Federal Register / Vol. 62, No. 169 / Tuesday, September 2, 1997 / Proposed Rules 46223

repair on the unsafe condition addressed by

this AD; and, if the unsafe condition has not

been eliminated, the request should include

specific proposed actions to address it.

Compliance: Required as indicated, unless

accomplished previously.

To prevent evacuee overload of the slide/

raft, and consequent impeded evacuation and

injury to the evacuees, accomplish the

following:

(a) Within 180 days after the effective date

of this AD, modify the sliding surfaces of the

door 1 left and door 1 right evacuation slide/

rafts, in accordance with Boeing Alert

Service Bulletin 777–25A0035, dated

December 2, 1996.

Note 2: The Boeing alert service bulletin

references Air Cruisers Company Service

Bulletin S.B. 777–107–25–02, dated October

29, 1996, as an additional source of service

information.

(b) An alternative method of compliance or

adjustment of the compliance time that

provides an acceptable level of safety may be

used if approved by the Manager, Seattle

Aircraft Certification Office (ACO), FAA,

Transport Airplane Directorate. Operators

shall submit their requests through an

appropriate FAA Principal Maintenance

Inspector, who may add comments and then

send it to the Manager, Seattle ACO.

Note 3: Information concerning the

existence of approved alternative methods of

compliance with this AD, if any, may be

obtained from the Seattle ACO.

(c) Special flight permits may be issued in

accordance with sections 21.197 and 21.199

of the Federal Aviation Regulations (14 CFR

21.197 and 21.199) to operate the airplane to

a location where the requirements of this AD

can be accomplished.

Issued in Renton, Washington, on August

26, 1997.

John J. Hickey,

Acting Manager, Transport Airplane

Directorate, Aircraft Certification Service.

[FR Doc. 97–23173 Filed 8–29–97; 8:45 am]

BILLING CODE 4910–13–U

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-theCounter Human Use; Proposed

Amendment to the Tentative Final

Monograph

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of proposed rulemaking.

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 § 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 § 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
46224 Federal Register / Vol. 62, No. 169 / Tuesday, September 2, 1997 / Proposed Rules

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 phenolphthaleincontaining 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 dosedependent 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,
Federal Register / Vol. 62, No. 169 / Tuesday, September 2, 1997 / Proposed Rules 46225

1The 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.

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 § 310.545(a)(12)(iv). The

current list in that section is

redesignated as § 310.545(a)(12)(iv)(A)

and danthron and phenolphthalein are

being included in new

§ 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
46226 Federal Register / Vol. 62, No. 169 / Tuesday, September 2, 1997 / Proposed Rules

2Based on data obtained from A.C. Nielsen, a

recognized provider of market research and

business information.

all manufacturers to move to alternative

products over time.

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.

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 inhouse 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

§ 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

§ 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
Federal Register / Vol. 62, No. 169 / Tuesday, September 2, 1997 / Proposed Rules 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:

§ 310.545 Drug products containing

certain active ingredients offered over-thecounter (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-THECOUNTER 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).

§ 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.

§ 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).

§ 334.32 [Amended]

6. Section 334.32 Bowel cleansing

systems is amended by removing and

reserving paragraph (b).

§ 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.

§ 334.66 [Amended]

8. Section 334.66 Labeling of bowel

cleansing systems identified in § 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

NATIONAL INDIAN GAMING

COMMISSION

25 CFR Part 502

Indian Gaming Regulatory Act of 1988;

Definitions

AGENCY: National Indian Gaming

Commission.

ACTION: Advance notice of proposed

rulemaking.