Repeated-dose toxicity and toxicokinetic study of isobutylparaben in rats subcutaneously treated for 13 weeks.

Parabens have historically served as antimicrobial preservatives in a range of consumables such as food, beverages, medications, and personal care products due to their broad-spectrum antibacterial and antifungal properties. Traditionally, these compounds were believed to exhibit low toxicity, causing minimal irritation, and possessing limited sensitization potential. However, recent evidence suggests that parabens might function as endocrine-disrupting chemicals (EDCs). Consequently, extensive research is underway to elucidate potential human health implications arising from exposure to these substances. Among these parabens, particular concerns have been raised regarding the potential adverse effects of iso-butylparaben (IBP). Studies have specifically highlighted its potential for inducing hormonal disruption, significant ocular damage, and allergic skin reactions. This study aimed to evaluate the prolonged systemic toxicity, semen quality, and estrus cycle in relation to endocrine disruption endpoints, alongside assessing the toxicokinetic behavior of IBP in Sprague-Dawley rats following a 13-week repeated subcutaneous administration. The rats were administered either the vehicle (4% Tween 80) or IBP at dosage levels of 2, 10, and 50 mg/kg/day for 13 weeks. Blood collection for toxicokinetic study was conducted on three specified days: day 1 (1st), day 30 (2nd), and day 91 (3rd). Systemic toxicity assessment and potential endocrine effects were based on various parameters including mortality rates, clinical signs, body weights, food and water consumption, ophthalmological findings, urinalysis, hematological and clinical biochemistry tests, organ weights, necropsy and histopathological findings, estrus cycle regularity, semen quality, and toxicokinetic behavior. The findings revealed that IBP induced local irritation at the injection site in males at doses ≥ 10 mg/kg/day and in females at 50 mg/kg/day; however, systemic toxicity was not observed. Consequently, the no-observed-adverse-effect level (NOAEL) for IBP was determined to be 50 mg/kg/day in rats of both sexes, indicating no impact on the endocrine system. The toxicokinetics of IBP exhibited dose-dependent systemic exposure, reaching a maximum dose of 50 mg/kg/day, and repeated administration over 13 weeks showed no signs of accumulation.

Amended Safety Assessment of Parabens as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 21 parabens as preservatives in cosmetic products. All of these ingredients are reported to function in cosmetics as preservatives; however, 5 are reported to also function as fragrance ingredients. The Panel reviewed relevant data relating to the safety of these ingredients under the reported conditions of use in cosmetic formulations. The Panel concluded that 20 of the 21 parabens included in this report are safe in cosmetics in the present practices of use and concentration described in this safety assessment when the sum of the total parabens in any given formulation does not exceed 0.8%. However, the available data are insufficient to support a conclusion of safety for benzylparaben in cosmetics.

Investigation of the Compatibility of the Skin PAMPA Model with Topical Formulation and Acceptor Media Additives Using Different Assay Setups.

The Skin Parallel Artificial Membrane Permeability Assay (PAMPA) is a 96-well plate-based skin model with an artificial membrane containing free fatty acid, cholesterol, and synthetic ceramide analogs to mimic the stratum corneum (SC) barrier. The current study evaluates the compatibility of lipophilic solvents/penetration enhancer, topical emulsions containing different emulsifier systems, and organic acceptor media additives with the artificial membrane of the assay. Additionally, different assay setups (standard setup: donor in bottom plate versus modified setup: donor in top plate) were compared. Methylparaben (MP), ethylparaben (EP), and propylparaben (PP) were used as model permeants and internal standards for proper assay execution. The permeation order of the parabens (MP > EP > PP) remained the same with different lipophilic solvents, and the ranking of lipophilic solvents was comparable under standard and modified conditions (isopropyl myristate, IPM > dimethyl isosorbide, DMI ≥ propylene glycol, PG > diisopropyl adipate, DIPA). Pre-incubation of the Skin PAMPA plates with IPM, DIPA, and DMI, as well as with formulations that contain non-ionic emulsifiers, and acceptor solutions containing DMSO or EtOH (≤ 50%) for 4 h did not increase the percentage of permeated parabens in the main experiment, suggesting that those compounds do not make the artificial membrane more permeable. High-resolution mass spectrometry confirmed that acceptor solutions with ≤ 50% DMSO or EtOH do not extract stearic acid, cholesterol, and certramides at standard assay conditions. Hence, if certain constraints are considered, the Skin PAMPA model can be used as a pre-screening tool for topical formulation selection.

