[Federal Register: August 29, 2006 (Volume 71, Number 167)]
[Proposed Rules]               
[Page 51146-51155]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29au06-17]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 1978N-0065 (formerly Docket No. 78N-0065)]
RIN 0910-AF53

 
Skin Bleaching Drug Products For Over-the-Counter Human Use; 
Proposed Rule

AGENCY: Food and Drug Administration, HHS.

ACTION:  Proposed rule; withdrawal of previous proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is issuing a notice of 
proposed rulemaking that would establish that over-the-counter (OTC) 
skin bleaching drug products are not generally recognized as safe and 
effective (GRASE) and are misbranded. FDA is also withdrawing the 
previous proposed rule on skin bleaching drug products for OTC human 
use, which was issued in the form of a tentative final monograph (TFM). 
FDA is issuing this proposed rule after considering new data and 
information on the safety of hydroquinone, the only active ingredient 
that had been proposed for inclusion in a monograph for these products. 
This proposal is part of FDA's ongoing review of OTC drug products. 
Further, upon issuance of a final rule, FDA intends to consider all 
skin bleaching drug products, whether currently marketed on a 
prescription or OTC basis, to be new drugs requiring an approved new 
drug application (NDA) for continued marketing.

DATES:  Submit written or electronic comments by December 27, 2006; 
submit written or electronic comments on FDA's economic impact 
determination by December 27, 2006. The September 3, 1982, proposed 
rule (47 FR 39108) is withdrawn as of August 29, 2006. See section IX 
for the proposed effective date of any final rule that may publish 
based on this proposal.

[[Page 51147]]


ADDRESSES:  You may submit comments, identified by Docket No. 1978N-
0065 and RIN number 0910-AF53, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided. For addtional 

information on submitting comments, see the ``Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm 

and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:  Michelle M. Jackson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 5486, Silver Spring, MD 20993-0002, 301-
796-0923.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. New Data
    A. Fertility Studies
    B. Toxicokinetic Studies
    C. Carcinogenicity Studies
    D. Occurrence of Exogenous Ochronosis
III. FDA's Tentative Conclusions on Skin Bleaching Drug Products
IV. Analysis of Impacts
V. Paperwork Reduction Act of 1995
VI. Environmental Impact
VII. Federalism
VIII. Request for Comments
IX. Proposed Effective Date
X. References

I. Background

    In the Federal Register of November 3, 1978 (43 FR 51546), FDA 
published an advance notice of proposed rulemaking to establish a 
monograph for OTC skin bleaching drug products, together with the 
recommendations of the Advisory Review Panel on OTC Miscellaneous 
External Drug Products (the Panel), which was the advisory review panel 
responsible for evaluating data on the active ingredients in this drug 
class. The data and information considered by the Panel were put on 
display in the Division of Dockets Management (see ADDRESSES).
    FDA's TFM for OTC skin bleaching drug products was published in the 
Federal Register of September 3, 1982 (47 FR 39108). In that TFM, FDA 
proposed that hydroquinone (1.5 to 2.0 percent) be GRASE as an active 
ingredient in OTC skin bleaching drug products. Six manufacturers, one 
cosmetic manufacturers' association, and one drug manufacturers' 
association submitted comments in response to the 1982 TFM. These 
comments and additional information that has come to FDA's attention 
since publication of the 1982 TFM are also on public display in the 
Division of Dockets Management (see ADDRESSES).
    FDA is now proposing a rule that would classify OTC skin bleaching 
drug products as not GRASE, misbranded, and new drugs within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 321(p)). This proposed rule would amend part 310 
(21 CFR part 310), subpart E by adding new Sec.  310.545(a)(17)(ii). 
Accordingly, the proposed monograph that published in the Federal 
Register of September 3, 1982, which would have added hydroquinone as a 
GRASE skin bleaching agent (part 358 (21 CFR part 358)), is withdrawn 
(see DATES).
    If this proposal becomes a final rule, FDA advises that the 
conditions under which the drug products that are subject to this rule 
are not GRASE and are misbranded (nonmonograph conditions) will be 
effective 30 days after the date of publication of the final rule in 
the Federal Register. On or after that date, no OTC drug product that 
is subject to the rule may be initially introduced or initially 
delivered for introduction into interstate commerce unless it is the 
subject of an approved application. Further, any OTC drug product 
subject to the final rule that is repackaged or relabeled after the 
effective date of the final rule must be in compliance with the final 
rule regardless of the date the product was initially introduced or 
initially delivered for introduction into interstate commerce.
    The comments to the TFM were primarily labeling comments related to 
skin bleaching drug products being GRASE. Because FDA is proposing in 
this current notice that there are no GRASE skin bleaching drug 
products, discussion of the submitted comments is unnecessary at this 
time. Instead, FDA is only discussing the new data that are the basis 
for the current proposal.

II. New Data

    A significant amount of research has been conducted on the skin 
bleaching ingredient hydroquinone, and a number of reports have 
appeared in the literature since publication of the TFM in 1982. As a 
result, FDA has evaluated significant additional new data on the safety 
of hydroquinone. Toxicology and carcinogenesis studies on orally 
administered hydroquinone conducted under the support of the National 
Toxicology Program (NTP) (Refs. 1 and 2) have indicated ``some 
evidence'' of carcinogenicity in male and female rats and in female 
mice. FDA's Center for Drug Evaluation and Research (CDER) 
Carcinogenicity Assessment Committee (CAC) has evaluated the design, 
results, and NTP interpretation of these studies, and concurs with the 
NTP's assessment. The CAC determined that additional safety studies are 
needed and, to date, those studies have not been submitted to FDA. 
Based on the evidence of carcinogenicity in animals, FDA cannot rule 
out the potential carcinogenic risk from topically applied hydroquinone 
in humans. In addition, hydroquinone has been shown to cause 
disfiguring effects (ochronosis) after use of concentrations as low as 
1 to 2-percent.

