[Federal Register Volume 62, Number 169 (Tuesday, September 2, 1997)]
[Proposed Rules]
[Pages 46223-46227]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-23122]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 334

[Docket No. 78N-036L]
RIN 0910-AA01


Laxative Drug Products for Over-the-Counter Human Use; Proposed 
Amendment to the Tentative Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is reopening the 
administrative record and proposing to amend the tentative final 
monograph for over-the-counter (OTC) laxative drug products to 
reclassify the stimulant laxative ingredients danthron and 
phenolphthalein from Category I (generally recognized as safe and 
effective and not misbranded) to Category II (not generally recognized 
as safe and effective or misbranded) and adding these ingredients to a 
list of nonmonograph active ingredients. FDA is issuing this proposed 
rulemaking after considering data and information on the safety of 
danthron and phenolphthalein. This proposal is part of the ongoing 
review of OTC drug products conducted by FDA.

DATES: Submit written comments by October 2, 1997. Written comments on 
the agency's economic impact determination by October 2, 1997. FDA is 
proposing that any final rule based on this proposal be effective on 
the date of its publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

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

SUPPLEMENTARY INFORMATION: 

I. Background

    In the Federal Register of March 21, 1975 (40 FR 12902), FDA 
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC 
laxative, antidiarrheal, emetic, and antiemetic drug products, together 
with the recommendations of the Advisory Review Panel on OTC Laxative, 
Antidiarrheal, Emetic, and Antiemetic Drug Products (the Panel), which 
was the advisory review panel responsible for evaluating data on the 
active ingredients in these classes. In the advance notice of proposed 
rulemaking, the Panel recommended Category I status for the OTC 
stimulant laxative ingredients aloe, bisacodyl, cascara sagrada 
preparations, danthron, phenolphthalein, and senna preparations (40 FR 
12902 at 12908 to 12910). The agency concurred with the Panel's 
Category I classification of these ingredients in the tentative final 
monograph published in the Federal Register of January 15, 1985 (50 FR 
2124 at 2152 to 2156).

II. Danthron

    Following publication of the laxative tentative final monograph in 
1985, FDA became aware of studies concerning the potential carcinogenic 
risk of danthron. In January 1987, a leading U.S. pharmaceutical 
manufacturer informed FDA that it would voluntarily cease manufacture 
and distribution of products containing danthron. The company's 
decision was partly in response to published studies in Britain and 
Japan that strongly suggested that chronic administration of high doses 
of danthron to rats and mice resulted in development of intestinal and 
liver tumors and that danthron is, therefore, a potential carcinogen in 
humans (Refs. 1 and 2). Danthron, in common with other anthraquinone 
compounds, has also been shown to exhibit a positive mutagenic effect 
in some in vitro models (Refs. 3 and 4). FDA subsequently initiated a 
recall that extended to the retail/dispensing level of all danthron-
containing drug products, by sending a recall letter to all registered 
drug firms and distributors (Ref. 5). FDA stated that ``danthron 
toxicity in humans has not been specifically demonstrated, but because 
of potential risk, FDA has requested an immediate halt to all 
manufacturing, relabeling, repackaging, and further distribution of 
human drug products containing danthron as an ingredient'' (Ref. 6). 
The agency notes that, although danthron was removed from OTC laxative 
drug products in 1987, it was not specifically included in part 310 (21 
CFR part 310) as a new drug. Therefore, in this rulemaking, the agency 
is proposing to amend Sec. 310.545 to include danthron as a 
nonmonograph ingredient.

