Principal and Owner of Sun Protection Facilitator GmbH
When I say “Nano means Big”, I do so in reference to UV filters. Of course, I am not contesting the etymology of the Latin word “nañus” (dwarf) and Ancient Greek word “nânos”. I am just comparing UV filters. In my column last month, “Are sunscreens safe”, we saw that organic UV filters usually penetrate and permeate the skin to some extent. This is now commonly known, leaving us with the question how to deal with it. That is where risk assessment and risk management come into play. Today we look into particulate UV filters of nano-size dimensions.
Preparations containing pigments have been used since ancient times to protect against negative effects of solar radiation. Since the 1950s, sunscreen products containing micronized TiO2 and ZnO have been marketed. These products were soon regarded as cosmetically unattractive due to their property of remaining as a white paste on the skin, a result of particle sizes. In order to eliminate these unfavourable properties, particle size distribution was lowered into a range below 100 nm, a size threshold for decreasing the particle’s optical property to reflect visible light. After 2000, new nanoparticulate organic filters were developed. Effects of both the inorganic and organic nanoparticulate substances – alone or in combination – with non-particulate UV filters were well documented and had shown great effectiveness1. At the time, nanotechnology fuelled great hope in the progress of science and technology, including the health sector and cosmetics industry. Instead, influenced by images from the science fiction literature of self-replicating nanorobots destroying all living matter or health and environmental disasters caused by asbestos, fear of this new unknown amongst the general population has hindered acceptance and progress of nano-enabled products. Consumers have started to suspect that the particles permeate through skin, are absorbed by the blood and are distributed throughout the body, causing disease. Not least because of public pressure, cosmetics – which include sunscreen products – became the first product segment in which appropriately manufactured substances were subject to stringent rules. Despite advanced regulation and rigorous approval procedures for nanoparticulate UV filters, widespread reservations remain. Possible reasons could be a lack of knowledge of current legislation and unclear ideas about nature and behaviour of nanoparticles.
Against this background, we first look at the definition, the regulatory framework and the determination of nano or non-nano. Then we will see that it is practically impossible that particulate UV filters permeate the skin and cause any harm, exactly because they are big in comparison to the molecularly dissolved organic UV filters that are commonly used2.
Under the regulatory definition of the Cosmetic regulation No. 1223/2009 (article 2 (1) (k)), nanomaterial means an insoluble or biopersistent and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm . To define a nanomaterial more precisely, the European Commission published a recommendation (2011/696/EU) revised 10th of June 2022 (2022/C229/01). In this recommended definition, which has in the meantime been adopted under REACH4, a nanomaterial means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions are in the size range 1 nm – 100 nm5,6.
There are currently 2 inorganic and 3 organic UV filters in nano form approved in Europe (Table 1)
Inorganic – Titanium dioxide (nano), max 25% – Zinc oxide (nano), max 25%
Organic – Methylene Bis-Benzotriazolyl Tetramethylbutylphenol (nano), max 10% – Tris Biphenyl Triazine (nano), max 5% – Bis-(Diethylaminohydroxybenzoyl Benzoyl) Piperazine (nano), max 10%
Table 1: Particulate UV filters approved in the EU. [3, Annex VI]
But, how can we know or find out whether a UV filter falls into the nano category or not? To do that, we need to know the particle size distribution. To get a first overview of the available methods, I decided to try out the currently very hyped chatbox Chat-GPT from OpenAI (https://chat.openai.com/chat). My query and the answer that was returned in a few seconds are both shown in Table 2.
QUERY: Describe what methods are available to determine if a cosmetic formulation contains UV filters in nano size and what size distribution they have.
ANSWER: There are several methods available to determine if a cosmetic formulation contains UV filters in nano size and to determine their size distribution. Here are some common methods: 1. Dynamic Light Scattering (DLS): This technique is often used to measure the size distribution of particles in a liquid sample. DLS can measure particle sizes ranging from a few nanometers to a few microns. It works by measuring the fluctuations in light scattering from particles in the sample. By analyzing these fluctuations, DLS can provide information about the size distribution of the particles. 2. Transmission Electron Microscopy (TEM): TEM is a micro-scopy technique that uses a beam of electrons to image the sample at very high resolution. This technique can provide information about the shape, size, and distribution of nanoparticles in a sample. TEM can also be used to identify the chemical composition of the particles. 3. Scanning Electron Microscopy (SEM): SEM is another microscopy technique that can be used to visualize nanoparticles in a sample. Unlike TEM, SEM uses a beam of electrons to scan the surface of the sample. This technique can provide information about the shape and size of nanoparticles, as well as their distribution. 4. UV-Vis Spectroscopy: UV-Vis spectroscopy can be used to determine if a formulation contains UV filters by measuring the absorption of light at specific wavelengths. However, this technique cannot provide information about the size distribution of the particles. 5. Atomic Force Microscopy (AFM): AFM is a microscopy technique that uses a small probe to scan the surface of a sample. It can provide information about the topography and size distribution of nanoparticles in a sample. In summary, there are several methods available to determine if a cosmetic formulation contains UV filters in nano size and to determine their size distribution. These include DLS, TEM, SEM, UV-Vis spectroscopy, and AFM. The choice of method depends on the specific characteristics of the sample and the information required.