A. Fertility Studies

    The Environmental Protection Agency (EPA) has been evaluating the 
safety of hydroquinone since 1979. In the Federal Register of December 
7, 1979 (44 FR 70664), the Interagency Testing Committee (ITC), in its 
Fifth Report,

[[Page 51148]]

designated hydroquinone for priority consideration. The ITC recommended 
that hydroquinone be considered for testing for carcinogenicity and 
teratogenicity, and that epidemiology, human metabolism, and 
environmental fate studies also be considered. Under section 4(a) of 
the Toxic Substances Control Act (15 U.S.C. 2603), EPA published two 
notices for manufacturers and processors of hydroquinone to perform 
studies to evaluate hydroquinone's: (1) Toxicokinetics and (2) 
potential nervous system, reproductive, and teratogenic effects. EPA 
did not propose oncogenicity testing of hydroquinone because the NTP 
was conducting a 2-year bioassay on hydroquinone. EPA's proposal was 
published in the Federal Register of January 4, 1984 (49 FR 438), and 
its final rule for hydroquinone testing requirements was published in 
the Federal Register of December 30, 1985 (50 FR 53145).
    EPA stated in its final rule (50 FR 53145 at 53148) (references 
omitted): ``Developmental toxicity and reproductive effects. At oral 
doses of 50 mg/kg/day [milligram/kilogram/day] and higher, Racz 
reported that hydroquinone prolonged the diestrus period of the sexual 
cycle in female albino rats. Skalka, subcutaneously injecting male rats 
at a dose of 100 mg/kg/day for 51 days, reported decreased weights in 
testes, epididymides, seminal vesicles and adrenal glands; histological 
changes in testes indicating disrupted spermiogenesis; and diminished 
DNA content of sperm heads. * * *''
    EPA provided FDA copies of several studies (Refs. 1 through 9) that 
had been submitted to EPA by the Chemical Manufacturers Association 
(CMA). These studies addressed the evaluation guidelines outlined in 
EPA's final rule for hydroquinone testing requirements. The data 
included the 2-year bioassay study of hydroquinone that was conducted 
by NTP. FDA has evaluated the data on hydroquinone provided by EPA, 
along with other new data submitted to FDA and found the following:
    In a study by Salzgeber (Ref. 3), hydroquinone was shown to inhibit 
the normal growth of ovaries from 10-day chick embryos cultured in 
vitro. Seven of the 15 ovaries were abnormal when examined 
histologically. The cortex was partially or totally inhibited. Only a 
medullary region remained, and it was poorly differentiated.
    Hydroquinone increased the resorption (pregnant rats reabsorbing 
their fetus as a marker for unsuccessful pregnancy) rate when given in 
the diet to pregnant rats (Ref. 4). One hundred percent of all 
hydroquinone-treated litters had resorptions, compared with 40.8 
percent for control litters; 26.8 percent of implantations resulted in 
resorptions in treated animals compared with 10.6 percent in control 
rats. In a developmental toxicity study submitted by CMA (Ref. 5), 
hydroquinone given orally at doses of 30, 100, and 300 milligrams (mg)/
kilograms (kg) to pregnant rats did not produce embryotoxic, fetotoxic, 
or teratogenic effects. Measurement of resorption rate was not reported 
in the study. Maternal toxicity was observed in the form of a slight, 
but statistically significant, reduction in maternal body weight gain 
and feed consumption in rats receiving the high dose (300 mg/kg).
    In a similar protocol, the embryotoxic, fetotoxic, and teratogenic 
potential of hydroquinone was evaluated in pregnant rabbits (Ref. 6). 
Hydroquinone was dissolved in degassed distilled water and administered 
by gastric intubation. A dose level of 25 mg/kg/day was without 
maternal toxic effects and was not considered to be embryotoxic, 
fetotoxic, or teratogenic. In the mid-dose group (75 mg/kg/day), the 
only maternal toxic effect seen was a statistically significant 
reduction (when compared to controls) in food consumption on days 11 
and 12 of gestation. In the high dose group (150 mg/kg/day), maternal 
toxicity was evident from the following statistically significant 
differences from the control data:
     Lower weights for days 16 and 18 of gestation
     Greater magnitude of weight loss over the treatment 
interval for days 6 to 18 of gestation
     Reduced food consumption for days 6 to 14 and 17 of 
gestation.
    An increase in incidence of fetuses with external, visceral, and 
skeletal malformations was seen in the high dose group, and the 
incidence of litters containing affected fetuses was also increased. 
These incidences did not differ statistically from the controls, and 
malformations seen were considered to be associated with the maternal 
toxicity evident at the same dose level.
    A reproduction study in rats was designed to assess the long-term 
effects of hydroquinone administered daily in an aqueous solution via 
gastric intubation at dose levels of 15, 50, and 150 mg/kg/day through 
two consecutive generations of rats (Ref. 7). The results showed that 
hydroquinone did not adversely affect the following:
     Maternal body weights (gestation/lactation periods)
     Gestational feed consumption
     Reproductive performance
     Fertility of parental animals
     Body weight or feed consumption during pre-mating 
treatment periods.
    No adverse effects of treatment were evident during either 
generation on pup body weight, pup sex distribution, or pup survival to 
weaning, including doses of hydroquinone as high as 150 mg/kg/day.
    Because some studies showed fertility was impaired and others did 
not, FDA cannot make a final determination on hydroquinone's potential 
to impair fertility related to decreased spermatogenesis or prolonged 
reproductive cycle in animals or humans. Additional studies are needed 
to make a better assessment.

B. Toxicokinetic Studies

    Toxicokinetic studies with hydroquinone were conducted in rats 
following oral gavage and dermal administration (Ref. 8). Elimination 
(87 to 92-percent) of a single oral dose of hydroquinone occurred 
primarily within the first 8 hours after dosing. Using the cumulative 
48 to 72 hour urine recovery data, dermal absorption was estimated to 
be 10.5 to 11.5 percent. All groups had similar chemical profiles 
following oral and dermal administration of hydroquinone.
    Hydroquinone (2-percent) in an alcoholic vehicle was found to 
penetrate readily in human forehead skin following a single topical 
exposure in vivo for a 24-hour duration (Ref. 9). The average 
percutaneous absorption of hydroquinone was 57 percent. The addition of 
azone (a penetration enhancer) increased the absorption to 66 percent. 
Addition of Escalol 507 (a sunscreen), with and without azone, 
decreased the absorption of hydroquinone (35 and 26 percent, 
respectively).

