Skip to main content

Advertisement

SpringerLink
Log in

Human safety review of “nano” titanium dioxide and zinc oxide

  • Perspective
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

Based on the current weight of evidence of all available data, the risk for humans from the use of nano-structured titanium dioxide (TiO2) or zinc oxide (ZnO) currently used in cosmetic preparations or sunscreens is considered negligible. There is a large body of information that when viewed in its entirety is considered as sufficient to demonstrate that these nano-structured ultraviolet (UV) filters, irrespective of various treatments (coatings) or crystalline structure, can be regarded as safe for use at concentrations up to 25% in cosmetic products to protect the skin from harmful effects of solar UV radiation. “Nano” TiO2 and ZnO formulated in topically applied sunscreen products exist as aggregates of primary particles ranging from 30-150 nm in size. These aggregates are bonded such that the force of sunscreen product application onto the skin would have no impact on their structure or result in the release of primary particles. Multiple studies have shown that under exaggerated test conditions neither nano-structured TiO2 nor ZnO penetrates beyond the stratum corneum of skin. Further, the distribution and persistence of these nano-structured metal oxides is the same compared to larger pigment-grade (i.e., >100 nm) particles, demonstrating equivalence in the recognition and elimination of such material from the body. Finally, the in vitro genotoxic and photogenotoxic profiles of these nano-structured metal oxides are of no consequence to human health. Whereas the most logical, straightforward conclusion based on data from internationally-recognized guideline studies and current 20+ year history of human use is that nano-structured TiO2 and ZnO are safe, there will continue to be questions as “nano” conjures images of technology gone awry. Despite this rather sober view, the public health benefits of sunscreens containing nano TiO2 and/or ZnO outweigh human safety concerns for these UV filters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AAS:

Atomic absorption spectrometry

NOS:

Not/non-otherwise specified

ICPMS:

Inductively coupled plasma mass spectrometer

TEM:

Transmission electron microscopy

SEM:

Scanning electron microscopy

LIFM:

Laser-induced fluorescence measurements

SLRSM:

Space-resolved laser scanning microscopy

SC:

Stratum corneum

%:

w/v

NP:

Nanoparticle

STIM:

Scanning ion transmission microscopy

PIXE:

Particle induced X-ray emission

SCID:

Severe combined immune deficiency

RBS:

Rutherford backscattering

IBA:

Ion beam analysis

PPS:

Primary particle size

ICP-AES:

Inductively coupled plasma-atomic emission spectrometry

ICP-MS:

Inductively coupled plasma-mass spectrometry

ICP-OES:

Inductively coupled plasma-optical emission spectrometry

GLP:

Good laboratory practice

MPM:

Multiphoton microscopy

EDX:

Energy-dispersive X-ray

TOF-SIMS:

Time-of-flight secondary ion mass spectrometry

SEM-EDX:

Scanning electron microscopy-energy dispersive X-ray analysis

References

  1. P. J. A. Borm, D. Robbins, S. Haubold, T. Kuhlbusch, H. Fissan, K. Donaldson, R. Schins, V. Stone, W. Kreyling, J. Lademann, J. Krutmann, D. B. Warheit and E. Oberdorster, The potential risks of nanomaterials: A review carried out for ECETOC Part. Fibre Toxicol. 2006 3 11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Y. Nakagawa, S. Wakuri, K. Sakamoto and N. Tanaka, The photogenotoxicity of titanium dioxide particles Mutat. Res., Genet. Toxicol. Environ. Mutagen. 1997 394 125–132.

    Article  CAS  Google Scholar 

  3. P. Kullavanijaya and H. W. Lim, Photoprotection J. Am. Acad. Dermatol. 2005 52 937–962.

    Article  PubMed  Google Scholar 

  4. S. Lautenschlager, H. C. Wulf and M. R. Pittelkow, Photoprotection Lancet 2007 370 528–537.

    Article  CAS  PubMed  Google Scholar 

  5. R. F. Wilson, Nanotechnology: the challenge of regulating known unknowns J. Law Med. Ethics 2006 34 704–713.

    Article  PubMed  Google Scholar 

  6. S. A. Edwards and M. A. Ratner, Nano-hype: The truth behind the nanotechnology buzz and the nanotech pioneers: Where are they taking us? Phys. Today 2007 60 60–62.

