DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration

Rockville MD 20857
APR 2 2 2014

.Dr. Charles H. Norman, President

Dr. Kathleen T. O'Loughlin, D.M.D., M.P.H., Executive Director
American Dental Association
211 East Chicago Ave.
Chicago, IL 60611

Re: Docket No. FDA-2009-P-0566

Dear Dr. Norman and Dr. O'Loughlin:

This responds to the citizen petition (Petition) submitted to the Food and Drug
Administration (FDA) by the American Dental Association (ADA) and received on
November 24, 2009. In the Petition, the ADA requests that FDA "review and establish
an appropriate regulatory classification" for peroxide-containing tooth-whitening
preparations that act by chemical means to lighten tooth color (referred to throughout this
response as peroxide-containing tooth whiteners, tooth-whitening products, etc.) (Petition
at cover page and p. 1). The Petition states that without appropriate regulation, the
application of chemically based tooth-whitening/bleaching agents may result in harm
(Petition at cover page). Further, you state that the ADA has concerns about the safe use
of tooth-whitening products without the benefit of professional consultation or
examination (Petition at cover page).

We have carefully reviewed the arguments in the Petition. For the reasons stated below,
we deny your request.

I. BACKGROUND

A. Regulatory History of Tooth Whiteners

In the 1980s, various dental manufacturers introduced to the marketplace peroxide-

containing tooth-bleaching kits dispensed by dentists and intended to be used by patients
at home. In 1991, FDA sent Warning Letters to several manufacturers stating that
peroxide-containing products that claim to whiten teeth through the bleaching process
were considered unapproved new drugs and that the products were being marketed in
violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Following the
receipt of one of those letters, Den-Mat Holdings, LLC (Den-Mat), the manufacturer of
the Rembrandt brand of bleaching tooth whiteners, sued FDA asserting that its peroxide-
containing tooth whitening product, Rembrandt Lighten Bleaching Gel (Rembrandt Gel),
was a cosmetic and not a drug as defined in the FD&C Act. DEN-MAT Corp. v. FDA,
No. MJG-92-444, 1992 WL 208962, at *1.

1
Den-Mat withdrew its case in 1992 1 after we agreed to review new information submitted
by Den-Mat and determine whether the new information would affect our assessment that
Rembrandt Gel is an unapproved new drug. 2 We have not issued a determination about
the classification of Rembrandt Gel since the issuance of those warning letters.

B. Definitions for Drugs and Cosmetics under the FD&C Act

Section 201(g)(l) of the FD&C Act (21 U.S.C. 321(g)(l)) defines a drug as:

(A) articles recognized in the official United States Pharmacopeia, official

Homeopathic Pharmacopeia of the United States, or official National Formulary,
or any supplement to any of them; and (B) articles intended for use in the
diagnosis, cure, mitigation, treatment, or prevention of disease in man or other
animals; and (C) articles (other than food) intended to affect the structure or any
function of the body of man or other animals; and (D) articles intended for use as
a component of any articles specified in clause (A), (B), or (C).

Section 201(p) of the FD&C Act (21 U.S.C. 321(p)) defines a new drug as:

( 1) Any drug (except a new animal drug or an animal feed bearing or containing
a new animal drug) the composition of which is such that such drug is not
generally recognized, among experts qualified by scientific training and
experience to evaluate the safety and effectiveness of drugs, as safe and effective
for use under the conditions prescribed, recommended, or suggested in the
labeling thereof, except that such a drug not so recognized shall not be deemed to
be a "new drug" if at any time prior to June 25, 1938, it was subject to the Food
and Drugs Act of June 30, 1906, as amended, and if at such time its labeling
contained the same representations concerning the conditions of its use; or

(2) Any drug (except a new animal drug or an animal feed bearing or containing
a new animal drug) the composition of which is such that such drug, as a result of
investigations to determine its safety and effectiveness for use under such
conditions, has become so recognized, but which has not, otherwise than in such
investigations, been used to a material extent or for a material time under such
conditions.

Section 201(i) of the FD&C Act (21 U.S.C. 321(i)) defines a cosmetic as:

( 1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced

into, or otherwise applied to the human body or any part thereof for cleansing,
beautifying, promoting attractiveness, or altering the appearance, and (2) articles
intended for use as a component of any such articles; except that such term shall
not include soap.

