Phototoxic assessment of a sunscreen formulation and its excipients: An in vivo and in vitro study.

BACKGROUND: Cosmetic preservatives are used to protect cosmetic formulations and improve its shelf-life. However, these substances may exert phototoxic effects when used under sunlight. OBJECTIVE: To assess safety, efficacy and putative phototoxic effects of a sunscreen formulation SPF 30 and its excipients. MATERIALS/METHODS: Irradiation was performed with solar simulated light (SSL) and the sunscreen from the School of Pharmacy/UFRJ/Brazil. We used albino hairless mice in different groups (control (G1), only irradiated (G2), sunscreen plus irradiation (G3) and vehicle plus irradiation (G4) for morphological assessment and immunefluorescence detection to OKL38. In vitro analyses were with a Saccharomyces cerevisiae (SC) strain plus SSL in the presence of methylparaben, propylparaben, imidazolidinyl urea, aminomethyl propanol and their association. RESULTS: G3 and G4 displayed photosensitization leading to thickening of the epidermis and increased dermal cellularity. G4 displayed strong OKL38 labeling when compared with other groups. Aminomethyl propanol, methylparaben and propylparaben are endowed with phototoxic activity against SC. Propylparaben displayed the highest phototoxic effect, followed by excipients association. CONCLUSIONS: The sunscreen's vehicle is endowed with phototoxic activity. Propylparaben was the most phototoxic agent, increasing the overall phototoxicity of excipient association, pointing to a critical concern regarding vehicle associations intended to cosmetic purposes.

Safety Assessment of Hydroxypropyl Bis(N-Hydroxyethyl-p-Phenylenediamine) HCl as Used in Cosmetics.

The Cosmetic Ingredient Review Expert Panel (CIR Panel) reviewed the safety of hydroxypropyl bis(N-Hydroxyethyl-p-Phenylenediamine) HCl, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that hydroxypropyl bis(N-hydroxyethyl-p-phenylenediamine) HCl is safe for use in oxidative hair dye formulations as described in this safety assessment.

High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment.

The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these drugs compared with concentration-effects curves. Binding kinetics to specific states were identified using a new HERG Markov model. The model was then modified to represent the canine rapid delayed rectifier K(+) current at 37°C and carry out AP predictions. Predictions were compared with a simpler model based on conductance reduction and were found to be much closer to experimental data. Improved sensitivity to concentration and pacing frequency variables was obtained when including binding kinetics. Our new electrophysiological protocol is suitable for high-throughput screening and is able to distinguish drug-binding kinetics. The association of this protocol with our modeling approach indicates that quantitative predictions of AP modulation can be obtained, which is a significant improvement compared with traditional conductance reduction methods.

Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor.

Drug-induced kidney injury (DIKI) results in attrition during drug development; new DIKI urinary biomarkers offer potential to detect and monitor DIKI progression and regression, but frequently only in rats. The triple reuptake inhibitor (TRI) PRC200-SS represents a new class of antidepressants that elevate synaptic levels of serotonin, norepinephrine, and dopamine and is expected to produce more rapid onset and better antidepressant efficacy than single or dual inhibitors. Although preclinical studies and recent clinical trials lend support to this concept of superior efficacy for TRIs, there is little information on the safety profile of this class of compounds. Using histopathology and DIKI biomarkers, in single- and repeat dose toxicological studies in cynomolgus monkeys, PRC200-SS demonstrated dose-proportional kidney toxicity. Characterization of the histopathological lesions, using a combination of immunohistochemistry (IHC) and urinary biomarker analysis, indicated that the compound is a distal tubule and collecting duct toxicant. Segment specificity for the lesions was shown using a newly developed triple IHC combination method with antibodies against calbindin D28, aquaporin 2, and aquaporin 1. Urinary biomarker analyses, using multiplex immunoassays, confirmed a dose-proportional increase in the excretion of calbindin D28 and clusterin in compound-treated monkeys with levels returning to baseline during the drug-free recovery period. These results constitute the validation of distal nephron DIKI biomarkers in the cynomolgus monkey and demonstrate the utility of calbindin D28 and clusterin to monitor the progression of distal nephron DIKI, representing potential early biomarkers of DIKI for the clinic.

