[Federal Register Volume 64, Number 19 (Friday, January 29, 1999)]
[Rules and Regulations]
[Pages 4535-4540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-1938]



Food and Drug Administration

21 CFR Part 310

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

Laxative Drug Products for Over-the-Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.


SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
establishing that the over-the-counter (OTC) stimulant laxative 
ingredients danthron and phenolphthalein are not generally recognized 
as safe and effective and are misbranded. FDA is issuing this final 
rule as part of its ongoing review of OTC drug products after 
considering data and information on the safety of danthron and 

EFFECTIVE DATE: January 29, 1999.

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.


 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 that evaluated data on the active 
ingredients in these classes. In the advance notice of proposed 
rulemaking, the Panel recommended Category I (generally recognized as 
safe and effective and not misbranded) status for the OTC stimulant 
laxative ingredients danthron and phenolphthalein (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).

     In the Federal Register of September 2, 1997 (62 FR 46223), FDA 

[[Page 4536]]

the administrative record and proposed to amend the tentative final 
monograph for OTC laxative drug products to reclassify danthron and 
phenolphthalein from Category I to Category II (not generally 
recognized as safe and effective or misbranded) and to add these 
ingredients to a list of nonmonograph active ingredients. Interested 
persons were invited to submit comments on or before October 2, 1997. 
Data and information received after the administrative record was 
reopened are on display in the Dockets Management Branch (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.
     This final rule declares OTC laxative drug products containing the 
active ingredients danthron or 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)), for which an application or 
abbreviated application (hereinafter called application) approved under 
section 505 of the act (21 U.S.C. 355) and 21 CFR part 314 is required 
for marketing. In the absence of an approved application, products 
containing these drugs for laxative use also would be misbranded under 
section 502 of the act (21 U.S.C. 352).
     The final rule amends part 310 (21 CFR part 310) to include the 
laxative active ingredients danthron and phenolphthalein by adding new 
Sec. 310.545(a)(12)(iv)(B). Because a safety problem has been 
identified for OTC drug products containing danthron and 
phenolphthalein, this final rule is effective on the date of its 
publication in the Federal Register. Therefore, on or after January 29, 
1999, no OTC drug products that are subject to this final rule may be 
initially introduced or initially delivered for introduction into 
interstate commerce unless they are the subject of an approved 
     Nineteen comments were received in response to the proposed rule 
on danthron and phenolphthalein. All comments addressed 
phenolphthalein. Copies of the comments received are on public display 
in the Dockets Management Branch (address above).