1
Den-Mat Corp. v. FDA, Civil Action No. MJG-92-444, D. Md., June 22, 1992.
2
Letter from Daniel L. Michels, Director, Office of Compliance, FDA to Robert L. Ibsen, President, Den-
Mat Corp., Ref: Warning Letter 91-HFD-312-24, June 12, 1992.

2
A product may meet the definition of a drug, a cosmetic, or both; the definitions are not
mutually exclusive.

II. DISCUSSION

A. Regulation of Peroxide-Containing Tooth-Whitening

Products as Drugs and Cosmetics

In the Petition, you request that FDA review and establish an appropriate regulatory
classification for peroxide-containing tooth-whitening preparations (Petition at cover
page). You also request that the classification be based on published scientific data and
new studies conducted by manufacturers to help assure public safety (Petition at p. 1).
The report you incorporate by reference into the Petition (the Tooth Whitening/Bleaching
Report) states that most whitening products available to consumers contain hydrogen
peroxide, although some contain carbamide peroxide. 3 You describe a variety of at-home
use whitening products containing concentrations ranging from 3- 7.5% hydrogen
peroxide and in-office use products containing 25- 38% hydrogen peroxide. 4

As stated above, the statutory definitions for drug and cosmetic are not mutually
exclusive. Cosmetics can be lawfully marketed without preapproval by FDA and without
the submission of data; new drugs, by contrast, require preapproval of a new drug
application containing data to support the safety and efficacy of the product (see section
505(d) of the FD&C Act and 21 CFR Part 314). Therefore, products that meet both the
definition of cosmetic and the definition of new drug in the FD&C Act must be approved
by FDA before being marketed and must meet all of FDA's regulatory requirements for
drugs.

We believe that most peroxide-containing tooth whiteners would meet the definition of a
cosmetic in the FD&C Act because they generally "are intended to be ... applied to the
human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering
the appearance." (See generally section 201(i)(l) of the FD&C Act). Based on an
application of the statutory definitions noted above, a better understanding of the
mechanisms of action, conditions ofuse, safety, and formulation of specific peroxide-
containing tooth whitener products is necessary to determine whether such products also
meet the definition of a drug under the FD&C Act.

Specifically, the exact mechanism of peroxide-containing tooth whitening is not well-

understood,5 making it difficult to determine whether the various formulations contained
in the marketed products affect the structure or function of the body. The precise

3
ADA Council on Scientific Affairs. Tooth Whitening/Bleaching: Treatment Considerations for Dentists
and Their Patients, September 2009, at 2.
4
Tooth Whitening/Bleaching Report at 2.
5
Kihn, P. W., "Vital Tooth Whitening," Dental Clinics of North America, 51 (2):319-331, 2007.

3
mechanism of action by which a particular peroxide-containing tooth whitening product
works may differ depending on the type of tooth staining an individual has.

An article by Nathoo explains tooth staining. 6 Staining on the tooth surface (extrinsic)
can be caused by deposits from solid and liquid food substances, tobacco, and the action
of antimicrobial agents, which can leave the remains of killed bacteria on the enamel
surface. These types of stains can be removed with regular professional cleanings and
lightened by the mechanical action of brushing with a toothpaste containing abrasives.
The chemical interactions that determine the tenacity of different types of materials that
cause extrinsic stains are not well understood. Certain extrinsic stains require the use of
chemical tooth whiteners, such as hydrogen peroxide (in some cases at high
concentrations) to lighten the stains. Not much data exist to establish how peroxide-
containing chemical tooth whiteners lighten these types of stains or whether they do so by
affecting the structure or function of the teeth. ·

Staining or discoloration also can occur within the enamel or dentin (intrinsic stains).
Unlike extrinsic discolorations that occur on the surface of the teeth, intrinsic stains are
caused by the presence of foreign material within the enamel or dentin. Intrinsic stains
may be caused, by, among other things, excessive fluoride ingestion during tooth
development or by ingestion of tetracycline, an antibiotic. Certain hematologic disorders
such as sickle cell anemia also may cause intrinsic discoloration due to the presence of
blood within the dentinal tubules. In the case of these intrinsic stains, hydrogen peroxide
and carbamide peroxide tooth whiteners may act by diffusing into and through the
enamel to reach the enamel-dentin junction and dentin regions. 7

Because of the differences between extrinsic and intrinsic stains, and the different causes
of the two categories of staining, we believe that the means by which whitening occurs
may be different. In addition to the differences in stain types, as described above and
noted in the Tooth Whitening/Bleaching Report, the ingredients used in peroxide-
containing tooth whiteners are found in a wide range of concentrations in various
products, which may affect the means by which the whitening occurs. These differences
in peroxide-containing tooth whitening products make it difficult to characterize them as
a group.

