Introduction

By 2022, the cosmetic industry, which includes personal care products and sunscreens, is expected to reach global sales close to 430 billion USD, overtaking markets such as regenerative medicine (30 billion USD) and HIV drugs (26 billion USD) [1,2,3,4]. The three main companies in the cosmetic sector represent one-third of the market, and they reach almost two billion people with their products [5,6,7]. The cosmetic industry is a global leader in the incorporation of emerging technologies like nanotechnology into new products [8,9,10]. For the past two decades, the cosmetic sector has incorporated nanotechnology in its manufacturing process and products. In this document, we define nanomaterials according to the ISO/TR 13014:2012. The first product, an anti-aging cream using liposomes at the nanoscale, was launched in 1986 [11]. Since then, between 174 and 250 nanotechnology-enabled cosmetic products (NCPs) have been commercialized in the USA, Europe, Japan, and Latin America [12, 13]. Here, we focus our work on these four markets since they correspond to almost 70% of the global cosmetic sales.

NCPs are available in almost all cosmetic formulations including creams, powders, lotions, soaps, and emulsions. These NCPs can be used over all parts of the skin body and mucosae (see Table 1. As a result, consumers are exposed to different sources of involuntary risk associated with NCPs especially when the nanomaterials (NMs) in the NCPs can be inhaled or ingested by accident. The NMs can be translocated to main organs like brain, kidney, or heart from different exposure routes; however, data regarding NM translocation through skin still are controversial [14, 15]. Considering the substantial number of cosmetic’s consumers, almost two billion, and the unknown potential hazards of NMs, the commercialization of NCPs can have major impacts on public health.

Table 1 NCPs in the markets (USA, EU, Asia, Latam)

Identifying and assessing the risks of NMs in cosmetic products is a complex task because of the variety of materials being used, the technical limitations of the characterization of NMs especially in situ, the lack of harmonization for their characterization, and the contradictory findings in safety studies. All of this leads to difficulty in determining the risk of NCPs for consumers [16,17,18,19].

After 30 years since the first NCPs hit the market, nongovernmental organizations (NGOs) like Greenpeace and political institutions such as the European Parliament, the German Federal Institute for Risk Assessment (BfR), the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), the World Health Organization (WHO), the Organization for Economic Cooperation and Development (OECD), the Royal Society and even a member of the British royal family have raised concerns and given warning about the potential risks by incorporating nanomaterials into consumer goods [20, 21]. They claim that even though the properties of NMs improve manufactured products by offering benefits like higher bioavailability, increased surface area, and photoreactivity, this can result in new risks not observed with bulk materials [8].

As a result, in 2006, two initiatives began to consider the potential risks of NMs in commercial products. One initiative was from the Food and Drug Administration (FDA) and another from European Commission (EC). However, the EC’s initiative was the only one that enacted a regulatory framework for NCPs, and it was not implemented until 2013 [22]. This regulation requires cosmetic manufacturers to provide information related to the presence of NMs in their products such as particle size, size distribution, concentration, and potential risk and notify the consumers the nano-ingredients contained in products [23, 24].

In this study, we reviewed the current gaps between the commercialization process of NCPs and the regulatory frameworks to assess these products in the USA, Europe, Japan, and Latin America prior and after commercialization. We identified the requirements for a proper assessment of the potential hazard of NMs in cosmetics considering the NM properties. That was also encouraged by initiatives such as the International Cooperation on Cosmetic Regulation (ICCR).

Cosmetic Products and Nanomaterials in the Market

Nanotechnology Advantages in Cosmetic Products

NMs have unique advantages in cosmetic products (CPs) due to their size; the most commonly used nanoparticles are solid lipid nanoparticles, titanium dioxide, zinc oxide, and silicon dioxide to improve CPs’ properties. Some examples of their use in the market are listed below:

  1. 1.

    Silicon dioxide (SiO2) nanoparticles allow dense formulation to easily spread on the skin surface, increasing the effective coated surface [25].

  2. 2.

    Carbon black (CB) used as an active color for lips sticks allows to obtain absolute color upon the application on the lips [26].

  3. 3.

    Gold nanoparticles (AuNPs) are commonly used as carriers that easily penetrate through the skin, transporting active enzymes [27].

  4. 4.