 II. The Agency's Conclusions on the Comments

     1. Three comments agreed that phenolphthalein should be removed 
from OTC laxative drug products because of the public health importance 
of this matter and the need for prompt closure by FDA. Eight comments 
contended that phenolphthalein should remain in OTC laxative drug 
products because the National Toxicology Program (NTP) data (Ref. 1) 
were insufficient to determine whether phenolphthalein posed a risk to 
humans, and because phenolphthalein has been safely and effectively 
used for many years. Several consumers indicated that they will not be 
able to find another laxative ingredient as effective as 
phenolphthalein, and believed that their health will be affected if 
they can no longer use phenolphthalein.
     As stated in this document, the agency concludes that 
phenolphthalein is not safe and not of sufficient medical value to 
outweigh the potential risks associated with its OTC use. As there are 
at least 25 other laxative ingredients available for OTC use, the 
agency concludes that consumers have access to sufficient alternative 
     2. Four comments offered alternatives to removing phenolphthalein 
from OTC laxative drug products. Three comments argued that stronger 
warning statements on the phenolphthalein product label and public 
education would adequately alert consumers of the potential health risk 
to humans and emphasize appropriate use of the drug.
     The agency concludes that stronger warning statements and public 
education will not change the potential risk of using phenolphthalein 
and that this risk is not acceptable given the benefit for laxative use 
in the OTC target population.
     3. Three manufacturers contended that actual carcinogenic effects 
of phenolphthalein in humans have not been determined and recommended 
that studies be conducted to evaluate the safe use of phenolphthalein 
in humans. One manufacturer stated that these additional data may take 
2 to 3 years to obtain and recommended a moratorium on the decision to 
remove phenolphthalein from OTC laxative drug products. One 
manufacturer offered to conduct a case control human surveillance 
safety study. Two manufacturers recommended that FDA or another agency 
conduct studies to evaluate the safe use of phenolphthalein in humans.
     The agency notes that it is the manufacturer's responsibility to 
conduct studies to determine whether phenolphthalein is safe for human 
use. Because of public health concerns, the agency disagrees that 
phenolphthalein should remain on the market while further human safety 
studies are being conducted and is stopping initial introduction or 
initial delivery for introduction into interstate commerce of OTC 
laxative drug products containing phenolphthalein as of the date this 
final rule is published in the Federal Register.
     4. Two manufacturers submitted comments (Refs. 2 through 8) 
questioning the validity of the NTP data (Ref. 1). They argued that: 
(1) The studies failed to demonstrate a proposed mechanism of genotoxic 
action for phenolphthalein that is relevant to humans, (2) alternative 
mechanisms were not considered, (3) the data obtained from the p53 
deficient mouse study are inconsistent with what was expected based on 
the 2-year carcinogenicity studies, (4) the NTP data do not provide a 
sufficient basis for FDA to draw firm conclusions regarding the 
potential human carcinogenicity of phenolphthalein, and (5) there are 
no relevant human data to draw any firm conclusions regarding potential 
risk of phenolphthalein in humans.
     One comment submitted four consultant reports (Refs. 2 through 5), 
which reanalyzed the NTP data. One report by Roe (Ref. 3) directed 
criticisms primarily at the p53 deficient mouse study and the ``null'' 
mouse, which lacks both wild type p53 alleles. Roe dismissed the 
positive genotoxicity results as apparent only under conditions of 
toxicity or in some cases as an estrogenic effect. Roe also rejected 
the findings of genotoxicity demonstrated for phenolphthalein in the 
Chinese Hamster Ovary (CHO) cell chromosome aberrations assays, in the 
several positive in vivo micronucleus assays, and in the mutation and 
chromosomal aberration findings in the Syrian hamster embryo cells 
(SHE) transformation assay by Tsutsui et al. (Ref. 9).
     Two reports from CanTox U.S., Inc., (Refs. 2 and 4) concurred with 
the estrogenic mechanism of carcinogenesis proposed by Roe. CanTox 
proposed that an aneugenic effect may be involved and questioned the 
validity of the mutagenicity data presented by Tsutsui et al. (Ref. 9) 
for the SHE cell assay, noting that the control data were not different 
from the treated groups.
     One comment included a position paper on phenolphthalein from the 
European Agency for the Evaluation of Medicinal Products, Committee for 
Proprietary Medicinal Products (CPMP) (Ref. 7). The CPMP argued that 
while carcinogenicity and genotoxicity for phenolphthalein were 
confirmed by data from a transgenic mouse model, the systemic exposures 
to active drug, both in the conventional rodent bioassays and p53 
mouse, appeared to be well in excess of those likely to be encountered 
in normal human use. CPMP stated that the extent of risk to humans 
cannot be established without adequate mechanistic data addressing 
whether a threshold exists for the carcinogenic

