Code of Federal Regulations

  Title 21, Volume 4, Parts 200 to 299

  Revised as of April 1, 1996

 From the U.S. Government Printing Office via GPO Access

  CITE: 21CFR250 .250

 

  Page 121-124

 

         TITLE 21--FOOD AND DRUGS

 

 CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

 PART 250--SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS--Table of Contents

 

              Subpart D--Requirements for Drugs and Cosmetics

 

 Sec. 250.250   Hexachlorophene, as a component of drug and cosmetic products.

 

     (a) Antibacterial component. The use of hexachlorophene as an

 antibacterial component in drug and cosmetic products has expanded

 widely in recent years. It is used in such products because of its

 bacteriostatic action against gram-positive organisms, especially

 against strains of staphylococcus; however, hexachlorophene offers no

 protection against gram-negative infections. In addition the

 antibacterial activity depends largely on repeated use. A notice

 published in the Federal Register of April 4, 1972 (37 FR 6775), invited

 data on OTC antimicrobial ingredients, including hexachlorophene, for

 review by an OTC Drug Advisory Review Panel to be convened under the

 procedures set forth in the Federal Register of May 11, 1972

 

   Page 122

 

 (37 FR 9464). This statement of policy will remain in effect unless and

 until replaced by a monograph resulting from the OTC Drug Advisory

 Review Panel.

     (b) Adverse effects. Though considered safe for many years, recent

 information has become available associating hexachlorophene with toxic

 effects, including deaths. Studies have shown that toxic amounts of

 hexachlorophene can be absorbed through the skin of humans, especially

 the skin of premature babies or damaged skin. Human toxicity reports

 include data on symptomatology, blood and tissue levels of

 hexachlorophene, and descriptions of neuropathologic lesions. Recent

 infant deaths due to use of baby powder accidentally contaminated with 6

 percent hexachlorophene have occurred. The accumulated evidence of

 toxicity is sufficient to require that continued marketing of

 hexachlorophene containing products be carefully defined in order to

 protect consumers.

     (c) Prescription drugs. (1) Because of their potential for harmful

 effect, drugs containing hexachlorophene, other than as a preservative

 as described below, are not considered to have been shown to be safe and

 effective, are regarded as new drugs requiring approved new drug

 applications, and would be misbranded for over-the-counter distribution.

 In the interest of public health protection, hexachlorophene containing

 drugs will be regarded as misbranded and subject to regulatory

 proceedings unless the label bears the legend ``Caution: Federal law

 prohibits dispensing without a prescription,'' and the labeling on or

 within the package from which the drug is to be dispensed bears adequate

 information for its safe and effective use by practitioners, in accord

 with Sec. 201.100(c) of this chapter.

     (2) The Food and Drug Administration recognizes that hexachlorophene

 is useful as a bacteriostatic skin cleanser. It further concludes that

 the margin of safety is such that products containing hexachlorophene

 may appropriately be used within clearly delineated conditions of use.

     (3) In order for such drugs to bear adequate information for safe

 and effective use the following statements are representative of the

 type of labeling for products shown to be effective bacteriostatic skin

 cleansers. Labeling for products other than bacteriostatic skin

 cleansers will be determined through the new drug procedures based on

 the available data.

     (i) In the labeling other than on the immediate container label.

 

Indications

 

     1. Bacteriostatic skin cleanser for surgical scrubbing or

 handwashing as part of patient care.

     2. For topical application to control an outbreak of gram-positive

 infection where other infection control procedures have been

 unsuccessful. Use only as long as necessary for infection control.

 

             Contraindications

 

     1. Not for use on burned or denuded skin or on mucous membranes.

     2. Not for routine prophylactic total body bathing.

 

 Warnings

 

     Rinse thoroughly after use. Patients should be closely monitored and

 use should be immediately discontinued at the first sign of any of the

 symptoms described below.

     Hexachlorophene is rapidly absorbed and may produce toxic blood

 levels when applied to skin lesions such as ichthyosis congenita or the

 dermatitis of Letterer-Siwe's syndrome or other generalized dermatologic

 conditions. Application to burns has also produced neurotoxicity and

 death.

     Infants have developed dermatitis, irritability, generalized clonic

 muscular contractions and decerebrate rigidity following application of

 a 6 percent hexachlorophene powder. Examination of brainstems of those

 infants revealed vacuolization like that which can be produced in

 newborn experimental animals following repeated topical application of 3

 percent hexachlorophene. Moreover, a study of histologic sections of

 premature infants who died of unrelated causes has shown a positive

 correlation between hexachlorophene baths and lesions in white matter of

 brains.

 

     (ii) On the immediate container label prominently displayed and in

 bold print:

 

     ``Special Warning: This compound may be toxic if used other than as

 directed. Rinse thoroughly after use. Monitor patients closely for

 toxicity symptoms.''