    Titanium dioxide (TiO2) nanoparticles increase the UVA and UVB ray protection on sunscreens without leaving white and chalky residues on the skin [28].

It is important to highlight that nanomaterials are divided into soluble and biopersistant types according to EU cosmetics directive 1223/2009 [22]. On the other hand, ISO and OECD limit the nanomaterial definition to the size range between 1 and 100 nm [29]. Here, we focus on the biopersistant nanomaterials since liposomes, micelles, nanoemulsions, lipid nanoparticle, and other soluble nanomaterials act more frequently as nanocarriers than an active principle [30].

These advantages, among others, have promoted the presence of NCPs in the market; currently, there are more than 200 NCPs [13]. These products are available in different forms like creams, shampoos, soaps, toothpaste, and lotion, which cover all possible surfaces of the body. Table 1 shows some commercialized NCPs on the market that expose consumers to voluntary and involuntary risk (e.g., intentional application for the former, collateral exposure, such as inhaling face powder, for the latter). The most frequent NMs used in cosmetic products are gold, silver, alumina, platinum, zinc oxide, titanium dioxide, carbon black, and tin oxide; however, a full characterization of the NMs is not reported by the manufacturer at the labels [13, 31].

Safety Assessments of NMs In Vivo Assays

Besides the benefits from NMs in CPs, there is evidence of in vivo toxicity. The target organ could change depending on the exposure pathway, i.e., skin, mucosae, airways, or digestive system. After inhalation, NMs can translocate from alveolar tissue to circulatory system and then be distributed across the whole body to vital organs like the heart and the brain where blood perfusion is higher [43, 44]. Intravenous exposure easily distributes the NMs into the bloodstream. Therefore, the NMs may quickly reach the reticuloendothelial system exposing organs like spleen, kidney, and ganglia, even the brain may be affected. NMs under 10 nm have been shown potential translocation across the blood-brain barrier [45]. Other routes of exposure such as the skin and the gastrointestinal pathways present more localized effects [9, 46]. Adverse effects reported with NMs exposure using in vivo mainly in rats are listed in Table 2.

Table 2 Adverse effects in vital organs identified after the exposure of NMs

The most common nanomaterial used in cosmetic industry is the TiO2. During the past two decades, high controversy has been discussed about their effects in health. Cosmetic products can include spray products; it means that potential inhalation of TiO2 in cosmetics can happen. As the result, Scientific Committee on Consumer Safety (SCCS) recommends not to use this nanomaterial (TiO2) in spray products (SCCS/1516/13). Another consideration must be taken regarding the photovoltaic actions of the TiO2 which are potentially harmful. Nowadays, it is considered safe to use if the TiO2 NPs are coated with aluminum which reduce their photo activity [74].

Cosmetic Products: the Current Assessment

Cosmetic products are thought to represent low risk for consumers since their effects are mainly external and because they are not intended as therapeutic products. Therefore, their approval path is less strict than medical products. As a result, most of the potential side effects are identified at the post-marketing stage. Figure 1 presents a flow chart of the step-by-step process for the approval of cosmetics for market release.

Fig. 1
figure 1

Process for approving CP ingredients in the USA, Latam, and Japan markets

Hazard Identification

The first part in the process of risk assessment is identifying the product’s hazard [75]. This identification is based on previous safety studies done by the manufacturer, literature, and reports from consumers when the product is on the market [76]. The parameters used in order to establish the relative hazard of an ingredient in CPs include information on chemistry, formula, chemical identity, molecular weight, purity, associated impurities (i.e., contaminants), solubility, and the partition coefficient [77].

Exposure Evaluation

A “toxicity profile analysis” is done to identify the adverse effects of an ingredient on living organisms, by both in vitro and in vivo assays. However, in vivo assays are currently restricted for cosmetic toxicity assessment in Europe and USA, to avoid animals’ mistreatment [78]. As a result, there is limited information about the adverse effects of NCPs in complex organisms. The data related with adverse events is discovered in the post-market stage [17].

