Safety Assessment Of Cosmetics Research Articles

P06-20: In silico contributions to Cosmetic Safety Assessment: latest examples

P06-20: In silico contributions to Cosmetic Safety Assessment: latest examples

Artificial Intelligence That Predicts Sensitizing Potential of Cosmetic Ingredients with Accuracy Comparable to Animal and In Vitro Tests-How Does the Infotechnomics Compare to Other "Omics" in the Cosmetics Safety Assessment?

The aim of the current study was to develop an in silico model to predict the sensitizing potential of cosmetic ingredients based on their physicochemical characteristics and to compare the predictions with historical animal data and results from "omics"-based in vitro studies. An in silico model was developed with the use of WEKA machine learning software fed with physicochemical and structural descriptors of haptens and trained with data from published epidemiological studies compiled into estimated odds ratio (eOR) and estimated attributable risk (eAR) indices. The outcome classification was compared to the results of animal studies and in vitro tests. Of all the models tested, the best results were obtained for the Naive Bayes classifier trained with 24 physicochemical descriptors and eAR, which yielded an accuracy of 86%, sensitivity of 80%, and specificity of 90%. This model was subsequently used to predict the sensitizing potential of 15 emerging and less-studied haptens, of which 7 were classified as sensitizers: cyclamen aldehyde, N,N-dimethylacrylamide, dimethylthiocarbamyl benzothiazole sulphide, geraniol hydroperoxide, isobornyl acrylate, neral, and prenyl caffeate. The best-performing model (NaiveBayes eAR, 24 parameters), along with an alternative model based on eOR (Random Comittee eOR, 17 parameters), are available for further tests by interested readers. In conclusion, the proposed infotechnomics approach allows for a prediction of the sensitizing potential of cosmetic ingredients (and possibly also other haptens) with accuracy comparable to historical animal tests and in vitro tests used nowadays. In silico models consume little resources, are free of ethical concerns, and can provide results for multiple chemicals almost instantly; therefore, the proposed approach seems useful in the safety assessment of cosmetics.

Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates

A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin’s barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calc mean square difference was 0.9 cm2 h−2.

A State-of-the-Art Review on the Alternatives to Animal Testing for the Safety Assessment of Cosmetics

Almost a decade after the stipulated deadline in the 7th amendment to the EU Cosmetics Directive, which bans the marketing of animal-tested cosmetics in the EU from 2013, animal experimentation for cosmetic-related purposes remains a topic of animated debate. Cosmetic industry continues to be scrutinised for the practice, despite its leading role in funding and adopting innovation in this field. This paper aims to provide a state-of-the-art review of the field on alternative testing methods, also known as New Approach Methodologies (NAMs), with the focus on assessing the safety of cosmetic ingredients and products. It starts with innovation drivers and global regulatory responses, followed by an extensive, endpoint-specific overview of accepted/prospective NAMs. The overview covers main developments in acute toxicity, skin corrosion/irritation, serious eye damage/irritation, skin sensitisation, repeated dose toxicity, reproductive toxicity/endocrine disruption, mutagenicity/genotoxicity, carcinogenicity, photo-induced toxicity, and toxicokinetics. Specific attention was paid to the emerging in silico methodology. This paper also provides a brief overview of the studies on public perception of animal testing in cosmetics. It concludes with a view that educating consumers and inviting them to take part in advocacy could be an effective tool to achieve policy changes, regulatory acceptance, and investment in innovation.

Skin Toxicity of Selected Hair Cosmetic Ingredients: A Review Focusing on Hairdressers

The safety assessment of cosmetics considers the exposure of a ‘common consumer’, not the occupational exposure of hairdressers. This review aims to compile and appraise evidence regarding the skin toxicity of cysteamine hydrochloride (cysteamine HCl; CAS no. 156-57-0), polyvinylpyrrolidone (PVP; CAS no. 9003-39-8), PVP copolymers (CAS no. 28211-18-9), sodium laureth sulfate (SLES; CAS no. 9004-82-4), cocamide diethanolamine (cocamide DEA; CAS no. 68603-42-9), and cocamidopropyl betaine (CAPB; CAS no. 61789-40-0). A total of 298 articles were identified, of which 70 were included. Meta-analysis revealed that hairdressers have a 1.7-fold increased risk of developing a contact allergy to CAPB compared to controls who are not hairdressers. Hairdressers might have a higher risk of acquiring quantum sensitization against cysteamine HCl compared to a consumer because of their job responsibilities. Regarding cocamide DEA, the irritant potential of this surfactant should not be overlooked. Original articles for PVP, PVP copolymers, and SLES are lacking. This systematic review indicates that the current standards do not effectively address the occupational risks associated with hairdressers’ usage of hair cosmetics. The considerable irritant and/or allergenic potential of substances used in hair cosmetics should prompt a reassessment of current risk assessment practices.

