1. INTRODUCTION:

Nanotechnology entered the field of cosmetics and health products nearly 40 years ago with liposome moisturizing creams. Nanotechnology is most often described as the manufacture and manipulation of purpose-made structures which are at least smaller than 100nm.

A ‘cosmetic product’ shall mean any substance or mixture intended to be placed in contact with the various external parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance and keeping them in good condition”.^[1]

The cosmetics industry therefore uses nanodispersion “encapsulation or carrier systems”, -so that agents penetrate into deeper skin layers ^[2]. The functions and benefits of these “encapsulation and carrier systems” are:

· The protection of sensitive agents.

· The controlled release.

· A reduction in the amount of agents and additives.

· Longer shelf life and hence greater product effectiveness.

In cosmetics, there are currently two main uses for nanotechnology. The first is the use of nanoparticles as UV filters. Titanium dioxide (TiO2) and Zinc Oxide (ZnO) are the main compounds used in these applications and organic alternatives to these have also been developed. The second use is nanotechnology for delivery. Liposomes and Niosomes are used in the cosmetic industry as delivery vehicles ^[3]. Newer structures such as Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) have been found to be better performers than liposomes. Nanocrystals, microemulsions, nanoemulsions and dendrimers are also being investigated for cosmetic applications. Other novel materials, such as Fullerene, have also appeared in a small number of beauty products ^[4].

2. Nanomaterials, Human and Environmental Risk Assessment

There is considerable concern regarding the safety of manufactured nanomaterials (nanoparticles, nanotubes, nanowires, fullerene derivatives, and other nanoscale materials), as nanoscale materials may have characteristics (e.g. chemical, physical, electrical, and biological) different from their large-scale counterparts and may behave differently than conventional materials, even when the basic material is the same ^[5]. The United States, Europe, and Japan, among other nations, have developed and supported programs to assess hazards posed by nanomaterials in realistic exposure conditions in order to promote and expand the use of nanotechnology for commercial use. The primary focus of these programs is to develop reliable and informative risk and safety evaluations for these materials to ensure their safety for human health and the environment ^[6]. As a consequence of their novel characteristics, risk assessments developed for ordinary nanomaterials may be of limited use in determining the health and environmental risks of nanotechnology products. Nanometer-scale particles can get to places in the environment and the human body that are inaccessible to larger particles and unusual or unexpected exposures can occur. Since nanoparticles have a larger surface-area-to-mass ratio than materials of the same composition and biological/chemical reactions typically take place at the nanomaterial’s surface, it has been hypothesized that nanoparticles will be more reactive than the bulk material ^{[7, 8]}. It is well documented that nanoparticles/nanomaterials undergo dynamic interactions with components of their environment with which they are in contact. As a consequence of this interaction, physical/chemical characteristics, such as dissolution, agglomeration, disagglomeration, coalescence and the adsorption of substances onto their surfaces, may change over time. These changes must be considered in conducting a risk assessment related to both human health and the environment, as changes in these physio-chemical properties affect the behavior of the nanomaterial. While new exposure routes and increased reactivity can be useful attributes for nanomaterials, they also carry the potential for health and environmental risk ^{[9, 10]}.

3. Characterization of Nanomaterials

Nanomaterial characterization is accomplished using a variety of different techniques drawn from interdisciplinary areas. A summary of investigative methods for nanoparticle characterization is listed in Table I.

Table 1 Investigation Methods for Nanoparticles Characterization^[11-16]

Method or Equipment	Measurement Consideration
Laser Light Scattering System/Particle Size Analyzer	Measurement of particle size and size distribution of nanoparticles in liquid solutions or Suspensions
Zeta Potential Analyzer	Measurement of surface charge of nanoparticles in aqueous solutions or suspensions
Scanning Electron Microscope (SEM)	Examination of the consistency of nanoparticle’s surface and the shape of nanoparticles
Transmission Electron Microscope (TEM)	Determination of surface property and shape morphology of nanoparticles
Atomic Force Microscope (AFM)	Measurement of the shape and surface morphology (including friction and softness) of nanoparticles with high lateral and vertical resolutions
Laser Scanning Confocal Microscope (LSCM)	Non-invasive measurement of nanoparticle’s morphology in 3D, investigating the migration of nanoparticles into bio-barrier
Surface Area Analyzers and Pore Size Analyzer	Determination of single and multipoint surface-area analysis, multigas capability and full adsorption capability for nanoparticles
X-Ray Photoelectron Spectroscope (XPS, ESCA)	Providing important chemical composition (both elemental and chemical state) information on nanoparticle’s surface
Fourier Transform Infrared Spectroscope (FTIR)	Assisted analytical tool for chemical composition of nanoparticle’s surface
Differential Scanning Calorimetry (DSC)	Providing thermal analysis (and component interactions) of nanoparticles and related materials during fabrication process
High Performance Liquid Chromatography (HPLC)	Detection, separation and quantification of nanoparticles/ nanomaterials with different particle size