In sum, there is insufficient data to determine whether, as a group, peroxide-containing

tooth whitening preparations that act by chemical means to lighten tooth color meet the
definition of a drug. Data on specific products would be necessary to determine whether
individual peroxide-containing tooth whiteners are intended to affect the structure or
function of the teeth and/or intended to mitigate or treat a disease and therefore meet the
definition of a drug - in addition to that of a cosmetic - under the FD&C Act. The vast

6
Nathoo, S., "The Chemistry and Mechanisms of Extrinsic and Intrinsic Discoloration," Journal of the
American Dental Association, 128 Supp1.:6S-10S, 1997.
7
Goldstein, R.E., and Garber, D.A., Complete Dental Bleaching, Chicago: Quintessence Publishing,
Chicago, 73-74 (1995); Dahl, J. and Pallesen, U., "Tooth Bleaching--A Critical Review ofthe Biological
Aspects," Critical Reviews in Oral Biology and Medicine, 14(4): 292-304, 2003.

4
majority of publicly available literature on these products, discussed below, addresses
their safety and efficacy; little is written about their mechanism of action. We would
need to examine each product on a case-by-case basis to determine whether it meets the
statutory definition of drug as well as the definition of cosmetic. Without further data
illuminating the mechanism of action of peroxide-containing tooth whiteners that work
by chemical means or knowing the intended uses of specific products, we cannot answer
the question of whether all tooth whiteners as a group meet the definition of a drug.

B. Safety Concerns

In your petition, you state that there are safety concerns with peroxide-containing tooth-
whitening products related to the risk of damage to mouth tissue, tooth structure, and
dental restorations, as well as related to the potential carcinogenicity of hydrogen
peroxide, which the Tooth Whitening/Bleaching Report attached to the Petition cites as
the most common tooth-bleaching agent (Petition at p. 2 and Tooth-Whitening/Bleaching
Report at pp. 2-4). In addition, the Report states that there are questions about the safety
of peroxide-containing tooth-whitening treatments when used during pregnancy, as well
as the safety oftooth bleaching for children and adolescents (Tooth-Whitening/Bleaching
Report at p. 4).

1. Available Data Regarding Safety Concerns

In your Petition, you submitted one 1996 peer-reviewed publication in support of your
concerns related to the risk of damage to mouth tissues, tooth structure, and dental
restoration. 8 This paper provides a review of the 100-year history of peroxide in oral
health care and provides a summary of numerous nonclinical toxicology studies as well
as results of exposure assessment in humans. The eight human clinical studies examining
adverse events caused by dentist-monitored at-home tooth whitening products that are
cited in the paper did not uncover any significant adverse events. The paper's conclusion
states that "peroxide-containing products, including those for tooth whitening, have been
used with minimal risks for many years. However, adverse events due to the use of
inappropriate products or the abuse of the products have been reported." 9 We believe
that this paper does not provide adequate scientific evidence to raise significant safety
concerns under intended conditions of use regarding peroxide-containing tooth whiteners
as a class of products.

We have also reviewed the ADA Statement on the Safety and Effectiveness of Tooth
Whitening Products 10 and believe it also provides insufficient data to raise safety
concerns about the entire class of products encompassing peroxide-containing tooth
whiteners. Tooth whiteners are sold with a range of concentrations and formulations of
8
Li, Y, "Biological Properties of Peroxide-containing Tooth Whiteners," Food and Chemical Toxicology,
34:887-904, 1996.
9
Id.
10
ADA Statement on the Safety and Effectiveness of Tooth Whitening (April2012), available at
http://www.ada.org/1902.aspx (ADA Statement).