In Silico Models for Skin Sensitization and Irritation.

The assessment of skin irritation, and in particular of skin sensitization, has undergone an evolution process over the last years, pushing forward to new heights of quality and innovation. Public and commercial in silico tools have been developed for skin sensitization and irritation, introducing the possibility to simplify the evaluation process and the development of topical products within the dogma of the computational methods, representing the new doctrine in the field of risk assessment.The possibility of using in silico methods is particularly appealing and advantageous due to their high speed and low-cost results.The most widespread and popular topical products are represented by cosmetics. The European Regulation 1223/2009 on cosmetic products represents a paradigm shift for the safety assessment of cosmetics transitioning from a classical toxicological approach based on animal testing, towards a completely novel strategy, where the use of animals for toxicity testing is completely banned. In this context sustainable alternatives to animal testing need to be developed, especially for skin sensitization and irritation, two critical and fundamental endpoints for the assessment of cosmetics.The Quantitative Risk Assessment (QRA) methodology and the risk assessment using New Approach Methodologies (NAM) represent new frontiers to further improve the risk assessment process for these endpoints, in particular for skin sensitization.In this chapter we present an overview of the already existing models for skin sensitization and irritation. Some examples are presented here to illustratetools and platforms used for the evaluation of chemicals.

Improved performance of the SH test as an in vitro skin sensitization test with a new predictive model and decision tree.

Demands for the elimination and replacement of animal experiments for cosmetic safety assessment have increased in recent years. Evaluation of skin sensitization, however, is a critical issue in cosmetic safety assessment. The SH test is an in vitro skin sensitization test method that evaluates protein binding of chemical substances, which is an important event in skin sensitization. We previously verified the technical transferability and between-laboratory reproducibility of the SH test, a domestic test method for which no scientific research has been conducted, and improved the protocol, but also noted some unresolved issues. Therefore, in the present study, we successfully improved the operational efficiency and clarity of the final judgment of the SH test by (i) developing a new decision-making system that can make a final judgment without statistical processing, (ii) changing the statistical method, and (iii) evaluating and determining the maximum number of repetitions necessary for optimal efficiency. The improved SH test was verified by comparing it with existing test methods already adopted by the Organization for Economic Cooperation and Development. The results of this study demonstrated excellent performance of the improved SH test, with high reproducibility, reliable predictability, and good operational efficiency. The predictive performance of the improved method does not differ significantly from that of the conventional method, although it is clearer and more efficient. Therefore, the results of the present improved method are consistent with those obtained using the conventional method, with higher efficiency.

Analysis of factors influencing patch test reactions: Results from a large- population-based study in Chinese.

Patch test, as a helpful tool in clinic diagnosis and safety assessment of cosmetics, is affected by many factors. To investigate the influencing factors of patch test reactions in a highly standardized large-scale dataset of Chinese. Patch test data (n=151,280) from safety assessments of cosmetic products were obtained following internationally standardized patch testing protocols during 2004-2017 in China. The frequency of patch test reactions was 1.45% (2,191/151,280), with majority of the reactions being "score 1" reactions (also known as doubtful reactions, n=2,075) and a small number being "score 2" reactions (weak reactions, n=116). Patch test reactions were 67% more frequent in winter (p<0.001), associated with temperatures (p<0.001), rather than relative humidity (P:0.29). The frequency of reactions was higher in men than in women (p:0.001), especially in winter. The risk to develop reactions clearly increased with age in women (p<0.001), but not in men (p:0.14). In women, the frequency of reactions in the old group (≥50years old) was 30% more than the young group (<30years old). The frequency of patch test reactions to cosmetic products was 1.45% in our large-scale study. The influencing factors of patch test include season, sex, and age, which should be considered when conducting and interpreting patch testing.