Effects of Temperature and Humidity on the Skin Permeation of Hydrophilic and Hydrophobic Drugs.

The humidity was a well-known method to hydrate the skin; however, the published data were varied, and systemic experiments in the previous papers were few. Therefore, the in vitro permeation of excised porcine ear skin by drugs with different polarities [aminopyrine (AMP), antipyrine (ANP), methylparaben (MP), and ibuprofen (IP)] was analyzed under a constant skin surface temperature with different temperatures and humidities to reveal the effects of temperature and humidity on the skin permeation enhancement effects. Applied formulations were prepared by mixing the drug and a hydrophilic vehicle containing glycerin. The disposition-distance profiles of water and the humectant glycerin in the stratum corneum were also investigated using confocal Raman microscopy. High absolute humidity (AH) significantly contributed to the high skin penetration of the hydrophilic penetrants AMP, ANP, and MP but not the hydrophobic penetrant IP. An increase in the partition parameter and a decrease in the diffusivity parameter occurred with an increase in AH, independent of drug polarity. Moreover, we found that dew condensation induced by high AH on temperature-controlled skin surface may effectively increase water content and may provide higher glycerin distribution in the skin barrier, the stratum corneum. Increasing the amount of water and hydrophilic vehicles such as glycerin in the stratum corneum may enhance the permeation of hydrophilic penetrants AMP, ANP, and MP. These data suggested a dew condensation on the skin surface induced by high AH at a constant skin surface temperature would be important to enhance hydrophilic penetrants.

Exposure to bisphenols and parabens during pregnancy and relations to steroid changes.

BACKGROUND: The harmful effects of endocrine disrupting compounds (EDCs) on human health are generally well-known, and exposure during fetal development may have lasting effects. Fetal exposure to bisphenol A (BPA) has been recently relatively well-studied; however, less is known about alternatives such as bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF), which have started to appear in consumer products. Parabens are another widespread group of EDCs, with confirmed transplacental passage. The usage of many cosmetic, pharmaceutical and consumer products during the pregnancy that may contain parabens and bisphenols has led to the need for investigation. OBJECTIVES: To shed more light into the transplacental transport of BPA, its alternatives, and parabens, and to study their relation to fetal steroidogenesis. METHODS: BPA, BPS, BPF, BPAF, methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben and 15 steroids including estrogens, corticoids, androgens and immunomodulatory ones were determined in 27 maternal (37th week of pregnancy) and cord plasma samples using liquid chromatography - tandem mass spectrometry methods. RESULTS: In cord blood, significantly higher BPA levels (p=0.0455) were observed compared to maternal plasma. The results from multiple regression models showed that in cord blood, methylparaben (ß=-0.027, p=0.027), propylparaben (ß=-0.025, p=0.03) and the sum of all measured parabens (ß=-0.037, p=0.015) were inversely associated with testosterone levels. CONCLUSION: To the best of our knowledge, this is the first study reporting the simultaneous detection of BPA, alternative bisphenols, parabens and steroids in maternal and cord plasma. Our study confirmed the transplacental transport of BPA, with likely accumulation in the fetal compartment. The negative association of cord blood parabens and testosterone levels points to possible risks with respect to importance of testosterone for prenatal male development.

Oxidation of propyl paraben by ferrate(VI): Kinetics, products, and toxicity assessment.

Propyl paraben (propyl 4-hydroxybenzoate, PPB), one of the typically used paraben species in various pharmaceutical and personal care products, has been found in different aquatic environment, which could affect the water quality and human health. In this paper, the degradation of PPB by aqueous ferrate (Fe(VI)) was investigated in different water matrix and reaction kinetics as a function of pH was determined. Intermediate products of the degradation process were isolated and characterized by the high performance liquid chromatography/mass spectrometry/mass spectrometry techniques. Acute and chronic toxicities during water treatment of PPB using Fe(VI) were calculated using the ECOSAR program at three trophic levels. The obtained apparent second-order rate constant (kapp) for PPB reaction with Fe(VI) ranged from 99.6 ± 0.4 M-1 s-1 to 15.0 ± 0.1 M-1 s-1 with the half-life (t1/2) ranging from 154 s to 1026 s at pH 6.5-10.0 for an Fe(VI) concentration of 600 µM. The proposed pathway for the oxidation of PPB by Fe(VI) involves one electron transfer of phenoxyl radical and breaking of the ether bond. In general, the oxidation of PPB by ferrate resulted in a significant decrease in toxicity at three trophic levels.