The goal at the exposure evaluation stage is to establish the values of the Lowest Observed Adverse Effect Level (LOAEL) and the No Observed Adverse Effect Level (NOAEL) from the dose-response relationship of the cosmetic product and its ingredients [79]. Both the LOAEL and the NOAEL are reported in mass of drug over mass of the subject, which does not identify relevant characteristics of NMs such as surface area, particle size, surface charge, shape, agglomeration, aggregation, and coatings that modify the hazard level of an ingredient at nanoscale [80, 81]. For example, a non-nanosized material such as copper did not express toxicity at a dosage of 5 mg/kg but the same material at the same concentration can induce renal damage if the copper is a nanoscale material [82].

Microbiological Testing

The purpose of microbiological testing is to ensure that no microorganisms (e.g. Staphylococcus colonies, Clostridium tetani, Pseudomona aeruginosa, fungi, yeast, and mold) could infect consumers’ skin or mucosa [83]. This is the final test of the CP evaluation before releasing the CP into the market.

Post-Marketing Surveillance

After the CP is approved for commercialization, the vigilance depends on consumer’s reports and the sanitary alerts. This helps to identify potential risk related with all factors not discovered at the premarket stages such as idiosyncrasies, environmental conditions, or interactions with other products. Here, the consumer’s involvement on the safety of the products is critical. However, since the information on the labels of NCPs does not always report the presence of NMs, the consumers are not aware of the risk and thus cannot ensure post-marketing surveillance.

NCPs: Current Gaps in Risk Assessment

The 2013 ICCR meeting established that additional information on NMs such as size, shape, specific surface area, concentration, and manufacturing process are required to create a complete profile of NCP hazards. However, currently there is no specific legal framework to assess these products in the market. Table 3 presents the most recommended techniques for characterizing NMs from the Organization for Economic Cooperation and Development (OECD), International Standardization Organization (ISO), and Nanotechnology Characterization Lab (NCL). It is worth noting that there is no single technique able to characterize all required parameters.

Table 3 Techniques to characterize the nanomaterials in cosmetics products

In the case of the European Community, the manufacturer is required to provide information of NMs’ characteristics 6 months prior the commercialization. However, this information is not fully accessible to the consumers. Emerging markets such as the Andean Community of Nations (CAN) or Common Market of the South (Mercosur) do not require the manufacturer to disclose the nano-ingredients.

Regulatory Timeline and Marketed NCPs

Since 1986, several NCPs have been commercialized around the world, and all of them have been approved under the traditional cosmetic requirements without considering the specific characteristic of the nano-ingredients; yet, by 2013, the EU Resolution 1223/2009 enforced the manufacturers to inform about any nanomaterial contained in the CPs. Figure 2 shows the dates of implementation for cosmetic regulations, the number of NCPs in the market, and nanotechnology milestones.

Fig. 2
figure 2

Timeline of NCP incorporation in the market and implementation of cosmetic regulation

In general, the surveillance systems guarantee consumer safety through cosmetovigilance programs (Resolution 1223/2009) [22, 85]. These systems are the result of the interaction between different actors (manufacturers, panels of experts, non-governmental organizations, regulatory institutions, and consumers) during the CPs’ life cycle [86].

The CPs’ life cycle has two main stages for consumer safety (see Fig. 3). The first is pre-marketing, where manufacturers and expert panels review the safety of ingredients and products [87]. The second stage is post-marketing, where consumer surveillance is the key aspect. While all CP surveillance and control systems share this basic structure, each system has differences depending on where the products are commercialized in the market [76, 87].

Fig. 3
figure 3

Interaction of the different actors in the CP surveillance and control systems during the different stages of development

When a new cosmetic product is developed or reformulated, the manufacturer is responsible for providing safety reports that include the ingredients. Then, expert panels review these reports and give recommendations to regulatory institutions such as ANSM in France or INVIMA in Colombia. These institutions then decide if the product needs to be restricted or not and establish the conditions of use, which is generally done by identifying the presence of banned ingredients [17, 30].

With the recommendations, manufacturers provide consumers with information about formulation, correct use, and product disposal. This can be done using product labels or advertising. Finally, consumers can provide feedback to manufacturers and regulatory entities regarding the side effects from the use of the CPs.

USA

In the USA, the FDA regulates the cosmetic market under the Food and Drug Act of 1938. The FDA focuses on the post-marketing stage, identifying adulterated or misbranded products. In 1972, the FDA created the Voluntary Cosmetic Registration Program (VCRP), which has two main purposes: it allows the FDA to identify the main ingredients in commercialized CPs and provides manufacturers with information from the tests of the FDA conducts on CPs’ ingredients. By February 2012, almost 39,000 cosmetic products had been registered in this program [88].