Evaluation of cytotoxicity, genotoxicity, and zebrafish embryo toxicity of mixtures containing Hyssopus officinalis, Morus alba, Engraulis japonicus, and 27 other extracts for cosmetic safety assessment

Although various natural ingredients and formulated reagents are used as ingredients in cosmetics, it is important to have alternatives to animal tests, such as in vitro tests of toxicity, as animal testing of cosmetics is prohibited in many countries. Here, cytotoxicity, genotoxicity, and embryotoxicity on zebrafish embryos were evaluated to confirm the safety of ingredients formulated with 30 extracts from natural resources used as cosmetic ingredients. The blended ingredients were tested by dividing them into mixtures of 25 natural products (NMA), 30 natural products (NMB), and concentrated NMB (NMC), depending on the number of blended natural components and their application. First, in vitro, HaCaT cells were treated with concentrations of 0 to 20% for 24 h to measure cell viability. DNA damage within the IC20 value was measured by comet assay. In the comet assay, 10 mM H2O2 was used as a positive control. Additionally, zebrafish embryos were used as a substitute for conventional animal testing to observe natural mixture toxicity. The olive tail moment (OTM) were not affected by NMA, NMB, or NMC in comparison with the positive control versus three representatives within the IC20 value concentration of each mixture. Zebrafish embryo results were analysed in a manner similar to the cytotoxicity test results. NMA mixtures showed no cytotoxicity, genotoxicity, or toxicity on zebrafish embryos. Other mixtures showed non-toxicity within the representatively concentrated range. Therefore, the 3 mixtures containing Hyssopus officinalis, Morus alba, Engraulis japonicus, and 27 other extracts were considered to be not significantly toxic in HaCaT cell and zebrafish, so it is suggested that they could be used as cosmetic ingredients.

In silico resources to assist in the development and evaluation of physiologically-based kinetic models

Since their inception in pharmaceutical applications, physiologically-based kinetic (PBK) models are increasingly being used across a range of sectors, such as safety assessment of cosmetics, food additives, consumer goods, pesticides and other chemicals. Such models can be used to construct organ-level concentration-time profiles of xenobiotics. These models are essential in determining the overall internal exposure to a chemical and hence its ability to elicit a biological response. There are a multitude of in silico resources available to assist in the construction and evaluation of PBK models. An overview of these resources is presented herein, encompassing all attributes required for PBK modelling. These include predictive tools and databases for physico-chemical properties and absorption, distribution, metabolism and elimination (ADME) related properties. Data sources for existing PBK models, bespoke PBK software and generic software that can assist in model development are also identified. On-going efforts to harmonise approaches to PBK model construction, evaluation and reporting that would help increase the uptake and acceptance of these models are also discussed.

Challenges in working towards an internal threshold of toxicological concern (iTTC) for use in the safety assessment of cosmetics: Discussions from the Cosmetics Europe iTTC Working Group workshop

The Threshold of Toxicological Concern (TTC) is an important risk assessment tool which establishes acceptable low-level exposure values to be applied to chemicals with limited toxicological data. One of the logical next steps in the continued evolution of TTC is to develop this concept further so that it is representative of internal exposures (TTC based on plasma concentration). An internal TTC (iTTC) would provide threshold values that could be utilized in exposure-based safety assessments. As part of a Cosmetics Europe (CosEu) research program, CosEu has initiated a project that is working towards the development of iTTCs that can be used for the human safety assessment. Knowing that the development of an iTTC is an ambitious and broad-spanning topic, CosEu organized a Working Group comprised a balance of multiple stakeholders (cosmetics and chemical industries, the EPA and JRC and academia) with relevant experience and expertise and workshop to critically evaluate the requirements to establish an iTTC. Outcomes from the workshop included an evaluation on the current state of the science for iTTC, the overall iTTC strategy, selection of chemical databases, capture and curation of chemical information, ADME and repeat dose data, expected challenges, as well as next steps and ongoing work.

