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Case studies are needed to demonstrate the use of human‐relevant New Approach Methodologies in cosmetics ingredient safety assessments. For read‐across assessments, it is crucial to compare the target chemical with the most appropriate analog; therefore, reliable analog selection should consider physicochemical properties, bioavailability, metabolism, as well as the bioactivity of potential analogs. To complement in vitro bioactivity assays, we evaluated the suitability of three potential analogs for the UV filters, homosalate and octisalate, according to their in vitro ADME properties. We describe how technical aspects of conducting assays for these highly lipophilic chemicals were addressed and interpreted. There were several properties that were common to all five chemicals: they all had similar stability in gastrointestinal fluids (in which no hydrolysis to salicylic occurred); were not substrates of the P‐glycoprotein efflux transporter; were highly protein bound; and were hydrolyzed to salicylic acid (which was also a major metabolite). The main properties differentiating the chemicals were their permeability in Caco‐2 cells, plasma stability, clearance in hepatic models, and the extent of hydrolysis to salicylic acid. Cyclohexyl salicylate, octisalate, and homosalate were identified suitable analogs for each other, whereas butyloctyl salicylate exhibited ADME properties that were markedly different, indicating it is unsuitable. Isoamyl salicylate can be a suitable analog with interpretation for octisalate. In conclusion, in vitro ADME properties of five chemicals were measured and used to pair target and potential analogs. This study demonstrates the importance of robust ADME data for the selection of analogs in a read‐across safety assessment. We evaluated the suitability of three potential analogues homosalate and octisalate (UV filters), according to their in vitro ADME properties. Technical aspects of testing these highly lipophilic chemicals were addressed. Main differentiating properties were plasma stability, hepatic clearance, and hydrolysis to salicylic acid. Cyclohexyl salicylate, octisalate, and homosalate were identified suitable analogues for each other, whereas butyloctyl salicylate exhibited ADME properties that were markedly different, as a unsuitable analogue. Isoamyl salicylate can be a suitable analogue with interpretation for octisalate. [ABSTRACT FROM AUTHOR]

Homosalate (HMS) is a UV filter used in sunscreens and personal care products as a mixture of cis- and trans-isomers. Systemic absorption after sunscreen use has been demonstrated in humans, and concerns have been raised about possible endocrine activity of HMS, making a general population exposure assessment desirable. In a previous study, it was shown that the oral bioavailability of cis-HMS (cHMS) is lower than that of trans-HMS (tHMS) by a factor of 10, calling for a separate evaluation of both isomers in exposure and risk assessment. The aim of the current study is the investigation of HMS toxicokinetics after dermal exposure. Four volunteers applied a commercial sunscreen containing 10% HMS to their whole body under regular-use conditions (18–40 mg HMS (kg bw)−1). Parent HMS isomers and hydroxylated and carboxylic acid metabolites were quantified using authentic standards and isotope dilution analysis. Further metabolites were investigated semi-quantitatively. Elimination was delayed and slower compared to the oral route, and terminal elimination half-times were around 24 h. After dermal exposure, the bioavailability of cHMS was a factor of 2 lower than that of tHMS. However, metabolite ratios in relation to the respective parent isomer were very similar to the oral route, supporting the applicability of the oral-route urinary excretion fractions for dermal-route exposure assessments. Exemplary calculations of intake doses showed margins of safety between 11 and 92 (depending on the approach) after single whole-body sunscreen application. Human biomonitoring can reliably quantify oral and dermal HMS exposures and support the monitoring of exposure reduction measures. [ABSTRACT FROM AUTHOR]