C. Carcinogenicity Studies

    The NTP 2-year bioassay studies (Refs. 1 and 2) were conducted by 
administering 0, 25, or 50 mg/kg hydroquinone in deionized water by 
gavage to groups of 65 Fischer 344/N rats of each sex, 5 days per week. 
Groups of 65 B6C3F1 mice of each sex were administered 0, 50, or 100 
mg/kg on the same schedule. Nearly all male rats and most female rats 
in all vehicle control and dosed groups had nephropathy. The severity 
of this disease was greater in the high dose male rat group. 
Hyperplasia of the renal pelvic transitional epithelium and renal 
cortical cysts, changes which are observed with advanced renal disease, 
were increased in male rats. Renal tubular hyperplasia was seen in 2/55 
high dose male rats, and renal tubular

[[Page 51149]]

adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none 
were seen in the vehicle controls.
    Mononuclear cell leukemia in female rats occurred with a dose-
related trend and the incidences in the dosed groups were greater than 
in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high 
dose, 22/55; p <  0.05). The historical incidence of leukemia in water 
gavage vehicle control female F344/N rats is 25  15 percent 
and in untreated controls is 19  7 percent.
    Compound-related lesions observed in the liver of male mice given 
0, 50, and 100 mg/kg hydroquinone included anisokaryosis (0/55, 2/54, 
12/55)\1\, syncytial alteration (5/55, 3/54, 25/55), and basophilic 
foci (2/55, 5/54, 11/55). The incidences of hepatocellular adenomas 
were increased in dosed male mice (9/55, 21/54, 20/55), but the 
increases were offset by decreases in the incidences of hepatocellular 
carcinomas (13/55, 11/54, 7/55). The incidences of hepatocellular 
neoplasms, primarily adenomas, were increased in dosed female mice (3/
55, 16/55, 13/55).
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    \1\ Numbers reported for the vehicle control, low dose, and high 
dose groups, respectively.
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    Follicular cell hyperplasia of the thyroid gland was increased in 
dosed mice (male: 5/55, 15/53, 19/54; female: 13/55, 47/55, 45/55). 
Follicular cell adenomas were seen in male mice (2/55, 1/53, and 2/54) 
and female mice (3/55, 5/55, and 6/55). A follicular cell carcinoma was 
seen in a seventh high dose female mouse. The highest observed 
incidence of follicular cell adenomas or carcinomas (combined) in 
historical water gavage vehicle control female B6C3F1 mice is 3/48 (6 
percent).
    In conclusion, these studies showed ``some evidence'' of 
carcinogenic activity of hydroquinone as follows:
     Male F344/N rats: Marked increases in tubular cell 
adenomas of the kidney
     Female F344/N rats: Increases in mononuclear cell leukemia
     Female B6C3F1 mice: Increases in hepatocellular neoplasms, 
mainly adenomas
     Female and male B6C3F1 mice: Thyroid follicular cell 
hyperplasia
     Male B6C3F1 mice: Anisokaryosis, multinucleated 
hepatocytes, and basophilic foci of the liver.
    NTP interprets the findings of each bioassay with regard to the 
strength of the experimental evidence. NTP defines ``some evidence'' of 
carcinogenicity as demonstrated by studies that are interpreted as 
showing a chemically related increased incidence of neoplasms 
(malignant, benign, or combined) in which the strength of the response 
is less than that required for clear evidence. ``Clear evidence'' of 
carcinogenicity is considered demonstrated by studies that are 
interpreted as showing one of the following:
     A dose-related increase of malignant neoplasms
     An increase of a combination of malignant and benign 
neoplasms
     A marked increase of benign neoplasms if there is an 
indication from this or other studies of the ability of such tumors to 
progress to malignancy.
    NTP's conclusion for these studies is that there was ``some 
evidence'' of carcinogenic activity in male and female rats and in 
female mice.
    On February 11, 1992, the Nonprescription Drug Manufacturers 
Association (NDMA) requested to meet with FDA to discuss the safety of 
hydroquinone, specifics of the NTP study, and its research plans 
related to that study (Ref. 10). That meeting was held on May 20, 1992 
(Ref. 11). NDMA presented a research program to further evaluate 
hydroquinone's carcinogenic potential based on the oral bioassay 
studies NTP performed. NDMA also discussed projected timelines for 
completing the proposed safety studies of hydroquinone. FDA also 
received additional data (Refs. 12 and 13) from NDMA, containing 
updates on chronic health effects testing for hydroquinone. These 
updates provided results of completed studies, including preliminary 
results for ongoing studies, and an outline of studies in the planning 
phase. FDA evaluated the studies and concluded that the available data 
are insufficient to rule out the potential carcinogenic risk from 
topically applied hydroquinone.
    On July 10, 1996 (Ref. 14), FDA and NDMA met to discuss the safety 
of hydroquinone as an active ingredient in OTC skin bleaching drug 
products. Safety discussion points included the following:
     Mechanism of action of hydroquinone in tumor formation,
     Two year gavage study of hydroquinone in rats,
     Genotoxicity test results, and
     In vitro percutaneous absorption of hydroquinone through 
human skin.
    FDA and NDMA agreed to present the data concerning the safety of 
hydroquinone with respect to an oral carcinogenicity study to FDA's 
CDER CAC. Subsequently, on December 4, 1996 (Ref. 15), information from 
the July 10, 1996, meeting and the 1989 NTP draft technical report were 
discussed at a CAC meeting. A majority of the CAC members agreed that 
the available data are insufficient to rule out the potential 
carcinogenic risk from topically applied hydroquinone and recommended 
that additional studies be performed to assess the safety of skin 
bleaching drug products containing 2-percent hydroquinone. The CAC 
indicated that a dermal carcinogenicity study, conducted in an 
appropriate model with functioning mellanocytes, must be performed on 
hydroquinone to assess both its topical and systemic tumorgenicity. In 
a December 7, 1998, letter (Ref. 16), FDA informed NDMA of our findings 
on its previous data submissions and the CAC recommendations. FDA also 
requested NDMA to provide an implementation schedule, which should 
include the timeframe for protocol development, protocol submission, 
study initiation and completion, and analysis of data. In an April 13, 
1999, letter (Ref. 17), the Consumer Healthcare Products Association 
(CHPA; formerly NDMA) provided the following projected dates for 
additional safety studies of hydroquinone:
     May 1999--submit draft protocols for FDA review
     August 1999--initiate 4-week range-finding study
     November 1999--submit revised 2-year study protocol to FDA
     January 2000--initiate the 2-year study
     January 2002--conduct terminal sacrifice and necropsy
Since April 13, 1999, CHPA has not provided any additional information.