5
peroxides to many different consumers who use them differently. According to the ADA
Statement, tooth whiteners with certain concentrations of peroxides appear to be well-
tolerated:

The most commonly observed side effects with these peroxide-based bleaching
agents are tooth sensitivity and occasional irritation of soft tissues in the mouth
(oral mucosa), particularly the gums. Tooth sensitivity often occurs during early
stages of bleaching treatment. Tissue irritation may result from an ill-fitting tray
used to contain bleaching product. Both tooth sensitivity and tissue irritation are
usually temporary and stop after the treatment. On rare occasions, irreversible
tooth damage has been reported.

We acknowledge that different products may raise additional safety concerns, but the
ADA Statement provides insufficient evidence to determine the degree to which these
safety concerns are associated with any particular peroxide-containing tooth-whitening
product.

The Petition also cites the 2007 European Commission Health and Consumer Protection
Directorate-General, Scientific Committee on Consumer Products (SCCP), Opinion on
tooth-whitening products (2007 SCCP Opinion) (Petition at p. 2). 11 As described in the
Tooth Whitening/Bleaching Report, the 2007 SCCP Opinion recommended that a
concentration of up to 6% hydrogen peroxide is a safe limit to use for at-home tooth
bleaching after dental consultation. 12 The majority of studies reviewed by the SCCP for
the 2007 report indicated that hydrogen peroxide- and carbamide peroxide-containing
products had no significant deleterious effects on human tooth enamel and dentin
14
morphology, 13 and pulpal damage caused by penetration of hydrogen peroxide was low.
The SCCP also noted, however, increased risks associated with increasing concentration
ofhydrogen peroxide and frequency ofuse. 15 Further, the SCCP noted that the effects of
peroxide-containing bleachinfl agents on the mechanical properties of tooth enamel had
not been extensively studied. 6 We believe this 2007 SCCP Opinion indicates that these
products cannot be assessed as a group for safety concerns.

"Health and Consumer Protection Directorate-General, Scientific Committee on Consumer Protection,

"Opinion on Hydrogen Peroxide, in Its Free Form or When Released, in Oral Hygiene Products and Tooth
Whitening Products" (available at
http:/I ec. europa. e u/health/ph_risk/ comm ittees/04 seep/docs/seep _o 122. pdf).
12
2009 Tooth Whitening/Bleaching Report at 3; 2007 SCCP Opinion at 71.
13
2007- SCCP Opinion at 60.
14
2007 SCCP Opinion at 59.
15
2007 SCCP Opinion at 71.
16
The 2007 SCCP Opinion did not include clinical data or long-term epidemiological studies assessing the
possible adverse effects ofperoxide-containing tooth whiteners. In addition the majority of studies with
carbamide peroxide reviewed were done with a type of product only available via the dental office and
evaluated only the efficacy of the product.

6
We have reviewed hydrogen peroxide as an active ingredient for safety as part of two
separate regulatory actions for specific oral uses that did not include tooth whitening.
FDA's tentative conclusions from those reviews indicate that different levels of hydrogen
peroxide pose different safety concerns. In 1991, we published "Oral Health Care Drug
Products for Over-the Counter Human Use; Amendment to Tentative Final Monograph to
Include OTC Relief of Oral Discomfort Drug Products" in which 3% hydrogen peroxide
was categorized as safe for use as an active ingredient in over-the-counter (OTC) oral
health care debriding agents and oral wound cleansers. 17 In 2003, we published the
findings of an expert panel (the Dental Plaque Subcommittee) in which they categorized
hydrogen peroxide as safe for use in OTC antigingivitis/antiplaque drugs at
concentrations ofup to 3%. 18 FDA did not definitively make determinations on the
efficacy of hydrogen peroxide and the safety of hydrogen peroxide in concentrations over
3%.19

Both of these documents are part of FDA's OTC Drug Review (often referred to as the
monograph process) in which OTC drugs in a therapeutic class are evaluated for safety
and efficacy based upon their active ingredients and intended uses. Pending finalization
ofthe two monographs mentioned above (neither of which include teeth whitening as an
indication), we have permitted the marketing of hydrogen peroxide-containing products
for other specific oral uses as part of the OTC Drug Review. We mention these
rulemakings simply to note our evaluation of the safety of hydrogen peroxide as an active
ingredient in other products with oral uses. We tentatively found, based on our safety
evaluation under the OTC Drug Review, that hydrogen peroxide was safe for other
specific oral uses noted above in concentrations up to 3%. The ingredients reviewed in
the OTC Drug Review were for different indications and would not have included every
concentration in which the ingredients may be found in peroxide-containing tooth
whiteners and the specific method and duration of use may vary. Nevertheless, our
review of peroxides in this other context does not raise significant safety concerns for
their use as tooth whiteners.