    Google Scholar 

  7. K. Kostarelos, A. Bianco and M. Prato, Hype around nanotubes creates unrealistic hopes Nature 2008 453 280

    Article  CAS  PubMed  Google Scholar 

  8. SCCNFP, 2000, Opinion of the Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers concerning Titanium Dioxide, Colipa No. S75, adopted by the SCCNFP during the 14th plenary meeting of 24 October 2000. ec. europe. eu

  9. SCCNFP, 2003, Opinion Concerning Zinc Oxide, Colipa No. S76; The Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers, adopted by the SCCNFP during the 24th plenary meeting of 24-25 June 2003. ec. europe. eu SCCNFP/0649-03

  10. SCCP, 2005, Statement on Zinc Oxide in sunscreen, SCCP/0932/05, adopted by the SCCP during the 5th plenary of 20 September 2005. ec. europe. eu

  11. SCCP, 2009, Clarification on the Opinion SCCNFP/0932/05 on Zinc Oxide, Colipa No. S76, SCCP/1215/09, adopted at its 19th plenary on 21 January 2009. ec. europe. eu

  12. SCCP, 2007, Opinion on the safety of nanomaterials in cosmetic products adopted by the SCCP after the public consultation on the 14th plenary of 18 December 2007. ec. europe. eu

  13. M. P. Holsapple, W. H. Farland, T. D. Landry, N. A. Monteiro-Riviere, J. M. Carter, N. J. Walker and K. V. Thomas, Research strategies for safety evaluation of nanomaterials, part II: Toxicological and safety evaluation of nanomaterials, current challenges and data needs Toxicol. Sci. 2005 88 12–17.

    Article  CAS  PubMed  Google Scholar 

  14. F. P. Gasparro, M. Mitchnick and J. F. Nash, A review of sunscreen safety and efficacy Photochem. Photobiol. 1998 68 243–256.

    Article  CAS  PubMed  Google Scholar 

  15. G. J. Nohynek and H. Schaefer, Benefit and risk of organic ultraviolet filters Regul. Toxicol. Pharmacol. 2001 33 285–299.

    Article  CAS  PubMed  Google Scholar 

  16. J. F. Nash, Human safety and efficacy of ultraviolet filters and sunscreen products Dermatol. Clin. 2006 24 35–51.

    Article  CAS  PubMed  Google Scholar 

  17. G. J. Nohynek, J. Lademann, C. Ribaud and M. S. Roberts, Grey Goo on the skin? Nanotechnology, cosmetic and sunscreen safety Crit. Rev. Toxicol. 2007 37 251–277.

    Article  CAS  PubMed  Google Scholar 

  18. T. Thomas, K. Thomas, N. Sadrieh, N. Savage, P. Adair and R. Bronaugh, Research Strategies for Safety Evaluation of Nanomaterials, Part VII: Evaluating Consumer Exposure to Nanoscale Materials Toxicol. Sci. 2006 91 14–19.

    Article  CAS  PubMed  Google Scholar 

  19. D. B. Warheit, P. J. Borm, C. Hennes and J. Lademann, Testing strategies to establish the safety of nanomaterials: conclusions of an ECETOC workshop Inhalation Toxicol. 2007 19 631–643.

    Article  CAS  Google Scholar 

  20. M. H. Tan, C. A. Commens, L. Burnett and P. J. Snitch, A pilot study on the percutaneous absorption of microfine titanium dioxide from sunscreens Australas. J. Dermatol. 1996 37 185–187.

    Article  CAS  PubMed  Google Scholar 

  21. J. Lademann, H. J. Weigmann, C. Rickmeyer, H. Barthelmes, H. Schaefer, G. Mueller and W. Sterry, Penetration of titanium dioxide microparticles in a sunscreen formulation into the horny layer and the follicular orifice Skin Pharmacol. Appl. Skin Physiol. 1999 12 247–256.

    Article  CAS  PubMed  Google Scholar 

  22. J. Schulz, H. Hohenberg, F. cker, E. rtner, T. Will, S. Pfeiffer, R. Wepf, V. Wendel, H. Gers-Barlag and K. P. Wittern, Distribution of sunscreens on skin Adv. Drug Delivery Rev. 2002 54 S157

    Article  CAS  Google Scholar 

  23. S. Gottbrath, M.-G. C. Penetration, and visualization of titanium dioxide microparticles in human stratum corneum - effect of different formulations on the penetration of titanium dioxide SOFW J. 2003 3 11–17.