Using the SENS-IS assay, to assess skin sensitization hazard of commercial cosmetics finished products

In silico approaches are becoming increasingly important tools in toxicology. This is especially the case for the cosmetics industry, where growing numbers of regions are implementing bans on the in vivo testing of ingredients and products, resulting in an increased need to be able to generate safety data in vitro and/or in silico. ‘In silico’ data include results obtained from (quantitative) structure activity relationship ((Q)SAR) models, chemical categories, grouping, read-across and physiologically-based (pharmaco)kinetic (PB(P)K) models, and ‘big data’ analysis. There are general and more specific factors to be considered when using different in silico methods, many of which are described in the multitude of guidance documents available to support their use for regulatory purposes. There are particular challenges associated with the use of in silico approaches for cosmetic safety assessment, but with proper consideration and justification as to how they have been addressed, none should be insurmountable. Whilst in silico methods are currently predominantly used for internal rather than regulatory decision making, as confidence grows in their applicability and predictivity, this is likely to change. Many of the most commonly cited issues with the use of in silico approaches relate to the need for better documentation and justification as to why the method used was appropriate. It is also frequently stated that they should be used within a weight of evidence (WoE) approach and with all available data, rather than meeting regulatory requirements as a stand-alone method. Whilst these considerations are important, it should be remembered that they are equally applicable to data generated using in vitro and in vivo methods.

EpiOcular time-to-toxicity protocol (ET-50 assay) in the safety assessment of cosmetics – A retrospective review

EpiOcular time-to-toxicity protocol (ET-50 assay) in the safety assessment of cosmetics – A retrospective review

Utility of integrated non-animal approaches for skin sensitisation for safety assessment of cosmetics

Utility of integrated non-animal approaches for skin sensitisation for safety assessment of cosmetics

Cosmetic Nanomaterials in Wastewater: Titanium Dioxide and Fullerenes

AbstractThe rapid growth in the cosmetic industry across the world is mainly due to the application of nanoingredients in cosmetics to enhance their properties and invention of new nanomolecules. Also, the weaker regulations on the application of nanoparticles as cosmetic ingredients and no safety assessment of cosmetics before release into the market has led to uncontrolled production and usage. Unavoidable release of a considerable amount of cosmetic nanoparticles into wastewater introduces them into the environment via treated wastewater effluent and sludge. This paper briefly gives the information about behavior of cosmetic nanomaterials, mainly titanium dioxide (TiO2) and fullerenes (C60), within the wastewater-treatment plant and current research on their characterization and toxicity. Considering the current analytical methods for evaluating the behavior of these nanomaterials in the wastewater, there is still a need to advance these technologies. Furthermore, a better understanding and modeling of...

Short term study of human skin irritation by single application closed patch test: assessment of four multiple emulsion formulations loaded with botanical extracts

Background: Assessment of skin irritation potential is a major concern in safety assessment of cosmetics, when long-term use of these products are expected. Non-invasive bioengineering probes have been used previously to measure skin irritation potential of cosmetic ingredients.Objectives: Experimentation carried out to weigh up the skin irritation potential of four multiple emulsion formulations via visual and non-invasive measurements. Immediate effects of formulations and comparison of two assessment techniques were also tried to establish.Methods: Four multiple emulsion formulations one control (without botanical active) and three containing the functional botanical actives plus additives were tested in this study using the following techniques: transepidermal water loss (TEWL), COLIPA visual scoring method (CVSM), Mexameter MPA 5 (Courage + Khazaka, Germany) and capacitance [Corneometer MPA 5 (Courage + Khazaka, Germany)]. Visual examination and non-invasive measurements were performed at baseline and after 24 h. The formulations were applied on the forearm of 12 healthy volunteers of same sexes aged 20–25 years.Results: We found that none of the formulation produced irritation both on visual and instrumental evaluation. However, formulations MeB and MeC have comparable immediate effects on dryness, erythema, melanin and TEWL. Formulation MeC produced more effective results on different parameters, may be due to synergistic effect of two extracts, while MeA failed to produce any immediate effects on skin parameters. Moreover results of both assessment methods are parallel to each other.Conclusions: None of the formulation produce irritant effects, barrier impairment effects or immediate effects except for the formulation MeC which produced appreciable results than other formulations but statistically these results were insignificant (p > 0.05). Based on these results, it could be concluded that formulations may be implied safely as skin rejuvenating candidates.