4. Nanomaterials AND Cosmetics (Dermal Absorption)

Nanoparticles used in drug delivery systems are of interest to the cosmetic industry. Examples include nano-encapsulation vesicular delivery systems, including nanoemulsions and nanocrystals, liposomes and niosomes, micelles, polymeric nanocapsules, solid lipid nanoparticles and nanostructured lipid carriers, carbon nanotubes and fullerenes, and dendrimers. Nanoparticles are also used as ultraviolet (UV) filters, such as insoluble mineral based nanoparticles titanium dioxide (TiO2), zinc oxide (ZnO) ^{[17, 18]}. They are produced in a variety of compositions, shapes, structures, sizes, and reactivity. The primary advantages of using nanoparticle formulations in cosmetic products are to i) improve the stability of various cosmetic ingredients like unsaturated fatty acids, vitamins, or antioxidants encapsulated within the nanoparticles; ii) enhance penetration of certain ingredients, such as vitamins and other antioxidants; iii) increase the efficacy and tolerance of UV filters on the skin surface; and iv) make the product more aesthetically pleasing (e.g., in mineral sunscreens, making the particles of the active mineral smaller allows them to be applied without leaving a noticeable white cast) ^[19,20]. Potential routes of exposure to nanomaterials contained in cosmetic products include dermal, inhalation, oral or ocular. A number of modern cosmetic-related products contain nano-sized components, such as moisturizers, haircare products and make-up. For instance, liposome-based anti-aging topical formulations (creams, lotions, gels and hydrogels) have been formulated into the cosmetic market since 1986 by L’Oreal in the form of niosomes and by Christian Dior in the form of liposomes (Capture™) ^[21]. Liposomes are used in cosmetic applications or for transdermal delivery with the expectation that their use will result in an increase in the concentration of active agents (e.g. vitamins A, E, and CoQ10) in the epidermis with no toxicity (acute and chronic). Fullerenes display potent scavenging capacities against radical oxygen species (ROS), and, as such, they have been considered for use in the preparation of skin rejuvenation cosmetic formulations; however, there is still some controversy regarding their safety. Nanocrystals could be formulated for dermal use. Dendrimers, which are unimolecular, monodisperse, micellar nanostructures with a well-defined, regularly branched symmetrical structure and a high density of functional end groups at their periphery, have been considered for use in both pharmaceutics and cosmetics. Solid lipid nanoparticles and nanostructured lipid carriers are well-tolerated carrier systems for dermal application of cosmetic products ^[22]. They provide controlled release profiles for many cosmetic agents, e.g. coenzyme Q10, ascorbyl palmitate, tocopherol (vitamin E) and retinol (vitamin A), over a prolonged period of time, exhibiting low toxicity and low Cytotoxicity. Lipid nanoparticles have also been investigated to improve the treatment of skin diseases such as atopic eczema, psoriasis, acne, skin mycosis and inflammations. Recently, nanoparticles of zinc oxide (ZnO) and titanium dioxide (TiO2) have become popular because they retain the UV filtration and absorption properties while eliminating the white chalky appearance of traditional sunscreens. Meanwhile, a number of modifications to the standard ZnO or TiO2 UV protection system have been reported to increase the sun protection factor (SPF) ^{[23, 24]}.

5. Nano-variegation in cosmetics

5.1. Mineral-based cosmetic ingredients with nano-sized dimensions

Some cosmetic products, such as sunscreens, use mineral-based materials and their performance depends on their particle size. In sunscreen products, titanium dioxide and zinc oxide, in the size range of 20 nm, are used as efficient UV filters. Their main advantage is that they provide broad UV-protection and do not cause cutaneous adverse health effects ^[25].

5.2. Other nano-sized materials employed in cosmetics

Many of the leading cosmetic companies claim their products to contain various types of nano-sized materials like fullerenes, nanotubes, liposomes, quantum dots etc ^[26].

