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PubMed1998

Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic.

The inadvertent estrogenicity of certain synthetic chemicals, and their subsequent effects on the endocrine system of humans and wildlife, is of concern. In this paper we report findings from in vitro and in vivo (uterotrophic) studies which confirm that a range of alkyl hydroxy benzoate preservatives (parabens) are weakly estrogenic. In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilboestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. Given their use in a wide range of commercially available topical preparations, it is suggested that the safety in use of these chemicals should be reassessed, with particular attention being paid to estimation of the actual levels of systemic exposure of humans exposed to these chemicals. The acquisition of such data is a prerequisite to the derivation of reliable estimates of the possible human risk of exposure to parabens.

Animals↗

PubMed2006

Influence of crystal structure on the compaction properties of n-alkyl 4-hydroxybenzoate esters (parabens).

PURPOSE: The aim of the study is to examine the influence of slip planes on the nanoindentation hardness and compaction properties of methyl, ethyl, n-propyl, and n-butyl 4-hydroxybenzoate (parabens). METHODS: Molecular modeling calculations, embodying the attachment energy concept, were performed to predict the slip planes in the crystal lattices, whereas the nanoindentation hardness of the crystals and the tensile strength of directly compressed compacts were measured. RESULTS: Unlike the other three parabens, methyl paraben has no slip planes in its crystal lattice, and its crystals showed greater nanoindentation hardness, corresponding to lower plasticity, whereas its tablets exhibited substantially lower tensile strength than those of ethyl, propyl, or butyl paraben. CONCLUSIONS: The nanoindentation hardness of the crystals and the tensile strength of directly compressed tablets were each found to correlate directly with the absence or presence of slip planes in the crystal structures of the parabens because slip planes confer greater plasticity. This work presents a molecular insight into the influence of crystal structural features on the tableting performance of molecular crystals in general and of crystalline pharmaceuticals in particular.

Crystallization↗

PubMed2006

Partitioning of parabens between phases of submicron emulsions stabilized with egg lecithin.

Partitioning of methyl and propyl parabens (methyl and propyl hydroxybenzoate, paraben M and P) between the major phases in the parenteral submicron emulsions was studied. The investigated emulsions contained 10% or 20% soya-bean oil, 1.2% or 2.4% egg lecithin, 0.18% or 0.36% paraben M and 0.02% or 0.04% paraben P. The aqueous phase was obtained by ultracentrifugation, and subsequently, it was subjected to ultrafiltration, which procedure allowed to distinguish between the fractions of free preservatives (Fw) and incorporated in the liposomal or micellar region (Flm). The fractions present in the oily phase and in the interface were calculated. Depending on the formulation, Fw was 17-31% and 2.3-6.0% for paraben M and P, respectively. The Flm values were in a very narrow range, i.e. 3.0-6.0% for both preservatives. Substantial accumulation, i.e. 38-58% was found in the interface and the partitioning into this region was related to the oil/lecithin ratio rather than to lipophilicity of the preservative.

Chemistry, Pharmaceutical↗

PubMed2001

ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR.

Estrogenic activities of the phenolic preservatives methylparaben, ethylparaben, propylparaben, butylparaben, isopropylparaben and isobutylparaben were examined by assaying estrogen-receptor (ER)-dependent proliferation of MCF-7 cells. All the compounds stimulated the proliferation to about the same level as the maximal cell yield attained with 3x10(-11) M 17beta-estradiol, but at a concentration in the order of 10(5) to 10(7) higher than 17beta-estradiol. The cell-proliferative effects of parabens were completely suppressed by anti-estrogen ICI 182,780. MCF-7 cells treated with butylparaben and isobutylparaben exhibited a decrease in gene expression of ERalpha and an increase in that of progesterone-receptor (PR), but the effects of these parabens were not as prominent as those of 17beta-estradiol. Western blot analysis indicated that these parabens caused a slight decrease in expression of ERalpha protein. Competitive binding to human ERalpha and ERbeta in vitro revealed that the parabens with longer side-chains showed greater affinity for estrogen receptors, and that they had similar relative binding affinity (RBA) values to both ERalpha and ERbeta. RBA values were much smaller than that of diethylstilbestrol. In conclusion, parabens have ER-dependent estrogenic activities, and their effects on the intracellular signaling pathway might be different from that of 17beta-estradiol.