III. New Information on Phenolphthalein

    Recently, FDA became aware of data indicating that phenolphthalein 
is a potential carcinogen in humans. Under the direction of the 
National Institute of Environmental Health Science (NIEHS) through the 
National Toxicology Program (NTP), phenolphthalein was studied for its 
carcinogenic potential in rats and mice. The National Cancer Institute 
(NCI) nominated phenolphthalein for study because of its widespread 
chronic use in OTC laxative drug products and the lack of adequate 
testing for carcinogenicity in experimental animals. The preliminary 
findings were reported in a 1995 NTP draft technical report (NTP TR 
465, NIH publication No. 95-3390), which indicated that phenolphthalein 
demonstrated evidence of carcinogenic

[[Page 46224]]

activity in rats and mice. The final version of this report was 
published in November 1996 (NTP TR 465, NIH publication No. 97-3390) 
(Ref. 7).
    In these studies, male and female F344/N rats and B6C3F1 mice were 
exposed to phenolphthalein (98 percent to 99 percent pure) in feed for 
14 days, 13 weeks, or 2 years. Genetic toxicology studies in Salmonella 
typhimurium (Ames test), cultured Chinese hamster ovary (CHO) cells, 
and mouse peripheral blood cells were also conducted. Phenolphthalein 
was not mutagenic in the Ames test and was inactive in the CHO cell 
sister chromatid exchange assay. It was, however, clastogenic in a CHO 
cell chromosomal aberration test in the presence of metabolic 
activation and in the mouse micronucleus assay.
    In the 2-year carcinogenicity studies, groups of 50 male and female 
rats were given 0, 12,000, 25,000, or 50,000 parts per million (ppm) 
phenolphthalein in feed for 2 years (equivalent to average daily doses 
of approximately 500, 1,000, or 2,000 milligrams (mg) phenolphthalein/
kilogram (kg) body weight to males and 500, 1,000, or 2,500 mg/kg to 
females). Groups of 50 male and female mice were given 0, 3,000, 6,000, 
or 12,000 ppm phenolphthalein in feed for 2 years (equivalent to 
average daily doses of approximately 300, 600, 1,200 mg 
phenolphthalein/kg body weight to males and 400, 800, 1,500 mg/kg to 
females).
    From these 2-year feeding studies, NTP concluded that there was 
clear evidence of carcinogenic activity of phenolphthalein in male rats 
based on the markedly increased incidences of benign pheochromocytoma 
of the adrenal medulla and renal tubule adenomas or adenomas and 
carcinomas. There was some evidence of carcinogenic activity of 
phenolphthalein in female rats based on the increased incidences of 
benign or benign and malignant pheochromocytoma of the adrenal medulla. 
There was clear evidence of the carcinogenic activity of 
phenolphthalein in male mice based on the increased incidences of 
histiocytic sarcoma and malignant lymphoma of thymic origin. There was 
clear evidence of carcinogenic activity of phenolphthalein in female 
mice based on the increased incidences of histiocytic sarcoma, 
malignant lymphoma of all types, lymphoma of thymic origin, and benign 
sex-cord stromal tumors of the ovary. Thus, the 1995 NTP draft 
technical report on the carcinogenicity studies of phenolphthalein 
concluded that phenolphthalein has carcinogenic activity in rodents.
    FDA held a public meeting on December 18, 1995 (Ref. 8), to discuss 
the 1995 NTP draft technical report with representatives of NTP and 
manufacturers of phenolphthalein-containing laxative drug products. 
Additional data were presented that suggested a genotoxic mechanism and 
demonstrated similar human and rodent metabolic pathways.
    Subsequently, on April 2, 1996 (Ref. 9), information from the 
December 1995 public meeting and the 1995 NTP draft technical report 
were discussed at an FDA Center for Drug Evaluation and Research (CDER) 
Carcinogenicity Assessment Committee (CAC) meeting. A majority of the 
CAC members agreed that the carcinogenicity studies as conducted 
provided a valid assessment of the carcinogenic potential of 
phenolphthalein and that the studies addressing genotoxic potential and 