Safety tests are conducted by an expert panel external to the FDA: the Cosmetic Ingredients Review (CIR) panel. This panel was created in 1978 and is comprised of the American Academy of Dermatology, the Society of Toxicology, the Consumer Federation of America, the cosmetic industry, and the Council’s Executive Vice President [31]. From its inception, this panel has tested 2295 ingredients, classifying eight as restricted and two as forbidden [31]. Consumers give feedback by reporting events associated with CP use on the Medwatch surveillance platform [89].

By 2014, the FDA published a guidance for NMs in CPs recommending that ingredients be characterized according to the NMs’ properties (size, size distribution, surface charge) [90]. The registry of NCPs is voluntary in the US market, but, three years later, cosmetic ingredients are not required to specify their nanoscale condition.

European Union

In the European Union (EU), there are two regulatory levels: multinational and national. The European Commission is in charge of the former and was responsible for introducing the first Cosmetic Guideline in 1976. The first guideline was updated 55 times between 1976 and 2009, when Regulation Number 1223/2009 was established; it took effect in 2013 including nanomaterials in cosmetics as “an insoluble or biopersistant and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm” [91]. The systems implemented by individual EU member countries of the EU adopt guidelines from the European Commission according to their own legislation. The objective of the 1223/2009 regulation was to improve the surveillance and control system, apply legislation uniformly, increase consumer safety, and reduce administrative costs. In 2012, the SCCS provided the guide for manufacturers to properly assess the safety of NMs in their cosmetic products following the SCCS/1484/12 Guide [92]. In 2013, the EC implemented the Decision 2013/674/EU in section 3.2.1., requiring manufacturers to include relevant information about nano-ingredients such as particle size, distribution, and physicochemical properties six months before entering in the market [93]. The manufacturers should inform about the presence of NMs in their products with the word nano in brackets.

The European Commission supervises products starting at the pre-marketing stage, asking manufacturers to submit all the information about the safety of the ingredients individually, as well as the final product, to the authorities in the EU country where it will be manufactured or imported. This information is contrasted with the safety information generated by the SCCS. If there is no available information, the SCCS starts the specific ingredient test with an expert panel comprised of 16 prestigious scientists [94].

The SCCS recommendations for the European Commission have restricted 1328 ingredients and forbidden 103 ingredients [95], and these recommendations are published in the Cosmetic Directive annexes II, III, and IV. Similar to the system in the USA, consumers inform the regulatory entity and the manufacturers of any side effects from the use of the CPs [95].

Japan

In Japan, the third most important market for the cosmetic industry, CPs are monitored by the Ministry of Health and Labor and Welfare (MHLW). As in the USA and the EU, manufacturers are responsible for the safety of their CPs in general and the evaluation of the safety of individual ingredients specifically. Legislation for CPs in Japan was created in 1943 with the Pharmaceutical Affairs Law (No. 145). This law had a significant change in 2001 when it removed the requirement of the approval prior to market release. At present, Japan has classified product ingredients into four lists: forbidden (30 ingredients), restricted (20 ingredients), permitted for UV filters, and permitted for preservatives [96]. Unlike the systems in the USA and the EU, there is no external panel that evaluates products. The Ministry of Health is directly in charge of these evaluations via the panel of safety for food and pharmaceuticals. Manufacturers must notify the Ministry of Health about safety information and product efficiency and include ingredients’ names, product amount, warning statements, storage, and user instructions [97].

Latin America

In Latin America, there are two markets of interest: the first is the Southern Common Market (Mercosur) formed by Argentina, Brazil, Paraguay, Uruguay, and Venezuela [98]. The second is the Andean Community of Nations (CAN) composed of Bolivia, Colombia, Ecuador, Peru, and Venezuela [99].

Mercosur

In the Mercosur, the cosmetic industry is regulated by Act 03 of 2003, Resolution 46/2010 and Resolution 04/2015. This Resolution has 91 restricted ingredients to date and it applies to all member countries [100]. The list is expected to be updated periodically to guarantee the correct use of raw materials for CPs. However, each country must adapt the resolution to include it in its own legislation, and its regulatory entities must supervise CP marketing. Manufacturers must provide information that describes the ingredients and their use. The control entities (ANMAT in Argentina, ANVISA in Brazil, the Ministry of Health in Uruguay and Paraguay) also receive the reports of adverse effects of CPs.