Binding, Competitive↗

PubMed2000

The effect of occlusion on epidermal penetration of parabens from a commercial allergy test ointment, acetone and ethanol vehicles.

The efficacy of topical allergy screening systems relies on the ability of test agents to effectively penetrate the stratum corneum from applied vehicles and reach the viable cells involved in the cutaneous immune response system. There is very little evidence in the dermatologic literature to justify the choice and suitability of vehicles used in many allergy test systems and the effectiveness of occlusion, reported to have variable effects on solute penetration, often employed in combination with these systems. In this study we evaluated the in vitro human epidermal penetration of a mixture of paraben ester preservatives from a commercially available test ointment and two commonly employed solvent vehicles (acetone and ethanol), together with the effect of occlusion on the rate of delivery from these systems. Parabens were applied as finite doses (5 mg per cm2) to epidermal membranes mounted in horizontal Franz-type diffusion cells. At intervals of 2 h for a total of 10 h the receptor phase (20% ethanol in distilled water) was completely removed and replaced. Occlusion was effected by the placement of a piece of high density polyethylene (20 microm) over the application site immediately after dosing. Concentrations of parabens in receptor fluid and remaining in the epidermis at the end of the study were determined by high-performance liquid chromatography. There was a significant change in the epidermal flux of parabens from each of the vehicles following occlusion. Whereas increases were observed for the acetone and ethanol vehicles a decrease was seen following occlusion of the ointment formulation. Changes in flux appeared to result from a significant decrease in the epidermal partitioning of the esters following occlusion of the ointment and primarily by an increase in paraben epidermal diffusivity (estimated from changes in flux/retention) following occlusion of the solvent vehicles. These studies show that the effects of occlusion are strongly vehicle dependent, having wide implications for optimization of this technique with a range of topically applied solutes.

Cell Membrane Permeability↗

PubMed2003

Purification and characterization of PrbA, a new esterase from Enterobacter cloacae hydrolyzing the esters of 4-hydroxybenzoic acid (parabens).

The esterase PrbA from Enterobacter cloacae strain EM has previously been shown to confer additional resistance to the esters of 4-hydroxybenzoic acid (parabens) to two species of Enterobacter. The PrbA protein has been purified from E. cloacae strain EM using a three-step protocol resulting in a 60-fold increase in specific activity. The molecular mass of the mature enzyme was determined to be 54,619 +/- 1 Da by mass spectrometry. It is highly active against a series of parabens with alkyl groups ranging from methyl to butyl, with K(m) and V(max) values ranging from 0.45 to 0.88 mM and 0.031 to 0.15 mM/min, respectively. The K(m) and V(max) values for p-nitrophenyl acetate were 3.7 mM and 0.051 mM/min. PrbA hydrolyzed a variety of structurally analogous compounds, with activities larger than 20% relative to propyl paraben for methyl 3-hydroxybenzoate, methyl 4-aminobenzoate, or methyl vanillate. The enzyme showed optimum activity at 31 degrees C and at pH 7.0. PrbA was able to transesterify parabens with alcohols of increasing chain length from methanol to n-butanol, achieving 64% transesterification of 0.5 mm propyl paraben with 5% methanol within 2 h. PrbA was inhibited by 1-chloro-3-tosylamido-4-phenyl-2-butanone and 1-chloro-3-tosylamido-7-amino-2-heptanone (TLCK), with K(i) values of 0.29 and 0.20 mM, respectively, and was irreversibly inhibited by Diisopropyl fluorophosphate (DFP) or diethyl pyrocarbonate. The stoichiometry of addition of DFP to the enzyme was 1:1 and only 1 TLCK molecule was found in TLCK-modified enzyme, as measured by mass spectrometry. Analysis of the tryptic digest of the DFP-modified PrbA demonstrated that the addition of a DFP molecule occurred at Ser-189, indicating the location of the active serine.

