What are parabens? How do they work?
Parabens, the alkyl esters of p-hydroxybenzoic acids (PHBA), are a group of non persistent chemicals used individually or in mixtures to reach preferred antimicrobial and preservative
Because of their substantial antimicrobial capacity, low toxicity, relatively non-irritating and non-sensitising properties, parabens have in various combinations been used as preservatives in cosmetics and toiletries for decades. Short chained parabens are more hydrophilic and the long chained are more lipophilic. When the chain length of the paraben increases, the resistance to hydrolysis and antimicrobial activity increase, but water solubility decreases. As a consequence, methylparaben and propylparaben which have shorter chains, are the ones most used in cosmetics. Methylparaben and propylparaben are however also preferred for use in foods.
Products found to contain parabens include hand soap, body lotion, shampoo, conditioner, face lotion, facial cleansers, foundation, lipstick, mascara, hair spray/mousse/gel, toothpaste and sunscreen. One study identified parabens in 44% of cosmetics tested. In personal care products tested in the US, concentrations of methylparaben up to 1.0% were found, with lipsticks containing the highest concentration ranging from 0.15% to 1.0%. The other parabens are used at concentrations lower than methylparaben in personal care products.
The estrogenic activity of parabens was first identified in 1998. and has since been validated in vitro and in vivo. Parabens bind human estrogen receptors, although with affinities 10,000 to 1,000,000 times less than estradiol. Butylparaben and propylparaben have higher estrogenic activity than methylparaben or ethylparaben, but butylparaben and propylparaben are detected at concentrations 10 to 1000 times less than methylparaben in humans. The estrogenic effects in vivo have been demonstrated by uterotrophic (uterine growth) assays in mice and rats. However, this effect did not prevent implantation of a fertilized egg, which is considered the most sensitive measure of estrogen toxicity. It has been hypothesized that the estrogenic activity of parabens may promote breast cancer development.
Dr Darbre reports finding parabens in samples of human breast tumour tissues but she also found quantities of parabens in “blank” samples that did not contain any tissue at all. Thus, the significance of her results is not easy to ascertain. Extensive independent research has previously shown that any traces of parabens that might enter the skin are completely broken down by skin cells to harmless substances that cannot pose any risk of breast cancer. The concentration of estradiol in normal human breast tissue is 55.3 pg/g, suggesting there is a safety margin of 10 to 1000 times for parabens to approximate normal estradiol activity. The paraben breast cancer data shows no or low parabens in a subset of patients and there are no comparisons with normal controls.
According to a number of leading cancer research organisations, there is no plausible biological mechanism by which antiperspirants and deodorants could cause breast cancer. Dr Chris Flower of the CTPA said “Extensive research available to our members continues to indicate that there is no proven link between rising breast cancer rates and the use of antiperspirants or deodorants. Dr Darbre’s research is based on an extremely small sample of 20 breast tumour cases and does not include any reference samples from normal tissues.” Hence, having not established a clear correlation, it is difficult to put forth a causal relationship between parabens and breast cancer development.
Another major area of study has been the effect of parabens on the male reproductive system, but findings are conflicting. One in vitro study found that human sperm were not viable when exposed to parabens at concentrations of 1 mg/mL. In vivo studies in mice did not replicate this result, with no spermatotoxic effects at paraben concentrations of 1%. Conflicting results have also been reported in rats, with one study showing decreased sperm number and activity while another study found no adverse reproductive effects. In humans, men with fertility problems including low sperm count and decreased motility were assayed for paraben exposure by measuring urine paraben levels. No correlation between sperm count or motility and parabens levels was found.
Parabens, as is the case for many preservatives, can be allergenic in a small subset of the population. This sensitization commonly manifests as an eczematous rash. The rates of reported sensitization to parabens range from 0.5% to 3.5%. These rates of sensitization are amongst the lowest of all preservatives. In addition, there are reports of immediate immunoglobulin E mediated allergic reactions to parabens resulting in urticaria and, in one case, bronchospasm. However, these immediate allergic reactions are extremely rare.
Regulatory control of Parabens
Government regulatory boards have examined parabens and most have agreed that current concentrations of parabens are safe for consumer use. The European Union (EU) has set up limits on paraben use that have also been reviewed by the European Scientific Committee on Consumer Products (SCCP). In 2006, the SCCP concluded that parabens can be safely used in cosmetic products at concentrations of 0.4% for any individual paraben and 0.8% for total paraben concentrations. These limits echo the legislative limits put in place by the EU. The Danish government went further in 2011. by banning the use of parabens in personal care products intended for children younger than 3 years of age. This decision is based on the possibility of high systemic absorption from an immature metabolism and skin barrier dysfunction. In the United States, the Cosmetic Ingredient Review (CIR) assesses ingredients for safety and is reviewed by the US Food and Drug Administration (FDA). The CIR has recommended the same maximum paraben concentrations as suggested by the SCCP and as legislated by the EU. However, it should be noted that the CIR recommendations are only guidelines and manufacturers are not required to follow them. Likewise in Canada, there are no laws regulating paraben concentrations, but Health Canada agrees with the FDA and the CIR in regards to the safety of parabens and the adoption of maximum concentration guidelines. The French Commission on Cosmetology 2005 was of the opinion that more information is needed to confirm the safe use of parabens (especially for propyl- and butyl paraben) in cosmetic products. They concluded that there are no safety concerns at the currently allowed maximum levels for methyl- and ethylparabens. Additional studies concerning reprotoxic effects and pharmacokinetic fate are required in order to evaluate the risk of butyl- and propyl parabens.