comparative metabolism and exposure provided information of potential 
relevance to human risk. The CAC indicated that phenolphthalein is a 
likely genotoxin for the rodent, but adequate data were not available 
to make a clear assessment for humans. The CAC concluded that further 
evaluation of the safety of phenolphthalein should be done following 
the completion of NTP's pending studies of phenolphthalein including in 
the p53 transgenic mouse.
    In a May 10, 1996, letter (Ref. 10), FDA informed laxative 
manufacturers of the NTP findings and the CDER CAC recommendations, and 
requested more safety data for certain stimulant laxative ingredients. 
FDA indicated that additional testing for the OTC stimulant laxative 
ingredients aloe, bisacodyl, cascara sagrada ingredients, and senna 
preparations would be necessary.
    NTP recently completed additional studies on phenolphthalein (Ref. 
11) and prepared draft manuscripts of the findings for publication 
(Ref. 12). This new information and the previous findings were the 
subject of an April 30, 1997, CAC meeting (Ref. 13) (the April 30, 
1997, meeting). The studies involve five areas: Human epidemiology, in 
vivo rodent metabolism and distribution, in vitro free radical 
metabolism, in vitro cell transformation and mutagenicity in Syrian 
hamster embryo (SHE) cells, and tumorigenicity and micronucleus studies 
in p53 deficient mice.
    The CAC members voted that the p53 heterozygous mice studies 
demonstrate that phenolphthalein may be carcinogenic through a 
genotoxic mechanism. There was a clear dose-dependent increase in the 
incidence of thymic lymphoma in the p53 assay, confirming one of the 
primary tumors of concern to the CAC based on its original evaluation 
of the 2-year assay data. These tumors occurred at doses that showed no 
other signs of toxicity.
    The CAC believed that several of the assays and data support a 
genotoxic mechanism. Phenolphthalein was positive in chromosome 
aberration tests and showed chromosomal abnormality and hypoxanthine 
phosphoribosyltransferase (hprt) mutations in the SHE cell assay. 
Nontoxic doses caused cell transformation, mutations, and chromosome 
aberration. Phenolphthalein was also positive in the peripheral blood 
micronucleus assay in p53 mice. The micronucleus assay showed that even 
at the low doses (about 15 times the human exposure), the micronuclei 
response occurred with increased duration of treatment. It might be 
expected with a free radical generator, such as phenolphthalein, and 
based on the observations in mice, that it will take time, at lower 
concentrations, for lesions to occur and be detected. Thus, it appears 
that this genotoxic event may not be observed with short term 
phenolphthalein use. The p53 protein accumulation in the nucleus of 
thymic lymphoma cells of the original bioassay, coupled with the 
deletion of the wild type p53 allele in the thymic lymphomas of p53 
mice, are indicative of interaction with the p53 gene as a target site. 
In vivo, repeated exposure resulted in micronuclei in both the original 
bioassay and in p53 mice studies. The exposures used to demonstrate 
these in vivo and in vitro genotoxic effects were in the range of those 
that could occur with human laxative use.
    Based on the totality of the evidence that has been evaluated thus 
far, FDA considers use of phenolphthalein a potential risk to humans. 
These findings of rodent carcinogenicity and genotoxicity in several 
test systems indicate that chronic use could lead to damage to the 
human genome (including p53, which is known to be a tumor suppressor 
gene) and could increase the risk of malignancy. Some human cancers are 
associated with alterations in the p53 gene. Such genetic damage and 
increased risk could occur at phenolphthalein doses that are likely to 
be used by humans. Because of this concern, the agency is proposing to 
declare all drug products containing phenolphthalein to be 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)). Accordingly, products 
without a new drug application would be subject to regulatory action 
under, among others,

