DeMerlis Schoneker

Global Challenges facing Titanium Dioxide and Aluminum Lakes
The Myths and the Reality

IACM Global Color Conference 11 13 September 2012 Dave Schoneker & Chris DeMerlis September 12, 2012
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Titanium Dioxide Update

IACM Global Color Conference 11 13 September 2012 Chris DeMerlis Colorcon, Inc. September 12, 2012
Pigmentary TiO2 Grade Titanium Dioxide (0.25-2.5um)

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 TiO2 is the most commonly used pigment for coloring tablets, confectionery products, etc. along with other colorants Issue: Significant confusion between pigment and nano grades of TiO2
Nanoparticle TiO2 (<0.10um)

Nanoparticle definition: A discrete entity which has three dimensions of the order of 100 nm or less (SCENIHR, 2007) 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 !!
Titanium Dioxide: The Most Globally Accepted Pigment

TiO2 approved in the US for coloring food up to 1% by weight of the finished food; approved as a color additive not subject to certification TiO2 approved for coloring drugs consistent with GMP; used in approved drug products in the US up to 358 mg per dosage form as listed in FDAs Inactive Ingredient Database (IID) TiO2 (E171) listed in the EU Annex II of regulation 1333/2008 as a permitted color additive in foods at GMP levels and is also permitted in medicinal products TiO2 listed in the JSFA for foods and JP for drugs in Japan ; TiO2 approved in countries globally
Pigmentary Titanium Dioxide Studies

ADME studies indicate titanium dioxide is not excreted in the urine and resulted in low accumulation in muscle tissue but was not retained in the liver, spleen, kidney, bone, plasma and red blood cells (West and Wyzan 1963) 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) National Cancer Institute conducted a 2 year bioassay study and concluded that titanium dioxide was not carcinogenetic by the oral route for Fischer 344 rats or B6C3F1 mice (NCI 1979) No significant safety issues have been identified for TiO2 (pigment grade) used orally by regulators worldwide
Expert Safety Evaluations of Titanium Dioxide

FDA approved in 21 CFR 73.575 The EU Scientific Committee for Food (SCF) evaluated TiO2 for food use in general and did not establish an acceptable daily intake (ADI) 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
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 TiO2 per kg bw per day Because of the large amount of TiO2 used annually, testing should focus on food grade TiO2 rather than nano grade due to the potential to enter the environment Pigment TiO2 represents an enormous source of nanoscale TiO2 entering sewage systems: NOT TRUE
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 IACM will respond with letter to the editor
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; use biorelevant fluids for analysis (simulated gastric and intestinal fluids) 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.
Inappropriate Journal and Media Publications- Example UCLA Paper

TDMA Issues with UCLA Paper1 No differentiation between pigmentary and nanoparticle TiO2 grades Study incorrectly implies that TiO2 nanoparticles are used in toothpaste and color additive applications Lack of internal particle controls High doses used in the study Only one type of nanoparticle TiO2 used (highly reactive photocatalyst ) TiO2 photocatalyst used consists largely of anatase, is not surface treated and has a primary particle size of 20 nm
Paper : Trouiller, B. et al (2009). Titanium Dioxide Nanoparticles Induce DNA Damage and Genetic Instability In vivo in Mice, Cancer Research, 69, 8784.
1UCLA
Conclusion
Pigment grades of TiO2 commonly have 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 IACM study underway to gain appropriate scientific understanding! MYTHS: Published papers confuse industry, government and the public that are not based on GOOD Science IACM will respond to the ACS paper with letter to the editor REALITY: There is no scientifically credible information available at this time that indicates a significant safety issue with the use of Pigment grade TiO2 in foods and ingested drugs
Aluminum Lakes Update

IACM Global Color Conference 11 13 September 2012 David Schoneker Colorcon, Inc. September 12, 2012
Aluminum Lakes
Aluminum Lakes are prepared by precipitating a soluble dye (FD&C, D&C, etc.) onto an insoluble substrate such as alumina. Substrate is prepared by adding sodium carbonate to a solution of aluminum sulfate. Certified dye is then added to the slurry followed by aluminum sulfate for conversion to the aluminum salt which is absorbed onto the surface of the alumina. Slurry is then washed, spray dried and milled to a fine powder Lakes are prepared with a range of pure dye content (3-42%) that provide a multitude of various color shades and strengths Lakes tend to provide highly desired colors for fairly low costs, typically much lower than natural color alternatives
Aluminum Lake Properties & Benefits