Amino Acid Sequence↗

PubMed2006

Transesterification of p-hydroxybenzoate esters (parabens) by human intestinal (Caco-2) cells.

p-Hydroxybenzoate ester (paraben) preservatives are used in numerous orally administered products. The recognized route of metabolism for parabens is hydrolysis to p-hydroxybenzoic acid followed by conjugation and excretion. However, in the presence of alcohols, a presystemic transesterification pathway not previously reported for the human intestine can occur. Using human intestinal (Caco-2) cells, it was observed that hydrolysis of parabens to p-hydroxybenzoic acid is reduced markedly by ethanol concentrations that can occur in the human intestine, 0.25-0.5% (v/v). Ethanol concentrations of 1.0-2.5% (v/v) were optimal for transesterification to ethylparaben in Caco-2 cell homogenates. The kinetics of the transesterification reaction with regard to ethanol concentration (0-20%), time, pH (3-9), protein concentration (1-5 mg ml-1) and substrate concentration (6.25-200 microM) as well as the effects of different alcohols were studied. The Km and Vmax values for transesterification with ethanol for methyl, propyl, butyl, heptyl and octyl parabens were 449.7, 165.7, 86.1, 24.2 and 45.9 microM and 114.4, 37.5, 19.5, 7.5 and 7.6 micromol h-1 mg-1 Caco-2 cell protein, respectively. The Vmax values for transesterification of methylparaben with ethanol, propan-1-ol, butan-1-ol were 114.4, 5.1 and 4.9 micromol h-1 mg-1, respectively. Collectively, the kinetic data demonstrate that the enzyme responsible for the transesterification reaction has a preference for short-chain esters and represents the first report of transesterification in human intestinal cells. An implication of this mechanism is that alcohol-containing in vitro biosystems or protocols for the study of parabens disposition could generate transesterified artefacts. The clinical or toxicological implication is that, following co-ingestion of ester compounds with ethanol, transesterification could provide the basis for a previously unrecognized drug-alcohol interaction.

Biological Transport↗

PubMed1996

Irreversible paraben inhibition of glycolysis by Streptococcus mutans GS-5.

Parabens were found to inhibit irreversibly glycolysis by the cariogenic dental plaque bacterium Streptococcus mutans GS-5 and to decrease the capacity of the bacterium to lower the pH in dense cell suspensions containing excess glucose. The hierarchy of effectiveness was butyl > propyl > ethyl > methyl paraben. Results of studies of the nature of glycolytic inhibition by butyl paraben indicated that it could act at millimolar concentrations as an irreversible inhibitor of the phosphotransferase system for sugar uptake and was lethal for the bacterium at these same levels. Butyl paraben acted also as a reversible inhibitor of the F-ATPase of the organism. Overall, it appeared that the lethal actions of parabens can be interpreted at least in part as due to irreversible damage to key enzymes, such as those of the phosphotransferase system.

Food Preservatives↗

PubMed1988

Routine patch testing with paraben esters.

Paraben esters are the most widely used preservatives in cosmetics and topical medicaments. Their sensitization potential is low, based on both experimental and human experience. A paraben mixture is included in the ICDRG standard series, and in patch test studies, approximately 1% of eczema patients react to it. The present study confirms this frequency in 8020 patients patch tested consecutively. Testing with the individual paraben esters was employed as confirmation, which makes it unlikely that the excited skin syndrome is a significant problem in this context. It remains undetermined whether the present paraben mixture is the optimal patch test material for diagnosing paraben sensitivity.

Female↗

PubMed2001

Hydrolysis of 4-hydroxybenzoic acid esters (parabens) and their aerobic transformation into phenol by the resistant Enterobacter cloacae strain EM.

Enterobacter cloacae strain EM was isolated from a commercial dietary mineral supplement stabilized by a mixture of methylparaben and propylparaben. It harbored a high-molecular-weight plasmid and was resistant to high concentrations of parabens. Strain EM was able to grow in liquid media containing similar amounts of parabens as found in the mineral supplement (1,700 and 180 mg of methyl and propylparaben, respectively, per liter or 11.2 and 1.0 mM) and in very high concentrations of methylparaben (3,000 mg liter(-1), or 19.7 mM). This strain was able to hydrolyze approximately 500 mg of methyl-, ethyl-, or propylparaben liter(-1) (3 mM) in less than 2 h in liquid culture, and the supernatant of a sonicated culture, after a 30-fold dilution, was able to hydrolyze 1,000 mg of methylparaben liter(-1) (6.6 mM) in 15 min. The first step of paraben degradation was the hydrolysis of the ester bond to produce 4-hydroxybenzoic acid, followed by a decarboxylation step to produce phenol under aerobic conditions. The transformation of 4-hydroxybenzoic acid into phenol was stoichiometric. The conversion of approximately 500 mg of parabens liter(-1) (3 mM) to phenol in liquid culture was completed within 5 h without significant hindrance to the growth of strain EM, while higher concentrations of parabens partially inhibited its growth.

