1. Safety and Benefits of Food Colors Sean Taylor, PhD Managing Director Verto Solutions Joseph Borzelleca, PhD Professor, Pharmacology & Toxicology VCU School of Medicine

2. Overview of Presentation About IACM History of FD&C colors Safety of FD&C colors Colors have not been proven to cause hyperactive behavior Colors: important ingredients

3. IACM’s Mission to actively represent the interests of the color industry by demonstrating the safety of color additives, and to promote the industry's economic growth by actively participating in new color approvals and regulatory and legislative issues that affect the industry worldwide

4. Current Members

5. History of Color Additives in the US Legal Framework Colors are food additives under 1958 Food, Drug, and Cosmetics Act All color additives require pre-market approval via color petition process Colors listed in US Code of Federal Regulations, Part 21, Section 73 & 74

6. Certified & Exempt Colors Colors can be generally divided into “certified” and “exempt from certification” categories –Certified: Testing of each batch by FDA confirms safety –“Exempt” colors: no batch testing required Certified colors: FD&C colors

7. Certified Colors (21 CFR 74) Uncertified name Allura Red AC Erythrosine Brilliant Blue FCF Indigotine Tartrazine Sunset Yellow FCF Fast Green FCF Certified color FD&C Red No. 40 FD&C Red No. 3 FD&C Blue No. 1 FD&C Blue No. 2 FD&C Yellow No. 5 FD&C Yellow No. 6 FD&C Green No. 3

8. Exempt Colors (21 CFR 73) Haematococcus algae meal Synthetic iron oxide Fruit juice Vegetable juice Dried algae meal Tagetes (Aztec marigold) meal and extract Carrot oil Corn endosperm oil Paprika/oleoresin (extract) Phaffia yeast Riboflavin Saffron Titanium dioxide Turmeric/oleoresin Annatto extract Astaxanthin Dehydrated beets (beet powder) Ultramarine blue Canthaxanthin Caramel beta-Apo-8'-carotenal beta-Carotene Cochineal extract; carmine Sodium copper chlorophyllin Toasted partially defatted cooked cottonseed flour Ferrous gluconate Ferrous lactate Grape color extract Grape skin extract (Enocianina)

9. Safety of FD&C Colors Approval process in US Color additive petition filing –Specifications/purity –Use/technological justification –Toxicological data FDA Redbook requirements –Exposure FDA review/public comment process Final rulemaking with allowed use

10. Food additive petition: FDA recommended toxicity testing Toxicity Tests Concern Level Low (I) Concern Level Intermediate (II) Concern Level High (III) Genetic Toxicity TestsXXX Short-term toxicity tests with rodentsXXX Subchronic toxicity studies with rodents XX Subchronic toxicity studies with non-rodents XX One-year toxicity studies with non-rodents X Chronic toxicity or Combined chronic toxicity/carcinogenicity studies with rodents X Carcinogenicity studies with rodents X Reproduction studies XX Developmental toxicity studies XX Metabolism and Pharmacokinetic studies XX Human studies X

11. Safety of FD&C Colors in the US Color Risk Assessment Substantial safety datasets for many colors –FDA review led to listing as allowed colors WHO/FAO JECFA Review –establish acceptable daily intakes (ADIs) Additional data collected –Genotoxicity –Allergenicity –other studies

12. Safety of FD&C Colors in the US FD&C Blue No. 1 and Green No. 3 Name of colorFD&C Blue No. 1 (Brilliant Blue FCF) FD&C Green No. 3 (Fast Green FCF) In use since19291927 Genetox In Vitro/In Vivo Acute/SubchronicRats ChronicRats/Mice CarcinogenicityRats/Mice Reproductive/TeratogenicRats & Rabbits Special studies Human studies ADMEKDiverse animalsRats JECFA ADI (mg/kg/d)0-12.50-25

13. Safety of FD&C Colors in the US FD&C Blue No. 2 Name of colorFD&C Blue No. 2 (Indigotine) In use since1907 Genetox In vitro/In vivo Acute/SubchronicRat, Mouse/90-day ChronicRats/Mice CarcinogenicityRats/Mice Reproductive/TeratogenicRats & Rabbits Special studies Human studies ADMEKRats JECFA ADI (mg/kg/d)0-17