UHPLC-MS/MS Determination, Pharmacokinetic, and Bioavailability Study of Taxifolin in Rat Plasma after Oral Administration of its Nanodispersion.

A rapid and sensitive LC-MS/MS method based on the Triple Quad system has been developed and validated for the determination and pharmacokinetics of taxifolin and its nanodispersion in rat plasma. Taxifolin plasma samples along with butylparaben (internal standard) were pre-treated by liquid-liquid extraction with ethyl acetate, and then separated on a SB-C18 RRHD column (150 mm × 2.1 mm × 1.8 µm) using isocratic elution with a run time of 3.0 min. The mobile phase was acetonitrile-water (90:10, v/v) containing 5 mM ammonium acetate at a flow rate of 0.4 mL/min. Quantification of taxifolin was performed by the electrospray ionization tandem mass spectrometry in the multiple reaction monitoring (MRM) mode with negative atmospheric ionization at m/z 303.0→285.0 for taxifolin and 193.1→92.0 for I.S., respectively. The calibration curve of taxifolin showed good linearity over a concentration range of 5.0-4280 ng/mL with a correlation coefficient of 0.9995. The limit of quantification (LLOQ) was 5.0 ng/mL. Intra-day, inter-day precision and accuracy (percent relative to standard deviation) were all within 8% at three concentration levels. A total recovery of taxifolin and I.S. was beyond 75%. The present LC-MS/MS method was successfully applied to pharmacokinetic studies of taxifolin after intravenous administration of taxifolin, oral administration of its physical mixture and nanodispersion. The absolute bioavailability of taxifolin was calculated as 0.75% for taxifolin nanodispersion and 0.49% for taxifolin, respectively.

An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates.

PURPOSE: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. METHODS: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. RESULTS: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h. CONCLUSIONS: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Elevated Accumulation of Parabens and their Metabolites in Marine Mammals from the United States Coastal Waters.

The widespread exposure of humans to parabens present in personal care products is well-known. Nevertheless, little is known about the accumulation of parabens in marine organisms. In this study, six parabens and four common metabolites of parabens were measured in 121 tissue samples from eight species of marine mammals collected along the coastal waters of Florida, California, Washington, and Alaska. Methyl paraben (MeP) was the predominant compound found in the majority of the marine mammal tissues analyzed, and the highest concentration found was 865 ng/g (wet weight [wet wt]) in the livers of bottlenose dolphins from Sarasota Bay, FL. 4-Hydroxybenzoic acid (4-HB) was the predominant paraben metabolite found in all tissue samples. The measured concentrations of 4-HB were on the order of hundreds to thousands of ng/g tissue, and these values are some of the highest ever reported in the literature. MeP and 4-HB concentrations showed a significant positive correlation (p < 0.05), which suggested a common source of exposure to these compounds in marine mammals. Trace concentrations of MeP and 4-HB were found in the livers of polar bears from the Chuckchi Sea and Beaufort Sea, which suggested widespread distribution of MeP and 4-HB in the oceanic environment.

Temporal variability of urinary concentrations of phthalate metabolites, parabens and benzophenone-3 in a Belgian adult population.

In the present study, we investigated the temporal within-person variability of the exposure biomarker for phthalates, parabens and benzophenone-3 (BP3) in 32 Belgian adults, each providing 11 urine spots during 4 months. We calculated the intraclass coefficient correlation (ICC), the sensitivity and the specificity to assess the temporal reproducibility and to investigate the predictive ability of the spot measurements for these classes of chemicals. Additionally, we explored the temporal variability of the estimation of the cumulative risk of exposure to phthalates (hazard index; HI). We observed fair ICC ranging from 0.55 to 0.68 for parabens, monoethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP) and BP3, but lower ICC, from 0.20 to 0.49, for monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MnBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxo-hexyl phthalate (5-oxo-MEHP) and mono-2-ethyl-5-hydroxy-hexyl phthalate (5-OH-MEHP). The ICC estimated for HI (0.49) reflected a moderate reproducibility. The measurements in spot samples were moderate to good predictor of the 4-month level of exposure for parabens, MEP, MnBP, MiBP, BP3 and HI (sensitivity ranging from 0.67 to 0.77), but lower predictor for MEHP, 5-oxo-MEHP, 5-OH-MEHP and MBzP (sensitivity ranging from 0.58 to 0.63). The sensitivity could be increased when several spot urinary levels were averaged to predict the long-term level of exposure. Globally, our results indicate that a single spot measurement seems to correctly represent the long-term exposure for parabens, BP3, MEP, MiBP and HI. Additional spot samples seemed to be needed for the proper exposure assessment of the other target compounds.