Biodegradation, Environmental↗

PubMed2002

Hypersensitivity to paraoxybenzoic Acid esters (parabens) in a dialysis patient.

A 24-year-old woman undergoing chronic dialysis therapy who had been diagnosed as having 'heparin allergy' presented acute allergic reaction after the intracatheter injection of a heparin agent. Further investigation revealed that mild eosinophilia had persisted for more than 3 years before this incidence despite avoiding the use of heparin agents. The leukocyte migration inhibition test (LMIT) showed that heparin agent A which was used for the patient showed positive reaction while heparin agent B which was not used for the patient showed a negative reaction. Paraoxybenzoic acid esters (parabens) are contained in heparin agent A but not in heparin agent B. Parabens showed positive reactions on LMIT. Parabens are the most common preservatives in drugs, foods, and cosmetics and they sometimes induce allergic reactions through percutaneous and possibly ingestive sensitization. However, they cause more severe allergic reactions when used intravenously. We concluded that the allergen in this patient was not heparin but parabens. Hypereosinophilia of unknown origin often occurs in dialysis patients. Such patients may be hypersensitive to parabens.

Adult↗

PubMed1977

Topical parabens: benefits and risks.

Parabens are the most frequently used preservative in dermatological medications. Some allergies have been reported to parabens, but these risks must be considered with respect to the benefits of parabens in concentrations used as preservatives in dermatological formulations. Considering the alternatives to parabens in preservat ives and placing perspective on the reported allergies we still find parabens to be a useful preservative with minimal risk to its benefits.

Administration, Topical↗

PubMed2001

Inhibition of Saccharomyces cerevisiae by slow release of propyl paraben from a polymer coating.

The inhibition of Saccharomyces cerevisiae by slow release of propyl paraben from a styrene-acrylate copolymer coating was examined and compared with the inhibition by direct addition of propyl paraben. Under slow release condition, a slow but continuous microbial inhibition was observed, whereas a cell outgrowth was observed under direct addition condition after a sufficient incubation time. S. cerevisiae cells isolated from the culture under direct addition condition were more tolerant of propyl paraben than cells isolated from the culture under slow release condition. The equilibrium propyl paraben concentrations under both conditions were 150 ppm. The release kinetics of propyl paraben from the coating at 30 degrees C was found to be controlled by Fickian diffusion within the coating. The estimated partition and diffusion coefficients were 4.65 x 10(-3) and 2.01 x 10(-10) cm2/s, respectively.

Food Contamination↗

PubMedDate not supplied

Acceleration of paraben sorption to polyethylene terephthalate: a freeze-thaw phenomenon.

The evaluation of preservative stability in a formulation throughout its life cycle (production, shipping, and storage) is an important part of product development and essential to ensuring that potential microbial contamination is satisfactorily controlled. This work investigates the unexpected losses of propyl and butylparaben in oral solutions packaged in polyethylene terephthalate (PET) bottles. The samples endured a temperature-cycling study that was designed to simulate extreme temperature fluctuations that could be encountered during product shipping and handling. An investigation into the preservative-package interaction indicated that the paraben preservatives precipitate as a result of the freezing process. The precipitated parabens at the bottom of the bottle dissolve as the solution warms. Without agitation of the solution, the local concentration of the parabens in the vicinity of the dissolving solids increases and is higher than in the oral solution at large. It appears that the combination of the localized high paraben concentration and increased temperature (50 degrees C) increases the kinetics of paraben sorption.

Adsorption↗

PubMedDate not supplied

Oestrogenic activity of p-hydroxybenzoic acid (common metabolite of paraben esters) and methylparaben in human breast cancer cell lines.