6. Types of nanomaterials used in cosmetics are the following

6.1. Liposomes

Liposomes are vesicular structures with an aqueous core surrounded by a hydrophobic lipid bilayer, created by the extrusion of phospholipids. They are most widely known cosmetic delivery systems. Liposomes can vary in size, from 15 nm up to several µm and can have either a single layer (unilamellar) or multilayer (multilamellar) structure. The first liposomal cosmetic product to appear on the market was the anti-ageing cream ‘Capture’ launched by Dior in 1986. Phosphatidylcholine, one of the main ingredients of liposomes, has been widely used in skin care products and shampoos due to its softening and conditioning properties ^[27]. Liposomes have been formed that facilitate the continuous supply of agents into the cells over a sustained period of time, making them an ideal candidate for the delivery of vitamins and other molecules to regenerate the epidermis. They have also been used in the treatment of hair loss. Minoxidil, a vasodilator, is in the active ingredient in products like Regaine that claim to prevent or slow hair loss. The skin care preparations with empty or moisture loaded liposome reduce the transdermal water loss and are suitable for the treatment of dry skin. They also enhance the supply of lipids and water to stratum corneum ^[28,
29].

Table 2- Some of the liposomal cosmetic formulations currently available in the market ^[30-35]

Product	Manufacturer	Liposomes and key Ingredients
Capture	Cristian Dior	Liposomes in gel
Efect du Soleil	L’Or´eal	Tanning agents in liposomes
Formule Liposome Gel	Payot (Ferdinand Muehlens)	Thymoxin, hyaluronic acid
Future Perfect Skin Gel	Estee Lauder	TMF, vitamins E, A palmitate, cerebrosideceramide, phospholipid
Symphatic 2000	Biopharm GmbH	Thymus extract, vitamin A palmitate
Natipide II	Nattermann PL	Liposomal gel for doit-yourself cosmetics
Flawless finish	Elizabeth Arden	Liquid make-up
Inovita	Pharm/Apotheke	Thymus extract, hyaluronic acid, vitaminE
Eye Perfector	Avon	Soothing cream to reduce eye irritation

6.2. Nanoemulsions

Nanoemulsions can be defined as “ultrafine emulsions” because of the formation of droplets in the submicron range. The average droplet size of nanoemulsions has been ranging from 50 to 1000 nm. They have attracted considerable attention in recent years for application in personal care products as potential vehicles for the controlled delivery of cosmetics. Nanoemulsions are transparent due to the droplets tiny size and they also remain stable for a longer period of time ^[36]. They are mostly used in deodorants, sunscreens, shampoos, and skin and hair care products. The nanoemulsions are easily valued in skin care because of their good sensorial properties i.e. rapid penetration, merging textures and their biophysical properties especially, hydrating power. A significant improvement in dry hair aspect (after several shampoos) is obtained with a prolonged effect after a cationic nanoemulsion use. Hair becomes more fluid and shiny, less brittle and non-greasy ^{[37, 38]}.

6.3. Microemulsions

Hoar and Schulman introduced the term microemulsion in 1943. Microemulsion is currently defined as nano - sized emulsion of water oil and amphiphile, an optically isotropic and thermodynamically stable liquid, containing particles with diameters of 100nm and less. In many cosmetic applications such as skin care products, hair products etc., emulsions are widely used with water as the continuous phase ^[39]. Cosmetic microemulsions of silicone oils, produced by emulsion polymerization are not thermodynamically stable products because of low solubility of silicone oil in the surfactants. Eli Lilly and Company had been assigned a patent for their stable w/o microemulsion i.e., non-irritating moisturizing composition which when applied to skin promoted the penetration of moisturizers into the skin and leave little residue on the surface of the skin ^[40].

6.4. Nanocapsules

Nanocapsules are submicroscopic particles that are made of a polymeric capsule surrounding an aqueous or oily core. It has been found that the use of nanocapsules decreases the penetration of UV filter octyl methoxycinnamate in pig skin when compared with conventional emulsions ^[41].

6.5. Solid lipid nanoparticles

They are oily droplets of lipids which are solid at body temperature and stabilized by surfactants. They can protect the encapsulated ingredients from degradation, used for the controlled delivery of cosmetic agents over a prolonged period of time and have been found to improve the penetration of active compounds into the stratum corneum. In vivo studies have shown that an SLN-containing formulation is more efficient in skin hydration than a placebo. They have also been found to show UV-resistant properties, which were enhanced when a molecular sunscreen was incorporated and tested. Enhanced UV blocking by 3, 4, 5-trimethoxybenzoylchitin (a good UV absorber) was seen when incorporated into SLNs ^{[42, 43]}.