Temperature influencing permeation pattern of alfuzosin: an investigation using DoE.

BACKGROUND AND OBJECTIVE: There has been relatively little investigation of the effect of temperature on skin permeation compared to other methods of penetration enhancement. A principal physicochemical factor which controls the passive diffusion of a solute from a vehicle into the skin arises from the skin temperature. The aim of this ex vivo study was to probe into the effect of heat on transdermal absorption of alfuzosin hydrochloride from ethyl cellulose-polyvinyl pyrrolidone (EC-PVP) based transdermal systems. MATERIALS AND METHODS: Principles of design of experiment (DoE) were used to systematically study the influence of temperature on transdermal permeation of alfuzosin. Ex vivo transdermal permeation studies were carried out at varied donor compartment temperatures. Permeation data analysis was carried out and activation energy for transdermal permeation was estimated. RESULTS: Temperature found to enhance ex vivo permeation parameters of alfuzosin hydrochloride from its transdermal systems. It was also noted that chemical permeation enhancers potentiate permeation enhancing effect of temperature. The permeation flux values approximately doubled after exposure to 45°C. The activation energy for transdermal permeation was found lower for the runs with chemical permeation enhancers indicating existence of a lower energy barrier in the presence of chemical permeation enhancers. CONCLUSION: The method reported here is a simple and useful tool for studying the effect of heat on percutaneous absorption. Such temperature dependent enhancement of flux can be more pronounced at skin surface temperatures >45°C.

Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status.

A framework for understanding the complexity of cancer development was established by Hanahan and Weinberg in their definition of the hallmarks of cancer. In this review, we consider the evidence that parabens can enable development in human breast epithelial cells of four of six of the basic hallmarks, one of two of the emerging hallmarks and one of two of the enabling characteristics. In Hallmark 1, parabens have been measured as present in 99% of human breast tissue samples, possess oestrogenic activity and can stimulate sustained proliferation of human breast cancer cells at concentrations measurable in the breast. In Hallmark 2, parabens can inhibit the suppression of breast cancer cell growth by hydroxytamoxifen, and through binding to the oestrogen-related receptor gamma may prevent its deactivation by growth inhibitors. In Hallmark 3, in the 10 nm-1 µm range, parabens give a dose-dependent evasion of apoptosis in high-risk donor breast epithelial cells. In Hallmark 4, long-term exposure (>20 weeks) to parabens leads to increased migratory and invasive activity in human breast cancer cells, properties that are linked to the metastatic process. As an emerging hallmark methylparaben has been shown in human breast epithelial cells to increase mTOR, a key regulator of energy metabolism. As an enabling characteristic parabens can cause DNA damage at high concentrations in the short term but more work is needed to investigate long-term, low-dose mixtures. The ability of parabens to enable multiple cancer hallmarks in human breast epithelial cells provides grounds for regulatory review of the implications of the presence of parabens in human breast tissue.

Absorbability, mechanism and structure-property relationship of three phenolic acids from the flowers of Trollius chinensis.

The absorption properties, mechanism of action, and structure-property relationship of three phenolic acids isolated from the flowers of Trollius chinensis Bunge, namely, proglobeflowery acid (PA), globeflowery acid (GA) and trolloside (TS), were investigated using the human Caco-2 cell monolayer model. The results showed that these three phenolic acids were transported across the Caco-2 cell monolayer in a time and concentration dependent manner at the Papp level of 10-5 cm/s, and their extent of absorption correlated with their polarity and molecular weight. In conclusion, all three of these compounds were easily absorbed through passive diffusion, which implied their high bioavailability and significant contribution to the effectiveness of T. chinensis.

Distribution of parabens and 4-HB in human blood.

