a bactericidal

agent that generates a hypertonic leading to disruption (cell shrinkage

flow out of the cell) environment, of the cell and dehydration,

of the fluid equilibrium due to loss of water


by osmosis), and eventual cell death. i. Safety. Sodium bicarbonate Sodium bicarbonate of 200 milliequivalent is GRAS for use in foods (21 CFR 184.1736). daily dose The usual

is listed as an OTC antacid up to a maximum (mEq) bicarbonate ion (21 CFR 331.11(k)(l)).

dose is 1 to 5 g, providing sodium bicarbonate a debriding ingredient

up to 60 mEq. In OTC mouthrinse


has been determined

to be safe and effective for use as of large

(47 FR 22712 at 22907, May 25, 1982). Ingestion causes several blood chemistry changes,

amounts of sodium bicarbonate including

increased sodium levels, resulting

in toxic effects that produce


(excessive amount of sodium in the blood) (Refs. 300, 301, and

302). The LDso is 7.57 to 8.9 g/kg body weight for the rat. Sodium bicarbonate conventional does not appear to be teratogenic or mutagenic using

testing, with no discernable

effects on fetal survival

in several or skin

species. It does not produce photosensitization, irritation by standard methods.

acute ocular irritation,

ii. E’ veness. ectl’ bicarbonate

Few studies examine the effectiveness Sodium bicarbonate

of sodium has been found

as a single active ingredient.

to be bactericidal that the killing

to several oral microorganisms

(Ref. 303). The authors suggest created within

effect might be more than an osmotic imbalance

the cells. This study showed several disturbing of this ingredient. For killing

aspects about the effectiveness long periods of exposure

to be effective, relatively

were required, ranging from several minutes agents is not intended to hours. While a comparison to

other antimicrobial bicarbonate

as a criteria for effectiveness, to sodium fluoride

sodium and

had a lo-fold

poorer MIC range compared

a l,OOO-fold poorer MIC range compared examining

to sodium lauryl sulfate. In a study on S. mutans, osmotic disruption cell lysis (Ref. 304). applications were

the effects of sodium bicarbonate salt concentration

occurred through


In a 20-day experiment ineffective comparing at reducing

on rats, sodium bicarbonate

plaque accumulations

(Ref. 305). In a 6-week study sodium bicarbonate with a

the effects of a toothpaste toothpaste,


standard fluoride

no increase in effectiveness

was observed (Ref.

306). In a similar 8-week study, no difference or gingivitis (Ref. 307). The Subcommittee are insufficient concludes

was observed in either plaque test toothpaste

scores between the control and sodium bicarbonate

that sodium bicarbonate its effectiveness

is safe, but there as an OTC

data available to determine agent.


f. Sodium lauryl sulfate. The Subcommittee sulfate is safe at concentrations


that sodium lauryl

of 0.1 to 5 percent, but there is insufficient as an antigingivitis/antiplaque active

evidence to support its effectiveness ingredient. The Subcommittee

notes, however,

that sodium lauryl sulfate is

a safe and effective foaming ingredient Sodium lauryl sulfate is a synthetic surfactant to lower surface tension. as a viscous liquid,

in toothpaste. detergent that acts as an anionic

Sodium lauryl sulfate is available paste, or powder. It may contain small


amounts of other sodium alkyl sulfates, although lauryl sulfate with a molecular

it consists mostly of sodium

weight of 288.4 and the formula


It is soluble in water and alcohols. It binds to charged side groups of (loss of biological activity)

positively proteins. through solutions

charged tooth surfaces and positively Protein binding conformational may lead to denaturation changes in the molecule.

It is stable in alkaline of water) at room

and will hydrolyze

(split into fragments by addition


below a pH of 5 (Ref. 308).

Sodium lauryl sulfate is used in cosmetics such as shampoos, deodorants, facial makeup, shaving preparations, care products. Its ubiquity It is approved and bath products, and in various oral
(21 CFR 172.822).

as a multipurpose

food additive

in personal care products

can be estimated by a 1981 FDA in 703

Cosmetic Product Formulation products

List that shows it as an ingredient

(Ref. 308). In oral care products, combined usually

sodium lauryl sulfate is used as a with other ingredients. It is found

foaming agent and is frequently in mouthrinses and dentifrices,

in concentrations

of 5 percent or less of less

(Refs. 308 and 309). In most mouthrinses, than 1 percent. In skin care products,

it is found in concentrations


of sodium lauryl sulfate

may range up to 50 percent. In the last two decades, sodium lauryl sulfate has replaced most other surfactants products. previously used for oral care drug

It is estimated that 4 to 5 million in the United

pounds of sodium lauryl sulfate alone (Ref.

are used annually

States for oral health care products

The estimated daily intake of sodium lauryl sulfate of about 1 to 10 mg originates, in part, from personal products (including oral hygiene products), or less

foods, and drinking

water. Personal products

account for about one-half

of this intake (Ref. 310).

i. Safety. Extensive sodium safety data, both in animals and humans, show that

lauryl sulfate has a very low level of toxicity is rapidly metabolized through

at doses used in oral the liver, and has no

health care products, genotoxic

or teratogenic

effects (Ref. 311). Sodium lauryl sulfate is poorly absorbed radio-

I. Absorption through

and excretion. lining

the epithelial

of the skin and mucosal surfaces. Aqueous

labeled sodium for 10 minutes,

lauryl sulfate was applied followed by washing

to guinea pig skin in vivo by rubbing of a nonocclusive was recovered on

and application

dressing for 24 hours (Ref. 308). Most of the radioactivity the skin at the experimental Radioactivity radioactivity concluded sodium site, in the washing fluid,

and in the dressing.

of 0.1 percent was recovered was found in the internal

from exhaled air and urine. No

organs, feces, or carcass. The studies terminal group impaired

that the presence of a strong anionic through

lauryl sulfate penetration

the skin. to radio-labeled (25 millimolar (mM))

Rat skin was exposed for 15 minutes sodium lauryl sulfate. Expired

carbon dioxide,

urine, feces, and skin were of

monitored sodium

for 24 hours. Autoradiography

showed heavy concentrations

lauryl sulfate on the skin surface and in the hair follicles. lauryl sulfate were also recovered sodium


levels of sodium

in the urine (Ref. 308). on

If linear alkyl sulfates, including

lauryl sulfate, are deposited only a small amount lauryl actually

the skin after a wash and rinse application, penetrates

the skin (Refs. 312 and 313). Sodium the intestine of mammals,

sulfate is rapidly through to (Ref. 314). the

absorbed through



liver, and is excreted in the urine. Sodium carboxylic acid with butyric acid-$-sulfate

lauryl sulfate is oxidized as the major metabolite

2. Acute

Sodium lauryl sulfate has an LD50 in rats ranging from

9.9 to 1.6 g/kg with a mean of around 1.3 g/kg (Refs. 315 and 316). Studies (Ref. 308) indicated included that sodium lauryl sulfate is slightly lacrimation, salivation, toxic. Signs of toxicity

diuresis, diarrhea,

tremors, convulsions,

sedation, anaesthesia, and death. Intraperitoneal administration of sodium lauryl sulfate (25 or 50 mg/kg P450

body weight per day for 3 days) decreased the level of some cytochrome species (Ref. 317), stimulated haem-oxygenase activity

(Ref. 318), and affected

serum lipids (Ref. 317). The concentrations routes of administration toxic effects, including to this ingredient 3. Chronic

of sodium lauryl sulfate and the designed to induce

in these studies were specifically

death, and have little in common with human exposure and dentifrices. up to 2.25 percent

with normal use of mouthrinses
toxicity studies.

Rats fed a diet containing

sodium lauryl sulfate for 13 weeks demonstrated increased liver weight, glutamic pyruvic

enlarged liver cells and phosphatase and

as well as elevated levels of alkaline


These changes were considered

to represent of


to the increased work load required

for the metabolism nonspecific

sodium lauryl sulfate. Other changes noted included of the kidneys, lymphatics. increased water consumption,


and enlarged intestinal no changes could

The sodium lauryl sulfate level below which

be detected was 0.14 percent of the dietary intake, or 116 mg/kg body weight (Ref. 319). Another 316). In a 16-week feeding study in rats, daily doses of different sodium lauryl sulfate in the diet had different death, 4 percent in significant percents of study found the “no change” level to be 0.1 percent (Ref.

results: 8 percent resulted in and 2 percent in some

growth retardation,

growth retardation that was not statistically significant (Ref. 320). In a l-year sulfate caused some

study in dogs, a Z-percent weight

dietary intake of sodium lauryl

loss. The “no change” level was 1 percent (Ref. 308). of alkyl sulfates has been extensively notes several hypothetical reviewed examples (Refs. 321 (Ref. 313)

The toxicology

and 322). The Subcommittee that place the above findings unlikely

in the context of human subject users. In the 10 mL of a mouthrinse containing

event of a 20-kg child ingesting

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 SO-kg adult ingesting 1 mL of the mouthwash daily would

be over 1,900. Based on the l-year study in dogs (Ref. 308), the safety factors for the child and adult would 4. Repro&&on toxicity. be greater than 500 and 13,000, respectively. Teratogenic studies in rats (Refs. 323 through Some embryotoxicity was noted

326) revealed no evidence

of teratogenicity.

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 There is no evidence care products that sodium in any increase in chromosome lauryl sulfate incorporated risk in humans. aberrations.

in oral health

is a teratogenic

or mutagenic

6. Skin irritation.
sulfate produces primary lauryl

At concentrations

of 2, 10, and 20 percent, sodium lauryl test score compatible with that of a of sodium

a Draize skin irritancy

skin irritant sulfate applied

(Ref. 308). The 1 to 6 percent concentrations to human skin under an occlusive no irritancy potential

patch for 21 days were


to the skin. However,

could be detected in the

absence of the occlusive sodium lauryl patch (Ref. 331). Therefore, little, if any, irritation lauryl open application of

sulfate produces

at these concentrations. sulfate applied to the A l-

7. Ocular irritation.

The 10 percent sodium

rabbit eye caused cornea1 damage if washing percent sodium lauryl sulfate application

was delayed or withheld.

caused little irritation

and no cornea1

damage (Refs. 309, 321, and 322).

8. Oral irritation potential. Sodium lauryl sulfate solutions
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 application not produce of the lips) and sloughing of 0.2 percent sodium any detectable were observed (Ref. 332). A single

lauryl sulfate to the oral mucosa of rats did cellularity was

changes, whereas increased

observed with a Z-percent application applications, the cellular reaction concludes

in half of the animals. After 3 weekly

decreased (Ref. 333). that, based upon the results of the extensive are referenced above), sodium lauryl sulfate

The Subcommittee toxicity

tests (only some of which

does not constitute health care products.

a risk to consumers The widespread

in the concentrations use of sodium lauryl

found in oral sulfate in numerous products, supports

oral health care products, without any reported

as well as in foods and other personal

side effects attributable

to normal use, further

the safety of this ingredient.

ectl’ ii. E’ veness. The Subcommittee
data available to permit final classification


that there are insufficient of sodium lauryl

of the effectiveness

sulfate as an antigingivitis/antiplaque Sodium

agent. because of

lauryl sulfate is used in oral health care products properties, which include: (1) Decreasing

certain desirable

surface tension

(Refs. 334 and 335), (2) affinity for enamel surfaces, leading to masking of (Ref. 336), (3) emulsification of food and

receptor sites for bacterial proteins bacterial components

(Refs. 334 and 337), (4) inhibition

of selective enzymes for bacterial

that help form dental plaque (Refs. 337, 338, and 339), (5) affinity proteins and ability to denature them (Ref. 337), (6) disruption (Ref. 34O), (7) inhibition of plaque formation

of cell decreased cells for of



surface tension and competition binding

with negatively

charged bacterial

sites on the tooth surface (Ref. 341), and (8) optimization properties of certain zinc salts (Ref. 340). of sodium lauryl sulfate contribute


These properties

to its usefulness


loosen and remove food particles (Refs. 342 through properties also allow sodium lauryl sulfate to inhibit

349). Some of these the formation of dental

plaque (Ref. 35O), exert a mild antibacterial

effect (Ref. 35l), 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 containing trials involving sodium lauryl sulfate, that

the types of products

this ingredient product

and the characteristics

make it desirable for a particular differences difficult in formulations

should be considered.

Because of it may be to some

and the presence of other ingredients,

to determine

to what extent sodium lauryl sulfate contributes

of the beneficial

effects claimed for marketed products. users is to reduce oral malodor.

For example, a major However, it is

objective for mouthrinse difficult

to compare the effect of rinses containing

sodium lauryl sulfate to factors (Refs. that contain

those that do not, since flavoring 352 through

agents are obvious confounding

357). The most common oral health care products mouthrinses, prebrushing

sodium lauryl sulfate include

rinses, and dentifrices.

Mouthrinses are designed to provide characteristics cosmetic and/or therapeutic benefits. for

The major desirable

of sodium

lauryl sulfate are its affinity which theoretically

enamel surfaces and its ability should interfere

to reduce surface tension, and provide

with dental plaque formation

a clean tooth

feeling. Prebrushing emulsifying activity,

rinses rely on these characteristics thereby maximizing

for additional that is largely

dental plaque removal

the result of bristle action. Finally, sodium superior reported lauryl sulfate is frequently properties

because of its properties used in toothpastes

as a surfactant, agent. Its were

as a foaming



to soap as a toothpaste


as early as 1937 (Ref. 358). studies have shown a moderate reduction

In general, human mouthrinse in plaque formation formulations, No significant in gingivitis Typical shown below. gingivitis

in the test groups using sodium

lauryl sulfate in various sulfate.

as compared difference studies.

to a control group using no sodium lauryl was observed between

the test and control groups

plaque and gingivitis

scores from two representative

studies are

The scores at the end of these studies represent following

plaque and prophylaxis:
End Plaque scores

score changes from a zero baseline,
TABLE 12.-PLAQUE Study Group (n)

an initial


Test Product

Test (13) Water
44% (13)


2.86 5.13


Net plaque reduction:

Gingivitis scores Test
(13) 0 0.88

Water (13) Net gingivrtis reduction: 2% (not srgnrficant) TABLE I3.-PLAQUE Study




Study Test Product (0.3% SLS) Test (7) 0 1% chlorhexidine Water (9) Net plaque reduction. 54% Gmgivitts scores Test (7) 0.1% chlorhexldine Water (9) Net gingwktls reductton: 21% (not significant) (9) 0 0 0 0.93 1 03 1 17 (9)

Group (n) Baselme 0 0 0 End 2 20 2.43 4.78

The statistically



in plaque scores in these studies, by a statistically

as compared to a water placebo, were not accompanied significant reduction in gingivitis scores.

No convincing

evidence exists to support the effectiveness effect of the rinses as compared

of prebrushing to placebo study

rinses, because the net beneficial is clinically insignificant.

