A critical review investigating the use of nanoparticles in cosmetic skin products

Abstract

The 1 to 100 nm nanoscale is a scale at which chemical reactions and biomolecular interactions can occur; the human skin is no exception. Regarding dermal exposure, engineered nanoparticles are used in numerous cosmetic formulations such as sunscreen, cleansers, creams, lotions, and makeup products. Their ability to improve ultraviolet protection, pigmentation, moisturization, and promote skin repair, and skin retention is appreciated. On the skin, nanomaterials first encounter resident bacteria and small molecules, i.e., the microbiome, and later interact with the superficial skin cells. The interaction of nanomaterials with the skin is complex because of their different compositions, reactivity, and scale. Physical and chemical features, composition, persistence in the environment, and transport across media are all factors that will affect nanomaterials' potential toxicity on humans and the environment. This review article focuses on current cosmetic ingredients claiming a nano nature, the unique characteristics of nanomaterials and their behaviour on the skin, how they can be suitable for natural cosmetics and how they behave in the environment.

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Thipphathong (Dorothy) Piluk

Thipphathong (Dorothy) Piluk is a PhD candidate at York University as a member of Professor Marina Freire-Gormaly's Lab. Her research interests include eco- and biotoxicity of nanomaterials. She earned her B.E.Sc. in Mechanical Engineering and M.E.Sc. in Civil and Environmental Engineering from Western University under the academic supervision of Dr. Ernest Yanful. She is a designated Professional Engineer (P.Eng.) with experience in indoor environmental quality (HVAC, plumbing and fire protection) and environmental assessment and monitoring (drinking water quality, phase I and II ESA and building audits). An application of her research includes drinking water purification and desalination systems. Her current research objective is to develop and evaluate the effectiveness of coatings on reverse osmosis (RO) membranes in preventing scaling and enhancing membrane longevity under intermittent operational conditions.

Greta Faccio

Greta Faccio, Ph.D., graduated from the University of Insubria, Italy, in Life Sciences with a focus on Biotechnology. She obtained a doctorate in Genetics by the University of Helsinki, Finland, with a thesis on novel enzyme with crosslinking enzymes for food texture engineering. Moving to Switzerland, she joined the Swiss Federal Laboratories for Materials Testing and Research and investigated the use of proteins and enzymes for materials science, diagnostics, and MedTech applications. Her work resulted in more than 50 publications, two book chapters, and one pending patent. She is currently active in the private sector in the field of intellectual property, innovation and technology transfer.

Sophia Letsiou

Dr. Sophia Letsiou is an Adjunct Assistant Professor in the Department of Biomedical Sciences at University of West Attica in Athens, Greece. Her primary research interests are the identification of molecular targets and mechanisms of action of molecules of natural origin with biological and cosmeceutical activity, the in vitro skin modelling to simulate physical or pathological human skin processes and the marine biotechnology for the development of novel products. She has more than 40 peer-reviewed scientific publications and she is a principal investigator of five patents in cosmetics as a mean of science valorization. She serves as an Ad hoc reviewer in different scientific journals related to life sciences and as a scientific evaluator in European research projects.

Robert Liang

Dr. Robert Liang is a Postdoctoral Fellow in the Department of Mechanical Engineering at York University in Toronto, Ontario, Canada. Dr. Liang obtained a doctorate at the University of Waterloo focusing on titanium dioxide nanomaterials for photocatalysis and multifunctional water treatment applications such as micropollutant abatement, filtration, and corrosion control. His research interests include desalination and aeration water process technologies, process intensification, photocatalysts for air and water remediation, and nanomaterials for applications such as functional coatings and cosmeceutical applications. Dr. Liang has over 30 academic peer-reviewed publications, several book chapters, and successful research project grant applications over $4 million.

Marina Freire-Gormaly

Dr. Marina Freire-Gormaly is an Assistant Professor in the Department of Mechanical Engineering at York University in Toronto, Ontario, Canada. Her research spans experimental research for reverse osmosis renewable powered water treatment systems, computational fluid dynamics simulation and modelling of aerosol transmission of COVID-19 for safer indoor environments, and the development of new materials for energy sustainability. She serves as an editor of the Desalination and Water Treatment, Elsevier Journal. Her work resulted in over 50 publications. She actively collaborates with industry, national laboratories and academia to develop innovative technologies.

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Environmental significance

Nanoparticles possess unique chemical and physical properties that allow them to penetrate deeper layers of the skin and offer prolonged effects. The interaction of these engineered particles with the skin's microbiome and their eventual fate underlines the environmental implications of their widespread use. The environmental significance of incorporating nanoparticles into cosmetic products extends beyond individual health and cosmetic benefits, encompassing broader ecological concerns. The persistence of nanoparticles in the environment, their interaction with wastewater treatment processes, and their potential accumulation in aquatic and terrestrial ecosystems underscore the necessity for a balanced approach. It highlights the importance of advancing nanotechnology in cosmetics within a framework that rigorously assesses both the human health impacts and the environmental footprint.

1. Introduction

Among nanomaterials, a nanoparticle (NP) is a particle with dimensions of 1 to 100 nm.¹ Chemical reactions and biomolecular interactions can occur at the nanoscale level, and the human skin surface is no exception. In cosmetic preparations, the skin is usually the first point of contact. The functions of the skin include regulating body temperature, preventing fluid loss, and preventing pathogen attacks. Dermal interaction with nanoparticles may lead to skin irritation, cytotoxicity, or genotoxicity.

Nanomaterials are often used as an additive to improve the intrinsic properties of cosmetic preparations, control active ingredient release, penetrate past the epidermal layer to the dermal layer, provide physicochemical stability, reduce irritability, improve the texture of the product to be applied or improve the dispersion of active ingredients. Previous reviews on nanomaterials and cosmetics have been published with a particular focus on the regulatory framework.^2–6 Other review articles have focused on technology and nanotechnology advances.^7–9 However, this review article will focus more on current commercial cosmetic ingredients categorized as nanoscale materials, the portrayal of the characteristics of nanomaterials, and how they may be included in cosmetics. The present review also investigates nanomaterials' fate and toxicity when applied to the skin and what happens after if released from the skin and into the environment. Both cellular and skin NP uptake will be reviewed in this article. The penetration and pathways will be described and discussed. Toxicological endpoints, including cytotoxicity, inflammation, and genotoxicity of the skin, will also be addressed.