2. Whether Peroxide-Containing Tooth-Whitening Products

Have the Potential to Promote Carcinogenicity

In the Petition, you state that concerns with carcinogenicity and co-carcinogenicity of
hydrogen peroxide have been raised, although these concerns so far have not been
substantiated through research (Tooth Whitening/Bleaching Report at p. 2). Our review
of available research leads us to a similar conclusion- that there is insufficient evidence
to deduce that peroxide-containing tooth-whitening products as a group have
carcinogenic risk.

17
56 FR 48302 at 48345.

18
"Oral Health Care Drug Products for Over-the-Counter Human Use; Antigingivitis/Antiplaque Drug
Products; Establishment of a Monograph," 68 FR 32232,32256-57 (May 29, 2003).

19
68 FR 32232 at 32260.

7
We have reviewed materials referenced in the Petition, including the 2007 SCCP Opinion
on tooth-whitening products, 20 and the Agency for Toxic Substances and Disease
Registry (ATSDR) guideline for hydrogen peroxide21 regarding information on hydrogen
peroxide and carcinogenicity. Neither document offers adequate support for the alleged
carcinogenic risk of hydrogen peroxide. The ATSDR guideline states that the
International Agency for Research on Cancer (IARC) has determined that hydrogen
peroxide is "not classifiable" as to its carcinogenicity in humans. Additionally, the
ATSDR guideline states that hydrogen peroxide is rapidly decomposed in the body and
thus is unlikely to cause chronic toxicity. The 2007 SCCP Opinion concluded that
hydrogen peroxide had only a weak potential to induce local carcinogenic effects?2

Our review of other information also leads us to believe that the potential of these
products to promote carcinogenicity is unknown; we are not aware of epidemiologic data
that address this question?3 While hydrogen peroxide is a known mutagen (in certain
concentrations and used in certain ways), it is also a byproduct of oxidative metabolism
and all humans have peroxides in their bodies. 24 Humans produce peroxidase enzymes
that rapidly metabolize peroxide, including in the mouth?

We also reviewed studies of hydrogen peroxide use in rodents. Hydrogen peroxide was
reported to promote carcinomas in rodents following intraperitoneal injections26 and
through its addition to drinking water. 27 Duodenal hyperplasia has been found in the rat

20
Health and Consumer Protection Directorate-General, Scientific Committee on Consumer Protection,
"Opinion on Hydrogen Peroxide, in Its Free Form or When Released, in Oral Hygiene Products and
Tooth Whitening Products", available at
http://ec.europa.eulhealthlph_risk/committees/04_seep/docs/seep_o_122.pdf.

21
Agency for Toxic Substances and Disease Registry (ATSDR). "Managing Hazardous Materials Incidents,
Volume III - Medical Management Guidelines for Acute Chemical Exposures: Hydrogen Peroxide,"
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, 2000, available at
http://www.atsdr.cdc.gov/MHMI/mmg 174.pdf.
22
2007 SCCP Opinion, at p. 35.
23
Minoux, M, and Serfaty, R, "Vital tooth bleaching: Biologic adverse effects- A review," Quintessence
International, 39:653, 2008.
24
Lee, S, Zhang W, Lee, D, Li Y, Tooth Whitening in Children and Adolescents: A Literature Review, Ped
Dent 2005; 27;5:362; Li 1996.
25
Minoux and Serfaty 2008; Li, Y, The Safety of Peroxide-Containing At-Home Tooth Whiteners,
Compendium of Continuing Education in Dentistry, 2003; Apr:24(4A): 385.
26
Hirota, N., and Yokoyama, T. "Enhancing Effect ofHydrogen Peroxide Upon Duodenal and Upper
Jejunal Carcinogenesis in Rats," Gann (Japanese Journal of Cancer Research), 72(5):811-812, 1981.
27
Ito, A. et al., "Induction of Duodenal Tumors in Mice by Oral Administration of Hydrogen Peroxide,"
Gann (Japanese Journal of Cancer Research), 72:174-175, 1981; Ito, A. et al., "Induction and
Characterization of Gastro-Duodenal Lesions in Mice Given Continuous Oral Administration of Hydrogen
Peroxide," Gann (Japanese Journal of Cancer Research), 73(2):315-322, 1982; Ito, A. et al., "Correlation
Between Induction of Duodenal Tumor by Hydrogen Peroxide and Catalase Activity in Mice," Gann