D. Occurrence of Exogenous Ochronosis

    Ochronosis refers to the deposition of polymerized homogentisic 
acid (HGA; 2,5-dihydroxyphenylacetic acid) as a grossly blue-black 
pigment in all collagen-containing structures. Ochronosis is 
classically associated with the autosomal recessively inherited 
metabolic disorder, alkaptonuria, in which the hepatic and renal enzyme 
HGA oxidase is absent (Refs. 18 and 19). Exogenous (acquired) 
ochronosis is a condition involving the deposition of blue-black 
pigment in the skin and is associated with the topical application of 
various chemicals. In severe cases, ochronosis may cause disfiguring 
and irreversible effects. FDA is aware that the occurrence of 
ochronosis has been reported following the topical application of 
hydroquinone.
    Studies have shown that exogenous ochronosis caused by short- or 
long-term use of high or low concentrations of hydroquinone-containing 
bleaching creams has been well described in African blacks (Refs. 20 
through 28). In 1975, Findlay, Morrison, and Simson (Ref. 20) first 
reported the development of exogenous ochronosis and pigmented

[[Page 51150]]

colloid milium on the faces of black women in South Africa caused by 
prolonged use of skin bleaching creams containing hydroquinone (5 
percent or greater). These lesions usually appeared after about 3 years 
of using the bleaching creams. The Panel reviewed this study and 
concluded that prolonged use of high concentrations (5 percent or more) 
of hydroquinone with exposure to sun may produce disfiguring effects 
(43 FR 51546 at 51549). Findlay and Beers (Ref. 21) found that up to 30 
percent of outpatients in a dermatology clinic in South Africa wanted 
treatment of ochronosis following the use of skin lightening 
preparations containing hydroquinone for 3 years on average.
    Phillips et al. (Ref. 22) reported 395 of 5,128 black patients who 
had used skin lightening products had ochronosis. The ochronosis was 
categorized as mild (darkening and thickening of the skin), moderate 
(large black bumps), or severe (larger intensively black caviar-like 
bumps).
    According to Hardwick et al. (Ref. 23), in 1983 South Africa passed 
legislation that limited the concentration of hydroquinone in OTC skin 
lightening products to 2-percent in response to the severity of 
exogenous ochronosis in its black population. In addition, all skin 
lightening products had to contain a sunscreen with a minimum Sun 
Protection Factor of 5. In 1986, Hardwick et al. conducted a survey of 
adult South African blacks (both sexes) to investigate the relationship 
between exogenous ochronosis and the use of skin lightening products 
containing hydroquinone. Of 12 individuals who had begun using skin 
lightening products after 1983, seven (58 percent) had developed 
exogenous ochronosis.
    Olumide, Odunowo, and Odiase (Ref. 24) discussed the common causes 
of facial hyperpigmentation in the black African population. One of the 
causes discussed was hydroquinone-induced exogenous ochronosis from 
bleaching creams containing hydroquinone. The physical signs included 
darkening and thickening of the skin, yellow-to-brown dome-shaped tiny 
bumps, and grayish-brown spots. Jordaan and Mulligan (Ref. 25) 
presented a case of a 39-year-old black South African woman with skin 
lesions on her face and neck. She had been using a skin bleaching cream 
containing an unknown concentration of hydroquinone for many years. 
Physical examination showed severe ochronosis on the cheeks, forehead, 
and neck. Weiss, de Fabbro, and Kolisang (Ref. 26) conducted a survey 
on black South African women, ages 16 to 40 years, to determine the 
prevalence of exogenous ochronosis caused by skin lightening products 
containing hydroquinone. Of 65 women who had used skin lightening 
products after 1983, 42 (65 percent) had developed exogenous 
ochronosis.
    Levin and Maibach (Ref. 27) presented some reasoning for the high 
prevalence of exogenous ochronosis among South African blacks. The high 
concentrations of hydroquinone used in South Africa skin-lightening 
products prior to 1984 were linked with increased incidence of 
exogenous ochronosis. Since the South African Government mandated a 
limit of 2-percent hydroquinone in skin bleaching creams in 1983, 
exogenous ochronosis still continues to occur and appears to be on the 
increase. Causes may be due to several factors in addition to 
hydroquinone. There was a marketed growth for use of an antiacne 
product containing resorcinol, also known as an ochronotic agent. 
Hydroquinone and resorcinol are often used together for a more rapid 
skin lightening agent. The predominant formulation for skin bleaching 
in South Africa includes hydroquinone and hydroalcoholic acid, which 
may contribute to the high incidence of exogenous ochronosis.
    Mahe et al. (Ref. 28) conducted a questionnaire study on cosmetic 
use of bleaching creams on 368 dark-skinned women from sub-Saharan 
Africa who were patients at the dermatological center in Senegal. Also 
in a separate study, Mahe et al. recorded information on 425 women who 
actually used bleaching creams on a regular basis. Of the 368 women 
questioned, 194 (52.7 percent) were current users of bleaching 
products. Of the 425 users enrolled, 92-percent used products on the 
body. The active ingredients used included hydroquinone (89 percent of 
users), glucocorticoids (70 percent), mercury iodide (10 percent), 
caustic agents (17 percent), and products of unknown composition (13-
percent). Complete skin examination of women using skin bleaching 
products revealed 14 cases of exogenous ochronosis.
    Exogenous ochronosis was not extensively reported in the United 
States or the United Kingdom as a result of using OTC skin bleaching 
drug products containing 2-percent hydroquinone until after publication 
of the TFM for these drug products in 1982. In 1983, Cullison, Abele, 
and O'Quinn reported blue-black darkening of the face of a 50-year-old 
black woman (Ref. 18). This condition started on the right cheek and 
soon thereafter involved the entire face. For over 2 years, the woman 
had used a proprietary bleaching cream containing 2-percent 
hydroquinone to ``brighten'' her complexion. When the darkening of the 
skin began to appear, the woman increased the application of the 
bleaching cream from twice a day to five or six times a day. Physical 
examination revealed a sooty blue-black darkening of the face without 
involvement of the eyes or ears. The darkening of the skin was 
relatively uniform, with some spots on the upper cheeks and the skin 
creases of the cheeks and forehead. A 2-millimeter (mm) biopsy specimen 
was taken and stained. The biopsy demonstrated a yellow-brown pigment 
present within mixed and swollen collagen bundles in the upper skin 
layer. These findings were interpreted as ochronosis.
    Hoshaw, Zimmerman, and Menter (Ref. 29) described two black 
American women who had ochronosis-like pigmentation and colloid milium 
formation following the topical use of a 2-percent hydroquinone 
bleaching cream. The first black woman was a 75-year-old who had a 10-
year history of pigmentation of the cheeks and nose in association with 
minimal itching. For the previous 2 years, she had used a 2-percent 
hydroquinone skin bleaching product to treat the pigmented areas. 
Physical examination disclosed multiple pigmented papules situated 
predominantly on the cheeks and extending around the lateral area of 
the eyes onto the forehead. There was an associated melasma-type 
macular pigmentation. The woman's condition was relatively unchanged 1 
year later.
    The second black woman was a 49-year-old who had a 2-year history 
of dark blotches on the face. During the previous 3-months, she had 
used a variety of 2-percent hydroquinone skin bleaching products to 
lighten her skin color. Instead of lightening, she noticed progressive 
darkening of the treated areas. Physical examination disclosed sharply 
separated areas of blue-black darkening of the skin over the cheeks, 
nose, and chin. The pigment was located essentially in discrete spots 
of less than 0.5 mm in size. In both cases, histological examination of 
a biopsy was consistent with ochronosis.
    Tidman, Horton, and MacDonald (Ref. 30) reported a case of a 45-
year-old Nigerian woman, resident in the United Kingdom for 7 years, 
who had a 7-month history of localized darkening of the face. This 
condition had been transiently preceded by erythema. Over a period of 
10 years, the woman had intermittently applied to her face a 
proprietary depigmenting cream which contained 2-percent hydroquinone. 
Physical examination revealed a pronounced symmetrical darkening of the 
skin involving the cheek regions and, to a lesser extent, the nose and