Human blood has been commonly and routinely analyzed to determine internal human exposure to parabens. However, data on the occurrence of parabens and their common metabolite, p-hydroxybenzoic acid (4-HB), in different human blood matrixes is still limited. In this study, 139 pairs of serum and whole blood samples were collected from Chinese adults, and then analyzed them for 5 parabens and 4-HB. Methylparaben (MeP) and propylparaben (PrP) were consistently the predominant parabens in human serum (mean 2.3 and 2.1 ng/mL, respectively) and whole blood (1.9 and 1.3 ng/mL, respectively). Mean concentrations of 4-HB in human serum and whole blood were 7.7 and 12 ng/mL, respectively. Concentrations of parabens, except benzylparaben (BzP), and 4-HB in human serum were significantly (p < 0.01) correlated with that in whole blood. Distribution pattern of parabens and 4-HB in human blood was evaluated, for the first time, based on their partitioning between human serum and whole blood (Kp). Mean Kp values of parabens, except BzP, increased with the alkyl chain length from 0.83 to 1.6. BzP (mean 1.4) had a comparable mean Kp value to PrP (mean 1.4). Among target analytes, 4-HB had the lowest mean Kp value (0.75). These data are important to select appropriate blood matrixes for conducting human exposure assessment and epidemiological studies on parabens.

A proposed study on the transplacental transport of parabens in the human placental perfusion model.

Human exposure to parabens as a preservative used in personal care products is of increasing concern, as there is evidence from in vivo and in vitro studies of hormone disruption in association with exposure to parabens. Transport across the placenta could be critical for risk assessment, but the available data are sparse. The aim is to develop a method for estimating fetal exposure, via the placenta, to the most commonly-used parabens, by using a human placental perfusion model. The use of human tissue is vital for determining human fetal exposure, because animal studies are of little relevance, since the placenta exhibits significant interspecies variation. An HPLC model is currently being established to simultaneously quantify four different parabens, namely, methylparaben, ethylparaben, propylparaben and butylparaben, and their main metabolite, p-hydroxybenzoic acid. With this model, we aim to determine the transport kinetics of these parabens across the human placenta, and to investigate placental metabolism, including differences in transport due to molecular characteristics. This will facilitate assessment of the risks associated with the use of paraben-containing products during pregnancy.

Use of external metabolizing systems when testing for endocrine disruption in the T-screen assay.

Although, it is well-established that information on the metabolism of a substance is important in the evaluation of its toxic potential, there is limited experience with incorporating metabolic aspects into in vitro tests for endocrine disrupters. The aim of the current study was a) to study different in vitro systems for biotransformation of ten known endocrine disrupting chemicals (EDs): five azole fungicides, three parabens and 2 phthalates, b) to determine possible changes in the ability of the EDs to bind and activate the thyroid receptor (TR) in the in vitro T-screen assay after biotransformation and c) to investigate the endogenous metabolic capacity of the GH3 cells, the cell line used in the T-screen assay, which is a proliferation assay used for the in vitro detection of agonistic and antagonistic properties of compounds at the level of the TR. The two in vitro metabolizing systems tested the human liver S9 mix and the PCB-induced rat microsomes gave an almost complete metabolic transformation of the tested parabens and phthalates. No marked difference the effects in the T-screen assay was observed between the parent compounds and the effects of the tested metabolic extracts. The GH3 cells themselves significantly metabolized the two tested phthalates dimethyl phthalate (DMP) and diethyl phthalate (DEP). Overall the results and qualitative data from the current study show that an in vitro metabolizing system using liver S9 or microsomes could be a convenient method for the incorporation of metabolic and toxicokinetic aspects into in vitro testing for endocrine disrupting effects.

Placental transport of parabens studied using an ex-vivo human perfusion model.