14. Safety of FD&C Colors in the US FD&C Red No. 3 Name of colorFD&C Red No. 3 (Erythrosine) In use since1907 Genetox In vitro/In vivo Acute/SubchronicRat, Mouse ChronicRats/Mice CarcinogenicityRats/Mice Reproductive/TeratogenicRats Special studiesThyroid/Mechanism of Action Human studiesThyroid ADMEKRats, Humans JECFA ADI (mg/kg/d)0-0.1

15. Safety of FD&C Colors in the US The Azo dyes: Red 40, Yellow 5, Yellow 6 Name of colorFD&C Red No. 40 (Allura Red AC) FD&C Yellow No. 5 (Tartrazine) FD&C Yellow No. 6 (Sunset Yellow FCF) In use since197119161929 GenetoxIn vitro/In vivo Acute/SubchronicAnimalsMiceR,M/90d ChronicRats/Mice CarcinogenicityRats/Mice Reproductive/TeratologicalRats/MiceRats & RabbitsRats Special studiesAllergenicity Human studiesAllergenicity ADMEKDogs, ratsHumans, Animals JECFA ADI (mg/kg/d)0-70-7.50-2.5

16. No Proven Causality to Hyperactivity Historical perspective Some research has suggested a link between intake of food colors and hyperactive behavior in children – Feingold diet – Hyperactivity studies (e.g., Isle of Wight) – Meta-analyses (e.g., Schab and Trinh) Nutrition Foundation: no links National Research Council: no links

17. No Proven Causality to Hyperactivity Southampton Study Limitations Undefined time for drink consumption – Time varied between additive intake and assessment of behavior Body weight not recorded – Dose could not be adjusted Behavior assessment data not collected for the respective placebo phases (weeks 1, 3 and 5) – No easy assessment of intra-individual variability

18. Observed Effects lack clear statistical significance – Across both age groups – Across both additive groups (Mix A and Mix B) Behavior changes only partially significant – Measured in the non-standard global hyperactivity audit No Proven Causality to Hyperactivity Southampton Study Limitations

19. The very weakly statistically significant effects were only measured under a constant seven-day treatment period – Would longer exposure exacerbate or eliminate the subtle effects? – Are the effects transient or persistent? If the effects are transient, probably not relevant within a human health discussion. No biological mechanism for causal association between the intake of the corresponding additives and the onset of hyperactivity can be derived from the results – Stevenson et al., 2011 No Proven Causality to Hyperactivity Southampton Study Limitations

20. Low mean levels of observed hyperactivity compared to normal inter- individual variation measured in other studies Behavioral changes – did not occur in all children in one group – did not occur uniformly across all age groups – not in an even manner for the intake of all additive groups Slightly amended behavior was observed in all groups given the additives But this does not necessarily lead to the conclusion that the additive mixes caused an increase in hyperactivity No Proven Causality to Hyperactivity Southampton Study Limitations

21. It is simply not possible to draw extensive conclusions from this study, which is considered the strongest, most robust thus far Extrapolation of the results is not possible when studying mixtures to each individual additive, or to other additives Interpretation/mis-interpretation of this study suggests the need for standard guidelines (would be helpful to evaluate conclusions) No Proven Causality to Hyperactivity Southampton Study Limitations

22. 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 Proven Causality to Hyperactivity Reviews of Southampton Work

23. EFSA Opinion EFSA’s AFC Panel were assisted by experts in behavior, child psychiatry, allergy and statistics Conclusions: –study provided limited evidence that the mixtures of additives tested had a small effect on the activity and attention of some children. –Effects observed were not consistent for the two age groups and for the two mixtures used in the study. –findings of the McCann et al study could not be used as a basis for altering the acceptable daily intakes Noted limitations: –inability to pinpoint which additives may have been responsible for the effects observed in the children given that mixtures and not individual additives were tested