[[Page 51151]]

chin. There was no evidence of spontaneous resolution after 11 months.
    Conner and Braunstein (Ref. 31) reported a case of a 72-year-old 
black woman with a 1-month history of progressive darkening of her 
face. Since childhood, the woman had been applying a bleaching cream 
containing hydroquinone to her face in an attempt to lighten her 
complexion. Physical examination revealed blue-black spots along with 
patches on the forehead, cheek, and temporal regions. A biopsy specimen 
from the darkened skin led to a diagnosis of exogenous ochronosis.
    Lawrence, et al. (Ref. 32) described two middle aged black women 
who reported unusual darkening of the face after using bleaching creams 
containing hydroquinone. One woman (62 years old) had applied a 1-
percent hydroquinone bleaching cream for 2 to 3 years to the cheek area 
for mild darkening of the skin. The woman noted mild lightening of her 
skin during the first few months of use. After extended use, she 
noticed the return of the pigmentation, followed by diffuse darkening 
of the skin that was limited to the areas treated with the cream. 
Physical examination revealed dark spots across her cheeks.
    The second woman (45 years old) had darkening of the skin on her 
face of 2 months' duration. The woman had used a 1-percent hydroquinone 
cream to lighten several post inflammatory lesions. After some initial 
lightening, she noted progressive darkening of the skin. Physical 
examination revealed a dark spot eruption extending over the bridge of 
her nose, the cheek, the eye areas, and across the forehead. The 
histopathologic findings of a biopsy specimen were consistent with 
ochronosis.
    Howard and Furner (Ref. 33) presented a case of a 36-year-old 
Mexican-American woman with symptoms of darkening of the skin on her 
face after she used an OTC skin bleaching cream containing 2-percent 
hydroquinone for 4 months. Physical examination of the woman's face 
showed even blue-black, dark spots on her cheeks, chin, and forehead, 
as well as several dark spots on her gum line and inner cheek area. A 
biopsy specimen was consistent with exogenous ochronosis.
    Diven, et al. (Ref. 34) reported a case of a 53-year-old black 
woman who noticed a progressive darkening of her face after applying a 
``skin whitener cream'' and a cream containing 2-percent hydroquinone 
for a 2 to 3 month duration. Examination showed sooty blue-black spots 
and patches, which were prominent around the eye and cheek areas. A 
biopsy specimen from the pigmented area showed the yellow-brown 
deposits in the skin characteristic of exogenous ochronosis.
    Jordaan and Van Niekerk (Ref. 35) reported two cases of severe 
ochronosis with superimposed papilar lesions after long-term 
application of skin lightening creams containing hydroquinone. The 
first case (a 56-year-old black man) had been using 6.5 to 7.5 percent 
hydroquinone periodically for many years. The second case (a 39-year-
old black woman) had been using a skin lightening cream containing an 
unknown concentration of hydroquinone for 5 years. The woman had severe 
papular ochronosis on her face, forehead, and neck.
    Martin, et al. (Ref. 36) reported two cases of exogenous ochronosis 
secondary to the topical use of hydroquinone containing bleaching 
creams. The first case (a 44-year-old woman) noticed progressive 
darkening of her skin for 3 years while using OTC bleaching creams. She 
had a grayish-black pigmentation localized to her cheeks, forehead, and 
the bridge of her nose, which corresponded to tiny grayish-black bumps. 
The second case (a 56-year-old black woman) had a history of facial 
pigmentation for 30 years while using many OTC skin bleaching creams. 
She had round dark spots localized to both temples and a purplish-black 
spot on the left lower eye area.
    Snider and Thiers (Ref. 37) reported a case of exogenous ochronosis 
in a 59-year-old black woman who had a 5-year history of progressive 
darkening of the skin around her eyes. She had been using 2-percent 
hydroquinone skin bleaching cream once daily for many years. About 9 
months before examination she had used 3-percent hydroquinone twice 
daily for 3 months, then 4-percent hydroquinone twice daily for 3 
months, and then 4-percent hydroquinone with a sunscreen twice daily 
for 3 months. Examination showed numerous pinpoint blue-black spots 
around the eye area. A biopsy specimen revealed multiple scattered, 
elongated, curved, and oval deposits of ochronotic pigment within the 
collagen bundles.
    Camarasa and Serra-Baldrich (Ref. 38) reported a case of a 45-year-
old woman who had a 9-month history of darkening of the cheeks and eye 
area from using a skin lightening cream containing 2-percent 
hydroquinone. She was patch tested with a standard series, cosmetics, 
vehicles, and hydroquinone. The results showed this woman's reaction 
was consistent with the diagnosis of exogenous ochronosis.
    Bowman and Lesher (Ref. 39) reported a 75-year-old black woman with 
numerous discrete, 2- to 3-mm, firm, yellowish bumps on her forehead, 
cheeks, and chin; many had surrounding areas of dark spots. She was 
diagnosed with a case of primary multiple miliary osteoma cutis (MMOC), 
a rare disorder characterized by the appearance of numerous bony 
nodules on the face. She had used OTC topical acne medications and 
bleaching creams for 3 years in an attempt to treat the disorder. 
Several biopsies showed collections of homogenous yellow-brown pigment 
in the upper dermis, which also led to the diagnosis of exogenous 
ochronosis.