    Google Scholar 

  24. T. Butz, T. Reinert, T. Pinheiro, P. Moretto, J. Pallon, Á. Z. Kiss, J. Stachura, W. Dąbroś, Z. Stachura, J. Lekki, M. Lekka, J. Hunyadi, T. Bíró, M. Sticherling, L. Van Vaeck, P. Van Royen, and J.-E. Surlève-Bazeille, Nanoderm, Quality of Skin as a Barrier to Ultra-fine Particles, Final Report, 2007, pp. 1–55, http://www.uni-leipzig.de/~nanoderm/index.html.

    Google Scholar 

  25. F. Menzel, T. Reinert, J. Vogt and T. Butz, Investigations of percutaneous uptake of ultrafine TiO2 particles at the high energy ion nanoprobe LIPSION Nucl. Instrum. Methods Phys. Res., Sect. B 2004 219-220 82–86.

    Article  CAS  Google Scholar 

  26. Z. Kertesz, Z. Szikszai, E. Gontier, P. Moretto, J. E. Surleve-Bazeille, B. Kiss, I. Juhasz, J. Hunyadi and A. Z. Kiss, Nuclear microprobe study of TiO2-penetration in the epidermis of human skin xenografts Nucl. Instrum. Methods Phys. Res., Sect. B 2005 231 280–285.

    Article  CAS  Google Scholar 

  27. A. Mavon, C. Miquel, O. Lejeune, B. Payre and P. Moretto, In vitro percutaneous absorption and in vivo stratum corneum distribution of an organic and a mineral sunscreen Skin Pharmacol. Physiol. 2007 20 10–20.

    Article  CAS  PubMed  Google Scholar 

  28. A. O. Gamer, E. Leibold and B. Van, Ravenzwaay, The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin Toxicol. in Vitro 2006 20 301–307.

    Article  CAS  PubMed  Google Scholar 

  29. A. V. Zvyagin, X. Zhao, A. Gierden, W. Sanchez, J. A. Ross and M. S. Roberts, Imaging of zinc oxide nanoparticle penetration in human skin in vitro and in vivo J. Biomed. Opt. 2008 13 064031

    Article  PubMed  CAS  Google Scholar 

  30. J. Wu, W. Liu, C. Xue, S. Zhou, F. Lan, L. Bi, H. Xu, X. Yang and F. D. Zeng, Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure Toxicol. Lett. 2009 191 1–8.

    Article  CAS  PubMed  Google Scholar 

  31. T. S. Jonaitis, J. W. Card and B. Magnuson, Concerns regarding nano-sized titanium dioxide dermal penetration and toxicity study Toxicol. Lett. 2010 192 268–269.

    Article  CAS  PubMed  Google Scholar 

  32. N. Sadrieh, A. M. Wokovich, N. V. Gopee, J. Zheng, D. Haines, D. Parmiter, P. H. Siitonen, C. R. Cozart, A. K. Patri, S. E. McNeil, P. C. Howard, W. H. Doub and L. F. Buhse, Lack of Significant Dermal Penetration of Titanium Dioxide (TiO2) from Sunscreen Formulations containing Nano- and Sub-Micron-Size TiO2 Particles Toxicol. Sci. 2010 10.1093/toxsci/kfq041

    Google Scholar 

  33. F. Pirot, J. Millet, Y. N. Kalia and P. Humbert, In vitro study of percutaneous absorption, cutaneous bioavailability and bioequivalence of zinc and copper from five topical formulations Skin Pharmacol. 1996 9 259–269.

    Article  CAS  PubMed  Google Scholar 

  34. A. B. G. Lansdown and A. Taylor, Zinc and titanium oxides: Promising UV-absorbers but what influence do they have on the intact skin? Int. J. Cosmet. Sci. 1997 19 167–172.

    Article  CAS  PubMed  Google Scholar 

  35. M. A. Mitchnick, D. Fairhurst and S. R. Pinnell, Microfine zinc oxide (Z-cote) as a photostable UVA/UVB sunblock agent J. Am. Acad. Dermatol. 1999 40 85–90.

    Article  CAS  PubMed  Google Scholar 

  36. X. Chen and S. S. Mao, Titanium dioxide nanomaterials: Synthesis, properties, modificationsand applications Chem. Rev. 2007 107 2891–2959.