Parabens preservative efficacy
Ideally a preservative should be effective against all types of organisms such as gram negative, gram positive, yeast and fungi. If there are gaps in its activity, then other preservatives will have to be added to ensure the formulation/product is adequately preserved.
Parabens has been efficiently used for many decades. There are many studies that prove their efficacy. In 1935. Loos reported that Benzylparaben at 0,01% was effective in preventing the growth of the fungi Epidermophyton interdigitale and Microsporum audouni. Lang and Rye in 1972. observed that the higher activity of the long chain esters over the shorter chain esters resulted from greater uptake of the former by bacterial cells. These authors suggested that because parabens are lipophilic, the action site was probably the cell membrane.
Bronswijk and Koekkoek in 1971. tested the activity of Methylparaben against Dermatophagoides pteronyssinus (house dust mite). Growth of mites was suppressed by 1% Methylparaben, at 5% and 7% mite growth was completely inhibited. According to Freese et al. (1973), parabens inhibit cellular oxidation by inhibiting compounds that donate electrons to the electron-transport mechanism of cell. In membrane vesicles of Bacilus subtilis, uptake of 1-serine, 1-leucine, and 1-malate was inhibited by Parabens. In 1973. Allwood reported that nonionic surfactants at low concentrations may have a synergistic effect with parabens, whereas higher concentrations of the surfactant inhibit preservative activity. Close and Neilson (1976) identified a Propylparaben resistant strain of Pseudomonas cepacia with esterases able to hydrolyze Propylparaben and use the metabolites as a carbon source.
According to Shiralkar et al. (1976), growth inhibition occurs only after a minimum concetration of paraben is reached, once this value is exceeded, inhibition is rapid. O’Neill and Mead in 1982. studied the preservative capacity of parabens against Aspergillus niger, Enterobacter hafnia, Enterobacter cloacae, Escherichia coli, Penicillium species, Pseudomonas aerugionosa, P. cepacia, Pseudomonas putida, Serratia liquifaciens, S. marcescens and Serratia rubidaea. Methylparaben at 0.8% and mix of 0.4% Methylparaben and 0.4% Ethylparaben was effective, but Methylparaben at 0.4% was not effective, nor was a mix of 0,4% Methylparaben and 0.4% Propylparaben. Nes and Eklund in 1983. reported the effect of Methyl-, Propyl- and Butylparaben on DNA, RNA and protein synthesis in E.coli and B.subtilis. Inhibition of DNA synthesis was greatest with Butylparaben and least with Methylparaben. For all parabens, DNA synthesis inhibition increased as a function of paraben concentration. The same pattern was seen for RNA synthesis. Although protein synthesis was inhibited by parabens, the effect was much less in B.subtilis compared to E.coli. The authors speculated that DNA, RNA, and protein synthesis could be targets by parabens.
Parabens are more effective against fungi than against bacteria. Their antibacterial activity is greatest against gram-positive organisms and poorest against Pseudomonas species. Enhancement of antimicrobial coverage is achieved by combining parabens with other biocides such as formaldehyde releasers, isothiazolinones, or phenoxyethanol. Cladosporium resinae, Pseudomonas aeruginosa, and Burkholderia cepacia have been reported to be resistant to parabens. Certain microorganisms, such as the gram-negative bacteria Enterobacter cloacae, Acinetobacter, Rhodopseudomona palustris, and Burkholderia cepacia, contain specific enzymes that degrade parabens. A recent study showed a para-hydroxybenzoate hydroxylase gene (POBA/PRBA) in Enterobacter cloacae and Enterobacter gergoviae strains. This enzyme catabolizes para-hydroxybenzoic acid to the central intermediate protocatechuate, which is ultimately degraded to form tricarboxylic acid intermediates. Blending of parabens also improves efficacy and this is one of the advantages of using various blends of parabens to improve efficacy. Some mixtures of parabens reduce efficacy while other mixtures show synergistic performance. This explains why there are so many blends of parabens on the market today.
Parabens have been used for over 80 years and, despite reports of adverse reactions, they have proven to be amongst the safest and most well tolerated preservatives. Although the possible association of parabens with decreased sperm quality and breast cancer does warrant continued examination, the current data does not support drastic regulations or personal restrictions to exposure. It is truly amazing that despite new preservatives launched during the last 30 years, parabens remains the first choice of preservative.