Quality / EHS
Micronisers continually strive to improve the Quality of our products and services through process excellence and our cGMP (current Good Manufacturing Practices) Quality Systems. Micronisers holds licenses with the TGA and APVMA in accordance with guidelines provided in PIC/S GMP (Pharmaceutical Inspection Co-Operation Scheme) which was developed by the International Conference on Harmonisation (ICH). Further information regarding guidance documents and licenses can be found at http://www.picscheme.org/pics.php and http://www.tga.gov.au/.
Micronisers also holds a licence with the Department of Health for the manufacture, sale and/or supply of scheduled poisons.
Environment, Health & Safety
Whilst Micronisers have systematically responded to the gaps in knowledge first raised by the United Kingdom’s Royal Society in 2004 , there has been continuing concern from various lobby groups expressing fears about the use and safety of nano ZnO, if absorbed through the skin.
The position of the consumer lobby groups remains unchanged
despite numerous recent publications from informed regulatory bodies indicating that nano ZnO is safe to use in sunscreens, and that there is no evidence of any significant skin absorption past the outermost layer. These publications include reviews by the Therapeutic Goods Administration of the Australian Government Department of Health and Ageing, in 2006, 2009 and 2013 . The U.S. Food and Drug Administration (FDA) has also published a scientific review with the same conclusions and their new “Over-The-Counter” Sunscreen Monograph details labelling requirements that favour the use of ZnO for enhanced protection against ultraviolet-A (UVA) sun rays . The EU Scientific Committee on Consumer Safety also recently “concluded on the basis of available evidence that the use of ZnO nanoparticles … at a concentration up to 25% as a UV-filter in sunscreens, can be considered not to pose a risk of adverse effects in humans after dermal application” . The same conclusion was also made in a report by the Environmental Working Group (EWG) in USA  – this lobby group has regularly updated their sunscreen advice and their current 2012 Sunscreen Report clearly states that mineral sunscreens provide the best broad spectrum protection, especially from UVA, without the use of potential hormone-disrupting chemicals like oxybenzone .
These changes in sunscreen regulations have been widely accepted and applauded by several dermatology groups, including the U.S. Personal Care Products Council and the American Academy of Dermatology (AAD). Comments from the AAD with its membership of more than 17,000 are particularly relevant as this professional society represents virtually all practicing dermatologists in the USA, as well as a growing number of international dermatologists. The AAD President, Dr Daniel M. Siegel, has stated that nanoparticle-containing sunscreens are safe to use, highlighting the effectiveness of nanotechnology amidst concerns over certain ingredients, i.e. "Scientific evidence supports the benefits of sunscreen usage to minimize short- and long-term damage to the skin from UV radiation and outweighs any unproven claims of toxicity or human health hazard." Dr Siegel also countered reports questioning the effectiveness of nanoparticles in sunscreens, by stating that “Considerable research on the use of nanoparticles on healthy, undamaged skin has shown that the stratum corneum - the outermost layer of the skin - is an effective barrier to preventing the entry of nanoparticles into the deeper layers of the skin. Titanium dioxide and zinc oxide have a long history of safe use in sunscreens and offer good options for broad-spectrum UV protection” .
Australia has the world’s highest incidence rate of melanoma of the skin. Disturbingly, it is interesting to note that since 1982 the Australian incidence rate of skin melanomas has continued to rise, despite the increased use of sunscreen. For males, the incidence rate has more than doubled over the 26 year period between 1982-2007 (from 27 cases per 100,000 males in 1982 to 57 cases per 100,000 males in 2007). Over this same period the rate in females increased by 47% (from 26 cases per 100,000 females in 1982 to 38 cases per 100,000 females in 2007) .
Thus, there are at least two obvious questions relating to this data – “Do existing sunscreens have a poor level of broad spectrum protection?” and “Are sunscreens not used properly?”.
Consumers are generally not aware of the how sunlight damages the skin, and especially the effects of specific UV sunrays. The UV sunrays are divided into the shorter wavelength UVB band and the longer wavelength UVA bands (including type I and II). Only 5% of the sun’s UV energy that penetrates the atmosphere is contained within the UVB range, while 95% of the energy is within the UVA range. Protection from the UVB damage that can be partly seen as sunburn, is measured by the Sun Protection Factor (SPF). Currently, in Australia there is no measurement for protection from UVA, which can penetrate deeper into the skin to be very damaging over the longer term and is related to melanoma and other skin cancers (table 1.)