One of the products

tested in the Truelove

(Ref. 349) (see Table 14 of this document)

contains a number of ingredients sodium lauryl sulfate that

other than sodium lauryl sulfate (Ref. 360). However, is listed as the only active component. prebrushing

The results of this study indicated

rinsing with two rinses that contain sodium lauryl sulfate as the is no more effective than rinsing with a suitable sodium placebo.

active ingredient lauryl sulfate-free

I 2 56 1 2.94 1 2.50 Prebrush score I Il.11 I 1 23 1 1.16 Postbrush score

Test product (0.25% SLS) Other product (0.3% SLS) Placebo

The results of the Emling study (Ref. 361) suggested a somewhat plaque score reduction with the test product containing


0.25 percent sodium However,

lauryl sulfate than the placebo (see Table 15 of this document). 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).
Agent Test oroduct (0 25% SLS) Placebo 3.12 3 09

Prebrush score 2.05 2.82 Postbrush score

In addition, significant


et al. (Ref. 364) were unable to detect a statistically between active and


in the degree of plaque reduction

placebo rinses. Van Dyke et al. (Ref. 365) also monitored conditions reductions to baseline of prebrushing rinsing. gingival changes under significant

They reported


of plaque scores for both the placebo and the test rinse as compared 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 Further, treatment, there were no differences or between were not clinically significant.

in gingivitis

scores before and after

test and placebo scores. (Ref. 366) found no difference between test and

Kohut and Mankodi placebo prebrushing reduction.

rinses, either in the degree of plaque or gingivitis by Singh (Ref. 367) and by Pontier orthodontic treatment. In a 6-month

Similar results were reported undergoing

et al. (Ref. 368) in children clinical

study, Lobene et al. (Ref. 369) failed to show that a test product 0.25 percent sodium plaque, gingivitis, lauryl sulfate was superior to a placebo in

containing reducing

or calculus. that sodium lauryl sulfate is effective and provide to a clean for

The Subcommittee facilitate the removal


of food and other particulate through its surfactant lauryl


tooth feeling, primarily binding


and its affinity

to tooth surfaces. Sodium

sulfate appears to have a minor

inhibitory Although effect on plaque formation, following an initial properties dental prophylaxis. in vitro, it is not

sodium lauryl sulfate has antibacterial

clear to what extent this antibacterial

effect is exerted in vivo. The antiplaque Sodium lauryl sulfate does sulfate

effect of sodium lauryl sulfate is at best moderate. not have a significant as a facilitator effect on gingivitis.

The role of sodium


of plaque removal when used in a prebrushing clinical formation. improvement, Sodium lauryl

rinse is marginal such as gingivitis sulfate is a safe

and does not result in any beneficial reduction or inhibition foaming of calculus ingredient concludes

and effective

when used in toothpaste. that sodium lauryl sulfate at 0.1 to 5 percent

The Subcommittee concentration insufficient an antiplaque
g. Zinc

in an oral rinse or dentifrice data available to permit

dosage is safe, but that there are of its effectiveness as

final classification

and antigingivitis

agent. concludes that zinc citrate is safe, but as an OTC

The Subcommittee evidence to support agent. formula

there is insufficient antigingivitis/antiplaque

its effectiveness

Zinc citrate has a chemical zinc carbonate that is slightly zinc to inhibit

of Zn3(&H507)2

and is prepared


and citric acid. It is described

as a dihydrate,

odorless powder, abilities of

soluble in water (Ref. 370). Based on the known crystal formation zinc chloride ingredient and of citrate to inhibit (highly

crystal aggregation,

zinc citrate replaced taste) as a toothpaste Zinc citrate trihydrate supragingival calculus

effective but with a disagreeable dental calculus formation (Ref. 371).

to inhibit

(Zn3(&H507)23H20) formation.

has been used to inhibit

i. Safety. Zinc is ubiquitous element in humans.

in our environment continues

and is an essential trace to be the subject of

Its role in humans

investigation. documented The overall safety of zinc citrate has been well and extensively (Ref. 372). Acute toxicity studies in animals have shown zinc

citrate to be only slightly produced toothpaste

toxic. Zinc citrate fed to rats for up to 13 weeks

toxic effects only at high levels. No toxic effects were observed when containing up to 10 percent zinc citrate was fed to rats and dogs relatively nontoxic

for up to 18 months. In humans, zinc salts are considered (Ref. 372). Zinc citrate had no adverse effects on fertility, rats and rabbits (Ref. 372). This finding other zinc salts. No mutagenic Zinc does not have genotoxic normally toothpastes toothpastes. ii. Effectiveness. studies, two 6-month citrate on gingivitis experimental The Subcommittee reviewed

the fetus, or neonate in findings on

correlates with published

effects have been reported effects or pose a carcinogenic

from in vivo studies. hazard at levels potential of

found in the body (Ref. 372). The oral irritation containing

zinc citrate is no greater than that of other marketed

five short-term


studies, and a 3-year trial assessing the effect of zinc (Ref. 373). The five studies had in common a 21-day a d-week period of tooth from brushing one lower

period in which subjects, following refrained

cleaning and oral hygiene instruction, quadrant of teeth. An impression

of each lower tooth arch was made and a shield” was heated and vacuum fitted to place a measured quantity

plaster mold prepared.

A plastic “tooth

to the plaster models. Subjects were instructed of dentifrice insertion into the indentations

in the tooth shield twice daily prior to its teeth. Plaque and gingivitis of zinc citrate in toothpaste

in the mouth, and brush the remaining

were assessed after 21 days. Various concentrations or other ingredients alone or in combination

with zinc citrate were used as

well as


were not as effective clinical

as active ingredients.


these studies were not randomized as evidence of the effectiveness

trials, they cannot be considered

of zinc citrate. to

The first &month evaluate the relative fluoride/zinc dentifrice essentially

study by Hefti and Marks (Ref. 374) was conducted effectiveness of a hydrogen peroxide/baking available antitartar soda/ fluoride

citrate dentifrice and a commercially a supragingival

with a commercially available fluoride


This was


study where subjects were selected based Calculus Index at the

on having a score of at least 6.0 on the Volpe-Manhold time of screening. Clinical exams during Gingival

the trial period were done at 45, 90,

and 180 days. The Modified used for gingival

Index by Lobene et al. (Ref. 112) was assessment

assessment. Only simple means for the 6 months

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 available toothpaste.

lower scores than the fluoride-only


Three means were given for 45 and 90 days, plus one was provided about subject

p value, showing characteristics, Calculus

similar results. No information inclusion or exclusion criteria

other than Volpe-Manhold indicators concerning of measurement zinc citrate to other agents/ error

Index scores, examiners, or blinding.


or uncertainty, effectiveness ingredients.

The conclusions

were based on a multiagent



The second 6-month selected from a population and medical


study (Ref. 375) included

295 subjects strict dental

of 330 adults of which No further

311 fulfilled

health requirements.

details on health requirements e.g., age,

were given. No information

was provided

about the study population,

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 performed information subjects were selected for plaque collection, which was

prior to disclosing

for the plaque assessment. There was no

on how these subjects were selected. used were described oz pump dispensers, as supplied by the sponsor in identical

The products two-chamber,

each with one of three three-letter control dentifrice,”

codes. The report (Ref. 375) describes the three as “negative “experimental summary stannous dentifrice,” and “experimental dentifrice.”

An accompanying containing


the products

only as “dual-phase


salts and/or zinc citrate.” One of the three-letter dentifrice.”

codes was identified

only as “the zinc citrate-containing about the composition differences

Thus, there was no information or details about

and concentration

of ingredients

in color, odor, and taste in the products

tested. The Subcommittee study

does not believe this study adhered to strict criteria for a double-blind because the following appeared in the report: “Except

for some complaints dentifrice ‘ ABC,’ the

about the taste and staining products were favorably

associated with experimental These complaints


were associated with differed

only one of the three tested products. from the others in taste and staining blind study. Examiners participated performed were described

This suggests that one product and, therefore,

the study was not a double-

only as “experimental



in a calibration

exercise prior to initiating

the investigation, The report did not whether calibration reliability.

the same assessments at each examination.” of examiners and their background,

discuss the number was successful,

or testing for intra-examiner

and inter-examiner

Mean gingival index scores plus standard 3 months, error were given for each of the (279 of 295 subjects at 3 and 6 significantly

three groups at baseline, completed 6 months).

and 6 months

All scores were reduced containing

from baseline

months. The dentifrice different

zinc citrate was statistically

(~~0.03) from the “control” dentifrice,

group. Mean scores at 3 months were 0.831tO.2 for the test dentifrice containing dentifrice, without zinc

0.87k.02 for the control

citrate, and 0.81k.02 for the test dentifrice the scores were 0.9BO.2 test dentifrice containing significant without for the control

zinc citrate. At 6 months 0.86kO.2 (~~0.04) for the

zinc citrate, and 0.85k.02

(~~0.04) for the test dentifrice evidence that a clinically

zinc citrate. The study does not provide improvement in gingival

index scoring was due to zinc citrate. results from the first 2 years were of the trial were to establish the level of sodium of 0.5 percent with a mean Two

The 3-year trial (Ref. 376), of which submitted,

was a caries study. The main objectives of caries increments

the reduction

caused by increasing whether


and to investigate

the inclusion children

zinc citrate affected caries increments. age of 12.5 years and all within clinicians

Three thousand

a l-year age range were recruited.

assessed all subjects, who were then randomly groups. One-half

assigned to one of containing Oral Health

six toothpaste

of the subjects used a toothpaste Simplified

zinc citrate. Plaque (using Greene and Vermillion’ s Index (OHI-S)) and gingivitis

(Loe and Silness Gingival

Index) were assessed and incisor in each

each year. Six teeth were assessed: One molar, premolar, arch, at four surfaces on each tooth. Differences with and without nonstatistically between cumulative

mean scores for groups using toothpastes One examiner showed

zinc citrate were calculated. significant differences

for years 1 and 2 and a second examiner

showed statistically differences examiner Clinically this study. The Subcommittee’ s trials include presenting criteria for data submitted information from randomized clinical significant differences. significant. When pooled together, the small about

were statistically calibration significant

There was no other information reliability.

or testing for intra and interexaminer

effects due to zinc citrate could not be determined


on all of the major study components, agents, outcomes, rationale concealment of allocation for statistical to study group,

e.g., the protocol

(study population,

analysis), methods of randomization, and method of blinding. indicators of measurement hypothesis

Results should be presented with appropriate error or uncertainty, avoiding dependence solely

on statistical

testing, such as the use of p values, which information.

fail to

convey important Subcommittee


Based on these criteria, the were insufficient to permit


that the data submitted

final classification antiplaque agent.

of the effectiveness

of zinc citrate as an OTC antigingivitis/

2. Category III Combinations Data to demonstrate agent will be required effectiveness Alkyl

of Active Ingredients as an antigingivitis/antiplaque on safety and

safety and effectiveness

in accordance with the general guidelines

in section 1I.H of this document. amine oxide and alkyl dimethyl and povidone iodine glycine


Hydrogen Hydrogen Hydrogen chloride Peppermint

peroxide peroxide peroxide,

and sodium bicarbonate sodium citrate, sodium lauryl sulfate, and zinc

oil and sage oil

Polydimethylsiloxane Stannous pyrophosphate a. Alkyl dimethyl Subcommittee and poloxamer and zinc citrate glycine. The

amine oxide and alkyl dimethyl that there is insufficient of the combination


evidence to support the amine oxide and agent. This

safety and effectiveness alkyl dimethyl combination properties) spectrum

of alkyl dimethyl

glycine as an OTC antigingivitis/antiplaque consists of two amphoteric

(having both acidic and basic said to have broad

quaternary antimicrobial

ammonium activity.

inner salt surfactants

i. Safety. An acute oral toxicity of alkyl dimethyl

study (Ref. 377) of a 3-percent solution glycine calculated that the

amine oxide and alkyl dimethyl

LD50 in Sprague-Dawley observations included

rats was greater than 6,000 mg/kg. Necropsy 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 abnormal findings, such as

pattern at necropsy, cortical congestion

all of the dogs displayed of the mesenteric

lymph nodes, white nodules on the gall of the lungs with a yellow-colored mucoid

bladder mucosa, and consolidation material in the bronchi.

A series of dermal toxicity concentration of the liquid

studies was carried out. Again, because the

used was not stated, these studies were difficult of a s-percent solution amine oxide

to evaluate. In one study (Ref. 379), the dermal toxicity of the combination was evaluated of alkyl dimethyl

glycine and alkyl dimethyl

on abraded skin of rabbits. Two of 20 animals displayed

minimal reaction. An additional study (Ref. 380) reported that 3.6 percent of rabbit skin.

an applied

dose was absorbed through

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 combination However, concluded that there was no evidence suggesting the can act as a sensitizer in the guinea pig. of the test material was used. In that repeated topical exposures has the potential

of these ingredients

it was unclear what concentration

the second study (Ref. 382), it was concluded of guinea pigs to a 3-percent solution

of these ingredients

to induce mild dermal sensitization. Based on the results of a Salmonellalmicrosome 383), the authors concluded oxide and alkyl dimethyl some concentrations. of S. typhimurium, reproducible a mutagenic limitations. Eye and vaginal solution irritant tests have also been conducted. amine oxide and alkyl dimethyl A 3-percent glycine was judged in rabbits [Ref. it was that the combination mutagenesis of alkyl dimethyl assay (Ref. amine at

glycine inhibits

the growth of microorganisms


small increases were observed in several strains

the authors stated that these increases were not to random fluctuations that do not represent

and were attributed

response to the test product.

The test, therefore, has some

of alkyl dimethyl

to be a mild irritant 384). In an additional concluded

in the eyes of dogs and a severe irritant study conducted solution by a different


that a 12.5percent

was not an irritant

to rabbits. Results

from vaginal irritation produced which

studies (Ref. 385) concluded vaginal irritation

that these ingredients it was unclear score. Six

an “acceptable”

score. However,


were tested and what is an “acceptable”

preparations appear to have been examined, in composition. a series of studies (Refs. 386, 387, and 388) of alkyl dimethyl amine oxide and alkyl The evaluations Adverse effects but no information was presented

on how they differed

The data also included evaluating dimethyl a lo-percent


glycine as a body wash in nursing home patients. or gathered from interviews.

appear to be largely subjective were not observed.

Dentists gave the combination a mouthrinse

of these ingredients

to subjects to use as tingling,

(Refs. 389 and 390). Overall adverse effects, including stain, and a peppery

mucosal irritation,

sensation on the tongue, were reported adverse effects

by 0.5 to 0.8 percent of users. Other dentists (Ref. 391) reported in 1.3 percent of subjects. The effects of the combination were examined (H6-60). using a chromium of these ingredients

on mammalian

cells cells

release assay from human leukemic occurred at concentrations

The release of chromium

of 0.025 to 0.005

percent. As the report notes, “these findings effective window 392). ii. E’ veness. ectl’ approximates

are of some concern since the

the MIC for several bacterial species” (Ref.

A number of studies have been carried out to assess the on the growth of oral bacteria and on the ability

effects of this combination of oral microorganisms The combination exhibits

to produce

acid from glucose. amine oxide and alkyl dimethyl glycine (Ref.

of alkyl dimethyl

an antimicrobial

effect against a wide range of microorganisms susceptible and is inhibited

393). Lactobacillus

casei is highly

by as little as

a 0.0004-percent to the combination.