2. What is special about nanomaterials?

Nanomaterials can be defined by their composition or dimensions.¹⁰ According to Medical Device Regulation (MDR), all particles whose dimensions are in the nano range belong to the nanomaterial class.¹¹ Nanomaterials can also be classified as either organic or inorganic but can also be categorized based on their dimensions in 0D, 1D, 2D, and 3D classes, depending on the confinement of their electrons and holes in one or more dimensions (Fig. 1, Table 1).

Fig. 1 Nanoparticles can be classified based on their composition, either organic (containing carbon and hydrogen) or inorganic (metals and oxides), but also according to their dimensions. Nanoparticles that are 0D can commonly be found in cosmetic applications. For nanomaterials in the 1D range with a wire or fibre shape, the nanomaterial only exhibits a length larger than 100 nm in one dimension and these materials are commonly applied in electronics and the energy industry. Two-dimensional (2D) nanomaterials include films, plates, and multi-layers. Three-dimensional (3D) nanomaterials contain equiaxial nanocrystals in different directions.¹² Relative sizes are not indicative of their representation in products or the market.

Table 1 Classification of nanomaterials that find application in cosmetic products

Sub-classification	Type	Properties	Common applications	Example (ref.)
Inorganics
Carbon	Fullerene	Anti-oxidant	Skin care	13
	Nanotubes	Carrier
Metal	Gold	Anti-bacterial	Skin treatment	14, 15
	Silver	Anti-bacterial	Odour-resistance, detergents, soaps
	Silica	Lipophilic	Skincare, cosmetics
Metal oxides	Titanium dioxide	UV-absorbent	Sunscreen	16
	Zinc oxide	UV-absorbent	Sunscreen

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Organics
Lipids and surfactants	Fullerene	UV-absorbent, anti-bacterial, carrier	Skin care	17
	Liposomes	Hydrophobic/hydrophilic	Skin treatment, hair loss treatment	18
	Solid lipid NPs	Protects active ingredients and regulates the rate of release	Make-up	19
	Niosomes
	Dendrimers	Provides controlled drug release and enhanced ingredient permeation	Sunscreen, shampoo, face creams, perfumes	20
	Ultrasomes	UV-absorbent	Sunscreen	21
	Photosomes
	Nanocrystals	Enhances lipophilic active ingredients' solubility	Moisturizers, lotions, sunscreen, hair conditioners	22
	Nanoemulsions	Enhances lipophilic active ingredients' solubility	Moisturizers, lotions, sunscreen, hair conditioners	23

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Polymeric
	Nanocapsules	Entraps both aqueous and oily liquid core	Cosmetics	24
	Nanospheres

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Nanomaterials are vital active ingredients in certain products, such as in sunscreens, either as sun-blocking agents or colour-change particles. Nanomaterials, like pigments that can cause a colour change in the product, are highly desirable for applications such as whitening creams, makeup, lipsticks, or nail polishes.^25,26 In contrast to these coloured products, sunscreens aim to achieve a function within a transparent product. Nanomaterials can also be utilized for their physio-chemical properties that offer advantages such as tuning the dermal penetration. To penetrate the skin, the cosmeceutical must get past the hydrophobic skin surface, and therefore, penetrating the skin requires that the NP also be hydrophobic.²⁷ It is known that negatively charged nanoparticles can cross the epidermis layer faster than nanomaterials with a positive charge.²⁸ Furthermore, in a paper evaluating the recovery of the skin barrier function after electroporation, it was observed that negatively charged particles increased the rate of skin recovery.²⁹ Regarding nanoparticle size, penetration via aqueous pores may occur for nanomaterials below 36 nm.²⁸ Intercellular lipidic matrix penetration may occur directly for nanomaterials smaller than 5–7 nm.²⁸

2.1 Public perception of nanomaterials in cosmetics

Regarding long-term exposure, potential toxicity may occur if the NP cannot degrade and cannot be chemically transformed or accumulated by human enzymes/molecules (Fig. 2).

Fig. 2 Schematic view of the three main exposure routes for skin to nanoparticles (NPs) in cosmetics. Professionals can be exposed during working phases such as manufacturing, consumers can be reached when they apply the cosmetic product, and all are exposed to NPs that are naturally present in the environment or as products of human activities. Arrows suggest the flow of NPs from production to use to disposal.

Nanomaterials for cosmetic applications come with different features, as seen in Table 1. Some of the public perceives the claim of ‘no nanomaterials’ as a guarantee that there will be no penetration in the skin. As an example, pigment grade ZnO (>100 nm) is officially considered safe as it does not penetrate the skin.³⁰ In a publication by the European Chemicals Agency, a study revealed that the respondents were fearsome of nanomaterials when discussing terms that may lead to potential toxicity such as ingestion by nanomaterial enrichment of foods with vitamins.³¹ However, the public took a positive or neutral outlook on applications where nanomaterials do not have direct contact with them in such cases where nanomaterials are used in strengthening rubber tires, environmental remediation, and electronics. The study was able to group the respondents into three categories: (1) a very positive attitude towards nanomaterials represented 65% of the population and were often highly educated (University level) within the age range of <29 years old, or 40–49 years of age (2) no clear perspective on nanomaterials, where the majority of respondents were within the age range of 30–39 years and (3) 23% of the studied population showed fear of nanomaterials, wherein this group mainly consisted of people >50 years, with lower than university-level education, in support of these findings. Murphy et al. 2022, used Twitter to determine the risk perception outside the scientific community.³² Using a sentiment analysis tool, this study reviewed over 270 000 Twitter posts related to silver, carbon, and titanium nanoparticles between October 2011 and October 2020. It was determined that the sentiment was positive towards nanomaterials, except for nanosilver (Ebola) and titanium dioxide (food additive). In a study comparing the perspectives of developed and developing countries, Rathore and Mahesh 2021, found that public perception was generally positive in both developed and developing countries.³³ However, in developed countries, religious people perceived nanotechnology negatively, whereas nanotechnology in a religious context was not discussed in developing countries. One way to make nanoparticles in cosmetics more appealing might be to market ‘natural nanomaterials’ by leveraging their composition, production process, or origin.