Andean Community of Nations

The approval for CPs’ commercialization in the CAN is regulated by Decision 516 of 2004, which was issued via an automatic Public Health Notification (Notificación Sanitaria Obligatoria or NSO in its Spanish acronym). In this market, manufacturers are responsible for guaranteeing the safety of their products. They must present CPs’ general information related to the ingredients used without having to specify the quantities and uses of the ingredients. There is no committee of experts to evaluate the products [92].

Cosmetic products cannot contain ingredients included on either restricted or forbidden lists. In the case of discrepancies between the safety evaluation of one list and another, the less restricted list will be used. In each member country, the consumer report is unfavorable to effects or situations related to the use of these products.

The main differences of the surveillance and control systems of different countries’ markets are summarized in Table 4. These differences include the presence or lack of a panel of experts, how the consulting committees are conformed, the requirements for disclosing and registering ingredients, and the number of restricted and/or forbidden ingredients. These differences pose difficulties for the initiative of global harmonization for pre-approval, registration, marketing, and surveillance of CPs. They show the need for the inclusion of specific evaluation criteria for ingredients at the nanoscale level in CPs formulation, as has been the case in other analyses [76, 89, 90], [99,100,101,102] (Table 5).

Table 4 Legal framework for cosmetics commercialization in the major markets and two emergent markets
Table 5 Nanomaterial definition by regulatory agencies for cosmetics in each market

Current Initiatives to Harmonize NCP Assessment

Since 2004, the FDA and the European Commission have worked together with researchers, consumers, and the industry to establish safety protocols. The following section presents different local and global initiatives developed to evaluate and harmonize NCP regulation.

USA

In 2006, the FDA formed the Nanotechnology Task Force, whose report concluded that cosmetics and food do not require previous authorization for their commercialization, putting the responsibility on manufacturers for guaranteeing the safety of cosmetics and food [103]. These manufacturers must perform long-term toxicity tests and voluntarily submit the results to the FDA.

European Union

In 2004, the European Commission started the program “Towards a European Strategy for Nanotechnology” [104]. This program included social, economic, cultural, and safety aspects, both for consumers and for the environment in all applied areas of nanotechnology, including cosmetics. The guidelines were very general and basically expressed the need for research to determine the effects and risk of using nanotechnology.

Later, in 2009, the European Parliament and the Council published the EC Regulation 1223/2009 specifically for cosmetics, which includes a testing methodology for ingredients, testing on animals, and nanotechnology. In Article 16, the European Commission establishes the need to know the safety profiles associated with the use of NMs in cosmetics. On January 11, 2013, information related to the identification of NMs includes their chemical name, size of the particles, the physicochemical properties, estimated quantity of NM in the final product, NM toxicological profile, and the predictable exposure conditions. These regulations clearly indicate the need for obtaining information about the particular characteristics of the NCP. It also demands, for the first time, that manufacturers inform consumers on product labels that the product contains nanomaterials [105].

ICCR

In 2007, the ICCR was created as a result of the need for guaranteeing safety in CPs and also to make marketing activities easier. This initiative includes regulatory entities from the USA, EU, Japan, and Canada. Early on, it discussed the importance of establishing specific conditions for NCPs (ICCR, 2007), but it was only in 2009 that preliminary international guidelines were drafted by the initiative. One of the main goals was to establish a definition of what constitutes a NM in CPs, which is given below:

“[…] a substance used in a cosmetic is considered a nanomaterial if it is an insoluble ingredient, intentionally manufactured, with one or more dimensions in the realm of 1 to 100 nanometers in the final formulation and is sufficiently stable and persistent in biological media to allow for the potential of interaction with biological systems” [22, 106].

The definition includes parameters for the evaluation of NCPs: solubility, stability, intention to manufacture, one or more dimensions in the 1–100-nm scales, and aggregate formation. It has yet to be defined how much nano-ingredient is required in order to consider a CP as an NCP.