[[Page 46225]]

sections 502 (misbranding) and 505 (new drug) of the act (21 U.S.C. 352 
and 355). The agency also notes that there is no evidence (Ref. 14) to 
suggest that there are any adverse effects from the abrupt 
discontinuation of phenolphthalein cathartics.
    On May 13, 1997 (Ref. 15), the agency informed known manufacturers 
of phenolphthalein drug products and trade associations that the NTP 
data discussed at the April 30, 1997, meeting (Ref. 13) were available 
for public examination in FDA's Dockets Management Branch. At that 
time, the agency notified interested persons that 30 days would be 
provided for comment on the NTP data. The agency is now providing an 
additional 30 days in response to this notice.
    The NTP data and the transcript of the April 30, 1997, meeting are 
available for public examination between 9 a.m. and 4 p.m., Monday 
through Friday, in the Dockets Management Branch (address above). 
Copies of the NTP data and the transcript of the April 30, 1997, 
meeting may be requested (by mail or fax) from the Freedom of 
Information Staff (HFI-35), 5600 Fishers Lane, rm. 12A-16, Rockville, 
MD 20857, 301-443-6310 or FAX 301-443-1726. Requests should specify the 
date of the meeting, name of the committee, a description of the 
document(s) requested, and the docket number found in brackets in the 
heading of this document.

IV. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Mori, H. et al., ``Induction of Intestinal Tumors in Rats by 
Chrysazin,'' British Journal of Cancer, 52:781-783, 1985, in OTC 
Vol. 090TFM2, Docket No. 78N-036L, Dockets Management Branch.
    2. Mori, H. et al., ``Carcinogenicity of Chrysazin in Large 
Intestine and Liver in Mice,'' Japanese Journal of Cancer Research, 
77:871-876, 1986, in OTC Vol. 090TFM2, Docket No. 78N-036L, Dockets 
Management Branch.
    3. Brown, J. P., and R. J. Brown, ``Mutagenesis by 9,10-
Anthraquinone Derivatives and Related Compounds in Salmonella 
Typhimurium,'' Mutation Research, 40:203-224, 1976, in OTC Vol. 
090TFM2, Docket No. 78N-036L, Dockets Management Branch.
    4. Tikkanen, L., T. Matsushima, and S. Natori, ``Mutagenicity of 
Anthraquinones in Salmonella Typhimurium,'' Mutation Research, 
116:297-303, 1983, in OTC Vol. 090TFM2, Docket No. 78N-036L, Dockets 
Management Branch.
    5. FDA Drug Recall Letter Concerning Danthron-containing Drug 
Products, in OTC Vol. 090TFM2, Docket No. 78N-036L, Dockets 
Management Branch.
    6. FDA Press Release on Danthron Drug Products, in OTC Vol. 
090TFM2, Docket No. 78N-036L, Dockets Management Branch.
    7. ``NTP Technical Report on the Toxicology and Carcinogenesis 
Studies of Phenolphthalein in F344/N Rats and B6C3F1 Mice (Feed 
Studies),'' NTP TR 465, NIH Publication No. 97-3390, Comment No. 
RPT8, Docket No. 78N-036L, Dockets Management Branch.
    8. Comment No. MM11, Docket No. 78N-036L, Dockets Management 
Branch.
    9. Comment No. MM12, Docket No. 78N-036L, Dockets Management 
Branch.
    10. Letter from D. Bowen, FDA, to R. W. Soller, Nonprescription 
Drug Manufacturers Association, coded LET111, Docket No. 78N-036L, 
Dockets Management Branch.
    11. Comment No. RPT7, Docket No. 78N-036L, Dockets Management 
Branch.
    12. Letter from the National Institute of Environmental Health 
Sciences, to D. L. Bowen, FDA, coded LET167, Docket No. 78N-036L, 
Dockets Management Branch.
    13. Comment No. MM13, Docket No. 78N-036L, Dockets Management 
Branch.
    14. Weiss, B., and G. Wood, ``Laxative Abuse Causing 
Gastrointestinal Bleeding,'' The Journal of Family Practice, 15:177-
181, 1982.
    15. Letters from D. L. Bowen, FDA, to Nonprescription Drug 
Manufacturers Association and various manufacturers, coded LET137 
through 165, Docket No. 78N-036L, Dockets Management Branch.