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Genotoxicity. A COLIPA analysis

For the assessment of genotoxic effects of cosmetic ingredients, a number of well-established and regulatory accepted in vitro assays are in place. A caveat to the use of these assays is their relatively low specificity and high rate of false or misleading positive results. Due to the 7th amendment to the EU Cosmetics Directive ban on in vivo genotoxicity testing for cosmetics that was enacted March 2009, it is no longer possible to conduct follow-up in vivo genotoxicity tests for cosmetic ingredients positive in in vitro genotoxicity tests to further assess the relevance of the in vitro findings. COLIPA, the European Cosmetics Association, has initiated a research programme to improve existing and develop new in vitro methods. A COLIPA workshop was held in Brussels in April 2008 to analyse the best possible use of available methods and approaches to enable a sound assessment of the genotoxic hazard of cosmetic ingredients. Common approaches of cosmetic companies are described, with recommendations for evaluating in vitro genotoxins using non-animal approaches. A weight of evidence approach was employed to set up a decision-tree for the integration of alternative methods into tiered testing strategies.

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Skin irritation

Evaluation of the skin irritancy and corrosivity potential of an ingredient is a necessity in the safety assessment of cosmetic ingredients. To date, there are two formally validated alternatives to the rabbit Draize test for skin corrosivity in place, namely the rat skin transcutaneous electrical resistance (TER) assay and the Human Skin Model Test using EpiSkin™, EpiDerm™ and SkinEthic™ reconstructed human epidermal equivalents. For skin irritation, EpiSkin™, EpiDerm™ and SkinEthic™ are validated as stand-alone test replacements for the rabbit Draize test. Data from these tests are rarely considered in isolation and are evaluated in combination with other factors to establish the overall irritating or corrosive potential of an ingredient. In light of the deadlines established in the Cosmetics Directive for cessation of animal testing for cosmetic ingredients, a COLIPA scientific meeting was held in Brussels on 30th January, 2008 to review the use of alternative approaches and to set up a decision tree approach for their integration into tiered testing strategies for hazard and safety assessment of cosmetic ingredients and their use in products. In conclusion, the safety assessments for skin irritation/corrosion of new chemicals for use in cosmetics can be confidently accomplished using exclusively alternative methods.

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Eye irritation

The need for alternative approaches to replace the in vivo rabbit Draize eye test for evaluation of eye irritation of cosmetic ingredients has been recognised by the cosmetics industry for many years. Extensive research has lead to the development of several assays, some of which have undergone formal validation. Even though, to date, no single in vitro assay has been validated as a full replacement for the rabbit Draize eye test, organotypic assays are accepted for specific and limited regulatory purposes. Although not formally validated, several other in vitro models have been used for over a decade by the cosmetics industry as valuable tools in a weight of evidence approach for the safety assessment of ingredients and finished products. In light of the deadlines established in the EU Cosmetics Directive for cessation of animal testing for cosmetic ingredients, a COLIPA scientific meeting was held in Brussels on 30th January, 2008 to review the use of alternative approaches and to set up a decision-tree approach for their integration into tiered testing strategies for hazard and safety assessment of cosmetic ingredients and their use in products. Furthermore, recommendations are given on how remaining data gaps and research needs can be addressed.

Safety of cosmetic products

SummaryBackground  While technological advances have spurred innovations in product development and testing, often dermatologists and consumers are not aware of the extensive processes that manufacturers use to ensure that products are safe. In all of the major markets around the world, laws require that every cosmetic or personal care product on store shelves be safe for their intended use. The assessment of cosmetic product safety is a multistep process that spans the various stages of the product development/marketing cycle. Extensive testing to ensure safety is an integral and ongoing part of this product development cycle.Aims  In this paper we attempt to distill the most relevant information on the science of cosmetic safety assessment in order to enhance our understanding of cosmetics and how to use this knowledge to increase consumer and patient safety. We will review a wide range of topics, including the current best practices of reputable manufacturers for ensuring product safety, the regulatory environment for cosmetics, as well as research in contact dermatitis related to cosmetics. We will also review the most recent data related to two topics that receive a significant amount of attention these days: preservatives and fragrances.Conclusion  Today, regulatory bodies around the world have set rigorous standards for product safety, while improved technology has made testing more efficient. Ongoing research continues to generate improvements in the way products are developed and evaluated – from start to finish. By using the latest scientific advances and good manufacturing practices, cosmetic manufacturers are putting products through cutting‐edge paces designed to maximize safety.