[[Page 4537]]

effects in mice and the in vivo genotoxic effects. CPMP added that it 
was unable to verify from original data FDA's statement that the 
``systemic exposures in rodents were approximately fortyfold to 
seventyfold and sixtyfold to hundredfold the human exposure for rats 
and mice, respectively.''
     Another comment (Ref. 8) also reanalyzed the NTP data and 
concluded that phenolphthalein was a genotoxic carcinogen in rodents. 
No new information was submitted.
     The comments did not submit any new data, but focused on 
interpreting findings that already were available. The issue of 
carcinogenicity through a genotoxic mechanism was discussed in the 
proposed rule (62 FR 46223 at 46224) and at the April 30, 1997, FDA 
Center for Drug Evaluation and Research (CDER) Carcinogenicity 
Assessment Committee (CAC) meeting (Ref. 10). The CAC concluded that 
the study in p53 heterozygous mice supports other evidence 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. Further, the CAC believed that the results of several of the 
assays and data support a genotoxic clastogenic mechanism. 
Phenolphthalein was positive in chromosome aberration tests and showed 
chromosomal abnormality and hypoxanthine phosphoribosyltransferase 
(hprt) mutations in the SHE cell assay, where nontoxic doses caused 
cell transformation, mutations, and chromosome aberration. The p53 
protein accumulation in the nucleus of thymic lymphoma cells of the 
original 2-year mouse bioassay, coupled with the deletion of the wild 
type p53 allele in the thymic lymphomas of p53 mice, is 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. In the p53 mice, an increase in peripheral blood 
micronucleus occurred even at the low doses (about 15 times the human 
exposure) with increased duration of treatment without establishing a 
no effect dose. Further, the exposures used to demonstrate these in 
vivo and in vitro genotoxic effects were in the range that could occur 
with human laxative use.
     With regard to use of the p53 assay and its usefulness for 
quantitative risk assessment, NTP used the p53 heterozygous mouse assay 
to test phenolphthalein; therefore, many of the comments in Roe's 
report regarding the ``null'' mouse (which lacks both wild type p53 
alleles) do not apply. Information is available regarding the 
responsiveness of the p53 model and the types of compounds to which it 
responds. To date, when using a 6-month protocol design, the p53 mouse 
only appears to respond to compounds known to be carcinogenic and 
genotoxic, and not to compounds that are carcinogenic and nongenotoxic. 
There is also no evidence to date that the p53 heterozygous mouse assay 
that was used responds to carcinogens at significantly lower doses than 
are positive in standard bioassays. Data for the micronucleus response 
from Tice et al. (Ref. 11) indicate that, while the maximal response in 
the p53 mouse is greater than for other strains of mice, response below 
2,000 milligram/kilogram/day is similar to that of normal CD-1 mice 
similarly treated with phenolphthalein. Furthermore, the tumor response 
to phenolphthalein in the p53 model occurred over a dose range that 
could have been predicted based on the results of the 2-year bioassay 
in mice (assuming a genotoxic mechanism). Thus, the agency considers it 
reasonable to use the p53 model as a part of the weight of evidence in 
assessing a drug suspected of being a genotoxic carcinogen.
     The agency further notes that the CAC's evaluation was not a 
quantitative assessment for either the standard bioassays or the p53 
