Click here to get more.
By Rajendran (Raj) Arunagiri
The EU regularly evaluates the safety of all food and consumer products, including titanium dioxide (TiO2) used as a food additive and pharmaceutical excipient. Food-grade TiO2, which is commonly used as a whitening and brightening agent in various food products like chewing gum, mayonnaise, candies, and chocolates, is identified and labeled as E171. It is also identified as INS171 in the International Numbering System for Food Additives.
In March , the Commission requested an updated opinion from the European Food Safety Authority (EFSA) on titanium dioxide's safety. Although EFSA's opinion found no immediate safety concerns, it noted data gaps, especially regarding particle size, which can affect its toxicological properties. The new EFSA opinion from May doesn't definitively label E171 as harmful but doesn't dismiss health risks like genotoxicity. Since the safety cannot be confirmed, the European Commission (EC) banned titanium dioxide (E171) as a food additive in the EU, starting with a six-month phasing out period from Feb. 7, , to Aug. 7, , after which a full ban applied. Following the ban in food application, the EC published the following (clause 17 and 18) in its Regulation (EC) No. /:1
It is of critical importance that the pharmaceutical industry makes any possible efforts to accelerate the research and development of alternatives that would be used as a replacement for titanium dioxide (E 171) in medicinal products, and to submit the necessary variation to the terms of the marketing authorisations concerned. In the absence of such efforts, competent authorities may request the concerned stakeholders to submit objective and verifiable reason explaining the non-feasibility of the replacement.
The Commission is committed to review the necessity to maintain titanium dioxide (E 171) or otherwise delete it from the Union list of food additives for exclusive use as a colour in medicinal products within three years after the date of entering into force of this Regulation. This review should be based on an updated assessment of the EMA to be performed before 1 April . It should take into account the progress made during this period to develop alternatives to titanium dioxide (E 171) in medicinal products both for new products and for replacing it in authorised products, and possible impacts on quality, safety and efficacy, as well as on the availability of medicinal products. Where replacement of titanium dioxide (E 171) in medicinal products has not taken place or been initiated within this period, only objective verifiable reasons related to the lack of feasibility of its replacement should be taken into account.
Given the EU&#;s scrutiny on TiO2, this article summarizes the technical purpose of TiO2, the impact of any potential ban in EU, and opinions expressed by regulators across the globe. This article will also highlight the Nov. 24, , opinion from the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) Joint Expert Committee on Food Additives (JECFA).2
In pharmaceuticals, TiO2 is commonly employed as an excipient in oral solid dosage forms like tablets, capsules, and granules for oral solutions, as well as in semi-solid forms for veterinary medications. It is estimated that at least 50,000 formulations contain titanium dioxide, making this excipient vital for pharma.
TiO2 has functionalities that need to be defined on a case-by-case basis. However, the following are the general uses of TiO2 as an excipient.
Coloring Agent: Like its use in the food industry, TiO2 is used as a coloring agent in pharmaceuticals. It can provide a white or opaque color to tablets, capsules, creams, ointments, and suspensions.
UV Protection: Titanium dioxide nanoparticles are sometimes used in sunscreens and topical medications for their ability to provide UV protection. They act as physical blockers, reflecting and scattering UV rays to protect the skin.
Coating Agent: TiO2 is used as a coating agent for tablets and capsules to enhance their appearance, protect them from moisture, improve swallowability, and control the release of the active ingredients.
Enhancing Drug Stability: In certain formulations, titanium dioxide can contribute to the stability of drugs by protecting them from degradation caused by light, moisture, or chemical reactions.
An alternative for TiO2 should meet the following criteria:
But currently there is no single alternative for TiO2 that is a drop-in replacement.
Possible alternatives identified include calcium carbonate, talc, and starch, but they have drawbacks like difficulties in obtaining thin films and elemental impurity risks.
Excipient manufacturers are working on TiO2-free formulations for tablet coatings and capsule shells, although these alternatives are not widely used yet, and information on their suitability is limited.
Replacing TiO2 with other pigments like iron oxides may lead to color differences and formulation adjustments, potentially affecting patient acceptability and compliance.
From a technical standpoint, finding alternatives to TiO2-containing coatings is feasible but challenging. Each medicinal product would require individual assessment and reformulation, which could lead to medicine shortages or discontinuations, especially for niche products or those with limited market share.
The potential removal of TiO2 could impact medicine quality, safety, and efficacy due to reformulation challenges, potential bioequivalence issues, and the need for alternative colorants to comply with regulations.
Indirect impacts include one-by-one reformulation, supply chain disruptions, and potential shortages caused by prioritization or manufacturing challenges.