2.2 Commercial availability of nano-sized cosmetic ingredients

Nanocosmetics began in 1975. Lancôme (L'Oréal, Paris) patented “niosomes”, as a nanomaterial delivery vehicle which showed the potential to increase product skin penetration.³⁴ In the 1980s, the first patent was filed claiming that TiO₂ and ZnO NPs have the ability to absorb UV radiation.³⁵ In 1986, Dior Science (Louis Vuitton Moët Hennessy, Paris) brought the anti-aging serum ‘Capture’ to market, which was a suspension of 100 nm-sized liposomes in a mixture of hyaluronic acid gel and carbomer.³⁴ The next major marketing launch for nanomaterials in cosmetics would not be for approximately another decade, when Plentitude Revitalift (L'Oréal, Paris), an anti-wrinkle cream, used polymeric nanocapsules to deliver retinol to the dermal region of the skin.³⁶ And then, the excitement for nanomaterials began. In the 2000s, brands including Pureology, Caudalie, Johnston & Johnston, Estèe Lauder, and Procter & Gamble all began to launch nanocosmetics to the general public.⁵ An illustration depicting this series of events can be found in Fig. 3.

Fig. 3 Timeline of the commercial introduction of nano-formulations.^37–39

2.3 Cosmetic ingredients and nano-sized actives

In response to customers' concerns, a large number of cosmetic ingredients openly claim not to have nanosized ingredients, non-nano but very thin particle sizes for mattifying and absorbent properties, such as the natural mineral Pumice PM from DKSH.⁴⁰ According to the most current information provided by the catalogue of nanomaterials in cosmetic products placed on the market, as notified to the European Commission by Responsible Persons,⁴¹ 27 nanomaterials are available in cosmetics (Table 2). Among them, zinc oxide nanoparticles, carbon black nanoparticles, methylene bis-benzo triazolyl tetramethyl butyl-phenol nanoparticles, and titanium dioxide nanoparticles carry restrictions in their use, their size, their concentration, and a warning of avoidance of possible inhalation.⁴²

Table 2 Summary of commercially available cosmetic ingredients with nano-features

Category	Type	Application	Associated manufacturing brands	Ref.
Carbon	Carbon black	Aesthetics, body care	Estée Lauder, Shiseido	43, 44
	Fullerenes (buckyballs)	Hair care	Zelens	45
Inorganics	Alumina	Skincare, UV absorber	Paula's Choice	46
	Gold	Body care, skincare, hair care, aesthetics	Orogold	47
	Silica	Skincare, body care, hair care, UV absorber, aesthetics	L'Oreal, Lancôme	48, 49
	Silver	Hair care, skincare, body care	Nano Cyclic	50
	Sodium magnesium fluorosilicate	Body care, skincare, aesthetics	Aurelia	51
	Sodium propoxyhydroxypropyl thiosulfate silica	Aesthetics, skincare, UV absorber	Biosil Technologies Inc.	52
	Titanium dioxide	Aesthetics, body care, UV absorber, skincare, hair care	Aubrey Organics, Decorte, Shiseido	53–55
	Zinc	Hair care	Sesderma	56
	Zinc oxide	Aesthetics, skincare, UV absorber	Christian Dior, Decorte, Shiseido, Clinique	38, 54, 57, 58
	Hydroxyapatite	Skincare	Apagard Royal	59
	Methylene bis-benzotriazolyl tetramethylbutylphenol	UV absorber, body care, skincare, aesthetics	Guinot, Synchroline	60, 61
	Silica dimethyl silyate	Skincare, body care, hair care, UV absorber, aesthetics	Lancôme, Helen Rubinstein	62, 63
	Silica silyate	Skincare, body care, hair care, UV absorber, aesthetics	Maybelline, Redken, Lancome	64–66
	Tris-biphenyl triazine	Skincare, body care, hair care, UV absorber, aesthetics	SUNdance	67
Polymers	Lithium magnesium sodium silicate	Skincare, body care, hair care, UV absorber, aesthetics	Eckart, R+Co	68, 69

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Nanomaterial cosmetics can be classified based on the product or the function they provide (Fig. 4) and commercially available NPs ingredients belong to various classes and provide a wide variety of functionalities (Table 2).

Fig. 4 Further classification of NPs in relation to the product and their role in it. Relative sizes are not indicative of their representation in products or the market.

USA, Brazil, UK, Germany, France, South Korea, Russia, Poland, Switzerland, and Malaysia are the top countries utilizing nano agents, which are in approximately 12% of consumer cosmetic products.⁵ Nanomaterials are also used as delivery vehicles for bioactive molecules and as active ingredients and thickening agents. Retinoids and antioxidants are chemicals with desirable anti-aging properties. However, they are inherently sensitive to UV light, oxygen, and heat. Nanoencapsulation may prevent chemical degradation. Though not yet popular on the market, nanogels have been shown to release antioxidants such as co-enzyme Q10 (CoQ10) or resveratrol after 24 hours.⁷⁰ Resveratrol has a half-life of 8–14 minutes; therefore, the timed control release will allow for penetration more profoundly into the skin layers before it begins to degrade. As discussed in section 2, lipids, peptides, and gold may enhance penetration and permeation through the skin barrier. La Cremerie manufactures a gold and hyaluronic acid facial serum to improve skin moisture.⁷¹ Gold is an extensively studied material and, as nanoparticles, has been proposed as a cosmetic ingredient by Spec-Chem Industry Inc (SpecKare™ Nano Au), claiming improved cell metabolism speed, anti-wrinkle, and anti-aging effects. Moreover, it is claimed to enhance collagen activity, increase skin's natural luster, restore healthy skin, promote cell repair, and improve skin anti-aging ability. However, it is found in the CosIng database without any reference to the nano form but as a colourant (CI 77480) or as a secondary ingredient in combination, for example, with minerals such as zeolite, or hyaluronic acid, fermentation products, or plant extracts.⁷² In addition, liposomes are made from phospholipids such as phosphatidylcholine from sunflower lecithin or phosphatidylethanolamine.⁷³ Lipomize is a commercial nano-scale liposomal solution that encapsulates a well-known cosmetic molecule, retinol, to improve the delivery of retinol through the outermost layers of the skin. In this direction, encapsulation to the nano-level can improve the stability, adsorption, and solubility in the water-based formulation of sensitive materials such as aromatics and oils undergoing oxidation (Plant Nano Essence Oil by Spec-Chem Industry Inc). Such ingredients are also called nanoemulsions (SunActin Mibelle AG Biochemistry). These formulations are often based on lecithin.

