Benzalkonium Chloride: A Safer Alternative to Parabens

The Function of Preservatives

Preservatives help protect cosmetic products from microbial spoilage. A preservative is a natural or synthetic substance intended to inhibit microorganisms’ development. Preservatives must be effective over a broad activity spectrum and have a duration that exceeds the expected shelf-life of the product plus the usage time. Additionally, the antimicrobial effects of a preservative must be strong enough to prevent a microorganism’s adaptation and resistance gain over time.

Parabens and their effects on health and

Parabens are a class of synthetic chemicals used as preservatives in various products, including pharmaceuticals and cosmetics. Chemically, they are esters of para-hydroxybenzoic acid, and common types include methylparaben, ethylparaben, propylparaben, and butylparaben.

Just as Benzalkonium Chloride (BKC), parabens are broad-spectrum antimicrobials effective against Gram-positive and Gram-negative bacteria, fungi and enveloped viruses.

Because of potential health and environmental impact, they have come under regulatory scrutiny. Several regulatory agencies have banned or restricted the allowable concentrations of parabens in products, which may complicate formulation and compliance.

At equivalent antimicrobial efficacy, Benzalkonium Chloride is a safer alternative with superior properties, including better stability, wider pH range of activity and easy formulation.

The regulatory situation

Parabens present safety concerns:

Parabens can persist in the environment, leading to potential ecological harm. They have been detected in water sources and wildlife.

Scientific studies suggest they can disrupt hormones and harm fertility and reproductive organs, affect birth outcomes, and increase the risk of cancer.

ASEAN countries have banned the use of isopropylparaben and isobutylparaben in cosmetics due to safety concerns.

EU limits the maximum concentration of Propylparaben and Butylparaben to 0.14%, used individually or together. Banned from leave-on products designed for the nappy area of young children below the age of three. Rules apply for products put on shelves after 16 April 2015. Isopropylparaben, Isobutylparaben, Phenylparaben, Benzylparaben, and Pentylparaben have been banned in cosmetic products within the EU due to insufficient safety data.

Denmark banned the use of butylparaben and propylparaben in products for children under three years of age in 2011.

Butylparaben is on the ECHA list of Substances of Very High Concern:

Benzalkonium Chloride is a safer alternative

EU and US authorities report that there is no indication that BKC has MCR effects (mutagenic, carcinogenic, reproductive).

EU/ECHA: Benzalkonium Chloride is REACH registered, also as a biocide with no specific safety concerns.

EU/EMA: Approved for use in pharmaceutical formulations without restrictions.

Approved in both OTC and Rx pharmaceuticals, globally.

1) (U.S. Environmental Protection Agency (EPA) 2006. Reregistration eligibility decision for alkyl dimethyl benzylammonium chloride (ADBAC) EPA739-R-06-009 U.S. Environmental Protection Agency, Washington, DC.).

2) EMA/CHMP/352187/2012” Report published in support of the ‘Questions and answers on benzalkonium chloride used as an excipient in medicinal products for human use”.

EMA/CHMP/495737/2013 “Questions and answers on benzalkonium chloride used as an excipient in medicinal products for human use”.

Comparing BKC with parabens

In terms of chemical properties, while BKC and parabens do show similarities, BKC is a more stable compound, not affected by pH and easy to mix and various product forms due to its surfactant properties.

Differences

Similarities

In Benzalkonium Chloride, different alkyl chain lengths are as a standard combined in one product, offering optimal solubility and efficacy. Combinations of several paraben types are often necessary to obtain a similar effect, e.g. methyl and propyl paraben.
Parabens are susceptible to base-catalyzed ester hydrolysis. Stability in solution is not markedly affected up to about pH 6.5, but degradation rates increase significantly at pH 7.5 and above. See also below table.
Parabens may need to be included in excess to compensate for chemical instability of the preservative system, including losses during manufacture.

Mode of action is similar for both products (membrane permeability, cytoplasmic membrane activity).
They are both broad-spectrum, and generally more active against Gram+ than Gram-bacteria, and more active against yeasts and moulds than bacteria.
Their activity increases with increased alkyl chainlength; (C18>C16>C14>C12) for BKC and (butyl > propyl > ethyl > methyl) for parabens. Their aqueous solubility commensurately decreases.
They show some synergy with EDTA, 2-phenylethanol and imidurea.

Replacing parabens with BKC in a formulation

The concentration of parabens used as a preservative in pharmaceutical products is similar to, or slightly higher, than BKC concentrations to obtain a similar antimicrobial effect. It will typically vary from 0.01% to 0.3%, depending on the type of paraben used.

Parabens are often used in combination to provide a broader spectrum of antimicrobial activity and to reduce the required concentration of each individual paraben. A common combination would include methylparaben and propylparaben.

An existing product can be re-formulated with BKC using similar concentrations. Below is an example provided by Intertek (UK), comparing preservative concentrations in nasal sprays to pass AET (Antimicrobial Testing Requirements).