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FDA Final Rule: Safety and Effectiveness of Consumer Antiseptics and Topical Antimicrobial Drug Products for Over-the-Counter Use

Posted on behalf of author, Angela Perez.

On September 2, 2016, the Food and Drug Administration (FDA) released its final rule regarding the safety and effectiveness of consumer antiseptics and topical antimicrobial drug products for over-the-counter (OTC) human use. The FDA concluded that 19 active ingredients used in OTC consumer antiseptic products intended for use with water (all the types of antiseptic products used on a frequent or daily basis by consumers; e.g., hand and body washes) are not generally recognized as safe and effective (GRAS/GRAE), and are misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 352). 

Misbranded Antimicrobials

1.      Cloflucarban

2.      Fluorosalan

3.      Hexachlorophene

4.      Hexylresorcinol

5.      Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan monolaurate)

6.      Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)

7.      Nonylphenoxypoly (ethyleneoxy) ethanoliodine

8.      Poloxamer--iodine complex

9.      Povidone-iodine 5 to 10 percent

10.  Undecoylium chloride iodine complex

11.  Methylbenzethonium chloride

12.  Phenol (greater than 1.5 percent)

13.  Phenol (less than 1.5 percent)

14.  Secondary amyltricresols

15.  Sodium oxychlorosene

16.  Tribromsalan

17.  Triclocarban

18.  Triclosan

19.  Triple dye

Accordingly, these 19 consumer antiseptic wash drug products are now considered “new drugs” under section 201(p) of the FD&C Act (21 U.S.C. 321(p)), for which approved applications under section 505 of the FD&C Act (21 U.S.C. 355) and part 314 (21 CFR part 314) of the regulations are required for marketing.  This final rule amends the 1994 tentative final monograph for OTC antiseptic drug products that was published in the Federal Register on June 17, 1994. Over 700 consumer antiseptic wash drug products are impacted by this new FDA rule.

Not covered in this Sept. 2, 2016 final rule, though, are health care antiseptics (80 FR 25166), consumer antiseptic rubs (81 FR 42912), antiseptics identified as "first aid antiseptics" in the 1991 First Aid TFM (56 FR 33644), or antiseptics used by the food industry. Moreover, the FDA deferred determining GRAS/GRAE for three active ingredients: benzalkonium chloride, benzethonium chloride, and chloroxylenol, all of which will be addressed at a later, unspecified date.

In separate rulemakings, the FDA will propose conditions under which OTC consumer antiseptic rubs (products that are not rinsed off after use, including hand rubs and antibacterial wipes) (81 FR 42912, June 30, 2016) and OTC antiseptics intended for use by health care professionals in hospital settings or other health care situations outside a hospital (80 FR 25166, May 1, 2015) are GRAS/GRAE.

Benefit-to-Risk Assessment

The 19 ingredients underwent a benefit-to-risk assessment to determine “clinical effectiveness” (i.e., whether or not washing with the product containing the antimicrobial ingredient is superior to washing with non-antimicrobial products). The data are insufficient to demonstrate any additional benefit from using these 19 antimicrobial ingredients.

One of the primary critiques of the FDA’s decision is that the time-kill assay, used to assess the effectiveness of the antimicrobial, should be used for characterizing the final product formulation, rather than for evaluating the effectiveness of the active ingredient, given that many characteristics of the formulation (e.g., stability, solubility, and pH) have a significant influence on the antiseptic product’s performance outcome. A reviewer comment recommended that the FDA adopt ASTM E2783, "Standard Test Method for Assessment of Antimicrobial Activity for Water Miscible Compounds Using a Time-Kill Procedure," as the standard for conducting the time-kill assay.  The performance criteria for the time-kill assay proposed in the 2013 Consumer Wash PR were also suggested to be more demanding than the performance abilities of approved health care antiseptic products.

Safety Assessment

The minimum data needed to demonstrate safety for all consumer antiseptic wash active ingredients falls into three broad categories: (1) safety data studies described in current FDA guidance (e.g., nonclinical and human pharmacokinetic studies, developmental and reproductive toxicity studies, and carcinogenicity studies); (2) data characterizing potential hormonal effects; and (3) data evaluating bacterial resistance development. The FDA concluded that systemic exposure to these ingredients is higher than previously thought, and that data are insufficient to establish the safety of long-term, daily repeated exposure.

Perceived Versus Realized Risk – The Case for Bacterial Resistance

The FDA noted that with respect to bacterial resistance, its decision is based on the possibility of increased risk, and not a realized risk. The FDA agreed that developing resistant mechanisms in natural settings has not been sufficiently studied, and noted that the extended use of antiseptics,  including potential consequences on systemic exposure and potential consequences on developing bacterial resistance, must be assessed.

Pre-publication of the final ruling issued on 09/02/2016 can be found here:

Angela L. Perez, Ph.D. is a Supervising Health Scientist and Regional Unit Manager for Cardno ChemRisk. She has three publications on the topic of triclosan:

1.     Triclosan occurrence in freshwater systems in the United States (1999-2012: A meta-analysis)

2.      The challenge of predicting problematic chemicals using a decision analysis tool: Triclosan as a case study

3.      Modeling triclosan down-the-drain – Published abstract

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Ms. Melanie Nembhard is an Associate Health Scientist with Cardno ChemRisk in the San Francisco, CA office. She earned her MSPH in Occupational and Environmental Hygiene from the Johns Hopkins Bloomberg School of Public Health. She also holds two certificates from Johns Hopkins, the Risk Sciences and Public Policy Certificate and the Population and Health Certificate. Ms. Nembhard’s principal areas of training and expertise include industrial hygiene and risk assessment. Since joining Cardno ChemRisk, she has provided litigation support for cases related to asbestos, benzene, butadiene, diacetyl, worker safety, welding, sunscreen, dermal exposures to various chemicals, and inhalation irritants. Additionally, she has participated in baseline exposure assessments at multiple oil refineries regarding occupational and environmental exposures to various chemical and physical agents, including particulates, volatile organic compounds, and noise.

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