|Table 1 Understanding the sun and sunscreen|
|Ultraviolet Radiation Energy Level||2-5%||95-98%|
|Wavelength of light||290-320nm||320-340nm||340-400nm|
|Risk||Sunburn||Increasing risk of melanoma|
|Type of Radiation||UVB||UVAII||UVA I|
|Measurement for Consumers||SPF 15+ to 50+||None in Australia|
Zinc oxide is widely recognised as one of the most effective ingredient in sunscreens for broad spectrum protection, covering both UVA and UVB. Thus, there is a reasonable hypothesis that the quality of many sunscreens used in Australia would be improved by the addition of ZnO. Furthermore, the wide use of chemical UVA/UVB filters by sunscreen manufacturers may have potential problems. Individual chemical UV filters absorb only narrow bands of UV light (with most only in the UVB range) and so a mixture of chemical UV filters are needed in sunscreens to get a broader UV filtering effect. Many chemical UV filters are unstable under UV exposure, requiring more frequent sunscreen applications, while the breakdown photo-products can cause irritation and allergic responses in sensitive people. Chemical UV filters are also absorbed into the skin (some up to 4% of applied dose), with some having suspected endocrine disruption properties, including benzophenone-3, one of the few chemical UVA filters . In addition to being questioned about their effectiveness to provide protection against skin melanoma, it is also disturbing that benzophenone-3 has been found in 96% of urine samples in the USA, and several other chemical UV filters were found in 85% of Swiss breast milk samples .
In relation to the second question about the proper use of sunscreens, in order to achieve good broad spectrum protection from the inclusion of “normal pharmaceutical grade zinc oxide” in sunscreens at recommended dosage levels, the skin looks white and the aesthetics of these types of sunscreens do not appeal to the consumer. The consequence is that consumers tend to use less sunscreen to avoid a “white” pasty appearance, but unfortunately this provides a lower level of protection from the UVA sun rays that penetrate deeper into the skin than UVB, and also cause cell damage that is closely linked with melanoma formation.
It is also important to realise that dermal exposure to nano sized ZnO has occurred for more than 60 years without any health concerns, since ZnO-containing sunscreens were first used – a fact of which most consumers are unaware. This is because the original French process used to make the highest pharmaceutical quality bulk ZnO was invented in the 1940’s and produces an average particle size of about 400-500 nm, but also contains small amounts of particles less than 100 nm.
A general comparison of the effectiveness of “organic chemical UV absorbers” and NanosunTM is shown in table 2 below. The data clearly shows the best broad spectrum protection is provided by NanosunTM nano Zinc Oxide.
|Table 2 Level of protection from different ingredients|
|Sunburn||Increasing risk of melanoma|
|Common UV absorbers||Type||UVB||UVAII||UVA I|
|NanosunTM Zinc Oxide||Mineral|
|Level of protection||None||
The use of NanosunTM with a particle size of about 30-50 nanometres, allows the sunscreen to be transparent, whilst still maintaining a high level of protection from both UVA and UVB exposure. As it is also aesthetically appealing, it ideally promotes greater use of a truly effective sunscreen.
Despite such compelling arguments concerning the safe use of nanoparticles in sunscreen, Micronisers has still sought to gather evidence that specifically demonstrates the safety of NanosunTM. Over the last 5-6 years Micronisers have conducted and supported a series of nano safety research projects with their NanosunTM for use in sunscreen.
The first of these studies involved an elaborate technique of using rare stable isotope tracing to quantitatively track where the zinc went in the body from either normal-quality ZnO and that of NanosunTM, which was applied as separate formulated sunscreens onto the skin of human volunteers . Both of these studies showed that negligible amounts of zinc from NanosunTM was absorbed through the skin, being less than 0.01% of the applied dose. Furthermore, the amount absorbed was equivalent to approximately 1/1000th of the total zinc naturally present in the blood. Importantly, the levels of absorption from either NanosunTM and that of the normal pharmaceutical grade of ZnO were very similar. Overall, these results show that there is negligible zinc uptake from using NanosunTM in sunscreens, which is extremely small compared to the normal levels of zinc required as an essential mineral for human nutrition, unlike the non-essential chemicals that are the more commonly used chemical UV filters and titanium dioxide.
The second series of studies on NanosunTM involved a global consortium of universities and research institutes sponsored under an OECD Nano safety testing program. The ZnO study focused on the full chemical and physical characterization of three materials; NanosunTM, another commercially available nano size product and a normal pharmaceutical grade of ZnO (micron size product). The results of this study showed that there were significant physicochemical differences between the three materials in a number of characteristics. Most notably, NanosunTM was the least variably-sized and shaped material and was considered to be the most uniform and consistent product for particle size.