assay, rather the data were viewed qualitatively considering exposure. 
The evidence from several experimental studies indicating that 
phenolphthalein acts through a genotoxic mechanism via deoxyribonucleic 
acid (DNA) structural damage decreases the utility of a direct 
quantitative risk assessment. The genotoxicity data were also 
considered in the evaluation of the 2-year bioassay results, which 
contributed significantly to the conclusion of a relevant risk to 
humans. The p53 mouse assay was conducted under test conditions where 
factors such as target organ toxicity did not confound its 
interpretation, and where exposures and pharmacodynamic effects were 
well characterized. Thus, the results of the p53 mouse assay appear to 
be more likely relevant to humans than the results from the 2-year 
bioassay as conducted.
     Further, the agency disagrees with Roe's dismissal of the 
genotoxic findings in the CHO cell chromosome aberration, micronucleus, 
and SHE cell transformation assays as apparent under conditions of 
toxicity or in some cases as an estrogenic effect. The agency is aware 
that phenolphthalein is known to have estrogenic activity. The 
information available on phenolphthalein indicates that its potency for 
binding at estrogen receptors and for induction of estrogenic effects 
is low compared to endogenous estrogens (by about a factor of 
103 and 104 less than estradiol). Given the 
concentrations of phenolphthalein achieved in the bioassays, this 
action may be considered to have little overall contribution to the 
estrogenic load in the rodent models tested. The types of tumors 
observed for phenolphthalein are generally unlike those observed with 
other estrogenic chemicals. While there may be some contribution by 
estrogenic effects in the tumor response, the estrogenic effects appear 
most relevant for the ovarian tumors observed only in the 2-year mouse 
     The genotoxic effects of phenolphthalein were observed under 
conditions compatible with the International Conference on 
Harmonization (ICH) guidance for the conduct of such genotoxicity 
studies. Although the repeat dose micronucleus assay that was 
originally reported was conducted at doses causing bone marrow 
toxicity, which could be viewed as confounding the results, the 
micronucleus assay conducted in the p53 mouse exhibited little evidence 
of toxicity and yielded results essentially identical to those of the 
prior assays. Thus, excessive toxicity is not essential to the 
micronucleus response for phenolphthalein. Further, this assay, 
although not part of the standard ICH test battery, is believed by many 
in the scientific community to be a more comprehensive assessment than 
the acute dose micronucleus assay, as it allows for any metabolic 
induction processes that might occur in vivo. This assay also allows 
exposures to achieve steady state conditions and reduces the 
uncertainty of appropriate sampling times, which can confound the 
standard acute assessments. Use of such tests is in accordance with ICH 
recommended guidelines for additional genotoxicity testing where 
positive findings have been observed in carcinogenicity studies.
     The agency notes that there was an error in the Tsutui et al. 
report (Ref. 9), in that the number of mutations found in the control 
group for the SHE cell transformation assay should have been reported 
as <0.25 x 10-6. The Tsutui et al. findings for the control 
treatment are consistent with historical experience and less than 1/16 
the response in phenolphthalein treated cells. The positive control 
produced an effect only

