Environmental Chemicals

Author: Paolo Geretto
Date: 18/02/2013



Parabens are esters derived from 4-hydroxybenzoic acid, which is an aromatic carboxylic acid containing a carboxyl group bonded directly to benzene ring, and a hydroxy group on the position 4. Parabens are obtained through an esterification process of para-hydroxybenzoic acid with an alcohol such as methanol, ethanol, butanol, propanol .

These compounds are nowadays obtained by industrial synthesis, nevertheless they can be found in plants such as blueberries or in grapefruit seeds extract (mainly the methylparaben), where they act as antimicrobials agents. The antibacterial and antifungal function has been largely demonstrated by the high grown inhibiting activity in culture against bacteria and yeasts.
PBs inhibit bacterial growth by hindering substrate uptake in bacterial cell, which can be observed for amminoacid such as L-Serine and L-Leucine. They also inhibit the electron transport system in respiratory chain, depleting ATP levels of strictly aerobic microorganisms by up to 90%. (Function of lypophilic acids as antimicrobial food additives,1973)

The germicidal function of parabens suggested a possible use of them as preservatives.
Indeed, the easy availability and the initial lack of evidence of a possible harmful activity of these compounds leaded them to be a largely used category of substances as preservative in cosmetics such as lotions, deodorants and creams, as well as in food. Typically, more than one paraben is used in a product, because it allows the use of lower levels while increasing their activity. They are often used also in combination with other types of preservatives.


Parabens is a wide family of compounds. Everyone have in common the derivation from para- hydroxybenzoic acid

Depending on the acid with which esterification is executed, a different paraben is obtained. Chemical and metabolic properties depend mainly on the length of the carbon chain, which also improves lipophilic properties of the substance (and then their ability to penetrate membranes) and estrogenic- agonist activity . The most commonly used parabens in industry are methylparaben, butylparaben, ethylparaben, propylparaben. Isobutyl, isopropyl and benzylparaben are less commonly used.


From several studies of the last few years, the ability of the organism to absorb parabens has been demonstrated. In vitro studies have shown that propylparaben penetrates the skin intact in rat skin in a large amount. In vivo studies have confirmed the absorption by the finding of a certain concentration of catabolites (4-hydroxybenzoate), conjugated parabens and also unconjugated parabens esters in urine, both in experimental animals, after topic administration, and in exposed humans. For instance, a research on 100 anonymous adults detected methyl and n-propyl parabens at the median concentrations of 43.9 ng/mL and 9.05 ng/mL, respectively in nearly all (> 96%) of the samples and also detected other parabens in more than half of the samples (ethyl, 58%; butyl, 69%) (Parabens as Urinary Biomarkers of Exposure in Humans, 2006). Furthermore, the uptake occurs also through gastro-intestinal system, after ingestion (PBs are commonly used as preservatives in food).

Consequently, the presence in urine (that is the main excretion way) confirms their systemic diffusion, and detection of conjugated compounds (the predominant form excreted in urine) and of catabolites demonstrates an active metabolic action on these substances.

The degradation into hydroxybenzoate is mediated by skin esterases if exposure is topical, or by intestinal and liver metabolic systems if exposure is oral, that means conjugation to glucuronate or hydrolysis trough epithelial esterases.

Nonetheless PBs frequently “escape” from the metabolic process; this explains the relatively high levels of paraben esters found in urine. Additionally, it has been observed that ethanol enhances dermal permeation of parabens and can also act to inhibit esterase breakdown of parabens in vitro. Thus common coingredients in cosmetic formulations may interact in mixtures, resulting in higher skin and body burdens of parabens.

It has recently also demonstrated that PBs weakly interact with human serum albumin (Reviewing the binding of a series of parabens to human serum albumin, 2013) and has been suggested that this fact could denote a high concentration of free PB esters in bloodstream and therefore a high availability in tissues.