24. EFSA Opinion Findings could be relevant for specific individuals showing sensitivity to food additives in general or to food colours in particular Not possible to assess how widespread such sensitivity, if present, would be in the general population (Stevenson et al., 2011) The significance of the effects on the behaviour of the children was unclear since it was not known if the small changes in attention and activity observed would interfere with schoolwork or other intellectual functioning The Panel noted that the majority of the previous studies used children described as hyperactive and these were therefore not representative of the general population

25. Norwegian Food Safety Authority The increase in hyperactivity reported in the Southampton study after children were challenged with artificial food colours and sodium benzoate in two different mixtures (A and B) were considered small Findings were not consistent between the two age groups and the two mixtures Study provides limited support to an increase in hyperactive behavior from mixtures of artificial food colors and sodium benzoate

26. BfR Expert Opinion Findings suggest indications of a possible association between the intake of specific food additives and increased hyperactivity in children Observed effects are low compared with normal inter-individual variation Behavioral changes do not occur in all children in a group; nor do they occur in a statistically significant manner in all age and additive groups. Trial does not supply any clear evidence of a possible causal association between additive intake and the observed effects; No biological mechanism be identified from the findings for a causal association of this kind. Additives must be listed on the label of packaged foods. This means that consumers wishing to avoid any intake of the additives concerned for precautionary reasons can refrain from consuming these foods.

27. FSANZ opinion Concluded that there are no public health and safety concerns due to the results of the study No public health and safety risk from the consumption of foods containing added colors as part of a balanced diet

28. What have other experts said? Attention Deficit Disorder Association No research proving that other treatments, such as neurobiofeedback, nutritional supplements, hypnosis, visual therapy, or changes in the diet are effective in relieving AD/HD symptoms.

29. What have other experts said? CHADD/Natl. Resource Ctr. on ADHD “Dietary treatments eliminate -- or take out -- one or more foods in someone's diet (for example, sugar, candy and food with red dye). The idea is that being sensitive to certain foods can cause symptoms of AD/HD. Careful research, however, has not supported this treatment.” http://www.help4adhd.org/en/treatment/complementary/WWK6S

30. Colors: Important Ingredients Offset color loss due to light, air, temperature extremes, moisture, and storage conditions –Natural color in foods fades Correct natural color variation Enhance naturally occurring color Add variety to wholesome and nutritious foods

31. Colors: Important Ingredients Provide colorful identity to foods that are otherwise colorless Add aesthetic appeal Protect flavors and vitamins that could be affected by sunlight Play a critical role in how we taste and enjoy food (palatability)

32. Colors: Important Ingredients A long, safe history of use in food Society has come to accept coloring not as fraudulent, but as a permissible and useful signal of food taste Simply, colors make food more enjoyable. Consumer studies shown consumers will not buy foods with color variations from the ‘norm’

33. Colors: Important Ingredients Technological limitations to natural colors Natural colors are great But, some technological limitations –Stability issues for some natural colors –Limitations in certain applications –Range of colors –Limited resources

34. European labeling In Europe, all food additives are given labeling codes commonly referred to as “E-numbers” So, colors were traditionally labeled not by name but by E-number The EU parliament has now required labeling for azo-dyes in Europe: –“may have effects on activity and attention in children”

35. Do US labels need a warning label? No proven causality to hyperactivity In the US, FD&C colors are already listed by name, not by a vague E-number As with all food ingredients, if consumers choose to not eat a specific ingredient, they can see it on the label and make an informed product choice

36. Carmine/Cochineal US Law: FD&C colors must appear on label Example: Carmine/cochineal is now labeled –Consumers have the clear knowledge needed to decide Consumers can make informed choices

37. Colors are important in many applications Drug dispensing and consumption errors are a significant health problem Pharmacists rate color and shape as the most important attributes for patients to identify medications Colored tablets significantly reduce medication errors

38. Why not use natural colors for drug identification? In some cases, this works great But some technological limitations related to the stability of natural colors –Shelf-life of the active ingredients >1 year –Shelf-life of a natural color may be <1 year –Limited palette of stable natural alternatives R&D continues

39. Summary Strong and robust dataset supports the safety of many synthetic colors No proven causality for hyperactive behavior Colors are useful additives that provide important and beneficial technical effects Colors are already clearly labeled and this allows consumers to make informed choices

40. Colors are Safe and Beneficial