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

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