Lakes are insoluble in most solvents including water allowing them to act as a pigment (not a dye) Lakes have high opacity and are easily incorporated into dry products in a very cost-effective manner. Lakes have superior stability to light and heat compared to dyes and most natural colors Lakes are very effective for confectionery and tablet coatings because they do not require removal of water before processing. Lakes are very effective for coloring hydrophobic foods in which the presence of water is undesirable; foods such as fats and oils, confectionery, bakery products, etc.
Aluminum Lake Regulatory Status

Aluminum lakes are approved for use in foods and drugs in most countries globally United States: Aluminum lakes are provisionally listed in the CFR since 1959 for foods, drugs and cosmetics. Only FD&C Red No. 40 is permanently listed European Union: Aluminum lakes are currently approved for use in foods and drugs under Regulation 1333/2008. New synthetic color & aluminum restrictions for various food categories have been implemented by an amendment to Annex II to regulation 1333/2008. These new restrictions for foods will apply from August 2014. The regulation only applies to food products, not drug products. Aluminum lakes in drug products will not be restricted under current proposals.
EU Restrictions
WHAT HAS HAPPENED TO RESULT IN THESE RESTRICTIONS?
European Union Synthetic Colors

The UK FSA funded Southampton study published in September 2007; included 6 colours:
E 129 allura red E110 sunset yellow E 102 tartrazine E104 quinoline yellow E 122 carmoisine E 124 ponceau 4R
EFSA evaluated the study and concluded in 2008 that the study cannot be used as a basis to alter the ADIs EFSA re-evaluation of synthetic colours started in 2009 This re-evaluation started with the synthetic colors and is going to involve so-called natural colors next and then the rest of the approved food additives
European Union Precautionary Thinking

Precautionary Principle thinking in Europe has created consumer concern about synthetic colors which is not based on good science Political decision was made by the European Parliament due to consumer pressure - Labeling was effective July 20, 2010 for a warning statement for 6 Southampton colors: E number may have an adverse effect on activity and attention in children UK Food Standards Agency has pushed a voluntary ban of synthetic colors even though there was no scientific data showing real safety concerns Interesting since they funded the study!
European Union
EFSA completed evaluation of the 6 Southampton colours:
Lowered ADI for Sunset Yellow (E 110), Quinoline Yellow (E104) and Ponceau 4R (E 124) Requested a 28-day study on Sunset Yellow for effects on male reproductive organs IACM has completed this study
EFSA used 2 studies from University of Rajasthan in Jaipur, India to temporarily lower the ADI for Sunset Yellow from 0-2.5 mg/kg bw/day to 1.0 mg/kg bw/day Data integrity is questionable! Studies from India did not meet GLP regulations since the test article was not identified and characterized Our understanding is the test article dyes were simply sourced from street vendors in India and no sample is now available for further assessment
Update on Synthetic Food Colours in the EU
As a result of the EFSA evaluation, Commission has proposed following:
Colour
Confectionery Current mg/kg Proposal mg/kg 30 35 20
Food Supplements Current mg/kg 300 300 300 Proposal mg/kg 35 10 35
Quinoline yellow 300 Sunset yellow P4R 50 50
Total limit for Group 3 colours is 300 mg/Kg. Potentially huge impact on colours that can be achieved..
New Levels - European Union Example

Example: levels for Sunset Yellow at 8 ppm and 50 ppm
No Proven Causality to Hyperactivity Reviews of Southampton Work U.S. Food & Drug Administration (FDA) European Food Safety Authority (EFSA) Norwegian Food Safety Authority German Federal Institute for Risk Assessment (BfR) Food Safety Australia/New Zealand (FSANZ) Others (e.g., UK Council on Toxicology) No official actions being taken to limit use of these colors or require special labeling outside of Europe at this time
JECFA Evaluation of Aluminum June 2006

Aluminum evaluated from all sources including food and color additives Based on limited data which was available JECFA established a provisional tolerable weekly intake (PTWI) of 1 mg/kg bw for all aluminum compounds JECFA withdrew previous PTWI of 0-7 mg/kg bw Committee concluded that aluminum has the potential to effect the reproductive system and developing nervous system at doses lower then previous PTWI Committee requested additional safety data on bioavailability of different aluminum containing additives, developmental study and a multigeneration study with neurobehavioural endpoints
Studies Conducted by Industry