Interactions between the popular sunscreen ingredients oxybenzone and homosalate and DNA bases have been studied using density functional theory and ab initio methods. Low-energy structures for each sunscreen ingredient interacting with each nucleotide base in either a pi-stacked or hydrogen-bonded fashion were found. The binding energies are comparable to those for the Watson–Crick–Franklin Ade-Thy and Cyt-Gua pairs. Pi-stacked and hydrogen-bonded structures are comparable in energy, with hydrogen-bonded structures having a more negative counterpoise-corrected binding energy, while the final pi-stacked structures are lower in energy. This is due to a geometrical rearrangement required to form the hydrogen bonds that raise the total energy of the complex. It was also found that when using the M06-2X density functional, the STO-3G basis set favors hydrogen bonding, but 6-31G(d) and 6–31 + G(s) basis sets predict similar binding geometries. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background: UV filters should be determined a strict toxicological safety prior to approval. Homosalate (HMS) is one of the most widely used organic UV filter. HMS accumulates in aquatic biota ecosystems and humans through the food chain; therefore, it is important to consider the effects on health and know its mechanisms of action. Aims: The study aimed to evaluate the cytotoxic and genotoxic effects of HMS in MCF‐7 cell line. Methods: Cell viability was examined by the 3‐(4,5‐dimethylthiazol‐2‐yl)2,5‐diphenyl tetrazolium bromide (MTT) and cell membrane integrity by the lactate dehydrogenase release assays (LDH), and genotoxicity by using the micronucleus test at 250, 500, 750, 1000, 1500, and 2000 µM concentrations with the human breast cell line MCF‐7. Results: Homosalate affected the cell viability dose‐dependently at a concentrations of above 1000 µM. Micronucleus formation was significantly induced at 750 and 1000 µM within 24 hours due to an increase in cytostatic effect, the cell viability of HMS decreased to 57% at a concentration of 2000 µM, and a sufficient number of binucleated cells could not be obtained to count. Homosalate was also clastogenic when the cells were incubated at cytotoxic concentrations. Conclusion: These results suggest that homosalate can be considered as a cytotoxic and genotoxic substance. [ABSTRACT FROM AUTHOR]

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Many cosmetics contain UV filters as active ingredients for skin protection. Homosalate (HMS) is one of the most widely used organic UV filter. Despite the widespread use of these products, data about their genotoxic effects are lacking. Genotoxicity assessment is an important part of biosafety evaluation; therefore, we aimed to investigate genotoxic effects of homosalate as organic UV filter. The cytotoxicity effects of homosalate were assessed by trypan blue exclusion. Homosalate was incubated with four different concentrations for 30 min and 120 min. Our results revealed that HMS increased the DNA migration both the time and concentration manner. DNA damage was higher in cells that had been incubated with the greatest concentration of 200 µg mL-1 (p<0.05). Results obtained by the present study indicate that homosalate would be genotoxic at higher concentration and incubation time. Further studies should be carried out with different test systems (in vivo and in vitro) related to its genotoxic effects and incubation time should be extended. This may be helpful for genotoxicity evaluation of compounds with similar characteristics and their impact of human population. [ABSTRACT FROM AUTHOR]

This reconnaissance study was undertaken to examine the occurrence of common ultraviolet filters (UVF) and light stabilizers (UVLS), and preservatives in four different estuaries in Port Philip Bay, Victoria, for the first time. In total, 11 UV filters, 10 UV stabilizers, 12 preservatives and a metabolite, and one fragrance were screened in grab samples of water and sediment using a combination of solid phase extraction and gas and liquid chromatography mass spectrometry measurement techniques. In that context, 16 of the UVF and UVLS and 5 of the preservatives screened were observed in water and/or sediment samples. There are no marine water quality guideline values for any of the fragrances, preservatives and UV filters and light stabilizers in Australia’s current national water quality guidelines, so potential risk was assessed using the risk quotient (RQ) and toxic unit (TU) concepts. In that context, only two chemicals (OC and EHMC) had both an RQ above 1 and a log10TU above − 3, suggesting that few of the screened chemicals would have posed an individual, short-term risk to organisms in the waters studied at the time of sampling. However, the detection of common UV filters, such as 4MBC, EHMC, OC and the common preservatives 2-PE, MP, and PB in these Victorian estuaries highlights that the existence of personal care products in the environment is not just an issue for more densley populated countries in the northern hemisphere, but also potentially of concern in Australia. And, in that context, more sampling campaigns in Port Philip Bay are of paramount importance to assess the potential risk posed by these compounds to aquatic ecosystems. [ABSTRACT FROM AUTHOR]