2.4 Nanoparticles produced from natural sources

Naturally occurring nanomaterials, i.e., those found in the environment without human intervention, are found in organic ash, and the air.⁷⁴ They can also be produced from algae, plants, and bacteria.⁷⁴ Plant-based approaches have been applied to various metals and might make the product more acceptable to the public. Polyphenol-rich solutions can spontaneously produce nano-sized materials, such as those from Salvia extracts.⁷⁵ It has been shown that wheat and oat biomasses can reduce AU(II) to Au(0).⁷⁶ Gold NPs can be found in luxury skincare creams such as Orogold, and L'Oreal.⁷⁷ Armendariz et al. observed that using cetyltrimethylammonium bromide or sodium citrate would produce small nanoparticles of about 10 or 18 nm.⁷⁶ Alfalfa plants can reduce gold and silver NP.⁷⁸ In two separate studies by Gardea-Torresdey, the formation of silver nanoparticles and gold nanoparticles as a result of alfalfa plant uptake was reported.^79,80 Alongside alfalfa plants, silver nanoparticles exist in aquatic waters.^81,82 Silver nanoparticles can be found in cosmetics products such as cleansers such as those manufactured by Nano Cyclic for their penetration attributes.⁸³ Also, naturally occurring alumina may be found in aquatic waters.⁸⁴ Alumina NPs are commercially available in products including face care products, sun protection products and nail products as per the European Commission.⁴¹ Silica nanoparticles can be found organically in volcanic eruptions.⁸⁵ L'Oreal uses silica NP in their cosmetics along with titanium dioxide NP, zinc oxide NP and carbon black NP.⁸⁶

Alongside using nanoparticles for cosmetic purposes, oil droplets that are on the nanoscale may be used to better penetrate the cutaneous barrier. Nanoemulsions are typically oil-in-water (O/W) or water-in-oil (W/O) colloidal dispersions that contain droplets that typically range from a few nanometer to 200 nm in diameter providing desirable optical, stability, rheological, and delivery properties that cannot be achieved with conventional emulsions.⁸⁷ Nanomulsions can be found in many skin care products such as Evidens de Beauté's Eclat cream or Mibelle's Nano-Lipobelle H-AECL.⁸⁸ Nanoemulsions can improve the solubility and bioavailability of poorly water-soluble compounds.⁸⁹ In nanoemulsions, a mixture of oil and water uses surfactants to prevent aggregation. The bacterial species Bacillus sp. has been used to formulate biosurfactants for emulsion purposes.⁹⁰ A current concern for nanoemulsions is destabilization caused by either Ostwald ripening, where small nanodroplets grow into larger particles or droplets, or depletion-induced flocculation as a result of polymer addition.⁹¹ In an attempt to increase stability, Ganesan et al. formulated a lipopeptide-type biosurfactant produced by Bacillus sp. as an emulsifier, used a phyto-based oil as a bioactive ingredient, and coconut oil as the base oil to make a green nanoemulsion.⁹² With the increasing rise in nanomaterial production, questions about long-term effects should be evaluated. However, current research in cosmetics scrutinizes in developing cost-effective methods of producing nanoemulsions from consumer-friendly ingredients as well as assessing their effectiveness by using in vivo models.

3. Nanoparticles and skin interaction

An excess of nanoparticle exposure to the skin can lead to dermatitis.⁹³ In more damaging scenarios, there is potential for skin cancer or DNA damage. To predict these outcomes better, skin penetration of nanomaterials must be understood. The human skin comprises three overlapping layers: the epidermal, dermal, and hypodermis. The epidermis is the most superficial layer and is composed of four distinct sub-layers (ranging from most outermost to deepest): stratum corneum (SC), stratum granulosum (SG), stratum spinosum (SS) and stratum basal (SB). Permeation across the SC may occur through intercellular, transcellular, or trans appendageal (e.g., hair follicles and sweat glands) transport. The intercellular route is the most used in cosmetics. It is the fastest pathway for a cosmetic drug to permeate the skin. To diffuse between the cells, the cosmetic ingredient must pass through the lipophilic cell membrane, lipid matrix, and lipophobic structures in the skin cells. The trans appendageal route through follicles, oil glands, and sweat ducts accounts for less than 0.01% of skin exposure passages, making the route not as available as SC application and transcellular pathways are highly compact. Silica nanoparticles are used to extend product shelf-life.⁹⁴ An in vivo study comparing penetration in the stratum corneum and hair follicular route by bare hydrophilic silica nanoparticles and hydrophobic lipid-coated silica was studied.⁹⁴ The most significant penetration occurred through the stratum corneum, where 42% of lipid-coated Si nanoparticles penetrated through to the deepest layer of the SC, whereas 18% of bare silica nanoparticles permeated until the deepest SC layers via topical application and 10% of bare silica nanoparticles reached the same depths via hair follicles. Soft nanoparticles (e.g., lipid carriers, dendrimers, and polymer-type nanoparticles) can penetrate as deep as the dermis layer.⁹⁵ Regarding follicular penetration, nanoparticles >640 nm have succeeded in dermal transportation across the epidermis.⁹⁶Fig. 5 shows possible routes of nanoparticle entry via skin adsorption.