V. Summary of the Agency's Changes to the Proposed Rule

    1. Based on new data and information, the agency is proposing to 
reclassify the stimulant laxative ingredients danthron and 
phenolphthalein from Category I (monograph) to Category II 
(nonmonograph).
    2. As a result of this reclassification, the agency would add 
danthron and phenolphthalein to the list of stimulant laxatives in 
Sec. 310.545(a)(12)(iv). The current list in that section is 
redesignated as Sec. 310.545(a)(12)(iv)(A) and danthron and 
phenolphthalein are being included in new Sec. 310.545(a)(12)(iv)(B).

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
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 has 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.
    Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et 
seq.) requires that agencies prepare a written statement and economic 
analysis before proposing any rule that may result in an expenditure in 
any 1 year by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million (adjusted annually for 
inflation).
    The agency believes that this proposed rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
The purpose of this proposed rule is to establish conditions under 
which the OTC stimulant laxative ingredients danthron and 
phenolphthalein are not generally recognized as safe and effective. 
Cessation of marketing of OTC laxative drug products containing 
danthron occurred in 1987. Therefore, no reformulation or relabeling 
will be necessary for this ingredient.
    Products containing phenolphthalein will need to be reformulated to 
replace the ingredient with another laxative active ingredient. There 
are a number of laxative ingredients in proposed part 334 (50 FR 2124 
at 2152) that could be used.
    The cost to reformulate a product will vary greatly depending on 
the nature of the change in formulation, the product, the process, and 
the size of the firm. Because of the large number of monograph active 
ingredients available for substitution, no manufacturer should need to 
change its dosage form; however, a manufacturer would have to redo the 
validation (product, process, new supplier), conduct stability tests, 
change master production records, and for some dosage forms, conduct 
palatability tests. The agency is aware, however, that most companies 
have either changed and are marketing reformulated products, are in the 
process of reformulating their products, or have decided to discontinue 
marketing products containing phenolphthalein.\1\ Competitive market 
forces and increased public awareness of the potential safety hazard of 
phenolphthalein would most likely lead

[[Page 46226]]