Benzophenone (BP)-1, BP-2, BP-3, octylmethoxycinnamate (OMC), 4-methylbenzilidenecamphor and homosalate are added to personal care products to absorb ultraviolet light. Their presence in human milk and their oestrogenic activity suggests a potential to influence breast cancer development. As metastatic tumour spread is the main cause of breast cancer mortality, we have investigated the effects of these compounds on migration and invasion of human breast cancer cell lines. Increased motility of oestrogen-responsive MCF-7 human breast cancer cells was observed after long-term exposure (>20 weeks) to each of the six compounds at ≥10−7 m concentrations using three independent assay systems (scratch assay, live cell imaging, xCELLigence technology) and increased invasive activity was observed through matrigel using the xCELLigence system. Increased motility of oestrogen-unresponsive MDA-MB-231 human breast cancer cells was observed after 15 weeks of exposure to each of the six compounds by live cell imaging and xCELLigence technology, implying the increased migratory activity was not confined to oestrogen-responsive cells. Molecular mechanisms varied between compounds and cell lines. Using MCF-7 cells, reduction in E-cadherin was observed following 24 weeks' exposure to 10−5 m BP-1 and 10−5 m homosalate, and reduction in β-catenin was noted following 24 weeks' exposure to 10−5 m OMC. Using MDA-MB-231 cells, increased levels of matrix metalloproteinase 2 were observed after 15 weeks exposure to 10−7 m OMC and 10−7 m 4-methylbenzilidenecamphor. Although molecular mechanisms differ, these results demonstrate that exposure to any of these six compounds can increase migration and invasion of human breast cancer cells. [ABSTRACT FROM AUTHOR]

Introduction: Considering that the research has shown that homosalate acts as endocrine-active substance, it is very important to develop quick and sensitive method for tracking its concentrations in sunscreen products. The aim of this paper is to develop and validate the method for determining homosalate in sunscreen preparations and controlling the content of the products found on the market of Bosnia and Herzegovina. Methods: A high-pressure liquid chromatography (HPLC) method for determination homosalate in sunscreen products has been developed and validated. Samples of six different manufacturers have been analyzed. HPLC method is a method of choice for this type of investigation. Results: According to the calibration curve, it has been found that the proposed analytical method in a given range of concentration is linear and that the correlation coefficient is R2 = 0.9998. Accuracy of the method is in the range of 94.26%-121.53%.The results have shown that the homosalate concentration in the tested samples did not exceed the maximally permissible concentration (10%). In the sample AV50, homosalate was not declared as an active ingredient, but it was identified and quantified at a concentration of 0.143%. Conclusion: Results of investigation of cosmetic products that are widely present on the market show the need of developing a sufficiently sensitive, easily accessible, analytical method for controlling the content of organic ultraviolet filters since the exceeding of the maximally permissible concentration can have a harmful effect on people who use these kinds of products. The results show that developed method meets conditions and is suitable for wide application. [ABSTRACT FROM AUTHOR]

UV light suppresses experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, in mice and may be responsible for the decreased incidence of MS in equatorial regions. To test this concept further, we applied commercially available sunblock preparations to mice before exposing them to UV radiation. Surprisingly, some of the sunblock preparations blocked EAE without UV radiation. Furthermore, various sunblock preparations had variable ability to suppress EAE. By examining the components of the most effective agents, we identified homosalate and octisalate as the components responsible for suppressing EAE. Thus, salates may be useful in stopping the progression of MS, and may provide new insight into mechanisms of controlling autoimmune disease. [ABSTRACT FROM AUTHOR]

Homosalate is a UV filtering agent used in sunscreens and cosmetics for skin protection purposes. Despite the widespread use of these products, the extent ofin vivoexposure to homosalate has not been elucidated. This study first reports the development of a rapid and sensitive high performance liquid chromatography-tanden mass spectrometry (HPLC-MS/MS) method for the analysis of homosalate in rat plasma and its pharmacokinetic characterization after topical application. Chromatographic separation was achieved using a Kinetex C18column (50 mm × 2.1 mm, 2.6 µm). The mobile phase was a mixture of acetonitrile and 0.05% formic acid (82.5:17.5 v/v). The multiple reaction monitoring was based on the transition ofm/z263.2 → 139.0 for homosalate and 251.2 → 139.0 for octyl salicylate (internal standard). The present method was found to be linear in the concentration range of 0.2–400 ng/mL (r > 0.999). The intra- and inter-day assay accuracy and precision ranged from 92.8 to 107.6% and 3.9 to 7.0%, respectively. The developed assay was successfully applied to a pharmacokinetic study in rats after topical application of gel containing homosalate (dose 1.8 mg). The maximum plasma concentration (7.9 ± 2.7 ng/mL) was achieved at 11.3 ± 1.6 hr, indicating a prolonged absorption of homosalate after topical application. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the photoprotective properties of propolis. The sun protection factor (SPF) of ethanol extract of propolis was evaluated by an in vitro method, using homosalate as control. This determination is based on the physical determination of the reduction of the energy in the UV range, through a film of product which has previously been spread on an adequate substrate. About 15 mg of O/W emulsion containing propolis at various concentrations were applied on roughened Polymethylmethacrylate (PMMA) plates and the transmission measurements were carried out using a spectrophotometer equipped with integrating sphere. The results may justify their use as a natural sunscreen agent. [ABSTRACT FROM AUTHOR]