Several isolates of Pseudomonas

are highly resistant organisms was

In general, the effect against gram-positive

independent influenced completely of pH. In contrast, the effect against gram-negative by pH values. A 0.5percent inhibited bacterial glycolysis concentration organisms was

of these ingredients the (0.05

for 7 hours and inhibited

adherence of S. sobrinus to michrome percent) had less effect.

wires. A lower concentration

Twelve subjects (Ref. 3%) rinsed with various concentrations dimethyl amine oxide and alkyl dimethyl

of alkyl with

glycine and other preparations Concentrations of 0.1

only 2 days allowed between testing each material. percent or higher reduced the population Streptococcus populations

of total cultivable

flora and total of 0.2

for at least 1 hour post rinse. Concentrations glycolysis

and 0.5 percent inhibited A clinical

in salivary sediment for several hours.

study involving

84 females and 42 males (aged 20 to 49) used (Ref. 395). Subjects were or a

a O.ZtS-percent solution divided positive

(pH 6.8) of this combination

into one of three groups using a placebo, the test ingredients, control. Gender distribution was not disclosed. Following

a complete


subjects rinsed twice daily for 6 weeks with 20 mL of solution. to continue their normal oral hygiene throughout of the Quigley-Hein Placebo, the

Subjects were instructed

study. Plaque was assessed using Turesky modification

Index. Mean plaque scores at the end of the study were as follows: 2.53 ? 0.56 (2.44 2- 0.38), test ingredients, control,

2.05 + 0.58 (2.45 k 0.36), and positive of variances) differences. An F

1.96 &-0.33 (2.46 f 0.31). An F test (test for equality of the final three numbers showed statistical and the positive


test between the test solution significant difference.

control showed no statistically Gingivitis was

No other statistical

tests were reported.

not assessed.

A brief report (Ref. 396) claimed that a toothpaste ingredients reduced plaque formation for 7 days. Gingivitis containing these

by 43 percent in 15 subjects who used apparently was not assessed. The report

these ingredients

lacked essential information. In a combined animal and human study (Ref. 397) and a separate human containing 1 percent of the combination glycine applied topically of alkyl three times

study (Ref. 398), a toothpaste dimethyl

amine oxide and alkyl dimethyl caries.

weekly had no effect in preventing In a more recent single-blind,


crossover study in 20 subjects the combination of alkyl with saline and

(Ref. 399), the effects of four ingredients, dimethyl amine oxide and alkyl dimethyl plaque regrowth.


glycine, were compared

in preventing suspended

Subjects rinsed twice daily for 1 minute

normal oral hygiene measures. Plaque was scored using a plaque of alkyl dimethyl amine

index and plaque area assessment. The combination oxide and alkyl dimethyl glycine was significantly

less effective than the other was not

three agents tested, but was more effective than saline. Gingivitis assessed. Based on the data submitted, insufficient the Subcommittee concludes

that there is

evidence to support the safety and effectiveness amine oxide and alkyl dimethyl agent.
and povidone iodine.

of the combination

of alkyl dimethyl

glycine as an OTC

antigingivitis/antiplaque b. Hydrogen determined effectiveness

The Subcommittee


that there is insufficient of the combination

evidence to support the safety and peroxide and povid ine iod ine as

of hydrogen agent.

an OTC antigingivitis/antiplaque i. Safety.

The Subcommittee concentrations peroxide solutions concludes that hydrogen peroxide is safe at of hydrogen

of up to 3 percent. Because the final concentration

in this combination

is 1.5 percent when the separately packaged considers this portion iodine component of the

are mixed, the Subcommittee to be safe. The povidone


of the combination

(5 percent final concentration), including


raises several safety concerns,

acute and chronic toxicity. toxicity study. An acute toxicity study (Ref. 400) was performed Ten animals were dosed that povidone

1. Acute

on rats to determine

the LDso iodine concentration. occurring.

with 5 g/kg with no fatalities iodine is not considered

The data established

toxic when the LDso is greater than 5 g/kg. The only (distention with urine) of

noted toxic effect at this level was hydronephrosis the kidneys of two male rats. 2. Oral mucosal

toxicity study. Oral mucosal toxicity containing

was also examined peroxide and

in rats (Ref. 401). A solution 5 percent povidone

1.5 percent hydrogen

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 the differences between the groups were not of ingredients, lethargy, 5 of the diarrhea,

not gain weight normally, significant.
12 animals

In the group that received the combination showed signs of acute iodine toxicity,


and abnormalities

in the GI tract. These signs suggest possible acute toxicity were not noted in the iodine solutions

in humans due to iodine overdose. These abnormalities two groups exposed to hydrogen individually. peroxide or povidone

No negative control group was included.

3. Acute dermal toxicity percent povidine study. In an acute dermal toxicity study, a loperoxide at

iodine solution

mixed with 3 percent hydrogen

2 g/kg of body weight was applied were recorded diarrhea,

to 10 albino rats (Ref. 402). Skin reactions

as slight, but 8 of 10 animals showed lethargy, nasal discharges, All 10 animals survived, defined the test mixture showing as

and other signs of GI disturbances. The investigators

only mild dermal irritation. nontoxic

because the LDso was greater than 2 g/kg of body weight. study. An eye irritation study was conducted on six albino

4. Eye irritation

rats by placing a standard mixture hydrogen peroxide

of 10 percent povidine

iodine and 3 percent

(Ref. 403) into the conjunctival

sac and scoring by the was irritation

Draize technique determined

at 1, 2, and 3 days after dosing. The test mixture

to be an irritant,

causing iritis and moderate conjunctival

in five of six animals. 5. Chronic toxicity study. Chronic toxicity ‘ the activity of iodine on the thyroid. function A 6-month is also of concern because of prospective study in 50 prolonged

subjects to assess thyroid exposure to the mouthrinse

and iodine levels following

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 normal limits. These tests included triiodiothyronine significant consistently function tests remained (T4), free T4, A small but (TSH) was within

serum thyroxine

(T3), and free T4 index measurements. stimulating hormone

rise in the serum thyroid noted. The investigators

suggested that this small increase in adaptive response

serum TSH should be considered

a normal physiological

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, was relatively population. concomitant there were several concerns. The total number of healthy small and may not reveal possible side effects in a larger While the investigators considered increased TSH without subjects

serious side effects as a sign that subjects were able to tolerate interpretation is that the increased TSH was properly. A

increased iodine, an alternative an early indication of a thyroid

system that is not functioning

larger and perhaps longer study is needed.
6. Chronic

use test in compromised



a second much containing

smaller study examined hydrogen thyroids, peroxide

the effects of chronic

use of a mouthrinse

and povidone

iodine in subjects with compromised inadequate to establish

the number of subjects was completely

possible side effects.
7. Mutagenicity

tests. Tests to determine

the mutagenicity

of povidone assay,

iodine were carried out using the Salmonella/microsome a micronucleus


test in rats, and a rat hepatocyte

DNA repair assay (Refs. 405, they did not indicate the cytotoxic effects on

and 407). While the tests indicated effect. A cytotoxicity

cell toxicity,

a mutagenic

study examining

Chinese hamster ovary cells was also reported that the combination report indicated rinse is cytotoxic

(Ref. 408). The study concluded of 2,500 pg/mL. The with the appropriate

at a concentrations activation mixture

that when a metabolic

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 examined iodine toxicity studies submitted, the Subcommittee

in general. Acute toxicity

of iodine tincture

percent has

iodine and 2.4 percent sodium iodine in a 50 percent ethanol solution)

been recorded at levels relevant to the concentration of povidone iodine (5

percent) in this combination. mL of tincture

Fatal events have occurred when as little as 30

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 resulting by foodstuffs. When large concentrations of iodine are ingested, of

shock and tissue hypoxia

have been noted (Ref. 409). Ingestion abdominal

lesser amounts can cause gastroenteritis, may be bloody. Nausea and vomiting The current product supervised

pain, and diarrhea that

are common with ingested iodine. that children under 12 be or

labeling recommends

while using the product

and warns against use by pregnant

nursing mothers, those with iodine sensitivity, thyroid include disorder. Because of the potential a warning that the product

and those with a history of

toxic side effects, the labeling should women

should not be used by children, from a thyroid

of child-bearing or ailment.

years, or anyone suffering long-term

disease, disorder, should

Subjects considering

use of these ingredients

consult their physician contraindicate use.

to determine

if any conditions

exist that might

ii. Effectiveness. 1. Six-month

Two 6-month

studies (Refs. 410 and 411), a s-week

study (Ref. 4X2), a 6-week study (Ref. 413), and a brief review of the antimicrobial submitted. effects of mouthrinses The 6-month on dental plaque (Ref. 414) were

studies (Refs. 410 and 411) were designed similarly, according to common exclusion criteria. Subjects

using subjects admitted received a thorough


and were then assigned to one of four groups peroxide and povidone iodine, a rinse water

using a test rinse containing containing


only one of these ingredients

in distilled

water, or a distilled

placebo. Because the subject pool was divided had a relatively limited number into four groups, each group total subjects completed

of subjects. Ninety

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 included measurements of plaque using the Turesky modification Bleeding assignments of the attempts sites.

Quigley-Hein to quantitatively

Plaque Index and the Papillary assess inflammation

Scoring, which

and bleeding

at the interproximal the value of the

Several troubling

aspects of the protocol


studies from the start. The overall sample size was immediately including groups that used only hydrogen different peroxide

halved by iodine.

or only povidone

The control rinse was substantially contain a placebo vehicle. irrigation

from the test rinse and did not professional

The protocol

for both studies included throughout


at 3-week intervals

the study. Further, for 30 minutes

subjects were instructed following the rinsing

not to rinse, drink, or eat anything

procedure. studies failed to provide For example, while convincing clinical

Results from the two 6-month data in support borderline Neither

of the tested ingredients.

one study showed

significant study reported

plaque index score differences, the overall gingival

the other study did not. index) scores. It index

index (bleeding

appears that there were no significant


overall for the gingival

in either study. Instead, only scores for sites greater than or equal to three were chosen for analysis. While both studies suggested that significant could be determined for these comparisons solution in this limited were unclear and skewed selection or not reported. differences

of sites, p values

Because use of the test in at least one of the condition was

did not significantly

affect plaque buildup

studies, it is possible that the positive

effect on the gingival

due to the subgingival irrigation professionally administered every 3 weeks flora but did

during the test period. If the test solution not significantly change the supragingival irrigation.

altered the subgingival

flora, the most likely contributing

factor would be the professional Further, somewhat

the two studies were tabulated difficult


and the results were sites while the other

to compare. One study compared

study examined


between subjects. The number of sites used in The investigators in one study chose in the number of sites it is possible subjects had

these analyses was unclear or unstated.

sites over subjects for analysis because of the variation between subjects with a bleeding

index greater than 3. Therefore,

that one or only a few subjects had many sites and the remaining few sites that qualified. realistically Such a distribution

could produce results that the group rather than the

represent only a few subjects within

group itself. As with several other important and standard errors for specific comparisons The studies included examination. a limited

aspects of these studies, p values were often unclear or unstated.

number of samples for microbiological selective media along that

The investigators

in both studies utilized

with other microbiological opportunistic themselves pathogens

assays. Both study reports indicated (Can&da

and enteric bacteria) did not establish samples tended

in any of the test groups sampled. The test solution periodontal pathogens compared

to show fewer presumed However,

to control samples. quite low or data hold the

the number of periodontal

pathogens was generally

absent depending

on the species studied. While the microbiological subgingival irrigations data difficult.

some interest, the use of professional studies made interpretation


of the microbiology

The design of these studies made definitive with no consistent gingivitis. or convincingly significant conclusions clinical very difficult,

effect on plaque or is safe, but

The toxicology

data suggested that the combination sized study of healthy

doubts linger. An appropriately compromised

and thyroid-

subjects should be considered Subjects should and professional

using a placebo that more closely not be instructed irrigation to refrain from

resembles the test product. eating, drinking, or rinsing

should not be included,

as such procedures

might significantly

alter the results. studies of 3 and 6 weeks in the clinical parameters

2. Three and 6-week studies. Two short-term (Refs. 412 and 413) showed significant reported. including However, several ingredients

improvement reviewed

by the Subcommittee, have shown positive short-

some formulations

of hydrogen

peroxide, studies.

term results only to fall short in long-term

Based on these studies, the Subcommittee evidence hydrogen agent. c. Hydrogen concludes peroxide and sodium to support peroxide the safety and effectiveness and povidone iodine

finds that there is insufficient of the combination of

as an OTC antigingivitis/antiplaque


The Subcommittee and hydrogen peroxide peroxide is safe, but

that the combination

of sodium bicarbonate

at concentrations

up to and including data available

3 percent hydrogen to permit

there are insufficient effectiveness

final classification

of the agent.

of the combination peroxide

as an antigingivitis/antiplaque can produce hydroxyl

i. Safety. Hydrogen

radicals in the

presence of iron (Fe+2) or copper (Cu+l) studies have shown that sister chromatic hydroxyl radicals. Experimental

(Refs. 188 and 189) and in vitro exchanges can be produced by a

and clinical

data are sparse demonstrating

significant mutagenic effect with the combination in oral health care products. a significant of hydrogen Experimental mutagenic peroxide and

sodium bicarbonate data, however, combination products peroxide likelihood

and clinical with the

do not demonstrate of hydrogen peroxide


and sodium bicarbonate

in oral health care of hydrogen

(Refs. 145,188,

and 189). The rapid decomposition

in the presence of sodium bicarbonate of a mutagenic effect occurring

(Ref. 145) further reduces the products.

with combination

A 1989 mutagenicity concentrations

study by Kuhn et al. (Ref. 415) tested varying levels of hydrogen peroxide up to 100 pg/ on several strains effects on the

of a gel containing

plate in a bacteriological of S. typhimurium.

assay for toxicity

and mutagenicity

The results showed no toxic or mutagenic

strains tested, which was approximately mutagenic

100 times greater than the optimal peroxide. This result is in

response seen with aqueous hydrogen

contrast to other studies using strains of S. typhimurium mutagenic action associated with hydrogen peroxide

that showed

(Refs. 163, 168, and 416). with peroxide in oxidant-

This result is also in agreement with studies conducted formulated in dental products that are uniformly

not mutagenic

sensitive bacterial After 1 minute

strains (Refs. 172 and 417). of brushing, recovery of hydrogen peroxide in the presence into the oral were

of baking soda was less than 5 percent of the amount introduced cavity (Ref. 145). Identical results on hydrogen peroxide


seen in control subjects and subjects with impaired Using a rat animal model, a combination hydrogen peroxide incorporated

salivary flow. and

of sodium bicarbonate

into a toothpaste

vehicle was tested for oral formulation was was found

mucosa irritancy

by Meyers et al. (Ref. 418). The particular irritant. However,

found to be a mild-to-moderate

the test toothpaste

to be less irritating control. compared to a common fluoridated of ingredients toothpaste used as a


the concentrations

did not appear to be and hydrogen et al.

listed, including peroxide.

the concentration

of sodium bicarbonate

These results do not agree with those reported by Marshall

(Ref. 184), in which no irritation administered dentifrice

was found to the oral mucosa of hamsters peroxide and sodium bicarbonate peroxide and 5

a dual phase hydrogen


0.75 percent or 1.5 percent hydrogen

percent or 7.5 percent sodium bicarbonate up to 20 weeks. Two animal studies examined hydrogen peroxide in combination


five times per week for

the potential

for oral mucosal irritation (Ref. 184). No peroxide


with sodium bicarbonate

mucosal irritation

was observed after administration

of a hydrogen

and baking soda dentifrice results support irritation clinical

once daily, five times a week for 20 weeks. These

and consumer studies that show no evidence of oral containing a combination of these of 10 percent


use of dentifrices


A study by Kuhn et al. (Ref. 419) used a combination and 1.5 percent hydrogen peroxide.