[[Page 4538]]

threefold greater than phenolphthalein. Thus, these data indicate a 
mutational effect for phenolphthalein.
     The data also indicate that both aneuploidy and structural damage 
are caused by phenolphthalein. Tice et al. (Ref. 11) showed a possible 
increase in aneuploidy based on the kinetochore analysis. There was 
also significant evidence of structural damage; phenolphthalein 
treatment caused an approximate fourfold increase in micronuclei with 
structural damage and an eightfold increase in aneugenic damage 
calculated based on the ratio of normochromatic erythrocytes and 
polychromatic erythrocytes, and the increase in micronuclei. Also, an 
effect on aneuploidy was not observed in the study by Tsutsui et al. 
(Ref. 9) with SHE cells, whereas DNA structural damage and mutation 
were reported. The view that aneuploidy is the primary mechanism of 
genetic damage related to the carcinogenic effect also ignores the 
evidence of structural damage observed in the CHO cell chromosomal 
aberration studies, including those done by NTP, with responses 
approaching those seen with the positive control. Although the loss of 
heterozygosity observed in tumors from the p53 mouse could be explained 
by an aneugenic mechanism, it could also be the result of a chromosome 
break or deletion of a significant segment of the p53 region targeted 
by the assay. This allele loss was also specific for the p53 wild-type 
gene, with no effect on the null allele. Such a selective effect would 
not be anticipated from chromosome loss by an aneugenic mechanism 
functioning at the spindle apparatus.
     One CanTox report (Ref. 5) presented information on the effects of 
phenolphthalein on thymidylate synthase (TS) activity and the potential 
relationship to the genotoxic and carcinogenic effects observed 
following phenolphthalein treatment in various systems. This report was 
evaluated by FDA's Executive CAC and Genetic Toxicology Committees (the 
Committees) (Ref. 12), which noted that the TS enzyme inhibitory 
activity was reported for a bacterial source and could differ between 
the bacterial and human or other mammalian forms, but there is no 
information available for assessing increased or decreased sensitivity. 
The Committees found no available information for estimation of 
intracellular versus extracellular concentrations of phenolphthalein to 
determine whether the in vivo phenolphthalein concentrations are within 
a reasonable range of those that were studied in vitro for TS 
inhibition. The inhibitor effects, however, appear to occur at plasma 
concentrations of phenolphthalein tenfold to hundredfold greater than 
the plasma concentrations associated with in vivo effects. There was 
also no information available on the TS activity of the glucuronide or 
other metabolites of phenolphthalein. In addition, the nucleotide pool 
disruption model lacked in vivo data and other information showing that 
a disruption of nucleotide pools was caused by phenolphthalein or that 
nucleotide pool effects were involved in the observed responses to 
phenolphthalein. The Committees noted that the effects of 
phenolphthalein on induction of micronuclei could be considered 
consistent with an effect on TS, based on comparisons of effects with 
5-fluorouracil (5-FU) and methotrexate (MTX) treatment. However, the TS 
inhibitory activity does not appear consistent with or explain the 
other observed effects of phenolphthalein. In contrast to the assays 
conducted on phenolphthalein, 5-FU and MTX failed to increase SHE cell 
transformation. This suggests that, if phenolphthalein is active as a 
TS inhibitor at the tested concentrations, its effects on SHE cells 
(such as transformation, mutation, and chromosomal aberration) appear 
independent of the TS activity. Also, phenolphthalein is associated 
with increased chromosomal aberrations in CHO cells only in the 
presence of metabolic activation. This contrasts with the ability of 
phenolphthalein to directly inhibit TS. The comment's suggestion that 
the effect in CHO cells is due to fragile site damage in the CHO cell 
genome is not consistent with data provided by Witt et al. (Ref. 6), 
nor with the observations on CHO cells discussed at the April 2, 1996, 
CAC meeting (Ref. 13). In both data sets, there were increases in both 
complex and simple chromosomal breaks. In the latter data set, the 
proportionate response of simple and complex breaks appears similar to 
that caused by cyclophosphamide (a known genotoxicant used as the 
positive control for the assay). There was no discussion by the comment 
as to why a fragile site response would not be relevant for human 
adverse effects. The Committees noted that in a chromosomal aberration 
assay on human peripheral blood lymphocytes tested in vitro (Ref. 14), 
there was evidence of a clastogenic response from one of two subjects 
tested. While there is evidence that phenolphthalein can inhibit TS in 
some in vitro systems, the Committees stated that the data do not 
support the argument that TS inhibition explains all of the genetic 
damage observed in tests conducted on phenolphthalein, and that TS 
inhibition is the underlying mechanism of tumor formation in the three 
in vivo assays conducted. The Committees concluded that the data on TS 
inhibition do not refute the potential relevance of phenolphthalein's 
toxicologic effects for humans.
     The CPMP (Ref. 7) contended that the extent of risk in humans 
cannot be established because the mechanistic data are inadequate and 
the phenolphthalein doses used in the study were excessive. The agency 
is not aware of any available data that would suggest that the 
mechanisms thought to account for tumor induction by phenolphthalein in 
experimental animals would not also operate in humans. Further, the 
phenolphthalein exposures used to demonstrate the in vivo and vitro 
genotoxic effects were in the range of those that humans use to cause 
laxation. The agency also notes that the exposure information for 
phenolphthalein that the CPMP could not verify was based on data 
obtained from a kinetic study (Ref. 15) sponsored by the 1992-1993 
Nonprescription Drug Manufacturers Association Phenolphthalein Study 
     After review of all the available data, the agency concludes that 
phenolphthalein caused chromosome aberrations, cell transformation, and 
mutagenicity in mammalian cells. Because benign and malignant tumor 
formation occurs at multiple tissue sites in multiple species of 
experimental animals, phenolphthalein is reasonably anticipated to have 
human carcinogenic potential.