all manufacturers to move to alternative products over time.
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    \1\ The agency's drug listing data base lists 60 manufacturers 
of products containing phenolphthalein; however, this number does 
not reflect the recent changes that have taken place in the market. 
Because many manufacturers have reformulated or discontinued 
production of their phenolphthalein products, FDA believes that not 
more than 20 manufacturers still produce phenolphthalein products.
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    Manufacturers will also incur costs to relabel their products to 
reflect the new formulation. The agency obtained estimates of 
relabeling costs for the type of changes required by this rule ranging 
from $2,700 to $10,000 per standard stock keeping unit (SKU) 
(individual products, package and size) for nationally branded products 
and from $500 to $1,500 per SKU for private label products. Because of 
the large number of products that have recently been reformulated, the 
agency cannot accurately calculate the number of SKU's that will need 
to be relabeled, but estimates the number to be approximately 300. Most 
of these label changes will be for private label products.
    Finally, some manufacturers that have not reformulated and 
validated their products by the effective date of the final rule may 
incur a loss in revenue. Nevertheless, because of the large number of 
substitute products, many in the same dosage form, there should be no 
significant drop in the overall consumption of laxative products. Some 
manufacturers of phenolphthalein laxative drug products also 
manufacture substitute products, some under the same brand name. 
Consumer brand loyalty should lessen the revenue losses to these firms.
    The agency is aware of only one phenolphthalein dosage form, a 
flavored chewable tablet, which does not currently have an adequate 
number of substitutes in the same dosage form. Sales of this dosage 
form by all manufacturers were about $20 million in 1995 (most 
attributed to one large manufacturer), comprising about 3 percent of 
the total retail market for laxative products.\2\ Manufacturers of this 
dosage form may incur greater revenue losses than those making other 
dosage forms, until an acceptable substitute product is reformulated. 
The agency requests additional information on the likelihood and 
economic costs of such reformulation alternatives.
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    \2\ Based on data obtained from A.C. Nielsen, a recognized 
provider of market research and business information.
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    Because these products must be manufactured in compliance with the 
pharmaceutical current good manufacturing practices (21 CFR parts 210 
and 211), all firms have the necessary skills and personnel to perform 
the tasks of reformulation, validation, and relabeling either in-house 
or by contractual arrangement. The rule will not require any new 
reporting and recordkeeping activities. No additional professional 
skills are needed. There are no other Federal rules that duplicate, 
overlap, or conflict with this rule.
    Small business impact. The agency believes that no more than 20 
firms are still producing phenolphthalein products and assumes that the 
size distribution of these firms is comparable to that for the entire 
drug industry, implying that 87 percent of the establishments are 
small. (Based on U.S. Census data on the total number of establishments 
for Standard Industrial Classification 2834, Pharmaceutical 
Preparations. The U.S. Small Business Administration designates an 
entity as small if it employs less that 750 employees.)
    Small firms that have not yet reformulated their phenolphthalein 
products may incur significant costs as a result of this rule. The 
agency has attempted to reduce this burden by keeping industry informed 
of the findings of the new research on these products through public 
meetings and letters to manufacturers of phenolphthalein products.
    The agency considered but rejected the following alternatives: (1) 
A longer effective date, and (2) an exemption from coverage for small 
entities. The agency does not consider either of these approaches 
acceptable because they do not assure that consumers will have safe and 
effective OTC laxative drug products at the earliest possible time. The 
agency does not believe that there are any significant alternatives to 
the proposed rule that would adequately provide for the safe and 
effective use of these OTC drug products.
    Based on the agency's understanding that most manufacturers have 
already reformulated or otherwise are in the process of reformulating, 
the agency expects that this proposed rule will not be economically 
significant under Executive Order 12866, nor would it impose an 
Unfunded Mandate (as that term is described in the Unfunded Mandate 
Act). The agency also believes that it has undertaken steps to reduce 
the burden to small entities. Nevertheless, some entities may incur 
significant impacts, especially manufacturers that still must 
reformulate their phenolphthalein products and, to a lesser extent, 
private label manufacturers that provide labeling for a number of the 
affected products. Danthron was removed from OTC laxative drug products 
in 1987 and has not been available for approximately 10 years. 
Therefore, it is unlikely that reclassification of danthron as a 
nonmonograph ingredient would have any economic impact. This economic 
analysis, together with other relevant sections of this document, 
serves as the agency's initial regulatory flexibility analysis, as 
required under the Regulatory Flexibility Act.
    Finally, the agency specifically invites public comment regarding 
any substantial or significant economic impact that this rulemaking 
would have on OTC laxative drug products containing phenolphthalein, 
particularly the costs associated with reformulation. Comments 
regarding the impact of this rulemaking on OTC laxative drug products 
containing this ingredient should be accompanied by appropriate 
documentation. The agency will evaluate any comments and supporting 
data that are received and will reassess the economic impact of this 
rulemaking in the preamble to the final rule.

VII. Comment Period and Effective Date

    Under 5 U.S.C. 553(d) and Sec. 10.40(c)(4) (21 CFR 10.40(c)(4)), 
the effective date of a final rule may not be less than 30 days after 
the date of its publication in the Federal Register, except when the 
regulation grants an exemption or relieves a restriction, or the 
Commissioner of Food and Drugs (the Commissioner) finds and states in 
the notice good cause for an earlier effective date. In addition, under 
Sec. 10.40(b)(2), the agency generally provides the public 60 days to 
comment on a proposed rule, although the Commissioner may shorten or 
lengthen this time period for good cause.
    FDA is limiting the comment period in this proceeding to 30 days, 
and is proposing to make any final rule that issues in this proceeding 
relating to danthron or phenolphthalein effective on the date of 
publication. FDA is taking both of these actions for the same reasons.
    Manufacturers have been aware for over 1 year (via three public 
meetings) of the public health concerns associated with the NTP study. 
Accordingly, many manufacturers have already reformulated their drug 
products. In addition, on May 13, 1997, the agency informed 
manufacturers of phenolphthalein drug products and trade associations, 
by letter, that the NTP data and the conclusions reached at the April 
30, 1997, joint CAC and NTP meeting would likely have a direct impact 
on the rulemaking for OTC laxative drug products. That letter also 
provided notice of the availability of the data and invited comment on 
the data. By the time the final rule publishes, manufacturers will have 
had sufficient notice and an ample opportunity to comment on the 
information regarding

