Use of Physiologically-Based Kinetics Modelling to Reliably Predict Internal Concentrations of the UV Filter, Homosalate, After Repeated Oral and Topical Application

Ethical and legal considerations have led to increased use of non-animal methods to evaluate the safety of chemicals for human use. We describe the development and qualification of a physiologically-based kinetics (PBK) model for the cosmetic UV filter ingredient, homosalate, to support its safety without the need of generating further animal data. The intravenous (IV) rat PBK model, using PK-Sim®, was developed and validated using legacy in vivo data generated prior to the 2013 EU animal-testing ban. Input data included literature or predicted physicochemical and pharmacokinetic properties. The refined IV rat PBK model was subject to sensitivity analysis to identify homosalate-specific sensitive parameters impacting the prediction of Cmax (more sensitive than AUC(0-∞)). These were then considered, together with population modeling, to calculate the confidence interval (CI) 95% Cmax and AUC(0-∞). Final model parameters were established by visual inspection of the simulations and biological plausibility. The IV rat model was extrapolated to oral administration, and used to estimate internal exposures to doses tested in an oral repeated dose toxicity study. Next, a human PBK dermal model was developed using measured human in vitro ADME data and a module to represent the dermal route. Model performance was confirmed by comparing predicted and measured values from a US-FDA clinical trial (Identifier: NCT03582215, https://clinicaltrials.gov/). Final exposure estimations were obtained in a virtual population and considering the in vitro and input parameter uncertainty. This model was then used to estimate the Cmax and AUC(0–24 h) of homosalate according to consumer use in a sunscreen. The developed rat and human PBK models had a good biological basis and reproduced in vivo legacy rat and human clinical kinetics data. They also complied with the most recent WHO and OECD recommendations for assessing the confidence level. In conclusion, we have developed a PBK model which predicted reasonably well the internal exposure of homosalate according to different exposure scenarios with a medium to high level of confidence. In the absence of in vivo data, such human PBK models will be the heart of future completely non-animal risk assessments; therefore, valid approaches will be key in gaining their regulatory acceptance.Clinical Trial Registration: https://clinicaltrials.gov/, identifier, NCT03582215

Preparation and Characterization of Organic/Inorganic Composite UV Filter Microcapsules by Sol-Gel Method

Octyl methoxycinnamate and butyl methoxydibenzoylmethane are organic UV filters with poor photostability and will become photoallergy or phototoxic substance when exposed to ultraviolet radiation. The organic UV filters coated by microcapsules can reduce the photodegradation and avoid direct contact with the skin. Through microencapsulation, the application of UV filters in cosmetics becomes more effective and safer. This study first used the sol-gel method to create organic/inorganic composite UV filter microcapsules. We used sodium alginate as a shell material of the microcapsule to encapsulate UV filters. CaCO3 and tetraethyl orthosilicate (TEOS) were used as cross-linking agents, and sorbitan monooleate (Span 80) and polyoxyethylenesorbitan monooleate (Tween 80) were used as emulsifiers in the interfacial polymerization method for preparation. The results indicated that the microcapsules with 3 g of CaCO3 cross-linking agents had a similar particle size and better entrapment efficiency. The average sizes were 61.0 ± 4.9 μm and 48.6 ± 4.7 μm, and entrapment efficiencies were 75.3 ± 1.9% and 74.8 ± 1.7% for octyl methoxycinnamate and butyl methoxydibenzoylmethane, respectively. Utilizing sodium alginate as a cross-linking agent is better than TEOS due to the higher calcium content. In vitro transdermal delivery analysis showed that the release rate became steady.

Complete genome sequence and Benzophenone-3 mineralisation potential of Rhodococcus sp. USK10, a bacterium isolated from riverbank sediment.

Benzophenone-3 (BP3) is an organic UV filter whose presence in the aquatic environment has been linked to detrimental developmental impacts in aquatic organisms such as coral and fish. The genus Rhodococcus has been extensively studied and is known for possessing large genomes housing genes for biodegradation of a wide range of compounds, including aromatic carbons. Here, we present the genome sequence of Rhodococcus sp. USK10, which was isolated from Chinese riverbank sediment and is capable of utilising BP3 as the sole carbon source, resulting in full BP3 mineralisation. The genome consisted of 9,870,030 bp in 3 replicons, a G+C content of 67.2%, and 9,722 coding DNA sequences (CDSs). Annotation of the genome revealed that 179 of these CDSs are involved in metabolism of aromatic carbons. The complete genome of Rhodococcus sp. USK10 is the first complete, annotated genome sequence of a Benzophenone-3 degrading bacterium. Through radiolabelling, it is also the first bacterium proven to mineralise Benzophenone-3. Due to the widespread environmental prevalence of Benzophenone-3, coupled to its adverse impact on aquatic organisms, this characterisation provides an integral first step in better understanding the environmentally relevant degradation pathway of the commonly used UV filter. Given USK10's ability to completely mineralise Benzophenone-3, it could prove to be a suitable candidate for bioremediation application.

Effectiveness of Frangipani Leaf Extract (Plumeria alba Linn.) as a UV Filter

UV filters are necessary since UV rays are harmful to human skin. UV filter compounds in commercial sunscreen products can cause adverse effects. Thus, natural UV filters containing flavonoids, e.g. Frangipani (Plumeria alba Linn.) leaves, are needed. This research examined the use of flavonoids from P. alba leaf as a UV filter with in vitro and in vivo. Maceration was performed with 70% ethyl alco-hol and liquid-liquid extraction for flavonoid purification. Parameters tested were total flavonoid compounds, SPF value, and clinical symptoms of the melanogenesis inhibition scoring. The purification result was 43.6%. The flavonoid concentration in pure extract (64.4 mg QE /g) was higher than crude extract (57.6 mg QE/g). The highest SPF value (33.88) was observed in pure extract at 1400 mg/mL, while the same concentration of crude extract resulted in a lower SPF value (33.06). Pearson correlation analysis (0.536) indicated a di-rectly proportional relationship between SPF value and extract concentration. In vivo analysis was performed by scoring between 0-4 following the severity of erythema. After 21 days of sunlight exposure, the worst erythema was found in the negative control group (score 1.292). The best result was found in the group treated with pure extract 1400 mg/ml (score 0.542).

(+)-Usnic Acid as a Promising Candidate for a Safe and Stable Topical Photoprotective Agent

The study aimed to examine whether usnic acid—a lichen compound with UV-absorbing properties—can be considered as a prospective photoprotective agent in cosmetic products. Moreover, a comparison of two usnic acid enantiomers was performed to preselect the more effective compound. To meet this aim, an in vitro model was created, comprising the determination of skin-penetrating properties via skin-PAMPA assay, safety assessment to normal human skin cells (keratinocytes, melanocytes, fibroblasts), and examination of photostability and photoprotective properties. Both enantiomers revealed comparable good skin-penetrating properties. Left-handed usnic acid was slightly more toxic to keratinocytes (IC50 80.82 and 40.12 µg/mL, after 48 and 72 h, respectively) than its right-handed counterpart. The latter enantiomer, in a cosmetic formulation, was characterized by good photoprotective properties and photostability, comparable to the UV filter octocrylene. Perhaps most interestingly, (+)-usnic acid combined with octocrylene in one formulation revealed enhanced photoprotection and photostability. Thus, the strategy can be considered for the potential use of (+)-usnic acid as a UV filter in cosmetic products. Moreover, the proposed model may be useful for the evaluation of candidates for UV filters.