8
 28
model following addition of 1.5 to 3 percent hydrogen peroxide to drinking water. Ito
29
et al. observed similar toxicity with higher doses of hydrogen peroxide, and in mice
with reduced catalase activity, hyperplastic and neoplastic duodenal nodules were
found. 30 However, FDA toxicologists concluded that the results of the Ito et al studies
31
did not provide sufficient evidence to designate hydrogen peroxide as a carcinogen.
Similar conclusions were drawn by a panel of toxicologists who reviewed the potential
carcinogenicity of hydrogen peroxide for the IARC. 32

Furthermore, we are aware of three studies in which the results indicated that hydrogen
peroxide was not a carcinogen. A study in rats in which hydrogen peroxide was
administered in drinking water at concentrations of up to 0.6 percent showed no evidence
of carcinogenicity. 33 Two studies in hamsters compared the effects of similar dentifrices
with and without the combination of hydrogen peroxide and sodium bicarbonate in the
presence of7, 12-dimethylbenz-alpha-anthracene (DMBA)?4 The results demonstrated
that an oral product containing hydrogen peroxide and sodium bicarbonate was not
carcinogenic and that the combination did not enhance the tumorigenicity ofDMBA.

Based on the available data, we do not have sufficient information to conclude that
peroxide-containing tooth-whitening products, as a group, have the potential to be
carcinogenic, and the limited existing data regarding hydrogen peroxide do not suggest
that it is likely to have that potential when used in a tooth whitening product.

3. Peroxide-Containing Tooth-Whitening Products Used by

Children, Adolescents, and Females During Pregnancy

The Petition raises general, unspecified concern regarding the use of peroxide-containing
tooth-whitening products by children, adolescents, and pregnant women (Tooth

(Japanese Journal of Cancer Research), 75(1):17-21, 1984.

28
68 FR 32232 at 32258.
29
Ito, R. et al., "Safety Study of Hydrogen Peroxide on Acute and Subacute Toxicity," English abstract,
Journal ofthe Medical Society ofToho University, 23(5-6):531-537, 1976.
30
Ito, A. et al., "Induction and Characterization of Gastro-Duodenal Lesions in Mice Given Continuous
Oral Administration of Hydrogen Peroxide," Gann (Japanese Journal of Cancer Research), 73(2):315-322,
1982.
31
"Irradiation in the Production, Processing, and Handling of Food," 53 FR 53176, 53198 (Dec. 30, 1988).
32
"Hydrogen Peroxide in Allyl Compounds, Aldehydes, Epoxides, and Peroxides," in !ARC Monographs
on the Evaluation of Carcinogenic Risks of Chemicals to Humans, 36: 85-314, 1985; "Alcohol Drinking,"
in/ARC Monographs on the Evaluation ofCarcinogenic Risks ofChemicals to Humans, 44: 101-151,251-
261, 1988.
33
Takayama, S., "The Toxicity and Carcinogenic Potential ofH2 0 2," in Japanese National Institutes of
Health Science Report JCT 77-02, p. 121, Transcript of the December 1995 Food and Drug Administration
Dental Plaque Subcommittee Meeting, OTC Vol. 210479.
34
Marshall, M. V. et al., "Hamster Cheek Pouch Bioassay of Dentifrices Containing Hydrogen Peroxide
and Baking Soda," Journal of the American College of Toxicology, 15:45-61, 1996.

9
Whitening/Bleaching Report at p. 4). However, the Petition neither referenced nor
contained data or other information to support your safety concern associated with the
use of peroxide-containing tooth-whitening products by children, adolescents, and
pregnant women.