    Article  CAS  PubMed  Google Scholar 

  37. H. Spielmann, M. Balls, J. Dupuis, W. J. Pape, G. Pechovitch, O. de Silva, H. G. Holzhutter, R. Clothier, P. Desolle, F. Gerberick, M. Liebsch, W. W. Lovell, T. Maurer, U. Pfannenbecker, J. M. Potthast, M. Csato, D. Sladowski, W. Steiling and P. Brantom, The international EU/COLIPA in vitro phototoxicity validation study: Results of phase II (blind trial). Part 1: The 3T3 NRU phototoxicity test Toxicol. in Vitro 1998 12 305–327.

    Article  CAS  PubMed  Google Scholar 

  38. H. Spielmann, B. Grune, M. Liebsch, A. Seiler and R. Vogel, Successful validation of in vitro methods in toxicology by ZEBET, the National Centre for Alternatives in Germany at the BfR (Federal Institute for Risk Assessment) Exp. Toxicol. Pathol. 2008 60 225–233.

    Article  CAS  PubMed  Google Scholar 

  39. H. Spielmann, M. Balls, J. Dupuis, W. J. Pape, O. de Silva, H.-G. Holzhutter, M. Liebsch, W. W. Lovell and U. Pfannenbecker, A Study on UV Filter Chemicals from Annex VII of European Union Directive 76/768/EEC, in the in Vitro 3T3 NRU Phototoxicity Test ATLA, Altern. Lab. Anim. 1998 26 679–708.

    Article  CAS  PubMed  Google Scholar 

  40. E. K. Dufour, T. Kumaravel, G. J. Nohynek, D. Kirkland and H. Toutain, Clastogenicity, photo-clastogenicity or pseudo-photo-clastogenicity: Genotoxic effects of zinc oxide in the dark, in pre-irradiated or simultaneously irradiated Chinese hamster ovary cells Mutat. Res., Genet. Toxicol. Environ. Mutagen. 2006 607 215–224.

    Article  CAS  Google Scholar 

  41. G. J. Nohynek, E. K. Dufour and M. S. Roberts, Nanotechnology, cosmetics and the skin: Is there a health risk? Skin Pharmacol. Physiol. 2008 21 136–149.

    Article  CAS  PubMed  Google Scholar 

  42. R. Landsiedel, M. D. Kapp, M. Schulz, K. Wiench and F. Oesch, Genotoxicity investigations on nanomaterials: Methods, preparation and characterization of test material, potential artifacts and limitations-Many questions, some answers Mutat. Res., Rev. Mutat. Res. 2009 681 241–258.

    Article  CAS  Google Scholar 

  43. N. Roney, M. Osier, S. J. Paikoff, C. V. Smith, M. Williams, C. T. De Rosa, ATSDR evaluation of the health effects of zinc and relevance to public health Toxicol. Ind. Health 2006 22 423–493.

    Article  CAS  PubMed  Google Scholar 

  44. C. J. Boreiko, Overview of health risk assessments for zinc J. Toxicol. Environ. Health, Part A 2010 73 166–174.

    Article  CAS  Google Scholar 

  45. A. S. Dussert, E. Gooris and J. Hemmerle, Characterization of the mineral content of a physical sunscreen emulsion and its distribution onto human stratum corneum Int. J. Cosmet. Sci. 1997 19 119–129.

    Article  CAS  PubMed  Google Scholar 

  46. F. Pflucker, V. Wendel, H. Hohenberg, E. Gartner, T. Will, S. Pfeiffer, R. Wepf, H. Gers-Barlag, The human stratum corneum layer: an effective barrier against dermal uptake of different forms of topically applied micronised titanium dioxide Skin Pharmacol. Appl. Skin Physiol. 2001 14 suppl. 1 92–97.

    Article  CAS  PubMed  Google Scholar 

  47. E. Gontier, M. D. Ynsa, T. Bíró, J. Hunyadi, B. Kiss, K. Gáspár, T. Pinheiro, J. N. Silva, P. Filipe, J. Stachura, W. Dabros, T. Reinert, T. Butz, P. Moretto, J. E. Surlève-Bazeille, Is there penetration of titania nanoparticles in sunscreens through skin? A comparative electron and ion microscopy study Nanotoxicology 2008 2 218–231.