III. FDA's Tentative Conclusions on Skin Bleaching Drug Products

    A significant amount of research has been conducted on the skin 
bleaching ingredient hydroquinone, and a number of reports have 
appeared in the literature since publication of the TFM in 1982. As a 
result, FDA evaluated significant additional new data on the safety of 
hydroquinone. Although we cannot make a final determination on 
hydroquinone's potential to impair fertility, toxicology and 
carcinogenesis studies on orally administered hydroquinone conducted 
under the support of NTP (Refs. 1 and 2) have indicated ``some 
evidence'' of carcinogenicity in male and female rats and in female 
mice after gavage administration. ``Some evidence'' of carcinogenic 
activity is defined as studies that are interpreted as showing a 
chemically related increased incidence of neoplasms (malignant, benign, 
or combined) in which the strength of the response is less than that 
required for ``clear evidence'' (e.g., same finding in two of the four 
sex/species groups, extensive malignancy, etc.). In these studies:
     Male rats had increased renal tubular cell adenomas 
without associated increases in nonneoplastic findings or bladder 
lesions;
     Female rats had increased mononuclear cell leukemia; and
     Female mice had increased hepatocellular neoplasms, mainly 
adenoma.
    FDA's CDER CAC has evaluated the design, results, and NTP 
interpretation of these studies, and concurs with the NTP assessment. 
The CAC recommended additional studies, which have not been submitted 
to date. The evidence of carcinogenicity in animals in combination with 
the high absorption rate (57 percent) of hydroquinone demonstrated in 
humans does not allow FDA to rule out the potential carcinogenic risk 
from topically applied hydroquinone in humans. Further,

[[Page 51152]]

hydroquinone has been shown to cause disfiguring effects (ochronosis) 
after use of high concentrations (5 percent or greater) and at 
concentrations as low as 1 to 2-percent.
    Skin bleaching products are drugs under section 201(g)(1)(C) of the 
act if they are intended to affect the structure or function of the 
body (e.g., products intended to suppress melanin pigment formation 
within skin cells). In evaluating the suitability of such drug products 
for OTC use, FDA considers, among other factors, the benefit-to-risk 
ratio of the drug. For OTC skin bleaching drug products, FDA 
tentatively concludes that there is no benefit to physical health that 
would justify the continued marketing of these products. Because the 
choice to use a drug is not considered an inadvertent exposure, risks 
may be outweighed by benefits, where they exist. Where the benefit 
appears low and use of the drug is proposed for an otherwise healthy 
target population, the risks should be minimal. For these OTC drug 
products, the sole intended benefit would be to improve the user's 
appearance by bleaching the skin.
    The actual risk to humans from the use of hydroquinone has yet to 
be fully determined. There is, however, evidence of carcinogenicity 
related to hydroquinone in animals and disfiguring effects (ochronosis) 
in humans. Under these circumstances, the use of hydroquinone as an 
active ingredient in OTC skin bleaching drug products cannot be 
justified. Therefore, in light of the new data discussed in this 
document, FDA has reassessed the position stated in the 1982 TFM (47 FR 
39108).
    FDA now proposes that skin bleaching drug products should not be 
available OTC. FDA finds that because of the carcinogenic and 
ochronotic potential of hydroquinone, its use in skin bleaching drug 
products should be restricted to prescription use only, and users of 
such products should be closely monitored under medical supervision. 
FDA now tentatively concludes that skin bleaching drug products, 
including but not limited to those that contain hydroquinone, which 
have been reviewed by the Panel and FDA should be considered not GRASE. 
Accordingly, the proposed monograph (TFM) published in the Federal 
Register of September 3, 1982, which proposed 21 CFR part 358, subpart 
A (Skin Bleaching Drug Products for Over-The-Counter Human Use), is 
hereby withdrawn.
    FDA emphasizes that this withdrawal does not in any way denigrate 
the scientific content of the Panel's report on these products or 
negate the excellent work of the Panel in its long efforts to produce 
it. FDA recognizes that OTC skin bleaching drug products constitute a 
very small segment of the marketplace and that withdrawal of the 
proposed monograph does not affect FDA's authority to take action 
against OTC skin bleaching drug products that are unsafe and 
misbranded.
    The only other skin bleaching active ingredient evaluated in this 
rulemaking was ammoniated mercury, which FDA declared to be not GRASE 
in the Federal Register of November 7, 1990 (55 FR 46914 at 46919). FDA 
now proposes that all skin bleaching drug products be considered new 
drugs within the meaning of section 201(p) of the act (21 U.S.C. 
321(p)), for which approved NDAs under section 505 of the act (21 
U.S.C. 355) and part 314 of the regulations (21 CFR part 314) are 
required for marketing. In the absence of an approved NDA, such a 
product would also be misbranded under section 502 of the act (21 
U.S.C. 352). This proposal applies only to drugs marketed OTC, and it 
would amend Sec.  310.545, which applies only to OTC drugs. However, 
FDA emphasizes that it regards all skin bleaching drug products, 
whether marketed on a prescription or OTC basis, to be new drugs. This 
does not preclude other OTC drugs from being considered for the OTC 
drug monograph on skin bleaching drug products (e.g., under the 
procedures in 21 CFR 330.14).

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule may have a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement and economic 
analysis before proposing ``any rule that includes any Federal mandate 
that may result in the expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.''
    FDA concludes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
The proposed rule is not a significant regulatory action as defined by 
the Executive order and so is not subject to review under the Executive 
order. The Unfunded Mandates Reform Act does not require FDA to prepare 
a statement of costs and benefits for this proposed rule, because the 
proposed rule is not expected to result in any 1-year expenditure that 
would exceed $100 million adjusted for inflation. The current threshold 
after adjustment for inflation is $115 million, using the most current 
(2003) Implicit Price Deflator for the Gross Domestic Product.
    The purpose of this proposed rule is to establish that OTC skin 
bleaching drug products are not GRASE and are misbranded. Most skin 
bleaching drug products that contain hydroquinone as an active 
ingredient are currently marketed as OTC drug products. Some such 
products (usually those containing above 2-percent hydroquinone) are 
marketed by prescription. FDA's Drug Listing System identifies 
approximately 200 products containing hydroquinone in strengths from 
0.4 to 5.0 percent (Table 1).

   Table 1.--Number of Skin Bleaching Drug Products Containing Various
          Concentrations of the Active Ingredient Hydroquinone
------------------------------------------------------------------------
        Percent Hydroquinone                  Number of Products
------------------------------------------------------------------------
5                                     2
------------------------------------------------------------------------
4                                     65
------------------------------------------------------------------------
3                                     8
------------------------------------------------------------------------
2                                     110
------------------------------------------------------------------------
< 2                                    21
------------------------------------------------------------------------

    About two-thirds of these products appear to be marketed as OTC 
drugs. These products are marketed by approximately 65 different 
manufacturers, most of which are considered to be small entities, using 
the U.S. Small Business Administration designations for this industry 
(750 employees). FDA believes that any other unidentified manufacturer 
of these products is also likely to be a small entity.