Bioavailability studies conducted by trade associations (IFAC, IACM and IAI) for 7 compounds including FD&C Red 40 Aluminum Lake International Aluminum Institute (IAI) submitted report to JECFA including data for exposure, bioavailability, repro/neurotoxicity Multigeneration reproductive study for aluminum sulfate and aluminum ammonium sulfate in drinking water Developmental toxicity study with aluminum chloride Neurotoxicity and neurobehaviour studies with aluminum chloride in drinking water Developmental and neurotoxicity study with aluminum citrate in drinking water
IACM FD&C Red 40 Aluminum Lake Bioavailability Study

Seven aluminum compounds studied Measure fraction of aluminum that enters the bloodstream of the rat using 26Al label Measured bioavailability for FD&C Red 40 lake was 9.0 X 10-4, similar to other soluble aluminum compounds studied Low bioavailability of Aluminum!
Study Conclusion:
FD&C Red 40 lake presents no unique biological hazard as a consequence of its bioavailability
Industry Study Conclusions

The IAI Industry association submission to JECFA concluded the following: In light of recent studies that either filled toxicological data gaps or reduced uncertainty in the toxicokinetic differences between test animals and humans, raising the value of the PTWI by a factor of up to 4 would be consistent with the currently available scientific data. IAI stated uncertainty factors already applied may be considered sufficient to address remaining data gaps and uncertainties.
JECFA Evaluation June 2011

The new industry studies were submitted for evaluation of bioavailability, reproductive, developmental and neurobehavioural effects JECFA Committee then established a PTWI of 2 mg/kg bw; the previous PTWI of 1 mg/kg bw was withdrawn Recommended that the provisions in the GSFA be compatible with the revised PTWI New data did not substantially change the LOAEL range of 5075 mg/kg bw per day; a NOAEL of 30 mg/kg bw per day from an aluminum citrate study was used to determine the revised PTWI of 2 mg/kg bw
European Union Evaluation of Aluminum

EFSA evaluation established a tolerable weekly intake (TWI) of 1 mg/kg bw in 2008 EU Commission than began drafting restrictions on the level of use of aluminum from lakes in various food categories to address the reduced TWI In 2010 EFSA refused to increase the TWI based on the new industry studies and on JECFAs revised TWI If they used JECFAs preliminary assessment to lower the TWI, why shouldnt they use JECFAs final assessment to increase and align the EU TWI with global standards? Instead, the EU Commission officially amended Annex II of regulation 1333/2008 to limit aluminum content in various food categories - Effective 1 August 2014
Impact on Food Categories- European Union

From August 2014 the level of Aluminum from lakes will be restricted by food category: Examples are: Category 17.1 Category 5.2 Category 5.3 Category 12.2.2 Solid Food Supplements Other Confectionery Chewing Gum Seasons and Condiments Category 14.1.4 Flavored Drinks 150 mg/kg 70 mg/kg 300 mg/kg 120 mg/kg 15 mg/kg
Typical Aluminum Content of Lakes

Aluminum Content Range %
Color
FD&C YELLOW #6/SUNSET YELLOW FCF ALUMINUM LAKES (INS 110)
Dye Range %
15-18 15-18 38-42 FD&C RED #40/ALLURA RED AC ALUMINUM LAKES (INS 129) 3-5 15-17 38-42 38-42 38-42 FD&C BLUE #2/INDIGO CARMINE ALUMINUM LAKES (INS 132) 3-5 11-14 30-36
20-26 20-26 13-19
21-27 20-26 13-19 13-19 13-19
21-27 20-26 15-21
Product Compliance
Example: Typical Food Supplement Tablet
Lake Dye Strength % in formula % Al in Lake % Al in formula
Sunset Allura Sunset Total
15-18% 15-17% 38-42%
3.82% 1.06% 0.46%
24.3% 22.4% 15.4%
0.93% 0.24% 0.07% 1.24%
For a 1313 mg tablet, at 3% coating weight gain: Al in coating on one tablet Total Al = 0.186 mg
= 361 mg/kg in the tablets = >twice the EU 150mg/kg limit
Result.reformulating
Industry Response - Aluminum Lakes in Europe