[[Page 46227]]

the concerns associated with phenolphthalein. Finally, the agency 
considers the phenolphthalein portion of this proposed rule to be a 
pressing public health concern because the ingredient is still being 
used in some drug products and genetic damage and risk of malignancy 
could occur at doses that are likely to be used by humans.
    FDA therefore finds that there is good cause for a 30-day comment 
period and an immediate effective date.

VIII. Paperwork Reduction Act of 1995

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

IX. Environmental Impact

    The agency has determined under 21 CFR 25.24(c)(6) 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.

X. Request for Comments

    Interested persons may, on or before October 2, 1997 submit written 
comments on this proposed rule to the Dockets Management Branch 
(address above). Written comments on the agency's economic impact 
determination may be submitted on or before October 2, 1997 Three 
copies of all comments or objections are to be submitted, except that 
individuals may submit one copy. Comments should 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 
and objections may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 334

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 310 and 334 (as proposed in the Federal 
Register of January 15, 1985 (50 FR 2124)) be amended as follows:

PART 310--NEW DRUGS

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

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).

    2. Section 310.545 is amended by redesignating the text of 
paragraph (a)(12)(iv) as (a)(12)(iv)(A), by adding new (a)(12)(iv)(B) 
heading and paragraphs (a)(12)(iv)(B) and (d)(29), and by revising 
paragraph (d) introductory text and paragraph (d)(1) to read as 
follows:


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

    (a) * * *
    (12) * * *
    (iv)(A) Stimulant laxatives--Approved as of May 7, 1991. * * *
    (B) Stimulant laxatives--Approved as of (date of publication in the 
Federal Register).
Danthron
Phenolphthalein
* * * * *
    (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)(29) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3) through (a)(4), (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), and (a)(16) through (a)(18) of this 
section.
* * * * *
    (29) September 2, 1997 for products subject to paragraph 
(a)(12)(iv)(B) of this section.

PART 334--LAXATIVE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    3. The authority citation for 21 CFR part 334 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371).

Sec. 334.18  [Amended]

    4. Section 334.18 Stimulant laxative active ingredients is amended 
by removing paragraphs (e) and (g) and redesignating paragraphs (f) and 
(h) as paragraphs (e) and (f), respectively.

Sec. 334.30  [Amended]

    5. Section 334.30 Permitted combinations of active laxative 
ingredients is amended by removing paragraph (e)(4) and removing and 
reserving paragraph (h)(2).

Sec. 334.32  [Amended]

    6. Section 334.32 Bowel cleansing systems is amended by removing 
and reserving paragraph (b).

Sec. 334.60  [Amended]

    7. Section 334.60 Labeling of stimulant laxative drug products is 
amended by removing paragraph (c)(2) and redesignating paragraph (c)(3) 
as paragraph (c)(2) and by removing paragraphs (d)(9) and (d)(11) and 
redesignating paragraphs (d)(10), (d)(12), and (d)(13) as paragraphs 
(d)(9), (d)(10), and (d)(11), respectively.

Sec. 334.66  [Amended]

    8. Section 334.66 Labeling of bowel cleansing systems identified in 
Sec. 334.32 is amended by removing the words ``and (b)'' in paragraph 
(a) and by removing and reserving paragraphs (c)(2) and (d)(3)(iii)(B).

    Dated: August 20, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-23122 Filed 8-29-97; 8:45 am]
BILLING CODE 4160-01-F