6.6. Nanocrystals

Nanocrystals are crystals having size less than 1µm. They are aggregates comprising several hundred to tens of thousands of atoms that combine into a "cluster". Typical sizes of these aggregates are between 10-400 nm ^[44]. Nanocrystals of poorly soluble drugs can also be incorporated in cosmetic products where they provide high penetration power through dermal application. The first cosmetic products appeared on the market recently; Juvena in 2007 (rutin) and La Prairie in 2008 (hesperidin). Rutin and hesperidin are two, poorly soluble, plant glycoside antioxidants that could not previously be used dermally. Once formulated as nanocrystals, they became dermally available as measured by antioxidant effect. The nanocrystals can be added to any cosmetic topical formulation, e. g. creams, lotions and liposomal dispersions ^[45].

6.7. Nanosilver and Nanogold

Cosmetic manufacturers are harnessing the enhanced antibacterial properties of nanosilver in a range of applications. Some manufacturers are already producing underarm deodorants with claims that the silver in the product will provide up to 24-hour antibacterial protection. Nano-sized gold, like nanosilver, is claimed to be highly effective in disinfecting the bacteria in the mouth and has also been added to toothpaste ^[46,
47].

6.8. Dendrimers

Dendrimers are unimolecular, monodisperse, micellar nanostructures, around 20 nm in size, with a well-defined, regularly branched symmetrical structure and a high density of functional end groups at their periphery. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. One of the very first dendrimers, the new kome dendrimer, was synthesized in 1985 ^[48]. Dendrimers have also been considered for use in the cosmetic industry. Several patents have been filed for the application of dendrimers in hair care, skin care and nail care products. Dendrimers have been reported to provide controlled release from the inner core. However, drugs are incorporated both in the interior as well as attached on the surface. Due to their versatility, both hydrophilic and hydrophobic drugs can be incorporated into dendrimers ^[49].

6.9. Cubosomes

Cubosomes are discrete, sub-micron, nanostructured particles of bi-continuous cubic liquid crystalline phase. It is formed by the self assembly of liquid crystalline particles of certain surfactants when mixed with water and a microstructure at a certain ratio ^[50]. Cubosomes offer a large surface area, low viscosity and can exist at almost any dilution level. They have high heat stability and are capable of carrying hydrophilic and hydrophobic molecules. Combined with the low cost of the raw materials and the potential for controlled release through functionalization, they are an attractive choice for cosmetic applications as well as for drug delivery ^[51].

6.10. Hydrogels

They are 3D hydrophilic polymer networks that swell in water or biological fluids without dissolving as a result of chemical or physical cross-links. They can predict future changes and change their property accordingly to prevent the damage ^[52].

6.11. Buckyballs

Buckminster fullerene, C60, is perhaps the most iconic nanomaterial and is approximately 1 nm in diameter ^[53]. It has found its way into some very expensive face creams. The motivation is to capitalize on its capacity to behave as a potent scavenger of free radicals ^[54].

6.12. Niosomes

Niosomes are vesicles composed of nonionic surfactants. The niosomes have been mainly studied because of their advantages compared with the liposomes: higher chemically stability of surfactant than phospholipid, require no special conditions for preparation and storage, they have no purity problems and the manufacturing costs are low ^[55]. The advantages of using niosomes in cosmetic and skin care applications include their ability to increase the stability of entrapped drugs, improved bioavailability of poorly absorbed ingredients and enhanced skin penetration ^[56].

6.13. Transfersomes

In the 1990s, transfersomes, i.e., lipid vesicles containing large fractions of fatty acids, were introduced by Cevc and coworkers. Transfersomes are vesicles composed of phospholipids as their main ingredient with 10-25 percent surfactant and 3-10 percent ethanol. In consequence, their bilayers are much more elastic than those of liposomes and thus well suited for the skin penetration. Transfersomes consist of phospholipids, cholesterol and additional surfactant molecules such as sodium cholate. The inventors claim that transfersomes are ultradeformable and squeeze through pores less than one-tenth of their diameter. Therefore 200 to 300nm-sized transfersomes are claimed to penetrate intact skin ^{[57, 58, 59]}.

6.14. Lipid Nanoparticle

The first generation of solid lipid nanoparticles (SLN) was developed at the beginning of the nineties as an alternative carrier system to emulsions, liposomes and polymeric nanoparticles. Solid lipid nanoparticles (SLNs) are nanometre sized particles with a solid lipid matrix. They are oily droplets of lipids which are solid at body temperature and stabilized by surfactants ^[60]. In the second generation technology of the nanostructured lipid carriers (NLC), the particles are produced by using a blend of a solid lipid with a liquid lipid, this blend also being solid at body temperature. SLNs have occlusive properties making them ideal for potential use in day creams. NLC were developed to overcome some potential limitations associated with SLN. Compared to SLN, NLC show a higher loading capacity for a number of active compounds, a lower water content of the particle suspension and minimize potential expulsion of active compounds during storage. Solid lipid nanoparticles (SLNs) and nano-structured lipid carriers (NLC) are novel colloidal delivery systems with many cosmetic and dermatological features; such as skin adhesive properties when applied to the skin resulting in occlusion, enhanced skin hydration, whitening effects, protection against degradation, absorption increasing effects, active penetration enhancement, and controlled-release properties ^{[61, 62]}.