 

     (4) Marketing of products for the indications listed in paragraph

 (c) (3) of this section may be continued without

 

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 an approved new drug application (or required supplement thereto) either

 until a notice of opportunity for hearing is issued on a proposal by the

 Director of the Center for Drug Evaluation and Research to refuse to

 approve such new drug application (or required supplement) or until

 January 31, 1978, whichever comes first, if all the following conditions

 were met after September 27, 1972:

     (i) The product is labeled with the prescription legend and adequate

 information for safe and effective use as set forth in paragraph (c) (3)

 of this section.

     (ii) Within 30 days, or by (10-27-72) the holder of an approved new

 drug application submits a supplement to provide for the revised label

 and full disclosure labeling. As the label and labeling will have been

 put into use, the supplement should be submitted under the provision of

 Sec. 314.70(c)(2) of this chapter.

     (iii) Within 30 days, or by (10-27-72) the holder of an approved new

 drug application submits a supplement to provide for a revised

 formulation where appropriate to comply with this order.

     (iv) Within 90 days, or by (12-26-72) the holder of an approved new

 drug application submits a supplement containing blood level data

 obtained from use of the drug as recommended, unless such information is

 a part of the new drug application file.

     (v) Within 90 days, or by (12-26-72), the manufacturer or

 distributor of such a drug for which a new drug approval is not in

 effect submits a new drug application in accord with Sec. 314.50 of the

 new drug regulations (21 CFR 314.50), including blood level data

 obtained from use of the drug as recommended.

     (5) Prescription drug products may contain hexachlorophene as part

 of an effective preservative system only under the conditions and

 limitations provided for under paragraph (d) of this section.

     (d) Over-the-counter (OTC) drugs. Over-the-counter drug products,

 other than those which in normal use may be applied to mucous membranes

 or which are intended to be used on mucous membranes, may contain

 hexachlorophene only as part of an effective preservative system, at a

 level that is no higher than necessary to achieve the intended

 preservative function, and in no event higher than 0.1 percent. Such use

 of hexachlorophene shall be limited to situations where an alternative

 preservative has not yet been shown to be as effective or where adequate

 integrity and stability data for the reformulated product are not yet

 available. This use of hexachlorophene will not, by itself, require an

 approved new drug application. Use of hexachlorophene as a preservative

 at a level higher than 0.1 percent is regarded as a new drug use

 requiring an approved new drug application, which must be submitted

 within the time set out in paragraph (c) (4) of this section.

     (e) Cosmetics. Hexachlorophene may be used as a preservative in

 cosmetic products other than those which in normal use may be applied to

 mucous membranes or which are intended to be used on mucous membranes,

 at a level that is no higher than necessary to achieve the intended

 preservative function, and in no event higher than 0.1 percent. Such use

 of hexachlorophene shall be limited to situations where an alternative

 preservative has not yet been shown to be as effective or where adequate

 integrity and stability data for the reformulated product are not yet

 available. The component of a preservative system whether

 hexachlorophene or other antimicrobial agent, should be selected on the

 basis of the effect on the total microbial ecology of the product, not

 merely on gram-positive bacteria.

     (1) Adequate safety data do not presently exist to justify wider use

 of hexachlorophene in cosmetics.

     (2) Antibacterial ingredients used as substitutes for

 hexachlorophene in cosmetic products, and finished cosmetic products

 containing such ingredients, shall be adequately tested for safety prior

 to marketing. Any such ingredient or product whose safety is not

 adequately substantiated prior to marketing may be adulterated and will

 in any event be deemed misbranded unless it contains a conspicuous front

 panel statement that the product has not been adequately tested for

 safety and may be hazardous.

 

   Page 124

 

     (f) Content statement. All reference to hexachlorophene limit in

 this order is on a weight-in-weight (w/w) basis. Quantitative

 declaration of hexachlorophene content on the labeling of the products,

 where required, shall be on a w/w basis.

     (g) Shipments of products. Shipments of products falling within the

 scope of paragraphs (c), (d), or (e) of this section which are not in

 compliance with the guidelines stated herein shall be the subject of

 regulatory proceedings after the effective date of the final order.

     (h) Prior notices. This order preempts any conditions for marketing

 products set forth in the following prior notices.

 

     1. DESI No. 4749 (34 FR 15389, October 2, 1969), ``Certain OTC Drugs

 for Topical Use.''

     2. DESI No. 2855 (35 FR 12423, August 4, 1970), ``Certain Mouthwash

 and Gargle Preparations.''

     3. DESI No. 8940 (36 FR 14510, August 6, 1971), ``Topical Cream

 Containing Pyrilamine Maleate, Benzocaine, Hexachlorophene, and

 Cetrimonium Bromide.''

     4. DESI No. 6615 (36 FR 18022, September 8, 1971), ``Deodorant/

 Antiperspirant.''

     5. DESI No. 6270 (36 FR 23330, December 8, 1971), ``Certain

 Preparations Containing Hexachlorophene''.

 

  40 FR 14033, Mar. 27, 1975, as amended at 42 FR 63773, Dec. 20, 1977;

 55 FR 11577, Mar. 29, 1990