Fig. 5 Nanoparticles can permeate the skin and move across the epidermis with three main routes such as (1) proceeding in the space between cells, (paracellular) cross-cell spaces (transcellular), or through the follicle (follicular).

Nanomaterials can dissolve, adsorb, absorb, or aggregate upon contact with the skin. The dissolution mechanism of nanoparticles is critical when estimating their safety and is influenced by their chemical and physical features. These factors may include surface bonds, strength, spatial arrangements, the presence of impurities or adatoms, as well as the storage conditions of the nanoparticles.⁹⁷ In the case of cosmetic nanomaterials, the dissolution of Zn²⁺, Cu²⁺, and Ag⁺ ions, which are known to be highly toxic, has been documented.⁹⁸

To better understand the toxicity induced by ZnO nanoparticles, Senapati and Kumar, observed ZnO dissolution in water at different pH levels (4 and 7) to mimic cellular cytoplasm and cellular organelles pH conditions, respectively.⁹⁹ After 72 hours, ZnO nanoparticles were detected in cytoplasm cells. Nanoparticle dissolution at pH 7 increased after 48 hours; no observable dissolution increase was reported at pH 4. Though no direct studies on TiO₂ dissolution in an acidic medium for the purpose of cellular cytoplasm mimicry have been conducted, it is well-documented that TiO₂ is insoluble.¹⁰⁰ In a study on zebrafish embryos, and the potential toxicity of silver nanoparticles upon contact, Lee et al. determined that two different types of coated silver nanoparticles (citrate and polyethylene glycol) showed a variance in dissolution, aggregation, or precipitation based on ionic conditions.¹⁰¹

Similarly, a correlation between dissolution and toxicity of Ag nanoparticles was demonstrated where low chloride concentrations led to the dissolution of Ag⁺ from Ag nanoparticles causing toxicity of zebrafish embryos.¹⁰¹ In general, it can be stated that the tendency to dissolve determines if nanoparticles will undergo cellular uptake, will not dissolve, or undergo endocytosis.

3.1 Nanomaterial behaviour and toxicology

Nanomaterials improve or limit active ingredient skin diffusion due to their size, chemical structure, and colloidal stability properties (Fig. 6). Regarding molecular weight and size, 500 Da is considered the uppermost threshold for nanoparticle weight to enter the epidermis.²⁸ Copper nanoparticles have been proven not to absorb through intact skin.¹⁰² In the case of silver nanoparticles, absorption by the skin is almost absolute.¹⁰³ A study monitored the permeability coefficient of different-sized silver nanoparticles as Ag nanoparticle size changed.¹⁰⁴ Upon increasing the size of the nanoparticle to a higher magnitude (e.g., from 101 to 102 nm), the permeability coefficient dropped to a lower magnitude, supporting the concept that smaller nanoparticles will tend to penetrate deeper.

Fig. 6 Schematic view of how the physical surface properties of nanoparticles can influence their behaviour and thus their use of cosmetics and their interaction with the skin. The features of the different types of NPs are described in the text and publications such as Nanocarriers for Skin Applications: Where Do We Stand? – Tiwari – 2022 – Angewandte Chemie International Edition – Wiley Online Library and Skin penetration/permeation success determinants of nanocarriers: pursuit of a perfect formulation – ScienceDirect and in section 3.2.

ZnO and TiO₂ nanoparticles are commonly used in cosmetics for sun-blocking. In a bioassay utilizing human epidermal keratinocytes (HEK), cellular uptake examination revealed that 8–20 μg ml⁻¹ of ZnO nanoparticles were internalized by the cells after 6–24 hours of exposure.¹⁰⁵ Furthermore, this skin internalization led to cytotoxic and genotoxic responses. In contrast, it is more common that peer-reviewed papers mention that ZnO nanoparticles do not cross the stratum corneum layer.^106,107 Consistently, TiO₂ has also shown that it will not penetrate the stratum corneum.¹⁰⁸ Titanium dioxide nanoparticle suspensions (concentration 1.0 g L⁻¹) were applied on HaCaT cells for 24 hours and observed after 24 hours, 48 hours, and seven days of exposure. No traces of TiO₂ nanoparticles were found in intact or damaged skin. TiO₂ is commonly applied to sunscreen applications, and in a lab bioassay determining the effects of photoinduction, it was concluded that TiO₂ nanoparticles will disaggregate and dermal penetration through the stratum corneum will occur.¹⁰⁹ An inquiry to be made is the ability to remove nanoparticles from the skin by washing. Zinc oxide nanoparticles were washed once from wounded human skin.¹¹⁰ Completing both ex vivo, i.e., experimentation done in or on tissues obtained from an organism and maintained under optimum conditions,¹¹¹ and in vivo research, it was concluded that washing the skin once will effectively remove ZnO nanoparticles (83–93% removal). However, for puncture wounds, this will not be adequate (28% removal). Toxicity assessments of nanoparticles are of primary importance since NPs are widely used in industry and medicine.¹¹² Most studies on the toxicity of NPs are based on in vitro methods as these experiments are relatively straightforward, several factors can be easily modified, and they provide information on the mechanism of action. The first step of toxicity assessments for NPs is usually the determination of cell viability using different assays such as ATP, XTT, MTS, and WST, where at least two of them are chosen.^113–115 The second step is the mechanism analysis in which different approaches can be chosen such as Western blot analysis of markers of oxidative stress, angiogenesis, and apoptosis or ELISA for inflammatory cytokines.^116–120 The selection of toxicity assays should ensure the safety of the NPs.

On the other hand, a major concern of in vivo studies is the use of laboratory animals. Thus 3D in vitro models are used currently to replace in vivo studies.^121–123 However, in vivo, studies for NPs in cosmetics are still used for either assessing the efficacy of final formulation in humans or evaluating the mechanism of analysis using, for example, Western blot analysis of apoptotic markers or microarray analysis for whole-genome or specific pathways.^124–126 Of note, well-designed combinations of in vitro and in vivo assays facilitate the proper evaluation of the toxicity of NPs and predict the possibility of clinical application of NP-based agents.