Final amended report on safety assessment on aminomethyl propanol and aminomethyl propanediol.

Aminomethyl propanol and aminomethyl propanediol are substituted aliphatic alcohols that function as pH adjusters in cosmetic products at concentrations less than 10%; additionally, aminomethyl propanediol is a fragrance. Extensive oral toxicity data are reviewed, with fewer inhalation toxicity data. Dermal toxicity data are presented that demonstrate, for example, that a mascara with 1.92% aminomethyl propanediol does not cause dermal irritation or allergic contact sensitization, suggesting that the maximum reported use concentration of 2% in mascara would be safe. Although these ingredients are primary amines that are not substrates for N-nitrosation, they may contain secondary amines as impurities in finished products that may undergo N-nitrosation. These ingredients should not be included in cosmetic formulations containing N-nitrosating agents. The Cosmetic Ingredient Review Expert Panel concludes that aminomethyl propanol and aminomethyl propanediol are safe as cosmetic ingredients in the practices of use and concentrations as described in this safety assessment.

Environmental assessment of the alkanolamines.

This review provides a summary of current information available on the environmental fate and aquatic toxicology of the alkanolamines. Because these materials are widely used, there is a need to understand their fate and effects in the environment. This assessment was confined to information regarding selected physical properties of the alkanolamines as well as their potential for degradation in the atmosphere, soil, surface water, and groundwater. In addition, their relevant aquatic toxicological information and bioconcentration potential were evaluated. In general, the alkanolamines have high water solubilities and low to moderate vapor pressures. Some are solids whereas others are liquids at room temperature. Aqueous solutions of the alkanolamines are basic, with the pKas decreasing with increased alkyl substitution. Predictions of the environmental distribution of these compounds, based on a unit world model of Mackay and Paterson, suggested that alkanolamines would partition primarily into the aqueous compartment at equilibrium, with the remainder distributed to the atmosphere. Only a very small fraction of these materials is expected to sorb to soil or sediments. However, adsorption mechanisms other than partitioning into the soil organic layer were not considered in this model. Since polar compounds may sorb to soil by alternate mechanisms, this model may underestimate the true adsorption potential and subsequent environmental distribution of the alkanolamines. Future work with these compounds should focus on other types of adsorption mechanisms that could impact the environmental distribution of the alkanolamines. Although only small amount of the alkanolamines are expected to partition to the atmosphere, they are expected to be removed by reactions with photochemically generated hydroxyl radicals. They may also be removed from the atmosphere by precipitation, due to their high water solubility. Because of the relatively low levels expected to be present in the atmosphere and the relatively short half-lives, the alkanolamines are not expected to adversely impact air quality. Alkanolamines have also been shown to be highly susceptible to biodegradation and are not expected to persist in the environment. Results from numerous studies have shown that these materials undergo rapid biodegradation in soil, surface waters, and wastewater treatment plants. Degradation rates for these compounds may vary, with half-lives routinely in the range of 1 d to 2 wk, depending on the length of acclimation period and other environmental factors. The relatively low bioconcentration factor (BCF) values reported for the alkanolamines indicate that they would not be expected to bioconcentrate in aquatic organisms. Available data on the toxicity of the alkanolamines to aquatic organisms suggest low toxicity to the majority of the species studied. Based on the facts that alkanolamines exhibit low aquatic toxicity, are shown to biodegrade in a wide range of environments, and exhibit no tendency to bioaccumulate, the routine manufacturing, use, and disposal of these materials are not expected to adversely impact the environment. With increased emphasis by consumers and regulatory agencies for industry to develop products that are "environmentally friendly," these properties of the alkanolamines make them an attractive choice for a wide range of applications.