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PharmTech.com Quality and Regulatory Sourcebook March eBook 2023 Pharmaceutical Technology ® 39 viewpoint assessment, EFSA dismissed the most relevant studies, which demonstrate the lack of potential genotoxicity of grades of TiO 2 that are actually representative of E171 as used in foods (2). An independent expert panel was also invited by the TDMA to develop a WoE assessment of the genotox- icity of TiO 2 based on the data identified in the EFSA evaluation, but also including additional studies which became available since the initial EFSA review. The panel included renowned experts in genetic tox- icology, general toxicology, bioavailability, and car- cinogenicity. They evaluated an extensive dataset of 337 studies that reported various genotoxicity inves- tigations on TiO 2 . Based on a weight of evidence eval- uation of the most robust studies, the panel recently concluded that existing evidence does not support a direct DNA damaging mechanism for TiO 2 , in nano and other forms. The panel has published the findings in a peer-reviewed scientific journal (3). There is simply no credible scientific data demon- strating there are any real safety concerns with con- tinued use of TiO 2 . Unfortunately, the EC decided to take an overly precautionary approach, based on some unsubstantiated data, and ban TiO2 for all food uses rather than recommend additional safety data be gen- erated to understand the actual risks of continued use of TiO 2 , if any. This is the normal process undertaken by EFSA when a data gap exists. However, EFSA did not give the industry the opportunity to provide addi- tional data to address any uncertainties in this case. If they had, the industry would have provided the data to resolve any uncertainties. Assessment by global regulators The United Kingdom's Scientific Advisory Committee on Toxicity of Chemicals in Food, Consumer Products, and Environment (COT) highlighted several incon- sistencies between the underlying dataset and the conclusions drawn by EFSA and reported that the weight of evidence did not support such conclusions. The Committee on Mutagenicit y (COM) also ques- tioned the quality/robustness of the data used by the EFSA panel and did not agree with the overall con- clusions on the genotoxicity of E171. They considered that a more reliable dataset would be required before any conclusions could be drawn on the mutagenicity of TiO 2 particles (4). Further, Health Canada have also recently re-eval- uated TiO 2 and did not identify any compelling health concerns on the use of TiO 2 as a food additive. They concluded that the adverse effects which have been proposed to be associated with oral exposure of TiO 2 mostly derive from non-standard studies that admin- istered homogenized suspensions of ultrasonically dispersed particles and that such preparations do not represent TiO 2 as a constituent of food. The WoE suggests the data gaps in the available studies are not significant enough to warrant a more precautionary approach currently (5). In September 2022, FSANZ, located in Australia/ New Zealand, published their review of the safety of TiO 2 as a food additive. Their review found that "there is currently no evidence to suggest dietar y exposure to food-grade titanium dioxide is a concern for human health" (6). Finally, the US FDA recently communicated to the TDMA that it had reviewed the findings of the EFSA 2021 opinion and noted that the opinion confirms no general or organ toxicity, as well as no effects on repro- ductive and developmental toxicity. Therefore, FDA continues to allow the use of TiO 2 as a food additive (7). The full US FDA statement follows: "The FDA reviewed the findings of EFSA's 2021 Opinion on titanium dioxide. The FDA notes that EFSA's 2021 Opinion continued to confirm no general and organ toxicity, as well as no effects on reproductive and developmental toxicity. In its 2021 Opinion, EFSA noted that it could not rule out genotoxicity and included genotoxicity tests on titanium dioxide nanomaterials. Some of the genotoxicity tests included test materials not representative of the color ad- ditive, and some tests included administration routes not relevant to human dietary exposure. The available safety studies do not demonstrate safety concerns connected to the use of titanium dioxide as a color additive. The FDA continues to allow for the safe use of titanium dioxide as a color additive in foods generally according to the spec- ifications and conditions, including that the quantity of titanium dioxide does not exceed 1% by weight of the food, found in FDA regulations at 21 CFR 73.575." (7) Global regulators who have done a thorough sci- entific review of all the credible data are coming to a different conclusion than what is contained in the EFSA opinion that triggered the ban of E171 in Europe. Based on these additional scientific safety reviews made by major globa l reg ulator y agencies, EFSA and the EC should reconsider their position on TiO 2 for food uses because there are no safety concerns which have been identified that justif y such a ban, in the author's opinion. Globally, the FAO/World Health Organization Joint Expert Committee on Food Additives (JECFA), a group of world-class toxicology experts from around the world, has launched a call for data for its own re-eval- uation of TiO 2 in food, in response to the 2021 EFSA opinion (8). The re-evaluation of E171 was added to JECFA's priority list during the 52nd Codex Commit- tee on Food Additives (CCFA) meeting, held virtually in September 2021, to minimize any further disrup- tion to international trade expected to be caused by the actions of the EC. JECFA will be doing their re- view of E171 during 2023 and early 2024 when they are expected to then provide their JECFA Opinion on