sodium bicarbonate

The study included and evaluated if

exposure of the test animals to DMBA, a known any of the test compounds carcinomas. (including


this combination)

resulted in additional in a X&week effects

The test and control compounds

were administered

cheek pouch mucosal irritation from the test combination

study and no additional


were found. These results and those seen in a second to those of Weitzman et al. (Ref. 183) only at a effects

hamster bioassay (Ref. 184) are contrary who found that, when combined concentration

with DMBA, hydrogen


of 30 percent, appeared to augment the carcinogenic of the carcinogenic

associated with DMBA. No augmentation

effects of DMBA

was seen with 3 percent hydrogen whose results support the previous hydrogen peroxide peroxide in the Weitzman study (Ref. l83), of


that concentrations

of 3 percent or less are safe for use in the oral cavity. human trial with concentrations peroxide of 10 percent sodium used as a dentifrice, Truelove

In a g-month


and 1.5 percent hydrogen

(Ref. 420) found no increase in yeast concentrations to subjects using a standard fluoridated There are reports in the literature producing marked gingival detrimental dentifrice.

in test subjects compared

of excessive use of these compounds changes, although these lesions appear

to be easily correctable ii. Effectiveness. sodium bicarbonate and clinical concentration bacteriocidal

(Refs. 421 and 422). of hydrogen peroxide and

The value of the combination has led to a continuing

debate within

the dental research bactericidal


An in vitro MIC and minimal

study found that both ingredients requiring

were weak extremely high

agents, with sodium bicarbonate

dosages to cause bacterial the concentration other concentrations of 3 percent hydrogen chloride

cell death (Ref. 423). Varying outcomes resulted from with some mixtures a synergistic inhibiting/killing while

of ingredients, produced peroxide,

effect. In one study, a combination and 10 g sodium

0.5 g of sodium bicarbonate,

was tested on 10 experimental

and 10 control subjects who had scaled and root planed at the subjects had the test and at biweekly

moderate periodontitis beginning ingredients professional applications.

and were carefully

of the study (Ref. 424). The experimental administered irrigations. at home with a toothbrush

Sites in the test group also received iodine that following scaling and root planing, sodium chloride and

The results indicated monitored

with a carefully

oral hygiene regimen including

and iodine reduction in addition to the hydrogen periodontal peroxide and sodium bicarbonate, occurred a

of several clinical


after 3 months

of treatment. be achieved

This study suggested a significant by subgingival irrigation

effect on the oral flora could

with these chemicals. hydrogen peroxide and a 2and negative of gingivitis

In a s-week study (Ref. 425), a 1.5-percent percent sodium bicarbonate parallel-control and gingival favorably mouthrinse

was tested in a positive significant control. control

study. The results indicated bleeding compared control

to the negative

The rinse compared rinse. The

to the positive

percent chlorhexidine

Subcommittee long-term

found that the study only evaluated

efficacy up to 3 weeks, and

results are unknown. design, Greenwell peroxide, et al. (Ref. 426) tested the effect sodium bicarbonate, and salt water) monitored

Using a split-mouth of this combination against standard indices


oral hygiene methods.

The effects on commonly

suggested no significant

effect over the standard However,

oral hygiene control these subjects were

except where initial diagnosed to 8 weeks. In a similar fluoridated peroxide

therapy was not instituted. periodontitis,

with treated or untreated

and the study was limited

study, four subjects with early periodontitis paste containing in a splitmouth differences

used either a

paste or an experimental and sodium bicarbonate no discernible

3 percent hydrogen

study design. Over the 3the groups could be study in which were applied

week test period, identified


(Ref. 427). Similar (hydrogen (Ref. 428).

results were found in a s-month peroxide

the test ingredients with a toothpick

and sodium bicarbonate)

In a Z-year study in which compared to conventional salts and hydrogen peroxide mixture was

oral hygiene methods,

no discernible parameters

differences (Ref. 429). In from the use

could be found using phase contrast microbiological another 2-year study, no positive clinical

effects were discernible peroxide,

of the combination and sodium

of test ingredients compared


sodium bicarbonate, (Ref.


to conventional

oral hygiene methods

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. 426), the subjects in this large-scale, long-term study had diagnosed early periodontitis. documented Keyes reports,

et al. (Refs. 432 and 433), in uncontrolled indicated reductions

and poorly

in signs and symptoms

associated with periodontal

diseases when using a regimen consisting slightly moistened

of a thick mix of sodium bicarbonate peroxide. that this

with a few drops of water and 3 percent hydrogen designed studies showing

Because of a lack of properly the combination combination oral hygiene of hydrogen

conclusively is effective,


and sodium bicarbonate

of ingredients products.

does not appear to present any added benefit to most reports indicated that the two ingredients currently on


were no better at controlling the market which published numbers

plaque and gingivitis these ingredients.

than products Moreover,

do not contain

many of the tested small

references exploring

the effects of these ingredients

of subjects, did not employ controls, disease entities,

and/or used subjects with periodontitis. Many

inappropriate of the published irrigations, ingredients

such as mild to moderate

references instituted oral hygiene

a variety of professional sessions, and additional clouding

cleanings, possibly active

instructional during

the test periods, thus further

the already

contradictory results. Several studies did not disclose the concentrations making it difficult


either ingredient, d. Hydrogen chloride. ingredients classification Subcommittee peroxide,

to make conclusions. citrate, sodium lauryl sulfate, and zinc of these final agent. The of hydrogen All of the in a mouth


The Subcommittee


that the combination evidence to permit

is safe, but there is insufficient of its effectiveness

as an OTC antigingivitis/antiplaque of a combination

is aware of three formulations citrate, sodium have potentially


lauryl sulfate, and zinc chloride. useful properties when included

active ingredients rinse.


(0.595 to 1.5 percent). properties



is used for

its antibacterial

and foaming

(see section 1II.C of this document). Sodium activity citrate is used as an of zinc chloride. Sodium lauryl sulfate is used


to 0.~2 percent).


and to enhance the antibacterial
lauryl sulfate

(0.06 to 0.15 percent). formation

for its emulsifying document).
Zinc chloride

and antiplaque


(see section 1II.C of this

(0.016 to 0.08 percent). and its ability

Zinc chloride

is used for its and acid in

antibacterial production inhibiting calcium


to reduce plaque accumulation

by plaque bacteria. Zinc has also been shown to be effective calculus phosphate formation by interfering with the conversion phosphate

of amorphous and

to more crystalline



their growth

(Ref. 434). The antibacterial sulfate.

effect of zinc salts may be enhanced

in the presence of sodium lauryl

i. Safety. Because the above ingredients and efficacy of these ingredients combined use. tests in rats (Ref. 435) indicated which one), of are used in combination, under conditions the safety of

must be examined

Toxicity in animals. Acute oral toxicity that one of the three formulations is relatively nontoxic.

(it is not clear from the protocol

The purpose of the study was to assess the toxicity administered observation

the combination

of ingredients

orally as a single dose to Spragueperiod. The combination was

Dawley rats, followed administered

by a l&day

by oral gavage to five male and five female rats at a dose of 40 14 days all animals survived hunched in

g/kg of body weight. Over the following apparent good health, although

they exhibited findings

postures and loose

stools for the first 2 days. No abnormal This dose is considerably ingredients in a rinse.

were observed at necropsy.

higher than the likely intake by subjects using these

In another study on the effect of topical application to hamster cheek pouches, 76 hamsters were divided

of this formulation 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 formulation of the test

to their cheek pouches for a 30-day period. The negative control applications of water. The positive control group

group received comparable

received 5 percent sodium lauryl sulfate. An additional received a fixed combination

group of 10 animals

of essential oils and water. At the end of the clinically and histologically.

W-day period, the cheek pouches were examined The results indicated damage, inflammation,

no evidence of mucosal irritation hyperplasia, atrophy,

in the form of epithelial when compared

or hyperkeratosis

to the water control (Ref. 436).

Another hamster study of so-days duration compared topical applications

of the test formulation with application hydrogen

to abraded and non-abraded

hamster cheek pouches 1, 2, and 3 percent

of 0.12 percent chlorhexidine 5 percent sodium lauryl



sulfate, and tap water. The normally and did not

animals on the test formulation demonstrate epithelial atrophy, any evidence

gained weight

of mucosal irritation (abnormal

in the form of inflammation, of cells in a tissue),




or hyperkeratosis


of the keratin

layer due to increase did not

in cell size), as compared interfere

to the water control.

The test formulation (Ref. 436).

with the healing of abraded pouches

ii. Effectiveness.
1. Mechanism of action.

It is not clear how this complex contains

mixture 0.6 percent


under conditions hydrogen peroxide

of normal use. One formulation and is dispensed

in a single bottle. In the other two in two bottles, one of which contains

formulations, hydrogen

the rinses are dispensed The directions


state that the contents According

of the two bottles

should be mixed just prior to rinsing. formulations

to the data, these latter two of the active ingredients with 1.5 percent hydrogen used in the first formulation. as the

have 2.5 to 3 times the concentration and are combined peroxide

found in the first formulation peroxide

versus 0.6 percent hydrogen

One of the latter two rinses also has 5 times as much zinc chloride first rinse. The proportions formulations, concentration peroxide, of the ingredients vary among the three

but are generally

found in relatively

low concentrations. Hydrogen


ranges for the active ingredients

are as follows:

0.595 to 1.5 percent; sodium

citrate, 0.024 to 0.12 percent;


lauryl sulfate, 0.06 to 0.15 percent; and zinc chloride, (Ref. 437). 2. In vitro studies. formulation Study 1 evaluated the effect of the combination by S. mutans and included three experimental
(2) S. mutans

0.016 to 0.08 percent

on acid production

groups: (1) S. mutans in an enriched combination

in an enriched growth medium


growth medium formulation

exposed for various durations
(3) S. mutans

to the

with a 1:4 dilution,

in an enriched formulation

growth medium

exposed for various durations After a 5-minute in combination

to the combination

with a 1:8 dilution. washed, resuspended The viability formulation,

exposure, the cells were centrifuged, formulation-free medium, and incubated.

of the bacterial cells was not affected by the exposure to the and the formulation did not kill the bacteria during a 5-minute by S. mutans was inhibited for 8 hours (Ref. 438).

exposure. However,

acid production

as a result of the 5-minute

exposure, as compared to the control

Study 2, carried out by Drake et al. (Ref. 439), was designed to determine the antimicrobial microorganisms formulation activity of the combination formulation. A spectrum of oral

was exposed to various dilutions

of the combination

(1:2 and 1:128) for times varying from 5 minutes to 2 hours. MIC’ s pathogens, including P. gingivalis,

varied among the species tested. Periodontal
F. mucleatum, E. corrodens,

and A. actinomycetemcomitans,

were among the dilutions of 1:64 S.

more susceptible

of the species tested, with MICs between tended to be less susceptible. by dilutions formulation

and 1:28. Streptococci

Under this protocol,

was inhibited

as low as 1:32, whereas in the previous appeared to be ineffective even at dilutions

study the combination

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 l:4, or 5-minutes at a dilution of 1:2, were needed are seldom used

to kill all S. mutans cells in this study. Because mouthrinses clinically for more than 30 to 60 seconds, it is doubtful effect of the mouthrinse clinical in actual use. parallel

that these results reflect

the antibacterial 3. Human

trials. One 6-week, blinded,



compared the relative efficacy of two of the three combination on plaque and gingivitis divided (control), toothpaste formulation a commercial in a human adult population


(Ref. 438). Subjects were toothpaste and toothbrush

into three groups, using either a commercial the “regular strength” (single-bottle)

formulation strength”

and a commercial (twin-bottle of zinc chloride) and

and toothbrush, not containing toothpaste

or the orthodontic

five times the concentration and toothbrush. Following

the baseline examination,

each subject was instructed mouthrinse,

to brush twice a day and, if assigned to a Baseline and 6-week data included

to use the rinse after brushing.

the Loe and Silness Gingival Index recorded on six surfaces per tooth, and Turesky’ modification s subject was calculated
Experimental Groups Group 1 (control) Group 2 (1 -bottle) Group 3 (2-bottle)

of the Quigley-Hein

Plaque Index. A mean score per

for each index. The results are in Table 16.
INDEX AND PLAOUE INDEX SCORES FROM THE GROSSMAN STUDY (REF. 438) Baseline Gingival Index 1.52 1.48 1 47 B-week Ginglval Index


Baseline Plaque index

g-week Plaque Index

1 32

19.91 19.15



the reduction

in gingival

index score was statistically of this reduction differences


for all three groups, the clinical at best. There were no statistically

significance significant

was marginal

among the three better for the

groups. The plaque index reduction mouthrinse

was statistically


groups than for the control group. However, whether

the control group in plaque reduction

lacked a placebo rinse to determine

the difference

was due to the rinsing effect or to some of the active ingredients rinses. The degree of plaque reduction clinical significance, score. clinical study (Ref. 44O), 119 adults were fitted quadrant) that was All in the test

for any of the groups is of questionable reduction of

because it did not result in any meaningful

the gingivitis

In another double-blind with a toothshield

(for either the right or left mandibular from disturbing

designed to prevent toothbrushing subjects received an initial experimental quadrant)

plaque accumulation.


and were assigned to one of three

groups, each of which brushed their teeth (except for the shielded mouthrinse formulation twice a day

once a day and used a different The final examination

for 1 minute. completed

took place after 3 weeks, and 102 subjects of the two-phase system

the trial. Two rinses were variations

formula used in the l-bottle was a control rinse dispensed statistically significant

and z-bottle formulations. as a two-phase in gingival

The third formulation

system. The results show no index scores or bleeding sites


among the three experimental teeth. Plaque scores (Modified versus nonshielded

regimens, either on the shielded

or nonshielded

Turesky Plaque Index) were higher on shielded

teeth. The plaque scores after 3 weeks were lower for the and nonshielded significant,

two test rinses compared to the control rinse for both shielded teeth. However, the differences significant.

in plaque scores, while statistically

were not clinically



440) Mean 2 Std. Error 3-Week

Experfmental Data for Shielded Teeth Group 1 (Test 1) Group 2 (Test 2) Group 3 (Control) Data for Nonshielded Teeth

Modified Plaque Index Baseline

2 21 I! 0.08 2.14 ?r 0 09 2.15 i 0 09

2.73 f 0 08 2.61 If 0.09 3.03 f 0.09

ExperImental Group 1 (Test 1) Group 2 (Test 2) Group 3 (Control) I I

Groups Modrfied Plaque Index Basehne 1 95 + 0.07 1.88 + 0.08 1.91 f007 I I Mean f Std. Error 3-Week 1 76 + 0.07 163?009 224+006

The study results indicated best, on plaque reduction, groups on shielded

that the test rinses had a marginal

effect, at

because plaque scores actually

increased for all rinses. None

teeth, although

less so, for the experimental

of the tested rinses had any effect to prevent development Data collected in individual

of gingivitis. (Ref.

dental offices by dental practitioners for controlled,

437) had no protocols randomized clinical

and lacked the basic requirements trials. Therefore, concludes

these data were of questionable of ingredients as an OTC

value. is safe,

The Subcommittee but there are insufficient antigingivitis/antiplaque e. Peppermint peppermint

that this combination

data to support its effectiveness agent.

oil and sage oil. The Subcommittee



oil and sage oil are safe, but there are insufficient of the combination

data to classify agent.

the effectiveness Peppermint

as an OTC antigingivitis/antiplaque oil distilled

oil is described as the volatile parts of the flowering and neither partially

with steam from linne, (Refs.

the fresh overground rectified by distillation

plant Mentha piperita nor wholly


441 and 442). Sage oil is derived from the dried leaves of the plant Salvia oficinalis, which contains the essential oil (Ref. 443). It is described as having carminative properties and is used as a flavoring for respiratory-tract agent. It is used with other disorders, and in

and astringent volatile

agents in preparations

mouthwashes in homeopathic

and gargles for disorders medicine.

of the mouth and throat. It is also used

Both peppermint oil and sage oil were reviewed which by the Advisory Review

Panel on OTC Oral Cavity Drug Products, ingredients (47 FR 22760 at 22764).

classified them as inactive

i. Safety. Peppermint

oil has been used as a food flavoring oil continue

for many years

(21 CFR 182.20). Safety studies on peppermint example, Spindler giving peppermint

to the present. For study in rats

and Madsen (Ref. 444) conducted

a toxicity

oil orally to groups of rats at dosage levels of 0, 10, 40, Some encephalopathy and nephropathy were seen

and 100 mg/kg body weight.

at the highest dose. The authors determined per day. Immunotoxicity including immune peppermint testing of commonly oil was reported

a NOAEL of 40 mg/kg body weight

used food flavoring


(Ref. 445). Humoral

and cell-mediated

responses in mice were evaluated. oil increase mortality

Only at very high dose levels did time in the host immunity. oil and


rate and reduce survival alter humoral containing

resistance assay, but it did not significantly Toothpaste and mouth rinse products

both peppermint

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 reported (Ref. 446).


or sensation relative to the oral mucosa was

ii. Effectiveness. data from controlled of peppermint

The Subcommittee


that there are insufficient of the effectiveness for the reduction of

studies to permit final classification

oil and sage oil as OTC active ingredients

plaque and gingivitis. A single-blind study (Ref. 447) showed significantly less bleeding and less and

plaque in 25 dental students following

1 month use of the test toothpaste

oral rinse compared to 25 students using the placebo. However, relatively low initial all the

young dental students (age 25.5 + 2.1 years) began with relatively scores. several efficacy studies of a toothpaste and an oral rinse (Ref. 448), these research. concludes that

Although containing


oil and sage oil have been conducted well-controlled

studies lack various aspects of double-blind, f. Polydimefhylsiloxane these ingredients final classification polydimethylsiloxane and poloxamer.