7. Route and extent of exposure

Health risks that nanoparticles pose to the humans also depend on the route and extent of exposure to such materials. Nanomaterials enter the body mainly through 3 routes.

7.1. Inhalation

It is the most common route of exposure of airborne nanoparticles according to the National Institute of Occupational Health and Safety. For example, workers may inhale nanomaterials while producing them if the appropriate safety devices are not used, while consumers may inhale nanomaterials when using products containing nanomaterials, such as spray versions of sunscreens containing nanoscale titanium dioxide ^[63]. According to officials at the National Institutes of Health, although the vast majority of inhaled particles enter the pulmonary tract, evidence from studies on laboratory animals suggest that some inhaled nanomaterials may travel via the nasal nerves to the brain and gain access to the blood, nervous system, and other organs, according to studies we reviewed ^[64].

7.2. Ingestion

Ingestion of nanomaterials may occur from unintentional hand-to-mouth transfer of nanomaterials or from the intentional ingestion of nanomaterials. A large fraction of nanoparticles, after ingestion, rapidly pass out of the body; however, according to some of the studies we reviewed, a small amount may be taken up by the body and then migrate into organs ^[65].

7.3. Through skin

Studies have shown that certain nanomaterials have penetrated layers of pig skin within 24 hours of exposure. According to some of the studies reviewed by the US Government Accountability Office (GAO), concerns have been raised that nanomaterials in sunscreens could penetrate damaged skin ^[66].

8. Safety requisites for a blooming beauty

Cosmetic manufacturers using nanotechnology confront an uncertain future from both consumer response and a regulatory standpoint. Eminent scientific bodies like the Royal Society, Britain's most prestigious scientific body, and the US Food and Drug Administration warn that the health risks of nanocosmetics require a thorough investigation before product commercialization. One of the major problems is that there is no much evidence about how much or what type of safety assessments are done by the various cosmetic manufacturers on their products ^[67].

Though there are increasing number of cosmetics and personal care products containing nanomaterials in the market, there are no specific regulations regarding their safety assessment. In Australia, the National Industry Chemicals Notification and Assessment Scheme (NICNAS) regulate the safety of ingredients in cosmetics and personal care products and the Therapeutic Goods Administration (TGA) regulates sunscreens ^[68]. However these regulators fail to distinguish between nanoparticles and larger sized particles. The EU's Scientific Committee on Consumer Products (SCCP) looked at the safety evaluation of nanomaterials for use in cosmetic products and considered the implications on animal testing and whether the previous opinions on nanomaterials currently used in sunscreen products would need to be revised ^[69].

The European Parliament approved the amended recast of the EU Cosmetics Directive, introducing the mention of ‘nanomaterials’ into EU legislation. As requested by the European Parliament, the new regulation introduces a safety assessment procedure for all products containing nanomaterials, which could lead to a ban on a substance if there is a risk to human health. The major excerpts from the act include the following: - ^[70-74]

· The ruling defines nanomaterial as “an insoluble or bio-persistent and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm”.

· The responsible person shall ensure compliance with safety, GMP, safety assessment, product information file, sampling and analysis, notification, restrictions for substances listed in Annexes, CMR, nanomaterial traces, animal testing and labeling, claims, information to the public, communication of SUE, information on substances.

· Prior to placing the cosmetic product on the market, the responsible person should submit the following information to the Commission:

· The presence of substances in the form of nanomaterials

· Their identification including the chemical name (IUPAC) and other descriptors

· The reasonably foreseeable exposure conditions

· In case the Commission has concerns regarding the safety of the nanomaterial, the Commission shall, without delay, request the SCCS to give its opinion on the safety of these nanomaterials for the relevant categories of cosmetic products and the reasonably foreseeable exposure conditions.

· All ingredients present in the form of nanomaterials shall be clearly indicated in the list of ingredients. The names of such ingredients shall be followed by the word “nano” in brackets.

· Particular consideration shall be given to any possible impacts on the toxicological profile due to

· Particle sizes, including nanomaterials;

· Impurities of the substances and raw material used; and

· Interaction of substances

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Received on 07.01.2014 Accepted on 14.03.2014

Research J. Topical and Cosmetic Sci. 5(1):Jan.–June 2014 page15-22