III. References

     1. Comment No. RPT7, Docket No. 78N-036L, Dockets Management 
     2. CanTox U.S., Inc., ``Discussion of New Data Related to 
Phenolphthalein Presented at the April 30, 1997 Meeting of the 
Carcinogenicity Assessment Committee of the U.S. Food and Drug 
Administration,'' June 9, 1997, in Comment No. C167, Docket No. 78N-
036L, Dockets Management Branch.
     3. Roe, F. J., ``Opinion on the Safety of Phenolphthalein as an 
Ingredient of OTC Laxative Preparations,'' August 28, 1996, in 
Comment No. C180, Docket No. 78N-036L, Dockets Management Branch.
     4. CanTox U.S., Inc., ``Evaluation of the Rodent 
Carcinogenicity of Phenolphthalein,'' October 1, 1997, in Comment 
No. C180, Docket No. 78N-036L, Dockets Management Branch.
     5. CanTox U.S., Inc., ``The Relevance of the Role of 
Phenolphthalein as an Inhibitor of Thymidylate Synthase for the 
Interpretation of the Genotoxic Potential and Carcinogenicity 
Assessment of this Compound,'' December 4, 1997, in Comment No. 
C186, Docket No. 78N-036L, Dockets Management Branch.

[[Page 4539]]

     6. Witt, K. L. et al., ``Phenolphthalein: Induction of 
Micronucleated Erythrocytes in Mice,'' Mutation Research, 341:151-
160, 1995, in Comment No. C186, Docket No. 78N-036L, Dockets 
Management Branch.
     7. Comment No. C189, Docket No. 78N-036L, Dockets Management 
     8. Comment No. RPT9, Docket No. 78N-036L, Dockets Management 
     9. Tsutsui, T. et al., ``Cell Transforming Activity and 
Genotoxicity of Phenolphthalein in Cultured Syrian Hamster Embryo 
Cells,'' unpublished manuscript, 1997, in Comment No. RPT7, Docket 
No. 78N-036L, Dockets Management Branch.
     10. Comment No. MM13, Docket No. 78N-036L, Dockets Management 
     11. Tice, R. R. et al., ``Tumorigenicity Studies of Dietary 
Phenolphthalein (CAS No. 77-09-8) in TSG-p53 Transgenic Female 
Mice,'' final report, April 11, 1997, in Comment No. RPT7, Docket 
No. 78N-036L, Dockets Management Branch.
     12. Comment No. MM15, Docket No. 78N-036L, Dockets Management 
     13. Comment No. MM12, Docket No. 78N-036L, Dockets Management 
     14. Comment No. RPT10, Docket No. 78N-036L, Dockets Management 
     15. BTC Study No. P0392002 in Comment No. RPT11, Docket No. 
78N-036L, Dockets Management Branch.
     5. One comment expressed concern about the availability of an 
acceptable bowel cleansing system for use by physicians if the use of 
phenolphthalein is banned. The comment argued that its bowel cleansing 
system containing phenolphthalein, magnesium citrate, and bisacodyl 
should not be considered an OTC laxative. The comment stated that if 
phenolphthalein cannot be used, patients may be misdiagnosed because 
adequate bowel cleansing was not achieved prior to undergoing a bowel 
examination. The comment requested that the agency allow the continued 
sale of phenolphthalein in bowel cleansing systems if the product is 
adequately labeled, limited to a one-time application, and purchased 
and used under a physician's supervision.
     This final rule prohibits the use of phenolphthalein in OTC 
laxative drug products. If an OTC bowel cleansing system is 
reformulated to contain a different laxative ingredient, data must be 
submitted to the rulemaking for OTC laxative ingredients to support the 
safety and effectiveness of the reformulated bowel cleansing system. 
Bowel cleansing systems that contain phenolphthalein and are limited to 
purchase and use under a physician's supervision may be submitted for 
agency review in a new drug application.
     6. One comment stated that if phenolphthalein is reclassified as a 
Category II ingredient in the final rule, an immediate effective date 
would be unfair because it would cause significant economic harm to 
manufacturers of phenolphthalein. The comment recommended that a 1-year 
transition period be allowed for manufacturers to reformulate their 
laxative products, which will involve the purchase and production of 
new materials and, possibly, new equipment. The comment did not present 
any information that was not previously addressed in the proposed rule.
     Because over 1 year has passed since the proposal was published, 
providing adequate time for reformulation, the agency denies the 
comment's request. In the preamble to the proposed rule (58 FR at 46226 
to 46227), FDA found good cause under 5 U.S.C. 553(d) and 21 CFR 
10.40(c)(4) for an immediate effective date for this final rule. In the 
reasons given in that preamble, as well as the fact that an additional 
period of more than 1 year has passed; the agency confirms the finding 
of good cause for an immediate effective date for this final rule.