[[Page 51153]]

    FDA tentatively concludes that the benefits of OTC skin bleaching 
drug products are insignificant when compared to the potential risks 
and that this proposed rule would benefit society because it would 
eliminate a potentially unsafe drug product. The proposed rule would 
prohibit the continued marketing of hydroquinone as an OTC drug product 
and require a NDA under 21 CFR part 314 for marketing.
    FDA acknowledges that this proposed rule would have an impact on 
consumers who use OTC skin bleaching drug products containing 
hydroquinone to lighten limited areas of hyperpigmented skin. They will 
no longer be able to purchase these OTC drug products after current 
inventories are depleted.
    The benefit of removing OTC skin bleaching drug products from the 
market will be a reduction in the number of cases of ochronosis that 
would otherwise occur each year. However, FDA has limited information 
to assign a monetary value to the prevention and treatment of 
ochronosis and the direct medical costs and indirect costs, such as 
psychological suffering, resulting from disfigurement due to 
ochronosis.
    The 65 manufacturers of these products will incur the majority of 
the costs of this proposed rule, in the form of lost sales. They would 
also incur the costs of obtaining an approved NDA if they wished to 
continue to market their product(s) by prescription. Manufacturers who 
have followed the FDA-NDMA (CHPA) dialogue on these hydroquinone drug 
products should have known for some time that if additional adequate 
data were not provided to support safety, a nonmonograph status for 
these products would occur. Thus, this economic analysis, together with 
other relevant sections of this document, serves as FDA's initial 
regulatory flexibility analysis, as required under the Regulatory 
Flexibility Act.

V. Paperwork Reduction Act of 1995

    This proposed rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 is not required.

VI. Environmental Impact

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

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized as proposed, would have a preemptive 
effect on State law. Section 4(a) of the Executive order requires 
agencies to ``construe * * * a Federal statute to preempt State law 
only where the statute contains an express preemption provision or 
there is some other clear evidence that the Congress intended 
preemption of State law, or where the exercise of State authority 
conflicts with the exercise of Federal authority under the Federal 
statute.'' Section 751 of the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 379r) is an express preemption provision. Section 
751(a) of the act (21 U.S.C. 379r(a)) provides that ``* * * no State or 
political subdivision of a State may establish or continue in effect 
any requirement-- * * * that relates to the regulation of a drug that 
is not subject to the requirements of section 503(b)(1) or 
503(f)(1)(A); and that is different from or in addition to, or that is 
otherwise not identical with, a requirement under this Act, the Poison 
Prevention Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or the Fair 
Packaging and Labeling Act (15 U.S.C. 1451 et seq.).''
    Currently, this provision operates to preempt States from imposing 
requirements related to the regulation of nonprescription drug 
products. (See Section 751(b) through (e) of the act for the scope of 
the express preemption provision, the exemption procedures, and the 
exceptions to the provision.) This proposed rule, if finalized as 
proposed, would establish that OTC skin bleaching drug products are not 
GRASE and are misbranded. Although any final rule would have a 
preemptive effect, in that it would preclude States from promulgating 
requirements related to OTC skin bleaching drug products that are 
different from or in addition to, or not otherwise identical with a 
requirement in the final rule, this preemptive effect is consistent 
with what Congress set forth in section 751 of the act. Section 751(a) 
of the act displaces both State legislative requirements and State 
common law duties. We also note that even where the express preemption 
provision is not applicable, implied preemption may arise. See Geier v. 
American Honda Co., 529 US 861 (2000).
    FDA believes that the preemptive effect of the proposed rule, if 
finalized as proposed, would be consistent with Executive Order 13132. 
Section 4(e) of the Executive order provides that ``when an agency 
proposes to act through adjudication or rulemaking to preempt State 
law, the agency shall provide all affected State and local officials 
notice and an opportunity for appropriate participation in the 
proceedings.'' FDA is providing an opportunity for State and local 
officials to comment on this rulemaking.

VIII. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document 
and on FDA's economic impact determination. Submit a single copy of 
electronic comments or two paper copies of any mailed comments, except 
that individuals may submit one paper copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document and may be accompanied by a supporting memorandum or 
brief. Received comments may be seen in the Division of Dockets 
Management (see ADDRESSES) between 9 a.m. and 4 p.m., Monday through 
Friday.

IX. Proposed Effective Date

    Because there will be no need to reformulate or relabel any of 
these products, FDA is proposing that any final rule that may issue 
based on this proposal become effective 30 days after its date of 
publication in the Federal Register.

X. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. 1978N-0065 and may be seen 
by interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Kari, F. W., ``NTP Technical Report of the Toxicology and 
Carcinogenesis Studies of Hydroquinone in F344/N Rats and B6C3F1 Mice 
(Gavage Studies),'' NTP TR366, NIH Publication No. 89-2821, 1989.
    2. Kari, F. W. et al., ``Toxicity and Carcinogenicity of 
Hydroquinone in F344/N Rats and B6C3F Mice,'' Food Chemistry 
Toxicology, 30:737-747, 1992.
    3. Salzgeber, B., ``Modifications Observed in Chick Embryo Genital 
Organs Explanted In Vitro, After Treatment With Different Teratogenic 
Substances,'' 1955, English translation included in OTC Vol. 16ATFM2.
    4. Telfold, I. R., C. S. Woodruff, and R. H. Linford, ``Fetal 
Resorption in the Rat as Influenced by Certain Antioxidants,'' American 
Journal of Anatomy, 110:29-36, 1962.