    Article  Google Scholar 

  48. A. P. Popov, M. Y. Kirillin, A. V. Priezzhev, J. Lademann, J. Hast, R. Myllylä, Optical, sensing of titanium dioxide nanoparticles within horny layer of human skin and their protecting effect against solar UV radiation Proc. SPIE 2005 5702 113–122.

    Article  CAS  Google Scholar 

  49. S. E. Cross, B. Innes, M. S. Roberts, T. Tsuzuki, T. A. Robertson and P. McCormick, Human skin penetration of sunscreen nanoparticles: In vitro assessment of a novel micronized zinc oxide formulation Skin Pharmacol. Physiol. 2007 20 148–154.

    Article  CAS  PubMed  Google Scholar 

  50. J. Lekki, Z. Stachura, W. Dabros, J. Stachura, F. Menzel, T. Reinert, T. Butz, J. Pallon, E. Gontier, M. D. Ynsa, P. Moretto, Z. Kertesz, Z. Szikszai and A. Z. Kiss, On the follicular pathway of percutaneous uptake of nanoparticles: Ion microscopy and autoradiography studies Nucl. Instrum. Methods Phys. Res., Sect. B 2007 260 174–177.

    Article  CAS  Google Scholar 

  51. T. Pinheiro, J. Pallon, L. C. Alves, A. ssimo, P. Filipe, J. N. Silva and R. Silva, The influence of corneocyte structure on the interpretation of permeation profiles of nanoparticles across skin Nucl. Instrum. Methods Phys. Res., Sect. B 2007 260 119–123.

    Article  CAS  Google Scholar 

  52. P. Filipe, J. N. Silva, R. Silva, J. L. Cirne De Castro, M. Marques Gomes, L. C. Alves, R. Santus and T. Pinheiro, Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption Skin Pharmacol. Physiol. 2009 22 266–275.

    Article  CAS  PubMed  Google Scholar 

  53. L. Durand, N. Habran, V. Henschel and K. Amighi, In vitro evaluation of the cutaneous penetration of sprayable sunscreen emulsions with high concentrations of UV filters Int. J. Cosmet. Sci. 2009 31 279–292.

    Article  CAS  PubMed  Google Scholar 

  54. T. R. Kuo, C. L. Wu, C. T. Hsu, W. Lo, S. J. Chiang, S. J. Lin, C. Y. Dong and C. C. Chen, Chemical enhancer induced changes in the mechanisms of transdermal delivery of zinc oxide nanoparticles Biomaterials 2009 30 3002–3008.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. IRSC - International Regulatory & Scientific Consulting, Paul-Lincke Strasse 36, 67304, Eisenberg, Germany

    Karsten Schilling

  2. Unilever - Safety & Environmental Assurance Centre, London, UK

    Bobbie Bradford

  3. Johnson & Johnson, Campus de Maigremont, Parc Industrielle d’Incarville, 27100, Val de Reuil, France

    Dominique Castelli

  4. L’Oreal, 25-29 Quai Aulagnier, 92665, Asnières-sur-Seine, France

    Eric Dufour

  5. The Procter & Gamble Company, 11530 Reed Hartman Hwy, Cincinnati, OH, USA

    J. Frank Nash

  6. Beiersdorf AG, Unnastrasse 48, 20245, Hamburg, Germany

    Wolfgang Pape

  7. BASF SE, Regulatory Affairs Cosmetics & Aroma Chemicals, 67056, Ludwigshafen, Germany

    Stefan Schulte

  8. Croda Europe Limited, Croda Suncare & Biopolymers, Foundry Lane, Widnes, Cheshire, WA8 8UB, UK

    Ian Tooley

  9. Umicore, Rue de Chênée 53/2, 4031, Angleur, Belgium

    Jeroen van den Bosch

  10. Colipa, Avenue Herrmann Debroux 15A, 1160, Brussels, Belgium

    Florian Schellauf

Authors
  1. Karsten Schilling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bobbie Bradford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dominique Castelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Dufour
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Frank Nash
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wolfgang Pape
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefan Schulte
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ian Tooley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jeroen van den Bosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Florian Schellauf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Florian Schellauf.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schilling, K., Bradford, B., Castelli, D. et al. Human safety review of “nano” titanium dioxide and zinc oxide. Photochem Photobiol Sci 9, 495–509 (2010). https://doi.org/10.1039/b9pp00180h

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/b9pp00180h

Search

Navigation