The Subcommittee

are safe, but there are insufficient of the effectiveness and poloxamer

data available to permit of

of the combination

as an OTC antigingivitis/antiplaque (dimethicone, used for its products such as

agent. The active ingredient simethicone), antifoaming

is polydimethylsiloxane

a fully methylated properties

linear siloxane polymer

in a number of marketed ingestible

antacids and certain foods (21 CFR 176.200). In order to insure the emulsification polyoxyethylene, of the active ingredient, is used as a nonionic poloxamer, surfactant. a polymer of


combines readily with a number of other ingredients formulations (including sprays,

and has been packaged into different mouthrinses, and dentifrices)

and incorporated

into oral hygiene devices (such

as floss and interdental poloxamer chewing emulsions,


and chewing gum. The ratio of the varies from 1OO:l in rinses to 1:l in and gel

to the polydimethylsiloxane gums. Concentrations including

range from 0.4 to 4 percent for liquid


and .Ol to 0.2 g per use for interdental as well as chewing gum and

cleansing devices coated with solid emulsion, mints. i. Safety.

I. Toxicity in animals. Toxicity data in animals (Ref. 449) and humans toxicity. The

(Ref. 450) indicate biological

that polydimethylsiloxane

has minimal

safety of polydimethysiloxane and subcutaneous

has been tested by subdermal, at greatly exaggerated followups chemistry, dose



levels in rats for periods of up to 26 weeks and further z years. Monitoring parameters, survival, weights, included hematological and urinary

of up to clinical

and gross and microscopic clinical


No effect was noted on the urine chemistry, organ

body weights,



or gross and microscopic


features of the test animals that testing of the doses via (Ref. 449). as a gel, was

could be related to the tested product poloxamer ingestion indicated minimal

(Ref. 449). Acute toxicity

or no side effects from exaggerated of the tested products packaged

and intraocular


The combination

of poloxamer

and dimethicone,

tested for acute oral toxicity application

in rats and in a 20-day hamster cheek pouch no deaths were

study. At a dose level of 10 g/kg of body weight

observed in the rat study. If this combination it would

were toxic, at this dose level

have been expected to kill one half or more of the animals. no abnormal changes were observed in the cheek pouches after three times daily for 4 weeks. data were submitted because

Additionally, topical


of 0.1 mL of the combination No human toxicity are categorized

2. Toxicity poloxamer

in humans.

and dimethicone

as safe (Ref. 450). The long-term and as an additive to certain is

use of the ingredients foods without

in antacids,


any report of harmful

effects indicates

that this combination

safe in the dosages and formulations

in current use. The estimated

daily intake

varies from 0.2 g or less for sprays, gels, dentifrices, a high of 0.4 g per breath mint or candy (Ref. 451).

rinses, or dental floss to

ii. Effecfiveness. I. Mechanisms of action. This combination acts by reducing the surface

energy of the tooth (Ref. 452). Glantz (Ref. 453) showed plaque formation reducing with increasing

a rapid increase in

surface energy in an in vitro assay. By the rate of dental plaque in the initial stages of dental

the surface energy with various surfactants, reduced, particularly

build up can be theoretically plaque formation. 2. Results from human have shown a marginal assorted formulations, studies that monitored observed between


trials. In general, most of the human studies in plaque formation in the test groups, using group. In those was

reduction as compared gingivitis,

to the placebo or control no detectable difference

in gingivitis

the test and control groups.




MEASURING (REF. 454) Baseline

I 1 2.04 2.10 1.62 1.78 2 06-2.16 2.30 2.73 2.69 1.87 2.11 1.47 1.56 End I



Study Study 1986-01 (OTC vol. 210259) Study 1986-02 (OTC vol. 210259) Study WHOIT(OTC vol. 210259) Study WHD-OOI (OTC vol. 210259) study 47-01 (OTC vol. 210260) (Grngival Index score)

Mean Difference

Test( 10) Control(i0) Test( 13) I Control( 13)

1 0.21 031 T vs C’ 1 0.16


Test(32) Control(32) Test(30) Control(30)

I T vs C
0.14-0.24 0.02 0.06 T vs C 1 0.24 T vs C 0.09

I Test(30)
1 Control(30) I Test(30)

IO lo lo
lo from one another,

I ControlfSOI
‘ vs C means Test versus Control T

The protocols formulations



as did the

of the test products.

Nevertheless, test and controls,

it was clear that the differential while statistically significant,

effect on plaque scores between was not clinically is responsible relevant.

Nor was it likely that the reduction cosmetic benefits

in plaque scores

for any potential

that might be claimed.

Therefore, inhibitory it is misleading to claim that this combination has a plaque therapeutic or at least

effect. Such a claim might suggest a beneficial

a cosmetic effect. While the plaque claim may be technically marginal benefit, nature of the effect is unlikely either therapeutic or cosmetic. to have any clinically

correct, the significant

g. Stannous pyrophosphate and zinc citrate. The Subcommittee
that this combination of its effectiveness pyrophosphate of ingredients is safe, but there is insufficient

concludes evidence

as an OTC antigingivitis/antiplaque

agent. Stannous

has the chemical formula powder

Sn2P207 and is a free flowing, form of stannous has been

odorless white to offwhite pyrophosphate

(Ref. 455). The commercial

is anhydrous

stannous pyrophosphate.

This ingredient

used in a dentifrice

based on prior demonstrated


effects, which

have been ascribed to the soluble stannous ion. Because of reported was combined antiplaque and anticalculus effectiveness, zinc citrate of

in a dentifrice

with stannous pyrophosphate

(see discussion

zinc citrate chemistry

in section 1II.C of this document).

i. Safety. Based on animal studies and human use, the two ingredients used in the combination toxicity, phototoxic chronic toxicity, sensitization, do not appear to present a risk in terms of acute reproduction toxicity, genotoxicity, carcinogenicity,

or oral irritation.

Oral ecology studies were done to agents does not result in a

ensure that long-term significant gingivitis

use of antimicrobial

change in the balance of the normal flora. In a 21-day experimental study by Watson, Jones, and Richie (Ref. 456) and a 6-month use of a dentifrice containing clinical stannous

trial by Jones et al. (Ref. 457), following pyrophosphate

(1 percent) and zinc citrate (0.5 percent), there were no

significant changes in plaque flora, no increase in opportunistic of resistance. effectiveness of a fluoride toothpaste organisms in

saliva, and no development ii. Effectiveness. containing included

Data on the clinical

stannous pyrophosphate

(I percent) and zinc citrate (0.5 percent) test, (2) a 2lbrushing trial, and

four studies: (1) An 18-hour plaque growth inhibition gingivitis trial, (3) a 12-week motivational trial.

day experimental (4) a 6-month

normal use clinical

The plaque growth inhibition

studies used an 18-hour protocol dentifrice

described on plaque

by Harrap (Ref. 458) to test the effect of the combination

growth in vivo. Lloyd (Ref. 459) reported that the formulation significantly activity compared to a placebo toothpaste, when formulated showing

reduced plaque

the antimicrobial

of the two ingredients

into a dentifrice. (Ref. 460)

A 21-day experimental enrolled following instruction.


study by Saxton and Cummins

37 subjects who were brought to a state of no gingival 4 weeks of repeated professional One posterior


cleaning and oral hygiene

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 of their dentition. The tooth shields

when the subjects cleaned the remainder

also served as carriers for the daily application toothpastes. Assessment of inflammation

of the control and test was done at baseline

and bleeding

and at 3 weeks. Mean scores were significantly weeks, which was interpreted development of gingivitis. brushing

lower for the test group at 3 being better in delaying

as the test dentifrice

A 12-week motivational

trial by Gaare et al. (Ref. 462) included a prophylaxis and motivation at

81 adult subjects described as receiving

baseline and then using the combination index and GI scores improved at 12 weeks; and bleeding A 6-month dentifrice at least twice daily. Plaque to improve

at 6 weeks; plaque scores continued at 12 weeks.

scores were maintained

normal use clinical

study by Saxton et al. (Ref. 463) enrolled the trial. Clinical assessments were made were done

268 subjects, with 251 completing

at baseline and at 1,4, and 6 months. Tooth scaling and polishing after baseline assessments, which included modified gingival

plaque index by Loe (Ref. 464), stain indices by Lobene

index by Lobene (Ref. 112), extrinsic

(Ref. 465), supragingival by Ainamo

calculus by Volpe (Ref. 466), and gingival bleeding

and Bay (Ref. 467). The results at 6 months showed no difference in mean modified significantly gingival index

in mean plaque scores and no difference scores. Gingival bleeding was statistically

lower for the test group

(~~0.01) as was the mean calculus scores (p<O.Ol). Tooth staining area mean scores were statistically significantly higher (~~0.05) and the stain intensity that

mean score was also higher (p<O.OO) for the test group. It was reported 17 percent of the test group observed tooth staining for themselves. staining was clinically detectable in approximately


40 percent of test dentifrice dentifrice subjects

subjects compared to approximately (53 versus 15 subjects at 6 months). The Subcommittee pyrophosphate However, concludes

10 percent of control

that the combination

of stannous is safe.

(1 percent) and zinc citrate (0.5 percent) in a dentifrice data to permit final classification agent. of its

there are insufficient

IV. Analysis

as an OTC antigingivitis/antiplaque
of Impacts

FDA seeks specific comment regarding

any substantial rule would

or significant have on

economic benefit or impact that this proposed

168 manufacturers Comments or consumers of antigingivitis/antiplaque drug products. rule on such

regarding the benefit or impact of this proposed or consumers should be accompanied

manufacturers documentation.

by appropriate and supporting data rule

The agency will evaluate any comments

that are received and will assess the economic in the preamble to the proposed rule. V. Paperwork Reduction Act of 1995

impact of this proposed

FDA tentatively


that the labeling requirements

in this document

are not subject to review by the Office of Management they do not constitute Reduction a “collection of information”

and Budget because under the Paperwork statements

Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the labeling disclosure of information originally supplied

are a “public government

by the Federal to the public” (5

to the recipient

for the purpose of disclosure

CFR 1320.3(c)(Z)). VI. Environmental Impact under 21 CFR 25.31(a) that this action is of or cumulatively neither have a significant effect on

The agency has determined a type that does not individually the human environment. an environmental


an environmental

assessment nor

impact statement is required.

VII. Request for Comments The agency is providing written or electronic interested persons a period of 90 days to submit Branch (see Three


to the Dockets Management


regarding this advance notice of proposed comments are to be submitted. electronic


copies of all written written comments

Individuals comments

submitting may submit one found in brackets

or anyone submitting are to be identified

copy. Comments

with the docket number

in the heading of this document

and may be accompanied

by a supporting



or brief. The agency is also providing replying


persons a period this advance

of 150 days to submit comments notice of proposed Management

to comments



Received comments

may be seen in the Dockets through Friday.

Branch between 9 a.m. and 4 p.m., Monday


The following Branch (see

references are on display

in the Dockets Management persons between 9 a.m.


and may be seen by interested Friday.
“Dental Calculus

and 4 p.m., Monday
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206. Boyd, R. L., “Effects of Clinical Periodontology,

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207. Clark, W. B. et al, “Efficacy Established Gingivitis: 1. Clinical

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208. Gangler, von P., and W. Staab, “Klinisch Plaquekontrolle Marginalis,” mit Chlorhexidindiglukonat English abstract, Zahn,




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211. “Introduction Revision

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abstract, in Homeopathic DC, 1993.


States, Washington,

212. “Acute 210303.

Oral LD50 Assay in Rats,” unpublished

study VS-14

in OTC Vol.

213. “Four-Week VS-139


Dietary Toxicity

Study in Rats,” unpublished


in OTC Vol. 210304. Oral Toxicity Study in Rats,” unpublished study VS-93 in

214. “Thirteen-Week OTC Vol. 210304. 215. “Four-Week in OTC Vol. 210304. 216. “Thirteen-Week study VS-143

Oral Gavage Study in Monkeys,”


study VS-143

Oral Toxicity

Study in Cynomolgus



in OTC Vol. 210306. Feeding Study in Rats,” unpublished study VS-07 in OTC

217. “Fourteen-day Vol. 210305. 218. “Thirty-day Vol. 210305.

Oral Gavage Study in Rats,” unpublished

study VS-62

in OTC

219. Lin, Y. et al, “Investigation and Sanguinaria Extract,” unpublished

of Benz Acridine study VPTS-59


From Sanguinarine

in OTC Vol. 210308.

220. “Biological
Disposition GLabeled of ‘ Sanguinarine in Rats,” unpublished

study VS-122(558-016)


Sanguinarine in Mice,” unpublished

221. “Biological


of 14C-Labeled

study VRTS-29(558-027) 222. “Cardiovascular


study VS-87 in OTC Vol.

Study in Dogs,” unpublished

and Reproductive / 120 in OTC Vol. 210309.

223. “Fertility


in Rats,” unpublished

study VS-

224. “Range-Finding
study VS-135



Study in Rabbits,” unpublished

in OTC Vol. 210309. Toxicity in Rats,” unpublished study VS-137 in OTC Vol.