INTRODUCTION: Parabens are a group of chemicals widely used as preservatives in daily consumer products such as cosmetics, food items, pharmaceuticals and household commodities. They have been broadly detected in human samples indicating a general human exposure, and concerns arose from their potential endocrine disrupting effect. Especially the exposure to parabens during pregnancy is concerning, as the time of fetal development is a particularly vulnerable period. The aim of this study was to investigate the transport and metabolism of four commonly used parabens: methyl-, ethyl-, propyl- and butylparaben (MeP, EtP, PrP and BuP) and the metabolite para-hydroxybenzoic acid (PHBA) across the human placenta. METHODS: An ex-vivo human placental perfusion model was used. The test compounds were added in the maternal compartment (with initial concentrations of 1 mM or 0.1 mM). Placental transport was evaluated by fetal-maternal concentration ratios (FM-ratio), transport index (TI) and indicative permeability (IP). RESULTS: Information about parabens kinetics was taken from 10 perfusions and PHBA from 7 perfusions. Paraben metabolism was not detected. The placental transport of MeP, EtP, PrP, BuP and PHBA revealed a transfer from maternal to fetal circulations with FM120 of 0.86 ± 0.27 (MeP), 0.98 ± 0.28 (EtP), 1.00 ± 0.28 (PrP), 1.12 ± 0.59 (BuP) and 0.82 ± 0.37 (PHBA). The test substances accumulated in the perfused tissue in some degree. The average kinetic parameters FM-ratio, TI and IP were not different between chemicals. DISCUSSION: The present study shows that the placenta barrier is permeable to all four parabens and the metabolite, which implies potential fetal exposure.

The controversies of parabens - an overview nowadays.

Effects of paraben toxicity, i.e., endocrine-disruption properties, are in the focus of researchers for decades, but still - they are a hot subject of debate. Parabens are aliphatic esters of p-hydroxybenzoic acid, which are widely used as antimicrobial agents for the preservation of cosmetics, pharmaceuticals and foods. Mostly used parabens are methyl-, ethyl-, propyl- and butylparaben. Although the toxicity of parabens is reported in animals and in in vitro studies, it cannot be taken for granted when discussing hazards for human health due to an unrealistic exposure -safety profile. Many studies have demonstrated that parabens are non-teratogenic, non-mutagenic, non-carcinogenic and the real evidence for their toxicity in humans has not been established. For now, methyl-, ethyl- and propylparaben are considered safe for use in cosmetics and pharmaceuticals within the recommended range of doses. Regarding alternatives for parabens, a variety of approaches have been proposed, but every substitute would need to be tested rigorously for toxicity and safety.

Mathematical model to predict skin concentration of drugs: toward utilization of silicone membrane to predict skin concentration of drugs as an animal testing alternative.

PURPOSE: To calculate the skin concentration of active ingredients in cosmetics and topical pharmaceuticals using silicone membrane permeation. METHODS: A series of parabens were used as model ingredients. Skin concentration of parabens was calculated using silicone membrane permeability. Their partition coefficient from formulations to the silicone membrane was determined by the membrane permeation profiles, and used to calculate their silicone membrane concentration, under an assumption that the membrane is one homogenous diffusion layer. The same procedure was applied for hairless rat skin. RESULTS: The calculated concentration of parabens in silicone membrane was very close to their observed values. However, the skin concentration calculated by skin permeability was not similar to the observed concentration. Re-calculation was performed under the assumption that the skin consists of two diffusion layers. This modification using permeation data through full-thickness and stripped skin enabled precise prediction of the skin concentration of parabens. In addition, the partition coefficient to the silicone membrane was useful to estimate their skin concentration. CONCLUSIONS: Ingredient concentration in skin can be precisely predicted using diffusion equations and partition coefficients through permeation experiments using a silicone membrane. The calculated in-skin concentration is useful for formulation studies of cosmetics and topical pharmaceuticals.

Mechanism of enhanced dermal permeation of 4-cyanophenol and methyl paraben from saturated aqueous solutions containing both solutes.

Dermal permeation through human epidermis and uptake into isolated human stratum corneum (SC) that was and was not delipidized were measured for 2 model compounds, 4-cyanophenol (CP) and methyl paraben (MP), from saturated aqueous solutions containing 1 or both compounds. Because the solutions were in equilibrium with the pure CP and MP, the thermodynamic activity of the compounds was constant. Compared with compounds that are known permeation enhancers, MP and CP would not normally be expected to act as enhancers. Nevertheless, when both compounds were present, the steady-state fluxes through the epidermis increased by factors of 5.2 and 2.6 for MP and CP, respectively. Within the variability of the measurements, this increase in MP flux is consistent with the 6.4-fold increase in the SC uptake, which occurs primarily into the nonlipid regions of the SC. In contrast, the 1.6-fold increase in CP uptake when MP is present is too small to explain the increase in CP flux. These results suggest that CP enhances the skin permeation of MP by primarily increasing the solubility of MP in the SC, especially in the nonlipid regions, while MP increases the skin permeation of CP by enhancing both the solubility and diffusivity of CP in the SC.