The potential of 3 sunscreens (p-aminobenzoic acid, 4-isopropyldibenzoylmethane and homosalate) and 2 known human photoallergens (musk ambrette and tetrachiorosalicylanilide) to cause photoallergy, phototoxicity, and/or contact sensitization was determined using a guinea pig photoallergy model, as previously described by Harber and associates. The model was slightly modified by employing 6 exposures over 2 weeks and using Hill Top Chambers® for application of the test material. Contact photoallergy was detected in guinea pigs treated with musk ambrette or tetrachiorosalicylanilide (TCSA), although with TCSA, a lower incidence of contact sensitivity and phototoxicity was also detected. The results of studies conducted with sunscreens showed that p-aminobenzoic acid was photoallergenic, whereas homosalate and 4-isopropyl-dibenzoylmethane (Eusolex® 8020) were not. However, contact sensitization, and to a lesser degree primary irritation, was detected with Eusolex® 8020 at the concentrations employed in this study. The results of these studies suggest that this guinea pig model is a suitable model for assessing the photoallergic potential of various compounds, including the sunscreens tested in this study. [ABSTRACT FROM AUTHOR]

Homosalate is a UV filter used in sunscreens and cosmetics for skin protection purposes. It can provide substantial skin protection against UVB radiation. The maximum authorized concentration for homosalate in sunscreens is 10% according to EU and Japanes legislation, whereas the US Federal Drug Administration authorizes maximum concentration of 15%. The aim of this research was to develop and validate a high pressure liquid chromatography method for identification of homosalate and determination of his content in sunscreens products. The chromatographic separation was achieved on a stationary phase C18 using a mobile phase: A solution (water + 0.1% formic acid) and B solution (acetonitrile + 1% formic acid) with a gradient elution at a flow rate of 0.5 ml/min. The optimum conditions for homosalat analysis were investigated. The calibration curve showed good linear regression with UV detection at the wawelength of 306 nm. The correlation coefficient was 0.9998. The method is simple, selective and reproducible and it is suitable for the determination of homosalate in commercial sunscreen products. Homosalate was determined in the 6 sunscreen samples in which was declared as an active ingredient, and was identified and quantitated in one sample in which was not declared as an active ingredient. [ABSTRACT FROM AUTHOR]

Homosalate is a UV filter used in sunscreens and cosmetics for skin protection purposes. It can provide substantial skin protection against UVB radiation. The maximum authorized concentration for homosalate in sunscreens is 10% according to EU and Japanes legislation, whereas the US Federal Drug Administration authorizes maximum concentration of 15%. The aim of this research was to develop and validate a high pressure liquid chromatography method for identification of homosalate and determination of his content in sunscreens products. The chromatographic separation was achieved on a stationary phase C18 using a mobile phase: A solution (water + 0.1% formic acid) and B solution (acetonitrile + 1% formic acid) with a gradient elution at a flow rate of 0.5 ml/min. The optimum conditions for homosalat analysis were investigated. The calibration curve showed good linear regression with UV detection at the wawelength of 306 nm. The correlation coefficient was 0.9998. The method is simple, selective and reproducible and it is suitable for the determination of homosalate in commercial sunscreen products. Homosalate was determined in the 6 sunscreen samples in which was declared as an active ingredient, and was identified and quantitated in one sample in which was not declared as an active ingredient. [ABSTRACT FROM AUTHOR]

Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children. [ABSTRACT FROM AUTHOR]