225. “Developmental

226. “Developmental
Vol. 210309.


in Rabbits,” unpublished

study VS-136 in OTC

227. “Perinatal
study VS-138

and Postnatal

Effects of Sanguinaria

Extract in Rats,” unpublishec

in OTC Vol. 210309. Plate Incorporation Mutagenicity Assay,”

228. “Salmonella/Mammalian-Microsome
Assay (Ames Test), and Escherichia unpublished study VS-97a

coli WPZuvr Reverse Mutation

in OTC Vol. 210310. Plate Incorporation Mutagenicity Assay,”

229. “Salmonella/Mammalian-Microsome Assay (Ames Test), and Escherichia unpublished study VS-97b

coli WPZuvr Reverse Mutation

in OTC Vol. 210310. DNA Synthesis in Rat Primary Hepatocytes,”

230. Curren, R. D., “Unscheduled unpublished

study VS-110 in OTC Vol. 210310. Cytogenic Assay in Mice,” unpublished study

231. Putnam, D. L., “Micronucleus VS-106 inOTCVol. 210310.

232. “Ames Test for Mutagenic VS-101 inOTCVol. 210310.


in Rat Urine,”



233. “Ames Test,” unpublished Mammalian study VS-00 Cell Forward
in OTC Vol. 210310.

234. “CHO/HGPRT unpublished

Gene Mutation


study VS-72

in OTC Vol. 210310. Primary Culture/DNA Repair Test,” unpublished study VS-

235. “Rat Hepatocyte 84 in OTC Vol. 210310. 236. “Two-Year
in OTC Vol. 210311.

Oral Oncogenicity

Study in Rats,” unpublished

study VS-108

237. “Two-Year unpublished

Oral Dietary


and Oncogenicity

Study in Rats,”

study VS-142

in OTC Vol. 210311.

238. Lord, G., E. I. Goldenthal, Controversy of Chid Concerning Dentistry,

and D. L. Meyer, “Sanguinarine to Glaucoma in Epidemic

and the Dropsy,” Journal

its Relationship


239. “Acute 210312. 240. “Acute
Vol. 210312.

Oral Toxicity

in Rats,” unpublished

study VS-10

in OTC Vol.

Oral Toxicity

Study in Rats,” unpublished

study VS-81a

in OTC

241. “Acute 210312. 242. “Primary OTC Vol. 210312. 243. “Primary Vol. 210312. 244. “Mucous unpublished

Oral Toxicity

Study in Rats,” unpublished

study VS-61

in OTC Vol.

Dermal Irritation

Study in Rabbits,” unpublished

study W-65


Eye Irritation

Study in Rabbits,” unpublished

study VS-51

in OTC



Assay: Hamster Cheek Pouch Method,”

study VS-09

in OTC Vol. 210312. Irritancy Study of a Dentifrice
in OTC Vol. 210312.

245. “Mucous Method),”



Cheek Pouch


study VS-23 Irritancy

246. “Mucous Method),”


Study of a Dentifrice in OTC Vol. 210312.


Cheek Pouch


study VS-31

247. “Mucous Membrane Irritancy Study of Viadent study VS-33 Membrane 1500 Formulation (Hamster

Cheek Pouch Method],” 248. “Twenty-One Method,” unpublished

unpublished Day Mucous

in OTC Vol. 210312. Assay: Hamster Cheek Pouch


study VS-50 in OTC Vol. 210312. Study in Rats,” unpublished study VS-95a in OTC

249. “Acute Vol. 210313.

Oral Toxicity

250. ‘ Mucous Membrane ,‘ Cheek Pouch Method),” 251. “Acute VS-15, VS-16,


Assay of a Formula study VS-95

and Dentifrice



in OTC Vol. 210313. studies VS-09, and VS-131 VS-11, in OTC

Oral Toxicity VS-19, VS-20,

Studies in Rats,” unpublished VS-39, VSt53, VS-8lb,


Vol. 210313. 252. “Mucous Membrane Irritancy Study of Oral Rinse,” unpublished study VS-

39 in OTC Vol. 210313. 253. “Mucous unpublished Membrane Irritancy Assay: Hamster Cheek Pouch Method,”

study VS-09 in OTC Vol. 210313. Potential Study,” unpublished study VS-53 in OTC Vol.

254. “Allergenicity 210313. 255. “Acute 210313. 256. “Repeated 210314. 257. “Repeated 210314. 258. “Repeated 210314. 259. “Repeated 210314.

Oral Toxicity

in Rats,” unpublished

study VS-11

in OTC Vol.

Insult Patch Test,” unpublished

study VS-13

in OTC Vol.

Insult Patch Test,” unpublished

study VS-6Ob in OTC Vol.

Insult Patch Test,” unpublished

study VS-82b

in OTC Vol.

Insult Patch Test,” unpublished

study VS-66

in OTC Vol.

260. “Irritation

and Sensitization


of Exaggerated

Use of Product,”


study VS-17 in OTC Vol. 210314. Safety/Efficacy Study,” unpublished study VS-42 in OTC Vol.

261. “Six-Month

262. “Six-Month 210314. 263. ‘ Six-Month ,‘


Study,” unpublished

study VS-56

in OTC Vol.


Study,” unpublished

study VS-100 in OTC Vol.

264. “Short-Term


of Dentifrice unpublished

Efficacy In Vivo: Evaluation

of Four


Slurry Formulations,”

study RS-78 in OTC Vol. 210314. and Sanguinarine on Gingivitis

265. Patel, A. R., “The Effects of Chlorhexidine

and Plaque in Orthodontic 266. “Repeated

Patients,” unpublished

study CS-52 in OTC Vol. 210314. study VS-6Oa in OTC Vol.

Insult Patch Test,” unpublished

267. “Repeated Insult Patch Test,” unpublished study VS-82a in OTC Vol.

268. “Repeated

Insult Patch Test,” unpublished

study VS-73 in OTC Vol.

269. “The Long-Term Sanguinarine Chloride,”

Safety and Efficacy Evaluation unpublished study VS41

of an Oral Rinse Conta ining

in OTC Vol. 210314. of an Oral Rinse Conta ining

270. “The Long-Term Sanguinarine Chloride,”

Safety and Efficacy Evaluation unpublished

study VS-55 in OTC Vol. 210314. Dentifrice Supplement on Plaque and 7:S185-S188,

271. Lobene, R. R. et al., “The Effects of a Sanguinaria Gingivitis,” 1986. 272. “Short-Term unpublished Evaluation of Toothpastes
Compendium Continuing Education Dentistry,

In Vivo Exaggerated

Use Study,”

study RS-67 in OTC Vol. 210318.

273. “The Effect of Dentifrice Children,” unpublished Formulations on Plaque and Gingivitis in School

study VS-123

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274. Klewansky, Periodontal Patients,”

P., and D. Roth, “Sanguinaria
Compendium Continuing

of Bleeding




7:S218-S220,1986. 275. “Short-Term Study,” unpublished Evaluation of Oral Hygiene Regimens In Vivo Exaggerated Use

study RS-64 in OTC Vol. 2;0319. K. G. et al., “Longitudinal
General Dentistry,

276. Palcanis,


of the Effect of Sanguinarine 7-19, 1990.

on Plaque and Gingivitis,” 277. A collection 278. “Efficacy Further


of 26 submitted

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Plaque Growth,”

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279. “The Long-Term Sanguinarine Chloride,”

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study VS-41

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280. “The Long-Term Rinse Containing 210320. 281. “Sanguinarine study VS-43

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282. “Short-Term Concentration,”


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283. “Short-Term on Oral Rinse Efficacy,” 284. “Short-Term unpublished


unpublished Evaluation

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study CS-51 in OTC Vol. 219319. Evaluation of Oral Rinse In Vivo Evaluation of Zinc Chloride

285. “Short-Term

in the Oral Rinse Formula,”


study RS-77 in OTC Vol. 210319.

286. “Short-Term Evaluation Evaluation of Oral Rinse In Vivo Exaggerated study RS-66 in OTC Vol. 210319. of Sanguinaria Journal Extract of Clinical Use Study;

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287. Southard, Concentration Periodontology,

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288. “Microbial 210319. 289. “Short-Term Study,” unpublished

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290. Greenfield,

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291. Nygaard-Oestby, in the Control Dentistry,

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292. Miller,

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297. ‘ Minimum ,‘


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299. “In Vivo Evaluation Dentifrice,” unpublished

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300. Puczynski, Observations: Remedy,” Sodium

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319. Munday,

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Agents,” Journal


321. Little,
Aspects of Major

A. D., “Alkyl

Sulfates Human,”
A Report

in Human

and Environmental Association,

to the Soap and Detergent


31, 1977, Arthur

D. Little,

Inc., Cambridge,

MA, pp. 165-232, in Human

and Environmental

322. Goyer, M. M. et al., “Alkyl
Aspects of Major Surfactants,



February 1981.

20, 1981, Arthur

D. Little,

Inc., Cambridge,

MA, Supplement 323. Ashmole, IV. Teratology unpublished

pp. 85-125,

R. et al., “ Mutagenicity Lauryl Sulphate:

and Teratology

of Alternative


of Sodium

Oral Administration

in the Rat,”

study in OTC Vol. 210010. T. et al., “The Synthetic 26:49-54, Surfactants 1980. AS and LAS Interrupt

324. Nomura, Pregnancy

in Mice,” Life Sciences,

325. Palmer, A. K., M. A. Readshaw,
Teratogenic Potential of Surfactants,” A. et al., “Effects and A. M. Neuff, “Assessment of the


3:91-106, 1975.
of Sodium Dodecyl

326. Takahashi,

of Dermal Application

Sulfate (SDS) on Pregnant Mice and Their Fetuses,” Japan, Annual
Metropolitan Research Laboratories


of Public


271113-118, 1976.
Actives on Bone Marrow: unpublished I. Acute study

327. Hope, J., “Cytogenetic
Administration of Sodium

Effects of Detergent Sulphate


to Chinese Hamsters,”

in OTC Vol. 210011.

328. Hope, J., “Absence
Fed Detergent Actives

of Chromosome

Damage in the Bone Marrow

of Rats

_ for 90 Days, ” Mutation

56:47-50, 1977.
of Various

329. Kawachi, Short-Term

T. et al., “Results

of Recent Studies on the Relevance
Methods in Oncology,


Tests in Japan,” Applicable


1980. 330. McGregor,
Cell Forward

D. B. et al., “Responses

of the L5178Y tk+ /tk- Mouse Lymphoma
Environmental and


Assay: III. 72 Coded Chemicals,”


12:85-154, 1988.
of Rabbit and Human

331. Phillips, to Certain Irritants,”

L. et al., “A Comparison
Toxicology and Applied

Skin Responses

21:369-382, 1972.
United States

332. Pader, M. et al., “Mouthwash:
Patent No. 4,150,151, April


of Invention,”

Induced Inflammation in Rat

333. Ahlfors,
Oral Mucosa,”

E. E., and A. Larsson, “Chemically


of Dental



by Detergents,”

334. Helenius,

A., and K. Simons,


of Membranes

et Biophysics


335. Miner, P., “Signal


and Close-Up



study in OTC Vol. 210009.

336. Rykke, M., G. Rolla, and T. Sonju, “Effect Protein Adsorption to Hydroxyapatite of Sodium Lauryl Sulfate on In Vivo,”

In Vitro and on Pellicle 98:135-143, “Inhibition 1990.




of Dental Research,

337. Jablonski, Streptococcal

W. M., and J. A. Hayashi,

of Extracellular 1970. and Some Other Acta

Enzymes,” Journal

of Dental Research, 49(1):178,

338. Christenson, Detergents Odontologica

F., and M. Kilian,

“The Effect of Chlorhexidine from Streptococcus

on the Activity Scandinavica,

of Dextransucrase 35:119-123,



339. Ciardi, J. E., W. H. Bowen, Compounds of OralBiology, on Glucosyltransferase 23:301-305,1978.

and G. Rolla, “The Effect of Antibacterial Activity From Streptococcus mutans,” Archives

340. Giertsen,

E., A. A. Scheie, and G. Rolla, “Plaque Lauryl Sulfate,”


by a Combination 1989. Between

of Zinc Citrate and Sodium 341. Barkvoll, Sodium Lauryl

Caries Research, 23:278-283, on the Interaction Transformed 1988.

P., G. Embery, and G. Rolla, “Studies Using Fourier 16:75-79,

Sulfate and Hydroxyapatite Journal of Biological



Buccale, “Food

342. Gabrielli,

E., and D. Consoli,

Debris Removal

Test: Signal Versus

Placebo,” unpublished 343. Manhold, Clearance,” Journal

study in OTC Vol. 210009. “A Study of Total Oral Debris 1967. to

B. S., and J. H. Manhold, of the NewJersey

State Dental Society, 39:64-77, “Ability

344. Payonk, G., and K. Snyder, Remove Food Debris (Toasted Muffin) OTC Vol. 210009. 345. Payonk, G., and K. Snyder,

of Signal and Scope jvfouthwash unpublished

from the Oral Cavity,”

study in


of Signal and Scope Mouthwash unpublished


Remove Party Snack Food Debris from the Oral Cavity,” Vol. 210009.

study in OTC

346. Payonk, G., and K. Snyder, “Ability of Signal and Listerine unpublished Mouthwash to

Remove Food Debris (Egg/Toast) from the Oral Cavity,” Vol. 210009. 347. Payonk, G., and K. Snyder, “Ability Remove Food Debris (Egg/Toast) Vol. 210009. 348. Pretara-Spanedda, P., and S. Birenz, “A,Clinical unpublished

study in OTC

of Signal and Scope Mouthwash


from the Oral Cavity,” unpublished

study in OTC

Trial to Determine

the Oral

Hygiene Benefits of Signal Mouthwash,” 349. Truelove, Versus Flavored 210009. 350. Lim, J. K. et al., “Minimum Plaque Antiadherents R., “Antiplaque

study in OTC Vol. 210009. of Signal VS Plax study in OTC Vol.


Study: Evaluation unpublished






of Surfactants

for 1982. Stannous

(Short Communication),”

Caries Research, 16:440-442, “The Effect of Triclosan, Bacterial

351. Jenkins, S., M. Addy, and R. Newcombe, Fluoride, Clinical and Chlorhexidine Products

on: (II) Salivary 1990. “Signal

Counts,” Journal of

Periodon tology, 17:698-701,

352. Gabrielli, Insult,” unpublished

E., and M. Carrabotta,

Versus Scope Against a Garlic

study in OTC Vol. 210009. E., and M. Carrabotta, “Signal Versus Listerine Against a Garlic

353. Gabrielli, Insult,” unpublished

study in OTC Vol. 210009. E., and M. Carrabotta, “Signal Versus Listerine Against Morning

354. Gabrielli, Mouth,”


study in OTC Vol. 210009. “Signal Versus Scope Against Morning

355. Gabrielli, Mouth,”

E., and M. Carrabotta,


study in OTC Vol. 210009. “In-Home Mouth Subjective Assessment of Signal

356. Gabrielli, Versus Listerine Vol. 210009.

E., and M. Carrabotta, for Clean and Refreshing

Feel,” unpublished

study in OTC

357. Gabrielli, -Signal E., and M. Carrabotta, “A Subjective Mouthwash Cleaning Test Versus Scope,” unpublished study in OTC Vol. 210009. Alkyl Sulfate as a Detergent and the Dental Cosmos,

358. Kitchin, in Toothpaste,” 24:736-755,1937.

P. C., and W. C. Graham, “Sodiurn Journal of the American

Dental Association

359. Birenz, S., and P. Pretara-Spanedda, Health Benefits of Signal Mouthwash: 210009. 360. OTC Vol. 210286. 361. Emiling, Prebrushing R. C., and S. L. Yankell, Compendium


Trial to Determine

the Oral

Trial II,” unpublished

study in OTC Vol.