TABLE 2: Use of ChatGPT (OpenAI, release 2023-02-13)
At first glance and considering that this is my first attempt to use ChatGPT; I think that this result is acceptable and useful for a first brief overview. There are apparently numerous techniques available to measure the size of particles; however, their scope depends on their measurement principle and the physicochemical parameters of the tested material. But to find out which method is suitable for what, we better do not rely on chat box results. The recent study by Sohn M et al, Nano or Non-Nano: The Key Aspect of the Measurement Method, concludes: Relying only on tier 1 methodologies such as AF4, X-Ray Disc Centrifuge or Dynamic Light Scattering to determine the non-nano property of a material is insufficient, since tier 1 methods are not able to detect constituent particles as part of agglomerates, which is often the case for Titanium Dioxide and Zinc Oxide. The status of being a non-nanomaterial can, in this case, only be certified with a tier 2 technique, particularly electron microscopy 7. This is nicely illustrated in Figure 1, taken from this study. Let’s leave the question of whether a sunscreen is declared “nano” or “non-nano” behind for a bit. The important point from a safety perspective is whether or not a UV filter can penetrate the skin. A look at Figures 2 and 3 suggests otherwise. Even particles as small as 20nm in diameter are huge. We cannot imagine any mechanism how such large particles could pass through the stratum corneum. The requirement for absorption by the skin is linked to very specific properties of the substance itself, its carrier, and the skin condition. 2 Let’s take a look at UV filters. Some key properties of substances are molecular weight and polarity. Bos and Meinardi developed the 500 Da rule for the development of transdermally applied drugs, which states that substances with a molecular weight of more than 500 Da pass the skin poorly or not at all. It is therefore not surprising that not only pharmaceutical agents for the skin but also allergens have molecular weights of less than 500 Da8. Figure 3 shows molecular weight, size, and particle diameter of soluble and insoluble (nanoparticulate) UV filters. Polarity is also important in estimating percutaneous absorption. Substances with a log poctanol/water (hydrophilic) ≤-1 or ≥4 (lipophilic) are unlikely to penetrate the skin2. The organic UV filters MBBT, TBPT, and PBDT have a Poctanol/water value of 12.7, 10.4, and 6.4, respectively, which is outside the range that allows permeation through the skin-especially in the case of MBBT and TBPT.
So, we have seen that it does not matter for safety, i.e. permeation through the skin, whether a particle has a diameter of 20 nm or 200 nm, because both are huge particles compared to single molecules that cannot penetrate the skin. But particle size does play a role in the effectiveness of the UV filter, as we can see in Figure 4. The smaller the particles, the higher their absorption of UV radiation and the lower their scattering in the visible light range (> 400nm).
To understand the pattern of the curves in Figure 4, it is important to recognize that the main protective mechanism of UV filters made of particles, both inorganic and organic, is also absorption. Scattering contributes to less than 10%, as experimentally found in 200511 and also reproduced by Kollias N and Cole C et al12,13. The larger the particles the more of the particle is wasted for absorption, i.e. most of the UV radiation is absorbed immediately after entering the particle before it can penetrate deeper into the particle. In conclusion, the particles in general, whether nano or non-nano, are too large to penetrate the skin. If there is anything at all to worry about, it is the UV filters that are dissolved at the molecular level. This is what the safety assessment in the cosmetics regulation is for. Therefore, Nano means BIG!
Osterwalder U, Sohn M, Herzog B, Global state of sunscreens. Photodermatol Photoimmunol Photomed. 2014;30(2–3):62–80. doi: 10.1111/phpp.12112. PMID: 24734281.
Surber C, Plautz J, Dähnhardt-Pfeiffer S, Osterwalder U, Size Matters! Issues and Challenges with Nanoparticulate UV Filters, Surber C, Osterwalder U (eds): Challenges in Sun Protection. Curr Probl Dermatol. Basel, Karger, 2021, vol 55, pp 203–222 (DOI:10.1159/000517632)
Commission Regulation (EC) No 2018/1881 of 3 December 2018 amending Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards Annexes I, III, VI, VII, VIII, IX, X, XI, and XII to address nanoforms of substances (Text with EEA relevance.) http://data.europa.eu/eli/reg/2018/1881/oj Accessed February 2022.
Mueller S, Herzog B, Giesinger J, Quass K, Osterwalder U, Micronization as a Tool in the Development of Innovative UV Filters, SÖFW-JOURNAL I 131 I 7-2005
Kollias N. The absorption properties of “physical” sunscreens. Arch Dermatol. 1999;135(2):209–10. doi: 10.1001/archderm.135.2.209-a
Cole C, Shyr T, Ou-Yang H. Metal oxide sunscreens protect skin by absorption, not by reflection or scattering. Photo-dermatol Photoimmunol Photomed. 2016;32(1):5–10. doi: 10.1111/phpp.12214
Uli Osterwalder studied Chemical Engineering at ETH Zurich, Switzerland and at the University of Houston in Houston, Texas. He joined Ciba-Geigy in Basel in 1979 where he first developed a Phosgene Generator in central process development. Later he developed his leadership skills in Project Management and Process Analytics. At Ciba Specialty Chemicals Uli Osterwalder helped establish new business development in Fabric Care and Personal Care. After the acquisition by BASF SE he became Senior Marketing Manager and Scientific Adviser in Sun Care in Ludwigshafen and Duesseldorf.
2016 he came back to Basel, working for DSM as senior Senior Scientific Adviser suncare for two years. 2018 he started his own company, Sun Protection Facilitator GmbH and is committed to contribute to further improvements in sun protection. Uli Osterwalder works for ISO on the development of new UV protection assessment methods and is now chairing the technical committee ISO TC/217 (Cosmetics). He is author and co-author of numerous scientific articles and book chapters on sun protection.
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