The European Aluminum Association (EAA) contacted the EU Commission to request that EFSA increase the TWI to 2 mg/kg bw to be harmonized with JECFA New exposure data was requested by DG Sanco in order to request that EFSA re-evaluate the TWI Why is this needed? The European food industry is currently reformulating food products to meet the new lower levels in the Commission Regulation 380/2012 (refers to the relevant amendment to Annex II) and will not develop new exposure data until this task is completed in 2014 EAA will not follow through with this request until new exposure data is available
JECFA Summary
Bioavailability studies result in low oral bioavailability of aluminum in the various forms (0.01 to 0.3%) JECFA increased the PTWI to 2 mg/kg bw JECFA concluded consumption of aluminum containing compounds would not be a concern provided that total dietary exposure is below PTWI of 2 mg/kg bw per day
European Reality
The EU Commission has decided to unilaterally ignore JECFAs conclusions and not increase their TWI to align with JECFAs recommendations PRECAUTIONARY THINKING!!! The EU Commission has moved forward to require overly tight restrictions on the aluminum from lakes that can be present in various foods effectively eliminates the levels of use of Aluminum Lakes typically needed to achieve desired colors in many food and dietary supplement products Only very light pastel colors can be acheived. Natural colors cannot be used as substitutes for aluminum lakes in all applications due to technical application and stability limitations
Future Considerations
Trade associations are considering the publication of an expert opinion report on aluminum additive safety to publicize the real facts concerning the safety of these materials!! Industry wants to ensure that the non-scientific, precautionary approach to evaluating the safety of aluminum lakes in the EU does not expand to other countries Some rumblings have already begun! Aluminum Lakes are safe, functional, stable, inexpensive pigments which are needed for coloring foods and drugs
Conclusions TiO2 & Aluminum Lakes

Rational scientific thinking and REAL safety information must rule the day, not simply the use of the Precautionary Principle to justify lower and lower levels of use of color additives which have been safely used for decades!! This type of Precautionary thinking will not end with Aluminum Lakes and TiO2 but will expand to all color additives, including natural colors, unless we all fight to make sure that good science is the basis for all decisions!! Requests from EFSA have already occurred for new toxicology studies on some natural colors
Where to go from here?
MYTH THERE ARE SAFETY ISSUES INVOLVED WITH

THE USE OF TIO2 AND ALUMINUM LAKES
REALITY -
THERE ARE NO SIGNIFICANT SAFETY ISSUES, BASED ON GOOD SCIENCE, THAT HAVE BEEN IDENTIFIED WITH THE USE OF TIO2 OR ALUMINUM LAKES THAT DICTATE ANY CHANGE IN THE USE OF THESE PIGMENTS. HOWEVER, MARKET ISSUES MAY NEED TO BE ADDRESSED FOR THE EUROPEAN MARKET
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Global Challenges facing Titanium Dioxide and Aluminum Lakes

The Myths and the Reality

Titanium Dioxide Update

Pigmentary TiO2 Grade Titanium Dioxide (0.25-2.5um)

Nanoparticle TiO2 (<0.10um)

Titanium Dioxide: The Most Globally Accepted Pigment

Pigmentary Titanium Dioxide Studies

Expert Safety Evaluations of Titanium Dioxide

ACS Environmental Science and Technology Article (18 Jan 2012)

IACM Comments on ACS Article

IACM Particle Size Analysis Project

Inappropriate Journal and Media Publications- Example UCLA Paper

Aluminum Lakes Update

Aluminum Lake Properties & Benefits

Aluminum Lake Regulatory Status

WHAT HAS HAPPENED TO RESULT IN THESE RESTRICTIONS?

European Union Synthetic Colors

European Union Precautionary Thinking

Update on Synthetic Food Colours in the EU

As a result of the EFSA evaluation, Commission has proposed following:

Confectionery Current mg/kg Proposal mg/kg 30 35 20

Food Supplements Current mg/kg 300 300 300 Proposal mg/kg 35 10 35

Quinoline yellow 300 Sunset yellow P4R 50 50

New Levels - European Union Example

JECFA Evaluation of Aluminum June 2006

Studies Conducted by Industry

IACM FD&C Red 40 Aluminum Lake Bioavailability Study

Industry Study Conclusions

JECFA Evaluation June 2011

European Union Evaluation of Aluminum

Impact on Food Categories- European Union

Typical Aluminum Content of Lakes

20-26 20-26 13-19

21-27 20-26 13-19 13-19 13-19

21-27 20-26 15-21

Sunset Allura Sunset Total

15-18% 15-17% 38-42%

3.82% 1.06% 0.46%

24.3% 22.4% 15.4%

0.93% 0.24% 0.07% 1.24%

= 361 mg/kg in the tablets = >twice the EU 150mg/kg limit

Industry Response - Aluminum Lakes in Europe

Conclusions TiO2 & Aluminum Lakes

Where to go from here?

MYTH THERE ARE SAFETY ISSUES INVOLVED WITH

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