[[Page 51154]]

    5. Krasavage, W. J., ``Hydroquinone: A Developmental Toxicity Study 
in Rats,'' Eastman Kodak Co., 1985, in OTC Vol.16ATFM2.
    6. Bio/dynamics Inc., ``A Developmental Toxicity Study in Rabbits 
With Hydroquinone,'' Project No. 87-3Z20, 1989, in OTC Vol. 16ATFM2.
    7. Bio/dynamics Inc., ``A Two-Generation Reproduction Study in Rats 
With Hydroquinone,'' Project No. 87-3219, 1989, in OTC Vol. 16ATFM2.
    8. English, J. C. et al., ``Toxicokinetics Studies With 
Hydroquinone in Male and Female Fischer 344 Rats,'' Eastman Kodak Co., 
1988, in OTC Vol. 16ATFM2.
    9. Bucks, D. A. W. et al., ``Percutaneous Absorption of 
Hydroquinone in Humans: Effect of 1-Dodecylazacycloheptan-2-One (Azone) 
and the 2-Ethylhexyl Ester of 4-(Dimethylamino)Benzoic Acid (Escalol 
507),'' Journal of Toxicology and Environmental Health, 24:279-288, 
1988.
    10. Comment No. LET2.
    11. Comment No. MM1.
    12. Comment No. RPT3.
    13. Comment No. RPT5.
    14. Comment No. MM2.
    15. Comment No. MM3.
    16. Comment No. LET16.
    17. Comment No. C24.
    18. Cullison D., D. C. Abele, and J. L. O'Quinn, ``Localized 
Exogenous Ochronosis,'' Journal of The American Academy of Dermatology, 
8:882-889, 1983.
    19. Fisher, A. A., ``Exogenous Ochronosis from Hydroquinone 
Bleaching Cream,'' Cutis, 62:11-12, 1998.
    20. Findlay, G. H., J. G. L. Morrison, and I. W. Simson, 
``Exogenous Ochronosis and Pigmented Colloid Milium From Hydroquinone 
Bleaching Creams,'' British Journal of Dermatology, 93:613-622, 1975.
    21. Findlay, G. H. and H. A. De Beer, ``Chronic Hydroquinone 
Poisoning of the Skin From Skin-Lightening Cosmetics,'' South African 
Medical Journal, 57:187-190, 1980.
    22. Phillips, J. I., C. Isaacson, and H. Carman, ``Ochronosis in 
Black South Africans Who Used Skin Lighteners,'' The American Journal 
of Dermatopathology, 8:14-21, 1986.
    23. Hardwick, N. et al., ``Exogenous Ochronosis: An Epidemiological 
Study,'' British Journal of Dermatology, 120:229-238, 1989.
    24. Olumide, Y. M., B. D. Odunowo, and A. O. Odiase, ``Regional 
Dermatoses in the African. Part I. Facial Hypermelanosis,'' 
International Journal of Dermatology, 30:186-189, 1991.
    25. Jordaan, H. F. and R. P. Mulligan, ``Actinic Granuloma-Like 
Change in Exogenous Ochronosis: Case Report,'' Journal of Cutaneous 
Pathology, 17:236-240, 1990.
    26. Weiss, R. M., E. DeFabbro, and P. Kolisang, ``Cosmetic 
Ochronosis Caused by Bleaching Creams Containing 2 Percent 
Hydroquinone,'' South African Medical Journal, 77:373, 1990.
    27. Levin, C. Y. and H. Maibach, ``Exogenous Ochronosis: An Update 
on Clinical Features, Causative Agents and Treatment Options,'' 
American Journal of Clinical Dermatology, 2:213-217, 2001.
    28. Mahe, A. et al., ``Skin Diseases Associated with the Cosmetic 
Use of Bleaching Products in Women from Dakar, Senegal,'' British 
Journal of Dermatology, 148:493-500, 2003.
    29. Hoshaw, R. A., K. G. Zimmerman, and A. Menter, ``Ochronosislike 
Pigmentation From Hydroquinone Bleaching Creams in American Blacks,'' 
Archives of Dermatology, 121:105-108, 1985.
    30. Tidman, M. J., J. J. Horton, and D. M. MacDonald, 
``Hydroquinone-Induced Ochronosis--Light and Electronmicroscopic 
Features,'' Clinical and Experimental Dermatology, II:224-228, 1986.
    31. Connor, T. and B. Braunstein, ``Hyperpigmentation Following the 
Use of Bleaching Creams,'' Archives of Dermatology, 123:105, 1987.
    32. Lawrence, N. et al., ``Exogenous Ochronosis in the United 
States,'' Journal of the American Academy of Dermatology, 18:1207-1211, 
1988.
    33. Howard, K. L., and B. B. Furner, ``Exogenous Ochronosis in a 
Mexican-American Woman,'' Cutis, 45:180-182, 1990.
    34. Diven, D. G. et al., ``Hydroquinone-Induced Localized Exogenous 
Ochronosis Treated with Dermabrasion and CO2 Laser,'' 
Journal of Dermatologic Surgery and Oncology, 16:1018-1022, 1990.
    35. Jordaan, H. F. and D. J. T. Van Niekerk, ``Transepidermal 
Elimination in Exogenous Ochronosis,'' The American Journal of 
Dermatopathology, 13:418-424, 1991.
    36. Martin, R. F. et al., ``Exogenous Ochronosis,'' Puerto Rico 
Health Science Journal, 11:23-26, 1992.
    37. Snider, R. L. and B. H. Thiers, ``Exogenous Ochronosis,'' 
Journal of the American Academy of Dermatology, 28:662-664, 1993.
    38. Camarasa, J. G. and E. Serra-Baldrich, ``Exogenous Ochronosis 
with Allergic Contact Dermatitis from Hydroquinone,'' Contact 
Dermatitis, 31:57-58, 1994.
    39. Bowman, P. H. and J. L. Lesher, ``Primary Multiple Miliary 
Osteoma Cutis and Exogenous Ochronosis,'' Cutis, 68:103-106, 2001.

List of Subjects in 21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, the proposed 
rule that published on September 3, 1982 (47 FR 39108), is withdrawn 
and it is proposed that 21 CFR part 310 be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.
    2. Section 310.545 is amended by revising paragraphs (a)(17), (d) 
introductory text, and (d)(1) and by adding new paragraph (d)(41) to 
read as follows:


Sec.  310.545   Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (17) Skin bleaching drug products--(i)  Ingredient--Approved as of 
May 7, 1991.
Mercury ammoniated
    (ii) Ingredients--Approved as of [date 30 days after date of 
publication in the Federal Register].
Hydroquinone
Any other ingredient
* * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initially introduced or 
initially delivered for introduction into interstate commerce after the 
dates specified in paragraphs (d)(1) through (d)(41) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), (a)(8)(i), 
(a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), 
(a)(14) through (a)(15)(i), (a)(16), (a)(17)(i), and (a)(18)(i)(A) of 
this section.
* * * * *
    (41) [30 days after date of publication in the Federal Register], 
for products subject to paragraph (a)(17)(ii) of this section.


[[Page 51155]]


    Dated: August 7, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-14263 Filed 8-28-06; 8:45 am]

BILLING CODE 4160-01-S