Literature addressing safet~ concerns associated with use of these products in children
and adolescents is sparse. 3 Most information on the safety of these products in children
and adolescents is surmised from adult use, which may not provide sufficient information
because primary teeth, which are the first set of teeth that humans develop and would be
the teeth studied in children, differ from permanent teeth in adults. 36 Among other
things, the primary tooth enamel is thinner and more permeable. The condition of the
enamel makes bleaching easier on primary teeth, but the pulp may get more exposure and
result in greater sensitivity. 37

The ATSDR guideline for hydrogen peroxide38 cited in the Petition states that hydrogen
peroxide has shown no evidence of developmental or reproductive effects in humans.
Several recent peer-reviewed publications have also provided evidence that peroxide-
containing tooth-whitening products do not appear to cause any deleterious effects on
adolescents or adults. 39 Further, we are not aware of any studies or other evidence
documenting use of tooth whiteners by pregnant women or children.

Based on our review, we do not have sufficient information to determine whether there
are significant safety concerns associated with the use of peroxide-containing tooth-
whitening products by children, adolescents, and females during pregnancy.

C. Whether Peroxide-Containing Tooth-Whitening Products May Be

Over-Used or Abused

You state that direct-to-consumer products may be easily over-used and abused by
individuals who assume that the products are safe because they are readily available

35
Lee. S., Zhang, W., Lee, D., and Li, Y., "Tooth Whitening in Children and Adolescents: A Literature
Review," Pediatric Dentistry, 72(5):362-368, 2005.
36 Id.

37
ld., p. 363.
38
Agency for Toxic Substances and Disease Registry (ATSDR). Managing Hazardous Materials Incidents,
Volume III- Medical Management Guidelines for Acute Chemical Exposures: Hydrogen Peroxide.
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, 2002.
39
Toteda, M., Philpotts, C.J., Cox, T.F., and Joiner, A., "Evaluation of a 6% Hydrogen Peroxide Tooth-
Whitening Gel on Enamel Microhardness After Extended Use. Quintessence International, 39(10):853-858,
2008; Gerlach, R. W., Barker, M.L., Karpinia, K., and Magnusson, I, Single Site Meta-Analysis of 6%
Hydrogen Peroxide Whitening Strip Effectiveness and Safety Over 2 Weeks. Journal of Dentistry,
37(5):360-365, 2009, Epub 2009 Feb 23; Donly, K.J., Kennedy, P., Segura, A., and Gerlach, R.W.,
Effectiveness and Safety of Tooth Bleaching in Teenagers, Pediatric Dentistry, 27(4):298-302, 2005;
Sulieman, A. M., Macdonald, E., and Rees, J.S., A Safety Study In Vitro for the Effects of an In-Office
Bleaching System on the Integrity ofEnamel and Dentine, Journal of Dentistry, 32:581-590,2004.

10
(Petition at p. 1). You also state that the rate of adverse events from use or abuse of
home-use products is unclear because consumers rarely report problems through the FDA
MedWatch system (Tooth-Whitening/Bleaching Report at p. 1).

There are a limited number of anecdotal reports in the literature about excessive use of
these products. 40 However, we are unaware of any studies on whether peroxide-
containing tooth whiteners may be over-used or abused. We also do not have sufficient
information to support your suggestion that consumers assume these products are safe
because they are widely available.

We have reviewed reports received by our Center for Food Safety and Applied Nutrition
(CFSAN) Adverse Event Reporting System (CAERS) and those received by our FDA
Adverse Event Reporting System (F AERS) and determined that there are a very small
number of complaints addressing the use of peroxide-containing tooth whiteners. Since
1990, CAERS received nine complaints concerning the use of peroxide-containing tooth
whiteners. The complaints involve gingival and oral irritation, tooth discoloration,
damage to enamel, gastrointestinal upset, fever, allergic reaction, and palpitations with
chest pain. As you mention, typically, adverse event reporting systems detect only a
small proportion of the events that actually occur. FDA's adverse event reporting
systems are no exception. Historically, adverse events associated with use of cosmetics
and nonprescription drugs have been substantially under-reported by consumers Finally,
consumers may be aware that they may experience transient gingival irritation, tooth
hypersensitivity, or miscellaneous oral irritations following the use of tooth whiteners and
thus may not report these reactions to FDA. Despite these limitations to the reporting
system generally, we note that there are millions of exposures and a minimal number of
complaints have been received. We have reviewed the information with all these
considerations in mind and conclude that current data from adverse event reports fail to
show that consumers are over-using or abusing peroxide-containing tooth whiteners.