“First Clinical of Continuing

Studies of a New Education, Article #2,


5(9):637-640,644-645,1985. 362. Lobene, R. R., “Plax Safety and Plaque Removal Study,” unpublished in OTC Vol. 210284. 363. Bailey, L., “Direct Preventive Dentistry, Plaque Removal by a Pre-Brushing 1989. Dental Rinse,” Clinical study


364. Beiswanger, Prebrushing 1990.

B. B. et al., “The Relative Plaque Removal Effect of a Journal of the American Dental Association, 120: 190-192,


365. Van Dyke, T. E. et al., “Plaque Dental Rinse,” unpublished

and Gingivitis


by a Prebrushing

study in OTC Vol. 210284. “The Effectiveness of a Prebrushing in Single-Use 1989. Dental Plaque,” and

366. Kohut, B. E., and S. Mankodi, Mouthrinse Extended-Use in Reducing Supragingival

Plaque and Gingivitis

Trials,” American

Journal of Dentistry, of a Prebrushing 3:15-16, 1990.


367. Singh, S. M., “Efficacy American Journal of Dentistry,

Rinse in Reducing

368. Pontier, J. et al., “Efficacy Clinical Preventive Dentistry,

of a Prebrushing 1990.

Rinse for Orthodontic



369. Lobene, R. R., P. M. Soparker, of a Prebrushing Clinical and M. B. Newman, “Long-Term Evaluation

Dental Rinse for the Control Dentistry, 12(2):26-30,

of Dental Plaque and Gingivitis,”


1990. et al., 12th ed., Merck and Co.,

370. The Merck Index, edited by S. Burdaveri Rahway, NJ, p. 1734,1996. 371. Mandel, I. D., “Calculus

Update: Prevalence,

Pathogenicity 1995.

and Prevention,”

Journal of the American

Dental Association, 210200.


372. OTC Vols. 210192 through 373. OTC Vols. 210427,210427&

210427B. Investigation of an Anti-Tartar

374. Hefti, A., and R. Marks, “A Clinical Dentifrice,” unpublished

study in OTC Vol. 210427B. Clinical Investigation of a Gum Health Dentifrice,”

375. Putt, M. S., “A 6-Month (Study #1094.3(3), unpublished 376. Burchell, Toothpaste

study in OTC Vol. 210427B. and

C. K. et al., “The Effect of 0.5% ZCT on Plaque Gingivitis in the Lanarkshire Clinical


Trial After 1 and 2 Years of

Use,” unpublished 377. Shmidl,

study in OTC Vol. 210427B. J. A., L. A. Hess, and M. L. Kohlenberg, unpublished “Oral LD 50 Evaluation

for C3lG 3.0% Liquid,”

study in OTC Vol. 210272. Study in Beagle Dogs; Antimicrobial Corp., unpublished

378. Dean, W., “Acute Solution NPA-l-18A,”

Oral Toxicity


Research and Development

study in OTC Vol. 210272. 379. Shmidl, J. A., L. A. Hess, and M. L. Kohlenberg, in Rabbits,” unpublished “Dermal LD50 Evaluation

for C3lG 3.0% Liquid 380. Michaels,

study in OTC Vol. 210272. “Mice and Rabbit Models Surfactant

E. B., E. C. Hahn, and A. J. Kenyon, Absorption and Disposition

for Oral and Percutaneous C31G,” American 381. “Delayed Concentrate,”

of Amphoteric 1983.

Journal of Veterinary Dermal Sensitization

Research, 44:1977-1983,

Study in the Guinea Pig; C3lG and B42


1979 study in OTC Vol. 210272.

382. Shmidl,

J. A., L. A. Hess, and M. L. Kohlenberg,


Sensitization 1983 study, in OTC

Evaluation Vol. 210272.

for C31G 3.0% Liquid

in Guinea Pigs,” unpublished

383. Munroe,

J. S., “Salmonella/Microsome


Assay on C3lG



study in OTC Vol. 210272. “Eye Irritation Evaluation

384. Shmidl,

J. A., L. A. Hess, and M. L. Kohlenberg, in Dogs,” unpublished Evaluation

for C31G 3.0% Liquid

1983 study in OTC Vol. 210272. Assay,”

385. Reel, J. R., “Drug

Report for Rabbit Vaginal Irritation


study in OTC Vol. 210272. J. S., “Report on the Use of TopiCare@ at Lincoln Park Nursing

386. Munroe,

Home, NJ,” unpublished

study in OTC Vol. 210272. Lincoln Park

387. Schroeter Research Services, “Nurses’ Interviews,” Intermediate Care Center, Weston, CT, unpublished J. V., “North Jersey Nursing

study in OTC Vol. 210272. Center Study,”

388. Haberman,

and Convalescent

Wayne, NJ, unpublished

study in OTC Vol. 210272. Post-Questionnaire,” OraTec Corp., Herndon,

389. Landers, W., “Observations, VA, unpublished

study, in OTC Vol. 210272. Usage Report,” OraTec Corp., Herndon, VA,

390. Landers, W., “Therasol unpublished

study in OTC Vol. 210272. Usage Report, 3rd Annual TheraSol Survey,” OraTec

391. Landers, W., “Therasol Corp., Herndon, VA, unpublished

study in OTC Vol. 210273. Activity of Toothpastes by Filter Paper study in OTC

392. “Determination Disk Method,”
Vol. 210273.

of Antimicrobial

Kema Nobel Consumer

Goods, Sweden, unpublished

393. Corner, A. M. et al., “C31G, a New Agent for Oral Use with Potent Antimicrobial and Antiadherence Properties,”
Antimicrobial Agents


Chemotherapy, University

of Pennsylvania,

School of Dental Medicine,

394. Corner, A. M. et al., “Clinical on Salivary Microorganisms,”

Study of a C3lG Containing of Clinical



2134-38, 1988. of Maryland Mouthrinse

395. Huber, K. M., “Clinical Study,” University 210273. of Maryland,

Summary: Baltimore,

C31G, University MD, unpublished

study in OTC Vol.

396. “Panel Studies on the Comparison OraTec Corp., Herndon, VA, unpublished

of PeridexB

to a C31G Mouth


study in OTC Vol. 210273. with an Amine-

397. Rotgans, J., and Stickforth, Containing Toothpaste

P., “The Effect of Brushing

(C31G) on Caries Incidence of Tubingen,

in Rats and Plaque Accumulation

and Gingivitis unpublished

in Man,” University

Dental School, West Germany,

study in OTC Vol. 210273. P., and J. Rotgans, “Die Wirkung auf Plaquebildung, Versuch,” einer Chemotherapeutischen, und Karies im Klinischen

ma. Stickforth,



und Tierexperimentellen 41:253-257,1991. 399. Renton-Harper, Chloride, Triclosan,

German (English abstract), Deutsch

P. et al., “A Comparison

of Chlorhexidine,


and C31G Mouthrinse 67:486-489, 1996.


for Plaque Inhibition,”

of Periodontology,

400. “Oral LDso Determination CT, unpublished

in Rats,” Study #4A-01,

Olin Corp., New Haven,

study in OTC Vol. 210007. Irritation in Rats,” Study #431, Olin Corp., New Haven, CT,

401. “Oral Mucosal unpublished

study in OTC Vol. 210007. Dermal Toxicity Study in Albino Rabbits,” Study #lO6A-01, Olin

402. “Acute

Corp., New Haven, CT, unpublished 403. “Eye Irritation unpublished

study in OTC Vol. 210007. Olin Corp., New Haven, CT,

in Rabbits,” Study #203-01,

study in OTC Vol. 210007.


Ader, A. W. et al., “Effect

of Mouth

Rinsing with Two PolyvinylpyrrolidoneFunction,” Journal of Clinical

Iodine Mixtures Endocrinology

on Iodine Absorption and Metabolism,

and Thyroid 1988.

66:632-635, Mutagenesis

405. “Salmonella/Microsome Hydrogen

Assay on a Mixture Iodine,”

of 3% Aqueous

Peroxide and 10% Aqueous


Olin Corp., New Haven,

CT, unpublished

study in OTC Vol. 210007. Test in Mice PerimedB Oral Hygiene Rinse,” Olin Corp.,

406. “Micronucleus

New Haven, CT, unpublished 407. “Rat Hepatocyte Haven, CT, unpublished 408. “Chinese

study in OTC Vol. 210007. Culture/DNA Repair T.est,” Olin Corp., New


study in OTC Vol. 210007. Cell Cytotoxicity Assay,” Olin Corp.,

Hamster Ovary Mammalian

New Haven, CT, unpublished 409. Goodman, of Therapeutics, pp. 995-996,1975.

study in OTC Vol. 210007. editors, 6th ed., The Pharmacological Tindall, London, Basis

L. S., and G. Gilman, Publishing


Co., Inc., Bailliere


410. Clark, W. B. et al., “Efficacy Established 635. Gingivitis: Clinical

of PerimedB


System on 16:630-

Results,” Journal of Clinical


411. Walker, C. B., “Effect of PerimedB Microbial Composition Associated


System on the Subgingival unpublished study

with Established


in OTC Vol. 210008. 412. “Statistical Peroxide Mixture Consumer Report on the Clinical in the Prevention Evaluation of a Povidone-Iodine Hydrogen

and Treatment

of Periodontal

Disease,” Olin

Products Group, unpublished

8-week study in OTC Vol. 210008. Iodine and Hydrogen study in OTC Vol.

413. Cutter, G. R., “A Controlled Peroxide, 210008. Povidone

Trial (6-week) of Povidone Water,” unpublished

Iodine and Distilled

414. Walker, C. B., “Microbiological Antimicrobials,” ]ournal of Clinical Effects of Mouthrinses 15:499-505. Mutagenicity on Containing


415. Kuhn, J. et al., “Salmonella/Microsome Gel PCR-OZ-56/Paste PCR-02-122 (l:l),"

Assay for Bacterial


study in OTC Vol. 210185. of Peracetic Acid

416. Agnet, Y., J. L. Dorange, and P. Dupuy, on Salmonella typhimurium, ” Mutation of Genotoxicity


Research, 38:119, 1976. of a Tooth Whitener,” 71~157, 1992. Test on an Experimental AADR Abstracts,

417. Li, I., “Evaluation Abstract

#413, Journal of Research Dentistry,

418. Meyers, D. et al., “Four-Day Paste/Gel Dentifrice Formulation,”

Rat Oral Irritation unpublished

study in OTC Vol. 210181. Irritation (Hamster Cheek Pouch study in OTC Vol.

419. Kuhn, J. et al., “Twenty-week Method) 210181. 420. Truelove, with 6 and 12 Week Interim

Oral Mucosal Sacrifices,”


R. B. et al., “Evaluation unpublished

of the Safety of a Hydrogen


Baking Soda Dentifrice,” 421. Austin, Inflicted 1985. Injuries

study in OTC Vol. 210181. “The Keyes Technique and Self-

G., M. Mesa, and C. Lambert,

(Three Case Reports),” Journal of Periodontology,


422. Levine, R. A., “The Keyes Technique Lesions: A Case Report,” Compendium 1987. 423. Miyaski, of Hydrogen

as Cofactor in Self-Inflicted Education Dentistry,

Gingival 8:266-269,


K. T., R. J. Genco, and M. E. Wilson, and Sodium Bicarbonate Facultative





and in Combination

Against Selected Oral, Gram-negative, Research, 65:1142-1148,1986.

Bacteria,” Journal of Dental

424. Rosling, B. G. et al., “Microbiological Subgingival Clinical Antimicrobial Treatment 10:487-514,

and Clinical

Effects of Topical Disease,” Journal of

on Human Periodontal 1983.


425. Putt, M. S., “Human Plaque Inhibitory Mouthrinses,” Clinical Study Final Report: Clinical Investigation of


report in OTC Vol. 210189. of Oral Hygiene on the

426. Greenwell, Subgingival of Clinical Microflora

H. et al., “The Effect of Keyes Method Compared

to the Effect of Scaling and/or Surgery,” Journal 1985. “The Effect of Sodium Bicarbonate and



427. Cerra, M. B., and W. J. Killoy, Hydrogen Peroxide on the Microbial 53:599-603, 1982.

Flora of PeriodontalPockets,”

Journal of


428. Walsh, M. M., and N. Kaufman, Peroxide/Baking Preventive Soda Mixture 7(2):21-24,



of a Hydrogen

with a Toothpick-Periodontal 1985. . Compared

Effects,” Clinical


429. Wolff, L. F. et al., “Salt and Peroxide Hygiene: II. Microbial

with Conventional 58:301-307, 1987.


Results,” Journal of Periodontology,

430. Pihlstrom, Hygiene: I. Clinical

B. L. et al., “Salt and Peroxide Compared Results,” Journal of Periodontology, Investigation

with Conventional 1987. Regimen



431. Wolff, L. F. et al., “Four-Year Compared Association, with Conventional 118:67-72, 1989.

of Salt and Peroxide

Oral Hygiene,” Journal of the American


432. Keyes, P. H., W. E. Wright, Hygiene, The Use of Phase-Contrast of Periodontal 9(1):51-56

and S. A. Howard, Microscopy

“V. Periodontics

and Oral

and Chemotherapy

in the Diagnosis

and Treatment International,

Lesions: An Initial

Report (I),” Quintessence

and 69-76, 1978. and S. A. Howard, Microscopy “V. Periodontics and Oral

433. Keyes, P. H., W. E. Wright, Hygiene, The Use of Phase-Contrast of Periodontal 9(1):69-76,1978. 210004.

and Chemotherapy

in the Diagnosis

and Treatment International,

Lesions: An Initial

Report (II),” Quintessence

434. OTCVol.

435. OTC Vol. 210207.

436. OTCVol. 437. OTCVol. 210428. 210001. Comparison of Regular and Orthodontic A Pilot Study study in OTC Vol. Strength

438. Grossman, M. L., “Clinical Prevention Conducted 210390. Mouth

Rinse in Controlling

Plaque and Gingivitis:

by New Institutional

Service Company,”


439. Drake, D. R. et al., “The Antimicrobial American Journal of Dentistry, Investigation 6:239-242, 1993.


of Prevention


440. “Clinical Literature

of a Plaque Inhibitory




in OTC Vol. 210428. National Formulary-18, United 1995. 1988. Press,

441. The United States Pharmacopeia-23, States Pharmacopeial Convention, Inc., Rockville,

MD, pp. 2276-2277, England,

442. The British Pharmacopoeia, 443. Martingale, London, England,

Vol. 1, London,

pp. 442-443,

The Extra Pharmacopoeia, p. 1410, 1993. P., and C. Madsen, “Subchronic Letters, 62:215-220, 1992.