All the widely used parabens has been shown to have an estrogenic activity both in vitro and in vivo in animals at high concentration. Affinity for estrogen receptors depends substantially on the length of alkyl chain: the more is long the chain the higher is the affinity for the receptor.
Para-hydroxybenzoate itself has a certain estrogenic activity, weaker than PBs one because of the absence of the alkyl chain, whilst he doesn't seem to have any androgen-antagonist function. Among the most common PBs, butylparaben is the most affine although it has an estrogenic activity 10.000-100.000 times weaker than estradiol.
Notwithstanding the weakness with which PBs bind estrogen receptors, their estrogenic activity is enhanced by inhibiting action on skin sulfotranferase, an enzyme which conjugates estrogens to sulfate groups in skin, lowing estrogen circulating levels. PBs would then increase free estrogen concentration in organism (Parabens inhibit human skin estrogen sulfotransferase activity: Possible link to paraben estrogenic effects, 2007).

Thence, the metabolic activity as estrogen agonist, family of hormones that is widely accepted to play a role in breast cancer development, and, overall, the observation of a remarkable concentration of parabens in human breast tumor (Concentrations of Parabens in Human Breast Tumours, 2004) , rose some concern about a possible harmfulness of PBs. Moreover, it was noted that breast tumors with a relatively high concentration of PBs were situated in the upper-outer side of the breast, near the armpit, that is a place commonly subjected to a chronic application of deodorants. Since these observations several studies have been performed, in order to demonstrate a significant correlation –or non-correlation- between the use of products containing parabens and breast cancer.

It was also seen that parabens may act as androgen antagonists. It has been demonstrated by in vitro studies, and it was also observed in rodents. Repeat oral dosage of propylparaben and butylparaben in diet to juvenile rodents has been reported to result in alterations to male reproductive functions including spermatogenesis, testosterone secretion and epididymal weights (Effects of butylparaben on the male reproductive system in rats.,2001). According to this, a possible role in reproductive dysfunctions, highly increased in the last 50 years, was hypothesized.

Furthermore an implication in melanoma development was considered. Some works suggested that long-term application of methylparaben to keratinocytes could infuence proliferation rate, induce oxidative stress in skin after reaction with singlet oxygen in visible light and also potentiate UV-induced damage of skin keratinocytes, including reactive oxygen species (ROS) and nitric oxide (NO) production and lipid peroxidation. ( from the review Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks, 2008)

Nearby these potential cytotoxic activities, also a mitochondrial dysfunction induced by 4hydroxybenzoate esters has been described. Indeed, the analogies between bacterial cells and human mitochondria lead to consider a possible harmful activity of PBs on the second ones, with a mechanism parallel to the one which make them toxic for bacteria. Effectively an analogue effect on mitochondria and hepatocytes isolated from rat liver has been observed, including mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation. This effect has been attributed to the induction of mitochondrial membrane permeability transition, mediated by PBs. (Role of mitochondrial membrane permeability transition in p-Hydroxybenzoate ester-induced cytotoxicity in rat hepatocytes,1999)
The mitochondrial damage has been confirmed also in melanoma culture cells, suggesting another possible mechanism which could participate in cytotoxicity PBs-mediated. (Metabolic Bioactivation and Toxicity of Ethyl 4-Hydroxybenzoate in Human SK-MEL-28 Melanoma Cells,2007)

The question is still controversial, but a significant correspondence between PBs and cancer, or any harmful activity, hasn’t already been demonstrated. Many critical reviews have been written against a possible dangerousness, denying a significant estrogenic activity of PBs in vivo (Personal care products and endocrine disruption: A critical review of the literature,2010) , mainly because of the very low concentration of PBs that can be found in cosmetics and food.
Because of this, as the EFSA adfirms, " the toxicological information available shows some inadequacies and uncertainties and further studies along the following lines are needed".


Because of the described lack of evidence, U.S. Food and Drug Administration still considers as safe the utilization of PBs in cosmetics and food, with a mean level in consumer goods of 0.01-0.3%. (FDA,2007)

The European regulation establishes an Acceptable Daily Intake of 0-10mg/kg for the most common parabens (methyl butyl ethylparabens), according to the lack of evidence of a significant estrogenic activity in vivo also at concentrations far higher than the commonly used ones. (EFSA Panel on Food additives, flavourings, processing aids and materials in contact with food (AFC), 2004)

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