Based on the information in the Petition and available to us, we do not have sufficient
information to determine how consumers use peroxide-containing tooth-whitening
products and whether they may be over-used or abused. We would need additional
information to draw any conclusions.

D. Peroxide-Containing Tooth Whiteners for OTC Use

In the Petition, you assert that the expansion of peroxide-containing tooth-whitening

products available directly to consumers, and application of these products in venues
such as shopping malls, cruise ships, and salons is troubling because consumers have
little or no assurance regarding the safety of product ingredients, doses, or the
professional qualifications of individuals employed in these non-dental settings (Petition
at cover page). You note concerns about the safe use of peroxide-containing tooth-
whitening products without the benefit of professional consultation or examination
(Petition at cover page), and you refer to States that have adopted legislation "preventing

40
Li 1996; Tooth Whitening/Bleaching Report p.3.

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non-dentists from applying or assisting a person in applying tooth-whitening material
being sold as a safe alternative to dental office whitening procedures" (Petition at p. 2).

More generally, you argue for dental professional involvement in tooth bleaching
(Petition at p. 2 and Tooth Whitening/Bleaching Report at pp. 3-5, 7-9). You note many
factors may influence the effectiveness of a chemical tooth whitener (e.g., tooth/enamel
cracks and related sensitivity, exposed root surfaces, inherited/developmental aspects,
among others (Tooth-Whitening/Bleaching Report at p. 5)), which are best assessed by a
dental professional.

As a preliminary matter, to restrict use of chemical tooth whiteners to dental

professionals (i.e. practitioners licensed by law), the products would have to meet the
definition of a drug (see section 201 (g) of the FD&C Act), and meet the standard for
classification as a prescription only product (see, e.g., section 503(b) of the FD&C Act).
There is not sufficient evidence for us to determine, even if the products meet the FD&C
Act's definition of a drug, that because of their "toxicity or other potentiality for harmful
effect, or the method of its use, or the collateral measures necessary to [their] use," they
would meet the standard for classification as prescription drugs. See section
503(b)(1)(A) ofthe FD&C Act. More information would be needed to establish specific
peroxide concentration ranges appropriate for use in different settings (e.g., consumer use
and practitioner-supervised use). In addition, factors other than peroxide concentration,
such as frequency and duration of exposure, may also be relevant to these determinations.

Peroxide tooth whiteners have been available for consumer use for 20 years, and we have
limited information regarding safety risks associated with their use. As mentioned above,
we have permitted marketing of hydrogen peroxide as an active ingredient in certain
OTC oral antiseptics 41 and antigingivitis/antiplaque agents (at concentrations of up to 3
percent)42 until a final monograph for these drug products is finalized. Hydrogen
peroxide has been a component of many OTC drugs, including topical anti-infectants,
canker sore treatments, and earwax softeners. A 3 percent hydrogen peroxide solution
can be marketed under the tentative final monograph and used by a consumer as a
debriding agent/oral wound cleanser. 43

FDA believes peroxide-containing tooth whiteners may be suitable for use without the
supervision of a licensed practitioner and used safely. However, there is insufficient data
regarding the risks posed by the use of hydrogen peroxide for tooth whitening to draw a
definitive conclusion. We also do not have sufficient evidence from literature as to what
an appropriate concentration limit would be for safe use of these products in the
consumer setting.

41
59 FR 6084 at 6121.
42
68 FR 32232 at 32257-60.
43
"Oral Health Care Drug Products for Over-the-Counter Human Use; Tentative Final Monograph," 53 FR
2436, 2460 (Jan. 27. 1988).

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III. CONCLUSION

For the reasons described in this response, we deny your request that FDA review and
establish a regulatory classification for tooth-whitening preparations that act by chemical
means to lighten tooth color. You did not provide information in your citizen petition
that would allow us to classify the group of chemical, peroxide-containing tooth whitener
products as drugs. Further information, including which ingredients and which
concentrations of peroxide-containing tooth whiteners may affect the structure or
function of the body and/or the intended uses of such products would be required before
we could evaluate whether such a regulatory classification would be appropriate. In
addition, to help improve reporting of any potential safety concerns associated with these
products we encourage the ADA to publicize information about FDA's adverse reporting
system to its members.

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