30th ed., The Pharmaceutical

444. Spindler, in Rats,” Toxicology 445. Gaworski, Ingredients,”


Study of Peppermint


C. L. et al., “An Immunotoxicity Toxicology, 32:409-415,

Assessment 1994.

of Food Flavoring

Food Chemical

446. Cuthbert, Mouthwash,”

J. A., and S. M. A. Car-r, “Parodontax study in OTC Vol. 210334.


and Perodontax


447. Willershausen, Ingredients Clinical

B., I. Guber, and G. Hamm, “The Influence Tendency

of Herbal Journal of

on the Plaque Index and Bleeding 2:77-80, 210334. 1991.

of the Gingiva,”


448. OTCVol.

449. OTC Vol. 210257. 450. OTCVol. 210258.

451. OTCVol. 452. OTCVol. 210256. 210262. and Adhesiveness,” Odontologisk Revy,

453. Glantz, P., “On Wetability 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 of Toothpastes Experimental Containing Gingivitis,” Stannous Pyrophosphate Unilever Technical Effects

and Zinc Citrate on Developing study in

Report #OLI2, unpublished

OTC Vol. 210174. 457. Jones, C. L. et al., “The Effect of 6 Months Stannous Pyrophosphate Report, unpublished Use of a Toothpaste Containing Technical

and Zinc Citrate on Oral Ecology,” Unilever

study in OTC Vol. 210173. of the Effect of Dentifrices

458. Harrap, G. J., “Assessment Dental Plaque,” Journal
of CZinical

on the Growth 1974.



459. Lloyd, A. M., “The Anti-Plaque Citrate in an Eighteen Hour Plaque Growth Report, unpublished


of Stannous Pyrophosphate/Zinc Test,” Unilever Technical


study in OTC Vol. 210177. “The Effect of a Dentifrice Fluoride Containing

460. Saxton, 0. A., and D. Cummins, Stannous Pyrophosphate, Gingivitis,” Unilever

Zinc Citrate and Sodium Report, unpublished

on Developing


study in OTC Vol. 210178. Experimental and a 0.2% 1977.

461. Bosman, C. W., and R. N. Powell, Gingivitis: A Comparison Mouthrinse,”

“The Reversal of Localized Toothbrushing

Between Mechanical

Procedures 4:161-172,


of Clinical

462. Gaare, D., G. Rolla, and J. I. Russel, “Clinical Regular Brushing with a Silica Based Dentifrice Technical

Study into the Benefits of Stannous Pyrophosphate study in OTC Vol. 210177.


and Zinc Citrate,” Unilever

Report, unpublished

463. Saxton, C. A. et al., “Six Month Pyrophosphate/Zinc Technical Citrate Dentifrice Study of the Effect of a Stannous Health and Calculus,” Unilever

on Gingival

Report, unpublished

study in OTC Vol. 210178. Index, the Plaque Index and the Retention 38:610, 1967. on Tooth Stains with Controlled , 77:849-855, 1968. Index

464. Loe, H., “The Gingival System,” ]ournal ofPerjdonto]ogy,

465. Lobene, R. R. et al., “Effects of Dentifrices Brushing,” / Journal of the American


466. Volpe, A. R., J. H. Manhold, Part I, A Method 32:292, 1965. 467. Ainamo, and Its Examiner

and S. P. Hazen, “In Vivo Calculus Assessment:


of Periodontology,

J., and I. Bay, “Problems of International

and Proposals for Recording 25(4):229-235, 1975.


and Plaque,” Journal

List of Subjects in 21 CFR Part 356 Over-the-counter Therefore, authority drugs, Antigingivitis/antiplaque drug products.

under the Federal Food, Drug, and Cosmetic Act and under of Food and Drugs, it is proposed

delegated to the Commissioner

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 COUNTER HEALTH CARE DRUG PRODUCTS FOR OVER-THE-

HUMAN USE citation for 21 CFR part 356 is revised to read as follows:

1. The authority Authority:

21 U.S.C. 321,351,352,353,355,360,371.

2. Section 356.3 is amended by adding paragraphs follows:
9 356.3 * * Definitions. * * * drug. A drug applied

(0) and (p) to read as

(0) Antigingivitis

to the oral cavity to help reduce

or prevent gingivitis. (p) Antigingivitis/antiplaque reduce or prevent gingivitis
drug. A drug applied

to the oral cavity to help

and dental plaque.

3. Section 356.13 is added to subpart B to read as follows:
5356.13 Antigingivitis active ingredients.

The active ingredient percent in a compatible

of the product dentifrice base.

consists of stannous fluoride


4. Section 356.15 is added to subpart B to read as follows:
s356.15 Antigingivitis/antiplaque active ingredients.

The active ingredient used within ingredient: (a) Cetylpyridinium

of the product

consists of any of the following for each


the dosage limits and in the dosage form established


0.045 to 0.1 percent in a mouthrinse chloride. when combined in


at least 72 to 77 percent available cetylpyridinium (b) EucalyptolO.092 accordance percent in a mouthrinse

with § 356.26(p). 0.042 percent in a mouthrinse when combined in accordance

(c) Menthol with § 356.26(p). (d) Methyl accordance


0.060 percent in a mouthrinse

when combined


with § 356.26(p). percent in a mouthrinse when combined in accordance

(e) ThymolO.064 with § 356.26(p).


5. Section 356.24 is amended by redesignating and by adding paragraph $j356.24
* * Package-size * * *

the text as paragraph


(b) to read as follows:

(b) Due to the toxicity

associated with fluoride package-size

active ingredients limitations

in for

§ 355.10 of this chapter, the following antigingivitis / drug products Dentifrice containing

are required

stannous fluoride: packages shall not contain more

(1) Dentifrices. than 276 milligrams (2) Exception. antiplaque


(mg) total fluorine

per package. do not apply to antigingivitis/ office use only and labeled

Package size limitations marketed

drug products

for professional

in accordance

with § 355.60 of this chapter. (p), (q), (r), and (s)

6. Section 356.26 is amended by adding paragraphs to read as follows: 6 356.26
* * Permitted * * combinations * of active ingredients.

(p) The ingredients combined


in § 356.15(b), (c), (d), and (e) may be 21.6 to 26.9 percent alcohol to § 356.65. in 5 356.15(a)

in a hydroalcoholic provided

vehicle containing

in a mouthrinse

the product

is labeled according active ingredient

(q) The antigingivitis/antiplaque or the combination of ingredients



in § 356.26(p) may be combined identified in § 355.10 of this

with any single anticaries chapter. (r) The antigingivitis antigingivitis/antiplaque combination of ingredients

active ingredient

active ingredient active ingredient identified

identified identified

in § 356.13(a) or the in § 356.15(a) or the with any

in § 356.26(p) may be combined identified in § 356.22.

single tooth desensitizer

active ingredient

(s) The antigingivitis/antiplaque or the combination of ingredients active ingredient identified identified in § 356.15(a)

in § 356.26(p) identified

may be combined

with any single anticaries

active ingredient

in § 355.10 of this identified in

chapter and any single tooth desensitizer
§ 356.22.

active ingredient

7. Section 356.65 is added to subpart C to read as follows:
9 356.65 I Labeling of antigingihtislantiplaquk ofidentity. drug products.

(a) Statement

The labeling

of the product

contains as


established “antigingivitis”

name of the drug, if any, and identifies or “antigingivitis/antiplaque” toothpaste, The labeling mouthrinse). of the product

the product


may include


form, e.g., dentifrice, (b) Indications.

states, under the heading (b), as appropriate. only the indications

“Uses,” one or more of the phrases listed in this paragraph Other truthful and nonmisleading statements, describing

for use that have been established as provided

and listed in this part, may also be used, of section to

in § 330.1(c)(Z) of this chapter, subject to the provisions

502 of the Federal Food, Drug, and Cosmetic Act (the act) relating misbranding introduction unapproved and the prohibition or delivery

in section 301(d) of the act against the into interstate commerce of

for introduction

new drugs in violation

of section 505(a) of the act. The labeling states “[bullet]1 helps

(1) For all antigingivitis

[select one of the following: of the following: ‘ [bullet]

‘ control,’ ‘ reduce,’ or ‘ prevent’ ] gingivitis,’ gums’ ].”
containing stannous

[select one or more



an early form of gum

disease,’ or ‘ [bullet]


(2) For antigingivitis



The labeling

states the indication

in paragraph

(b)(l) of this section and/or the following:
of bullet symbol.

‘ See § 201.66(b)(4) of this chapter for definition

“[bullet] gingivitis”. (3) For all antigingivitis/antiplaque helps [select one of the following: products. The labeling states “[bullet] helps interfere with harmful effects of plaque associated with

‘ control,’ ‘ reduce,’ ‘ prevent,’ or ‘ remove’ ] ‘ [bullet] gingivitis,’ gums’ ].” warnings

plaque that leads to [select one or more of the following: ‘ [bullet] gingivitis,

an early form of gum disease,’ or ‘ [bullet]


(c) Warnings. The labeling of the product under the heading “Warnings”: (1) For all antigingivitis

contains the following

and antigingivitis/antiplaque gingivitis,

products. bleeding,

(i) “Stop or redness

use and ask a dentist2 if [in bold type] [bullet] persists for more than 2 weeks [bullet]

you have painful

or swollen gums, pus

from the gum line, loose teeth, or increasing may be signs or symptoms (ii) The following of periodontitis,

spacing between the teeth. These a serious form of gum disease.”


shall be used in place of the general warning

statements required by § 330.1(g) of this chapter. (A) “Keep out of reach of children bold type] (B) “If more than used for [select appropriate is accidentally right away.” (2) [Reserved] (d) Directions. “Directions,” The labeling of the product directions dentifrice for use: containing 0.454 percent stannous concentration
in the heading

under 6 years of age.” [highlighted


word: ‘ brushing’ or ‘ rinsing’ ]


get medical help or contact a Poison Control Center

states, under the heading

the following

(1) For antigingivitis fluoride


in a paste dosage form with a theoretical

total fluorine

2For these products, the word “dentist” should be substituted for “doctor” “Stop use and ask a doctor if’ required by 5 201.66(c)(5)(vii) of this chapter.

of 850 to 1,150 parts per million


in § 355.1 O(c)(l) of this chapter.

“[bullet] preferably

adults and children

z years of age and older: brush teeth thoroughly,

after each meal or at least twice a day, or as directed by a dentist instruct children under 6 years of age in good brushing [bullet] supervise children as under and

or doctor [bullet]

rinsing habits (to minimize


necessary until capable of using without 2 years of age: ask a dentist or doctor”. (2) For antigingivitis/antiplaque percent cetylpyridinium and older: vigorously chloride.



oral rinse products “[bullet]


0.045 to 0.1

adults and children

12 years of age

swish 20 milliliters

of rinse between your teeth twice the rinse. [bullet] children under

a day for 30 seconds and then spit out. Do not swallow children

6 years to under 12 years of age: supervise use [bullet]

6 years of age: do not use”. (3) For antigingivitis/antiplaque combination
of ingredients

oral rinse products “[bullet]


the 12

in 5 356.26(p).

adults and children

years of age and older: vigorously

swish 20 milliliters

of rinse between your the rinse.

teeth twice a day for 30 seconds and then spit out. Do not swallow [bullet] children children

6 years to under 12 years of age: supervise use. [bullet]

under 6 years of age: do not use”. The labeling of the product information”: containing stannous fluoride. The contains the following

(e) Other information. information

under the heading “Other dentifrice this product

(1) For antigingivitis labeling states “[bullet] Adequate permanent tooth brushing


may produce surface staining of the teeth. are not harmful or

may prevent these stains which

and may be removed by a dentist.”


(2) For antigingivitis/antiplaque “[bullet] this rinse is not intended

oral rinse products. to replace brushing

The labeling or flossing”. (b)(lo),


8. Section 356.66 is amended by adding paragraphs (d)(3) to read as follows: 5 356.66
* * Labeling * * of combination * drug products.

(c)(5), and

(W *, * *
(10) For permitted the product combinations identified in 5 35626(p). The labeling of states, under the heading “Uses, ” one or ‘ more of the indications active ingredients in § 356.65(b)(3), or the or

for antigingivitis/antiplaque following: ‘ ] kill’ “[bullet]

helps [select one of the following: to the development ‘[bullet] gingivitis,

‘ control,’ ‘ inhibit,’

plaque bacteria that contribute ‘ [bullet] gingivitis,’ gums’ ].”

of [select one or more an early form of gum

of the following:

disease,’ or ‘ [bullet] (c) * * * (5) For permitted




in $356.26.

The warnings


§ 356.65(c) should be used. (d) * * * (3) For permitted § 356.65(d) combinations identified in § 356.26. The directions in

should be used.

9. Section 356.92 is added to subpart D to read as follows: Q 356.92
Testing of antigingivitis/antiplaque drug products.

The following

testing should be conducted with effectiveness

on the product

formulation, trials, and

a standard formulation a negative control. (a) Cetylpyridinium conducted:


by clinical


rinse. One of the following

tests should be

(1) Determine representative Representative Actinomyces Prevotella mutans, the in vitro antimicrobial commonly activity of the product against

plaque organisms organisms include,


with gingivitis. to, typed stains of: gingivalis,

but are not limited nucleatum,

viscosus, Fusobacterium inter-media, Bacteroides




species, Streptococcus a product’ s in

and gram negative enteric rods. Testing to determine activity should kill-time include minimal inhibitory

vitro antimicrobial


(MIC) assays, or so-second (2) Demonstrate Retention

studies, as appropriate. of the active ingredient using a Disk

the availability

Assay (DRA). the biological and Regrowth
of ingredients

(3) Demonstrate Plaque Glycolysis (b) Combination following


of the product

using an ex vivo

Model (PGRM). identified in 5 35626(p). One of the

tests should be conducted: the in vitro antimicrobial studies with both standard from saliva sampling. activity laboratory Representative of the product using 30-

(1) Determine second kill-time organisms

strains and wild-type organisms include,


but are not limited nucleatum, forsythus,

to, typed stains of: Actinomyces gingivalis, Prevotella mutans,

viscosus, Fusobacterium intermedia, Bacteroides

Porphyromonas Candida

species, Streptococcus

and gram negative enteric time of 30 of 1 percent

rods. Kill-time

testing should be conducted

using an exposure An initial

seconds in the presence of exogenous transmission should be used. the in vivo activity



(2) Demonstrate experimental comparability

of the product

in a short-term Formulation formulation


study of at least 2 weeks duration.

in this test is established

if the new mouthrinse

satisfies the “at least as good as ” statistical gingivitis with respect to the clinically test of clinical significant criteria for both plaque and or another generally for study

tested standard,

accepted statistical validation

comparability. differences

The criterion

is statistically

in plaque and gingivitis

between the clinically

tested standard and the negative control. dentifrice.

(c) Stannous fluoride (1) In addition include

to tests required by § 355.70 of this chapter, testing should of the antimicrobial activity against

an in vitro determination

representative Representative Actinomyces Prevotella

plaque organisms commonly organisms include,

associated with gingivitis. to, typed stains of: gingivalis,

but are not limited nucleatum,

viscosus, Fusobacterium



Bacteroides forsythus,


species, Streptococcus a product’ s in

mutans, and gram negative enteric rods. Testing to determine vitro antimicrobial activity should include

MIC assays, SO-second kill-time

studies, or plaque biofilm (2) Demonstrate

assays, as appropriate. activity of the product ex vivo using PGRM. of in this

the biological

(d) Test modifications. certain products

The formulation

or mode of administration of the testing procedures automated as the

may require modification alternative

section. In addition, procedures)

assay methods (including


the same basic chemistry

or microbiology

methods described in this section may be used. Any proposed modification or alternative assay method shall be submitted as a petition in accordance with

§ 10.30 of this chapter. The petition modification or data demonstrating

should contain data to support the that an alternative assay method provides will be subject to the

results of equivalent disclosure

accuracy. All information


rules in part 20 of this chapter.

Dated: May 12, 4Jo 2003. cd0263

Jeffrey Assistant [FR Dot.

St&en, Commissioner 03-????? Filed


Policy. 8:45 am]


CODE 4160-01-S