A third series of studies on NanosunTM was supported by VCAMM, a Victorian Government sponsored company with a charter to assist the commercialisation of innovative technology; the Advanced Manufacturing Co-operative Research Centre, an Australian Government Company set up to promote and assist innovative manufacturing in Australia; Monash University and RMIT University. Micronisers Pty Ltd and Baxter Laboratories Pty Ltd were the industry participants. Baxter Laboratories is a large manufacturer of sunscreen in Australia and participated in the study in order to determine the safe use of ZnO as a UV filter. This significant and large research project focused on the question, “If nanoparticles are absorbed through the skin, how would human skin and immune cells react to the presence of NanosunTM?”
The study looked at the toxic and immune responses of a range of human cell types exposed in vitro to a wide dose range of UV filters and nanoparticles. The findings were used to develop an “Immune Balance Rating” (IBR™) for the test materials, comprising five criteria, i.e.:
- Immunostimulation – No inappropriate activation of the immune system (hypoallergenic)
- Immunosuppression – No unwanted inhibition of immunity
- Phototoxicity – Material not activated by UV exposure to become toxic
- Protection against UV Damage – Protection against photo-ageing (this is the closest analogy to the commonly used SPF rating of sunscreens)
- Protection against UV Immunosuppression – Effective protection against UV exposure suppressing the immune system
The IBR™ value = lowest product indicator score (from best ««««« to worst «). A higher score indicates that the human body would have a favourable response to the test material, and a low score indicates that the body and cells are under stress. The IBR score for a NanosunTM dispersion used to make sunscreen is ««««, clearly indicating that human cells respond favourably to ZnO nanoparticles.
The fourth research study examined the potential effects of NanosunTM on the wider environment, for which NanosunTM in either powder form or in a sunscreen, was added to sewage sludge in the wastewater processing pathway . The results of the study showed that nanoparticle ZnO behaves the same as normal soluble sources of zinc in that both are rapidly converted to insoluble sulfides, thereby posing no new threat to the environment.
In summary, whilst we have unequivocally established that Micronisers’ NanosunTM is an excellent and safe product for sunscreens, similar extensive research and development studies have not been extended to other types or forms of nano ZnO made by different manufacturing processes. Since products in the nano scale may behave differently, each manufacturer should conduct their own R&D studies to demonstrate specific product safety.
 UK Royal Society (2004) “Nanoscience and nanotechnologies: opportunities and uncertainties”, published 29 July 2004. http://www.nanotec.org.uk/finalReport.htm Accessed 02/10/2012.
 Therapeutic Goods Administration, Australian Government Department of Health and Ageing (2013) “A review of the Scientific Literature on the Safety of Nanoparticulate Titanium Dioxide and Zinc Oxide in Sunscreens”. http://www.tga.gov.au/industry/sunscreens-nanoparticles-review-2013.htm Accessed 17/03/2014.
 U.S. Food and Drug Administration (FDA) (2012) “Over-The-Counter” Sunscreen Monograph 21 CFR 352. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=352 Accessed 02/10/2012.
 EU Scientific Committee on Consumer Safety (2012) “Opinion on Zinc oxide (nano form) COLIPA S 76 - SCCS/1489/12. 18 Sep. 2012.
Environmental Working Group (EWG) (2009) “Sunscreen Investigation. Section 4. Nanotechnology & Sunscreens”. http://www.ewg.org/nanotechnology-sunscreens Accessed 02/10/2012.
 Environmental Working Group (EWG) (2012) Highlights of the “2012 Sunscreen Report”. May 2012. http://breakingnews.ewg.org/2012sunscreen/sunscreens-exposed/executive-summary/ Accessed 02/10/2012.
 American Academy of Dermatology (AAD) (2012) “Sunscreen remains a safe, effective form of sun protection”. News release 16 May, 2012. http://www.aad.org/stories-and-news/news-releases/sunscreen-remains-a-safe-effective-form-of-sun-protection Accessed 02/10/2012.
 Australian Institute of Health and Welfare (AIHW) Australian Cancer Database “Cancer in Australia 2010 – an overview”. 29 Nov. 2010. http://www.aihw.gov.au/ Accessed 02/10/2012.
 Krause M. et al. (2012) “Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters”. International Journal of Andrology, 35:424-436.
 Gulson B. et al. (2010) Toxicological Sciences, 118:140-149; and Gulson B. et al. (2012) Science of the Total Environment, 420:313-318.
 Lombi E. et al. (2012) “Fate of Zinc Oxide Nanoparticles during Anaerobic Digestion of Wastewater and Post-Treatment Processing of Sewage Sludge”. Environmental Science and Technology, 46(16):9089-9096.