 IV. The Agency's Final Conclusions on Danthron and Phenolphthalein

     Based on new data and information, the agency is reclassifying the 
stimulant laxative ingredients danthron and phenolphthalein from 
Category I (monograph) to Category II (nonmonograph) and is adding 
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). 
As a result of this reclassification of danthron and phenolphthalein, 
the amendments proposed in Secs. 334.18, 334.30, 334.32, 334.60, and 
344.66 (62 FR 46223 at 46227) will be finalized in the final rule for 
OTC laxative drug products, to be published in a future issue of the 
Federal Register.

 V. Analysis of Impacts

     One comment was received in response to the agency's request in 
the proposal for specific comment on the economic impact of this 
rulemaking (62 FR 46223 at 46225). (See comment 6 of this document.)
     FDA has examined the impacts of this final 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 
     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 
     The agency believes that this final rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
The purpose of this final 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 
     Products containing phenolphthalein will need to be reformulated 
to replace the ingredient with another laxative active ingredient. A 
number of laxative ingredients in proposed part 334 (50 FR 2124 at 
2152) could be used. In addition, most OTC laxative drug products 
containing phenolphthalein have already been reformulated since the 
proposal was published.
     When the proposed rule was published, the agency was aware of only 
one phenolphthalein dosage form, a flavored chewable tablet. 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. The major 
manufacturer of this product informed the agency on August 29, 1997 ( 
Ref. 1), that it planned to reformulate the product with another OTC 
laxative ingredient within 60 days.
     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

[[Page 4540]]

that duplicate, overlap, or conflict with this rule.
     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 final 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 
Reform 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 final regulatory flexibility analysis, as 
required under the Regulatory Flexibility Act.

 VI. Reference

    1. Comment No. C173, Docket No. 78N-036L, Dockets Management 

 VII. Paperwork Reduction Act of 1995

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

 VIII. Environmental Impact

     The agency has determined under 21 CFR 25.31(c) 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 

 List of Subjects in 21 CFR Part 310

     Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.
     Therefore, under the Federal Food, Drug, and Cosmetic Act and 
under authority delegated to the Commissioner of Food and Drugs, 21 CFR 
part 310 is amended as follows:


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

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 

     2. Section 310.545 is amended by redesignating paragraph 
(a)(12)(iv) as paragraph (a)(12)(iv)(A) and by revising the newly 
redesignated heading, by adding 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. * *  *
     (iv)(B) Stimulant laxatives--Approved as of January 29, 1999.
* * * * *
     (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 
* * * * *
     (29) January 29, 1999, for products subject to paragraph 
(a)(12)(iv)(B) of this section.

    Dated: January 20, 1999.
 William K. Hubbard,
 Associate Commissioner for Policy Coordination.
[FR Doc. 99-1938 Filed 1-28-99; 8:45 am]