4. Nanoparticles and the influence of the protein corona

The corona, or protein corona, is a dynamic process that occurs when proteins adsorb onto nanomaterials¹²⁷ (Fig. 7). Protein corona gives the nanoparticles a new biological identity and changes their fate within an environment. Protein corona is spontaneously formed on nanoparticles when exposed to proteins; here, the crystal structure of bovine serum albumin is presented because it is often used to study protein–nanoparticle interaction.¹²⁸ Protein corona has various effects on the physico-chemical features of the nanoparticle and their behaviour. In the context of skin, this spontaneous morphology can either be beneficial or cause risk to the person applying the cosmetic. Further research into the subject matter should be investigated. Protein corona formation is a dynamic process resulting in the formation of a protein layer, e.g. blood or interstitial fluid from the human body, on the material's surface, whose composition and size might change with time and environmental conditions. A study on the effects of graphene oxide for topical administration showed skin absorption after 6 hours of exposure.¹²⁹ After 24 hours of incubation, no effect on human skin fibroblasts was observed. However, in a review article prepared by Liu et al.,¹³⁰ protein corona has also been shown to increase cytotoxicity or even cause apoptosis. Graphene oxide NPs are currently in the research phase and have not been launched onto the market. Protein corona can change the size and surface chemistry of the nanomaterial, leading to a variation in cellular uptake.¹³¹ Regarding size dependence, larger nanoparticles have a slower uptake rate.¹³² To reduce potential cytotoxicity, reducing cell intake will prevent nanomaterial ingestion by cells.¹³³ Hydrophobic and hydrophilic properties of nanomaterials also play a role in determining cell uptake. Hydrophobic nanomaterials can pass through the lipophilic core of cell membranes. Meanwhile, semi-hydrophilic nanoparticles will adsorb onto the skin. Moreover, introducing protein corona may mitigate or aggravate the cytotoxicity of cell membranes or induce complex immune responses, including immunosuppression and immune activation.

Fig. 7 The protein corona formation is spontaneous and influences nanoparticle features. Protein corona can alter the physico-chemical properties of the NP according to the protein nature and thus affect its interaction with the skin surface and layers. The manuscript reports the relevant works used for the preparation of this scheme.

In vitro studies have been investigated to determine how physicochemical characteristics affect protein corona formation. Larger nanoparticles will generally cause more corona formation.¹³⁴ Surface charge and nanoparticle size change with the introduction of the protein corona. One benefit of protein corona has been to intentionally adsorb them onto nanoparticles to mitigate or eliminate the toxic effects of nanoparticles. Current studies utilize polyethylene glycol (PEG) sorbed onto nanoparticle surfaces to evade macrophage uptake by reducing protein adsorption. Zou et al. proposed polyglycerol (PG) grafting as an alternative to PEG for better uptake evasion performance.¹³⁴ PG and PEG were grafted with heterogeneous nanoparticle sizes at 30, 20, and 10 wt% contents. Transmission electron microscopy (TEM) and extinction spectroscopy or inductively coupled plasma-mass spectrometry (ICP-MS) bioassays confirmed that PG prevented more macrophage uptake than PEG. In another PEG PC evaluation Ag nanoparticles with PC, formation was shown to not reduce bactericidal impact.^135,136

5. Risks for humans and the environment

To determine how dangerous a nanoparticle may be, a risk assessment can be conducted to determine if a nanoparticle can exhibit very high, high, medium, low, and very low hazard levels. The standard approach to risk assessment of nanoparticles includes determining three factors: (1) hazard estimation, (2) exposure estimation, and (3) risk estimation.¹³⁷ Databases, including NaKnowBase, NanoE-Tox, and NanoWerk, provide experimental data about environmental fate, transport, and transformations.^138–140 In addition, there is information on the potential effects on humans and the ecosystem. It should be noted that the data is not complete due to gaps in research gaps; characterization is often evaluated using biological tests, e.g., in vitro, in vivo, and in silico. Despite these being pre-emptive tests to determine the potential effects of nanomaterials on humans, there is still room for unforeseen circumstances when scaled up to actual human exposure. The second factor in risk assessment of nanoparticle toxicity is exposure assessment. The exposure assessment takes into account the detrimental impact of nanotoxicity, e.g., diseases that may occur and where and how the nanoparticle may be distributed to the population. Assessing exposure includes measuring the number of nanoparticles at risk of entering the body. The final determinant of the risk factor is the risk estimation. Studies that characterize the risk of nanomaterials exist to date and have been assessed, namely, those published by Sotiriou et al. and Tolaymat et al.^141,142 In most circumstances, risk profiling aims to answer how toxic nanomaterials are regarding an affected population. This is done by analysing the nanoparticle contact with various environmental mediums (soil, water, and air) and determining the physicochemical and morphological properties, which may be affected by their fate, transport, time elapsed, quantity, and duration of exposure.

5.1 Risk assessment and prediction of risk of the use of nanoparticles

Artificial intelligence (AI) is currently under active research to provide various approaches to estimate possible nanomaterial toxicity. Artificial Intelligence for the usage of forecasting toxicity saves time and costs and does not require physical animal and human samples. Bates et al. used decision analysis methods more commonly administered to financial applications to classify hazard risks of silver and titanium dioxide nanoparticles and multi-walled carbon nanotubes.¹⁴³ Sources from the literature were used to provide input parameters using the Control Band Nanotool hazard assessment method.⁸ Subsequently, a Monte Carlo simulation was used to assess the hazard classifications' value of information (VOI). As a result of this computation, it was concluded that particle shape, diameter, solubility, and surface reactivity precision will have the most impact on hazard classification improvement while remaining relatively inexpensive. In research conducted by Li and Barnard, a multi-target random forest regression algorithm using direct structure/product relationship predicted nanoparticle size, shape, and concentration of titanium nanoparticles.¹⁴⁴ The models were then inverted, reoptimized, and re-trained to predict potential toxicity, with a normalized mean absolute error of less than 2%. Quantitative structure–activity relationship (QSAR) computational strategies can be used to perform toxicological predictions for inorganic nanomaterials.^145–147 Nano-QSAR models are built on the framework that similar molecules have similar properties. The model draws a relationship between independent variables, structure or descriptors, and dependent variables, activities, or endpoints. Quantitative structure–permeability relationships (QSPRs) are subsets of QSAR where the focus of percutaneous absorption may be observed.¹⁴⁸ Based on literature, molecular size and hydrophobicity (log k_ow) are the main constituents of transdermal penetration.¹⁴⁹ The main shortcoming of QSPR is that the accuracy of the results is highly dependent on the input datasets, and gaps in knowledge on nanomaterial characteristics are still considerable.