This paper addresses the question of whether p-hydroxybenzoic acid, the common metabolite of parabens, possesses oestrogenic activity in human breast cancer cell lines. The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in consumer products to which the human population is exposed and have been shown previously to possess oestrogenic activity and to be present in human breast tumour tissue, which is an oestrogen-responsive tissue. Recent work has shown p-hydroxybenzoic acid to give an oestrogenic response in the rodent uterotrophic assay. We report here that p-hydroxybenzoic acid possesses oestrogenic activity in a panel of assays in human breast cancer cell lines. p-Hydroxybenzoic acid was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor of MCF7 human breast cancer cells by 54% at 5 x 10(6)-fold molar excess and by 99% at 10(7)-fold molar excess. It was able to increase the expression of a stably integrated oestrogen responsive reporter gene (ERE-CAT) at a concentration of 5 x 10(-4) M in MCF7 cells after 24 h and 7 days, which could be inhibited by the anti-oestrogen ICI 182 780 (Faslodex, fulvestrant). Proliferation of two human breast cancer cell lines (MCF7, ZR-75-1) could be increased by 10(-5) M p-hydroxybenzoic acid. Following on from previous studies showing a decrease in oestrogenic activity of parabens with shortening of the linear alkyl chain length, this study has compared the oestrogenic activity of p-hydroxybenzoic acid where the alkyl grouping is no longer present with methylparaben, which has the shortest alkyl group. Intrinsic oestrogenic activity of p-hydroxybenzoic acid was similar to that of methylparaben in terms of relative binding to the oestrogen receptor but its oestrogenic activity on gene expression and cell proliferation was lower than that of methylparaben. It can be concluded that removal of the ester group from parabens does not abrogate its oestrogenic activity and that p-hydroxybenzoic acid can give oestrogenic responses in human breast cancer cells.

Binding, Competitive↗

PubMed1989

In vitro spermicidal activity of parabens against human spermatozoa.

Potent in vitro spermicidal activity of parabens against human spermatozoa was demonstrated in this study. The "pass" point concentration of the four parabens--methylparaben, ethylparaben, propylparaben, and butylparaben, at which all spermatozoa were immobilized and no immobilized spermatozoon revived after 30 min incubation in phosphate buffered glucose solution, was 6, 8, 3, and 1 mg/ml, respectively, as tested by Harris' method. These parabens are used as food and pharmaceutic preservatives; less toxicity and side effects were expected for the development of parabens as vaginal contraceptive agents.

Dose-Response Relationship, Drug↗

PubMed1993

LC studies on the potential interaction of paraben preservatives with sorbitol and glycerol.

Pharmaceutical formulations often contain one or more paraben preservatives in conjunction with a polyol such as sorbitol or glycerol. In one of these experimental formulations a number of unknown polar peaks have been detected near the solvent front by reversed-phase LC. These degradation products were not attributable to the active drug component or a hydrolysis product. The possibility of an interaction between the polyols and paraben preservatives has been explored using a three-variable, two-level, factorial design to determine the relative significance of the factors involved in the formation of these unknown peaks. The factors examined were pH, temperature and the ratio of polyol to paraben. This study has shown that pH and temperature are key factors affecting the formation of these unknown peaks. On the basis of these results suitable conditions can be suggested for minimizing the production of these unknown peaks. It seems clear that a number of pharmaceutical formulations containing a polyol and a paraben would present potential problems for assay validation on storage owing to the formation of these degradation products, particularly if the drug component is polar and elutes near the solvent front.

Chromatography, Liquid↗

PubMed2006

Optimisation of a solid-phase microextraction method for the determination of parabens in water samples at the low ng per litre level.

A procedure for the determination of five esters of p-hydroxybenzoic acid (parabens) in water samples is presented. Analytes (methyl, ethyl, propyl, butyl and benzyl paraben) are concentrated on a solid-phase microextraction (SPME) fibre, converted on their tert-butyldimethylsilyl derivatives and selectively determined using gas chromatography in combination with tandem mass spectrometry (GC-MS/MS). Influence of different factors on the efficiency of extraction and on-fibre derivatization steps is described in detail. For all species, the highest enrichment factors were achieved using a polyacrylate (PA) fibre exposed directly to stirred water samples, containing 150 mg/ml of sodium chloride, at room temperature. Performance of the further on-fibre derivatization reaction was also maximum at room temperature, considering a short exposition period of the SPME fibre to vapours of the silylation reagent. Under optimised conditions, the proposed method achieved quantification limits from 0.001 to 0.025 ng/ml and it was free of matrix effects; therefore, external calibration can be used as the quantification technique. From our knowledge, this work describes the first application of SPME and gas chromatography to the determination of parabens in water. The analysis of a limited number of real samples revealed the presence of parabens in raw sewage water at concentrations up to 3 ng/ml.

Calibration↗