Figure 4 summarizes the main initiatives (yellow boxes), the panels of experts (red boxes), and industrial associations (green boxes) geographically. It allows for a global interpretation of the different actors, initiatives, and the interaction with emerging markets in Latin America.

Fig. 4
figure 4

Interaction of the control systems currently in place and their NCP initiatives

The initiatives demonstrate a contrast between local legislation and multilateral ICCR agenda. However, these initiatives will require a trial period before applying them to the current markets. In the EU, it took four years to enforce the regulation. In the USA, the FDA has postponed the Nanotechnology Taskforce until further information can be gathered. For emerging markets like CAN or Mercosur, it has not been considered yet.

Conclusion

Advances in the cosmetic industry have included the use of NMs as manufacturing materials and as main active ingredients in CP formulas since 1986. After three decades, the advances in NCPs have been translated into almost 250 commercialized products around the world. The incorporation of NMs introduces new desirable properties in cosmetics, including sunscreens that do not leave white and chalky residues, bright colors in lipsticks, long-lasting effects in anti-aging creams, anti-bacterial properties on vaginal creams, and so on. Besides the benefits, actors from NGOs, the scientific community, and government institutions have expressed their concerns about potential risks of using NMs for the environment and consumer health, particularly those related to properties of these that can have negative effects in the context of involuntary exposure. As a result, a moratorium on NMs in commercialized products was requested in 2003 until new data supporting their safety was released. The word “nano” as a marketing label gradually disappeared from advertisement of commercialized products, including cosmetics in the past 10 years. Anti-bacterial products using silver nanoparticles have been removed from US market by the Environmental and Protection Agency in 2016, also anatase TiO2 have been considered as carcinogenic material by European Chemical Agency on Jun 2017 [ECHA/PR/17/10]. In France, the General Directorate for Competition Policy, Consumer Affairs and Fraud Control (DGCCRF) informed in January 2018 that eight out of the 40 cosmetic brands did not accurately label their nano-products [107]. By 2017, neither major alerts nor warnings associated with specific properties of NMs in cosmetics have been issued by the regulatory agencies. Therefore, the question of whether NMs in cosmetic products represent a threat arises, as do doubts about whether the current regulatory framework and agency capabilities are sufficient to identify and prevent public health risks associated with them.

After the review of the current cosmetic regulatory systems in the main markets, we conclude that only the EC has established specific requirements for NMs in cosmetic products, specifically by labeling their presence and identifying health hazards. The other markets are more likely to produce self-regulatory approaches by providing some voluntary guidelines. The EC decision has been a challenge to both manufacturers and regulatory agencies given the lack of harmonized terminology and standardized techniques to identify the NM characteristics in the final product and describe the contact with humans and other organisms in the environment. Additionally, there has been a long-lasting debate around contradictory results on the adverse effects of NMs in bio-interactions where unrealistic doses, wrong administration procedures, and poor characterization of NMs limited the accurate prediction of the risk associated with human exposure to NMs. As a result, yet no definitive decision can be made on NMs used in cosmetics according to the information summarized in this study. One major example was the TiO2 nanoparticle in sunscreens. After almost ten years of debate, agencies like the Therapeutic Goods Administration (TGA) in Australia and the FDA in the USA removed the ban on some forms of TiO2 nanoparticles. Long debates like these hurt the potential development of the technology and at once do not provide real protection to consumers. This is principally due to the fact that the major surveillance activities are post-marketing. A new approach that provides a balance between consumer safety and incorporation of NMs in cosmetics is required for sustainable development of the technology.

Regulatory frameworks have been described for NCPs in countries with the highest consumption of CPs, as well as in some emerging markets. This study shows the heterogeneity in the regulatory systems supporting the surveillance and control process involving a range of actors, legislation maturity, registration standardization, safety testing, and the number of restricted and forbidden ingredients. The results show that there is not a multilateral harmonized framework; therefore, the ICCR initiative is a remarkable effort, and their success could represent a framework applicable for other nanoscale products. It would be beneficial to have the participation of the emerging markets to extend consumer protection globally and benefit international trade.

The uncertainty about the potential side effects and the lack of information provided to the consumer about NCPs requires the consensus of the actors in order to minimize risk and guarantee safety. Any additional delay in creating and implementing a common regulatory framework involuntarily exposes consumers to products whose risks have not yet been determined.