5.2 The environmental impact of nanomaterials

Nanomaterials have the potential to undergo various surface transformations within the environment and through wastewater treatment.¹⁵⁰ In addition, understanding the fate and transport of aging nanomaterials is vital to predicting human toxicity. Nanoparticles cross many environments during their preparation, use and disposal that can happen during use as in the case of sunscreens that get released in the sea, or under the shower; a potential life cycle flow diagram for a nanoparticle found in a cosmetic can be found in Fig. 8.

Fig. 8 This flowchart highlights the introduction of nanoparticles into the water system through the release of sunscreen. Sunscreen containing TiO₂ or ZnO NP may be applied before entering a water body. The NP may desorb from the swimmer's body and release into the water. Within the aquatic system, nanoparticles may transform, agglomerate, aggregate, degrade, dissolve, deposit, adsorb or be transported over time. Nanoparticles persisting in the aquatic system may then bioaccumulate within plant or animal life. Plants may also be used for cosmetic products.

In the case of sunscreens, the occurrence of nanoparticles' release into the water system will be a result of sunscreen desorption during water activities such as swimming. Titanium dioxide, TiO₂, and nanoparticles are commonly used in sunscreen. A study to comprehend the aggregation behaviour of TiO₂ nanoparticles (5 nm) in the river water near a TiO₂ production plant determined the attachment efficiency coefficients and the potential aggregation process.¹⁵¹ Using filtered water from Suwannee River, it was concluded upstream of the production plant certain concentrations of fulvic acid caused TiO₂ nanoparticle aggregate size to decrease. TiO₂ nanoparticles were adsorbed onto illite (clay) particles, even at low concentrations once Ca²⁺ ions were added. These conditions mimicked the natural environment at the TiO₂ nanoparticle production site. Downstream, when TiO₂ concentrations were introduced at 10 mg L⁻¹, nanoparticle aggregation did not occur with illite. Along with TiO₂, zinc oxide, ZnO, nanoparticles can be used for sunscreen applications. In terms of environmental fate, nanosized UV filters may absorb to each other or other molecules, bioaccumulate in plants or animals, chemically produce metal ions, and/or generate reactive oxygen species.¹⁵² These processes may lead to toxic effects on humans. Water chemistry plays a role in determining these outcomes.¹⁵³ Three different locations of Suwannee River wastewater were tested for ZnO nanoparticle outcomes (1) a textile factory located in Tainan County (2) a marble factory in Pingtung County, and (3) a plastics factory in Changhua County, Taiwan. In wastewater 1, the hydrodynamic size of ZnO NPs remained constant within the recorded time frame. In wastewater 2 and 3, hydrodynamic ZnO nanoparticle sizes increased with time rapidly with aggregates exceeding micrometer sizes in approximately 8 minutes in wastewater 2 and 3600 nm after 60 min in wastewater 3. The results varied due to the stability of ZnO nanoparticles which showed greater precipitation in seawater. Dissolution was also monitored. In wastewater 1, the concentration of Zn²⁺ reduced after 11 days and the concentration in the other two wastewater samples remained constant. The result of this was due to the lower pH value and higher concentration of TOC in wastewater 1. The temperature was insignificant when compared to enhanced ionic strength and water chemistry in ZnO aggregation.¹⁵⁴

ZnO and silver, Ag, nanoparticles have been proven to agglomerate better in aquatic conditions where higher ionic strength exists.¹⁵⁵ In terms of photodegradation in this study, ZnO nanoparticles showed dissolution in dark, visible, and UV light conditions, ranging from lowest to highest amount dissolved, respectively. Visible light increased Ag nanoparticle dissolution and UV light decreased Ag nanoparticle dissolution. Seasonal changes bring about variance in water chemistry in freshwaters. Ag nanoparticles were collected seasonally from the same freshwater source and observed for dissolution, aggregation, and sedimentation.¹⁵⁶ Two different coatings were used for Ag nanoparticles, polyvinylpyrrolidone (PVP) and citrate. PVP–Ag nanoparticle transformations were insignificant throughout the experiment. Citrate–Ag nanoparticles showed high susceptibility to water chemistry changes throughout the seasons. In summer, citrate–Ag nanoparticles showed a range of 46–72% dissolution. This may be a result of incomplete coatings over the available surface areas resulting in exposed Ag nanoparticle surfaces. In the fall, the Ag nanoparticle concentration increased up to day 6 and then decreased up to day 12. Theories on the variance in concentration may have been due to aggregation and settling. Dissolution during this time was low (8% at low depths). In the winter months, there was an increase in Ag nanoparticle concentration over time, which is potentially caused by the reprecipitation of dissolved Ag. Another study examining freshwater chemistry and its effects on three surface-coated Ag nanoparticles (citrate, polyvinyl pyrrolidone, and lipoic acid) determined the impact of dissolved organic matter on nanoparticle stability.¹⁵⁷ Similar to the previous study, the surface coating was a predominant factor in the fate of the Ag nanoparticles in the Suwannee River. PVP-coated Ag nanoparticles did not agglomerate as much as citrate and lipoic acid-coated Ag nanoparticles. The presence of dissolved oxygen showed an increase in nanoparticle stability.

