Outline 4/25/2013. Titanium Dioxide Pigment and Nano Grades. Disclaimer

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1 Titanium Dioxide Pigment and Nano Grades Chris DeMerlis Colorcon, Inc. April 29, 2013 Disclaimer This presentation reports on work completed by Chris DeMerlis in support of IPEC and IACM and does not necessarily represent recommendations of Colorcon, Inc. Outline TiO2 nano vs. pigmentary grades TiO2 regulatory and safety status ACS Environmental Science and Technology article IACM particle size analysis project ILSI NanoRelease Food Additive Project 1

2 Pigmentary TiO2 Grade Titanium Dioxide Occurs in three crystalline forms, anatase, rutile and brookite Obtained from naturally occurring mineral ilmenite Very stable; used for opacity and whiteness for foods and drugs Most commonly used pigment for coloring tablets, confectionery products, etc. along with other colorants Issue: Significant confusion between pigment and nano grades of TiO2 Titanium Dioxide: Regulatory Status Approved in the US for coloring food up to 1% by weight; approved as a color additive not subject to certification Approved for coloring drugs consistent with GMP; used in approved drug products in the US up to 358 mg per dosage form (FDA s IID) E171 listed in the EU Annex II of regulation 1333/2008 as a permitted color additive in foods at GMP levels; also permitted in medicinal products Listed in JSFA for foods and JP for drugs in Japan; Approved in many countries globally Safety Evaluations of Titanium Dioxide FDA approved color additive 21 CFR The EU Scientific Committee for Food (SCF) evaluated TiO2 food use; acceptable daily intake (ADI) not established JECFA evaluated TiO2 and concluded: TiO2 shows neither significant absorption nor tissue storage Establishment of an acceptable daily intake for man is considered unnecessary Concluded not limited except for good manufacturing practice 2

3 Titanium Dioxide Studies Pigment Grade ADME studies indicate TiO2 is not excreted in the urine; resulted in low accumulation in muscle tissue; not retained in the liver, spleen, kidney, bone, plasma and red blood cells (West and Wyzan 1963) National Cancer Institute 2 year bioassay study; concluded that titanium dioxide was not carcinogenic by the oral route for Fischer 344 rats or B6C3F1 mice (NCI 1979) Absorption, distribution and excretion study conducted with platelet form of TiO2 using pigmentary TiO2 as the control. Main route of excretion was the faeces. Results suggest no substantial accumulation of titanium in tissues (Colorcon 2003) Nanoparticle TiO2 Intentionally engineered nanoparticles: transparent and has property of UV absorbency desirable for cosmetics and catalysts TiO2 Nano particles do not have pigmentary properties due to transparency Total TiO2 world production is a significant amount; production of nanoparticle TiO2 is less than 1% of the pigment grade of TiO2 Regulatory Information for Nanoparticles FDA Guidance for Industry: Considering Whether an FDA Regulated Product Involves the Application of Nanotechnology Engineering (i.e., deliberate manipulation, manufacture or selection) of materials that have at least one dimension in the size range of approximately 1 to 100 nanometers FDA issued for public comment two product-specific draft guidance documents to address the use of nanotechnology by the foods and cosmetics industries ntsadditivesgraspackaging/ucm htm#_ftn1 3

4 ACS Environmental Science and Technology Article (18 Jan 2012) ACS Environmental Science and Technology Article (18 Jan 2012) Quantify amount of TiO2 in foods; estimate human exposure to dietary nano TiO2; discuss impact of nano TiO2 on environment Electron microscopy analysis resulted in 36% of the particles being less than 100 nm in at least one dimension Consumer products solubilized and filtered and <5% of titanium passed through 0.45 or 0.7 um pores Children have the highest exposure to TiO2 due to consumption of sweets; typical exposure of US adult may be 1 mg Ti per kg bw per day Pigment TiO2 represents and enormous source of nanoscale TiO2 entering sewage systems IACM Comments on ACS Article Statement 36% of particles are <100 nm is misleading and may be factually incorrect. Put number of particles into perspective. Overall mass of particles must be considered Only 100 particles were analyzed by TEM; ASTM Electron Microscopy Test Method D3849 recommends recording data for 2000 particles Data presented is not representative of pigment grades of TiO2 and is insufficient to draw the conclusions stated 4

5 Weir Article Particle Size Data Particle Size Analysis Laser diffraction Light scattering Number distribution: each particle has equal weighting Volume distribution: larger particles represent a larger total volume Malvern Zetasizer Nano ZS IACM Particle Size Analysis Project Objective: generate particle size data on pigment and nano grades of TiO2 to differentiate the grades Correlate standard light scattering methods and Transmission Electron Microscopy (TEM) Analyze samples from multiple TiO2 manufacturers Collaborate with Titanium Dioxide Manufacturers Association (CEFIC) regarding sampling, sample preparation and analytical methods Identify issues with methods, e.g. particle agglomeration occurs in sample preparation etc. 5

6 ILSI NanoRelease Food Additive Project NanoRelease Food Additive is a project that aims to identify, evaluate, and develop methods needed to confidently detect and characterize engineered nanoparticles released from food along the alimentary canal, as occurring through direct food additives or indirect incorporation in food through migration from food contact materials or environmental contamination. ILSI NanoRelease Food Additive Project Five expert task groups have been gathering information and compiling white papers on specific topics relevant to assessing the oral uptake of engineered nanomaterials. Task Group 1: Material Characteristics Task Group 2: Alimentary Canal Environment Task Group 3: Alimentary Canal Models Task Group 4: Measurement Methods Task Group 5: Risk Management Aspects website< Conclusion Pigment grades of TiO2 have commonly been used in foods and drugs for many years Data on the particle size analysis of pigmentary TiO2 is needed to differentiate from nano grades Published papers confuse industry, government and the public IACM will respond to the ACS paper with letter to the editor 6