Wastewater treatment plants (WWTP) that utilize activated sludge are capable of removing the majority of nanoparticles, including Ag, Cu, ZnO, CuO, and TiO₂.¹⁵⁸ In certain conditions, redox transformations have been reported for zinc oxide, copper, and silver nanoparticles. SiO₂ is an exception in the removal of nanoparticles from wastewater. The removal of SiO₂ nanoparticles is low due to low biosorption and high colloidal stability of SiO₂ NPs in wastewater treatment.¹⁵⁸ Furthermore, a study that evaluated the environmental impact of nanomaterials from cosmetic products, TiO₂ and AgO₂ in Johannesburg, South Africa, showed a high correlation with the number of nanomaterials released into the aquatic or soil ecosystem depended on the WWTP efficiency.¹⁵⁹ A mathematical model using design variables such as nanomaterial quantity, fate and transport of nanomaterials through different types of ecosystems (aquatic and terrestrial), and wastewater treatment plant efficiency computed nanocosmetic product flow into the Johannesburg Metropolitan City ecosystems. A batch scale experiment on coagulation, flocculation, and sedimentation estimation of TiO₂ removal using coagulants (1) iron chloride (FeCl₃), (2) iron sulfate (FeSO₄), and (3) alum [Al₂(SO₄)³], determined the effectiveness of wastewater treatment.¹⁶⁰ Artificial groundwater and artificial surface water (ASW) were compared as mediums for contamination. After applying a constant dosage of 50 mg L⁻¹ in concentrations ranging from 10–100 mg L⁻¹, FeSO₄ and Al₂(SO₄)³ showed a 90% particulate removal of TiO₂ and less than 60% when FeCl₃ was the coagulant. In artificial groundwater, there was greater than one-log removal of TiO₂. Zeta potential showed a relation to treatment effectiveness, where the smallest magnitude of charge (<10 mV) showed the greatest amount of TiO₂ removal.

Another potential path to human dermal interaction can be from plants' natural uptake of nanoparticles. Often, plant extracts are used in cosmetics, and the effects of potential nanoparticle contamination can lead to dermal toxicity. Silver nanoparticles may be engineered and naturally produced in the soil. Upon plant uptake, nanoparticles can undergo oxidative dissolution, chlorination, sulfidation, and complexation with organics. Huang et al., examined Ag₂S nanoparticle uptake by soybean leaves via root exposure and observed that Ag₂S nanoparticles bioaccumulated into the leaves.¹⁶¹ Furthermore, Ag₂S nanoparticles were consumed by snails on the leaves of a plant. As a result, it is inferred that the leaves remained palatable. Protein corona has been discovered to form in the presence of nanoparticles when abundant amounts of proteins, lipids, and carbohydrates in the plant's phloem are present.¹⁶² Bing et al. tested TiO₂ nanoparticle and plant protein (glutenin, gliadin, zein, and soy protein) interactions and for changes in surface potential.¹⁶³ Protein corona was observed, sized 4–60 nm, formed on TiO₂, and the surface potential switched from negative to positive for glutenin, gliadin, and zein protein interactions, respectively.

When introduced into an aquatic environment, nanoparticles' fate may be altered biologically, physically, or chemically.¹⁶⁴ Microorganisms may biotransform nanoparticles. Physically, nanoparticles may agglomerate, adsorb or aggregate. With respect to chemical composition, the nanoparticle can reduce or oxidize, sulfidize, dissolve, or photochemically transform (Fig. 9). Time is an important factor as well, because these changes may occur instantaneously or over a period of time. In the environment, multiple transformations of these nanoparticles may occur simultaneously. Their transformation is regulated by size, zeta potential, surface area, composition, and stability. Commercial cosmetics risk re-exposure to dermal contact when sunscreen is applied on the skin and then the person proceeds to swim, or when washing nanoparticles off the skin such as makeup – nanoparticle transfer onto hands or other cutaneous surfaces is likely.

Fig. 9 The diagram shows a nanoparticle undergoing three transformations: biological (e.g., biodegradation), physical (e.g., aggregation), and chemical (e.g., oxidation).

6. Conclusions

On the positive side, nanomaterials have intrinsic properties desirable to cosmetic applications. They can provide better ingredient stability and deeper skin permeation, allow for control of drug release, improve textural quality, and protect from potential skin irritation and toxicity. On the other hand, nanomaterials risk microbiome alteration, possible unwanted penetration of the skin barrier, bioaccumulation, and environmental persistence. Potential toxicological effects on cutaneous cells include cytotoxicity, inflammatory response, and genotoxicity. Factors in determining hazards include release properties, e.g., dissolution rate, aggregation and distribution, physicochemical properties, and integrity of the epidermis layer. Without design, nanomaterials tend to remain in the stratum corneum or will not pass through the follicular route due to size restrictions and blockage, such as hair. Based on findings in this review, potential future topics of research include a more comprehensive range of research on the skin biome in response to the application of cosmetics, variations in skin type, including elderly skin, which tends to be thinner and less robust, a broader spectrum of currently operating water treatment systems and their ability to prevent nanoparticles from entering drinking water and rapid testing equipment for municipalities. The field would also benefit from the inclusion of more in vivo research. Nanoparticle production can proceed via chemical synthesis or ‘green’ approaches based on plant extracts. The question about whether or not natural nanoparticles will behave the same as their engineered counterparts remains an open question.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Author contributions

The project was initiated and led by Marina Freire-Gormaly, Greta Faccio, and Sophia Letsiou. The literature search and data analysis were performed by Thipphathong Piluk, Greta Faccio, and Sophia Letsiou. The initial manuscript draft was written by Thipphathong Piluk, Greta Faccio, and Sophia Letsiou, reviewed and revised by Robert Liang, Marina Freire-Gormaly, Greta Faccio, and Sophia Letsiou. All authors read and approved the final manuscript.

Conflicts of interest

The authors declare no competing interests.

Acknowledgements

This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant (Number: RGPIN-2020-06087) and the financial support of the Department of Mechanical Engineering at York University.

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