While it is extremely important to address any safety concerns of an excipient, banning the material that is used in several thousands of formulations would impact patients&#; health. However, this issue should create a sense of urgency to find new solutions that have no concerns, however remote, about safety.
Several international regulatory bodies, including the United Kingdom&#;s Food Standards Agency (FSA), Health Canada, Food Standards Australia New Zealand (FSANZ), and the U.S. FDA, have different opinions than the EFSA when it comes to TiO2 safety.
FDA notes that some of the genotoxicity tests considered in the EFSA assessment included test materials not representative of the color additive, and some tests included administration routes not relevant to human dietary exposure. FDA did not identify concerns related to potential genotoxicity based on the data available and noted that TiO2 did not cause cancer in National Toxicology Program (NTP) carcinogenicity studies.
On balance, the Committee on Toxicity of Chemicals in Food, consumer Products and the Environment (COT) considered that the weight of evidence did not support the conclusions drawn by EFSA. The Committee also agreed with the comments of the Committee on Mutagenicity of Chemicals in Food, consumer Products and the Environment (COM) with regard to risk communication that &#;As it stands the conclusion is highly risk adverse based on the weak evidence available, and it might create unnecessary concern to the public.&#; They considered that care should be taken when expressing the conclusions as they might cause unnecessary concern and they were uncomfortable with EFSA&#;s binary communication on a data set with a lot of uncertainties.
Overall, the Food Directorate's comprehensive review of the available science of TiO2 as a food additive showed no evidence of cancer or other adverse effects in mice and rats exposed to high concentrations of food-grade TiO2 (long-term or lifetime study), no changes to DNA in various animal studies, and no adverse effects on reproduction, development, immune, gastrointestinal or nervous systems, or general health when rats were exposed from preconception to adulthood.
In summary, the Food Directorate's position is that there is no conclusive scientific evidence that the food additive TiO2 is a concern for human health. This is based on a review of the available scientific data relevant to food uses of TiO2. However, the directorate will continue to monitor the emerging science on the safety of TiO2 as a food additive and may revisit its position if new scientific information becomes available.
FSANZ has completed a review of the safety of titanium dioxide (TiO2) as a food additive. The review found there is currently no evidence to suggest dietary exposure to food-grade titanium dioxide is a concern for human health.
Other regulatory bodies such as India&#;s Central Drugs Standard Control Organisation (CDSCO), China&#;s National Medical Products Administration (NMPA), and Japan&#;s Pharmaceuticals and Medical Devices Agency (PMDA) have not commented much on the subject.
The Joint Expert Committee on Food Additives (JECFA),2 in collaboration with the WHO and the Food and Agriculture Organization (FAO), conducted an assessment on the health effects of TiO2 as a food additive. The key findings of the JECFA assessment are as follows:
Regulatory agencies such as EFSA have a critical role to play in human health. Perceived safety concerns about TiO2 highlighted by EFSA should be given careful consideration, and further research needs to be done to reach conclusions on the safety of TiO2. However, banning TiO2&#;s use in pharma without an alternative identified would also put patients&#; health at risk. On one hand, the pharma industry is justified in arguing against a ban until a replacement is found, but on the other hand the pharma industry should increase the sense of urgency to find an alternative material to potentially replace TiO2. Concerns expressed by EFSA should be used to disrupt the status quo and look for alternatives for TiO2.
References
About The Author:
Rajendran (Raj) Arunagiri has been in the pharma industry for a decade and has successfully developed and launched a new excipient. He is a co-author of technical articles and is an invited speaker at conferences focused on excipients and drug delivery. He specializes in the area of poorly soluble APIs and modified release. Arunagiri welcomes you to reach out to him for questions, comments, and collaboration ideas at .
Titanium dioxide is a food additive that can be found in over 3,000 different products in EWG&#;s Food Scores database.
Most commonly used in candy, it can also be found in salad dressings, chewing gum, ice cream, frozen pizzas, drink and jello mixes and many other food categories. Titanium dioxide creates a smooth finish and adds shine and brightness to other colors.
This food chemical has been used in food for more than half a century, but recent studies show it may be harmful.
Health effects
For years scientists have raised concerns about the potential toxicity of titanium dioxide.
In , the European Food Safety Authority, or EFSA, assessed titanium dioxide and determined that the evidence available at the time didn&#;t conclusively point to any health problems for consumers.
But in , EFSA reevaluated titanium dioxide to consider the impacts of its nanoparticle. After considering more studies, EFSA concluded that nanoparticle-size titanium dioxide can accumulate in the body, break DNA strands and cause chromosomal damage.
European food safety regulators have since labeled titanium dioxide as no longer safe for human consumption, due to its potential toxicity.
Animal studies show exposure to titanium dioxide is linked to immunotoxicity, inflammation and neurotoxicity.
A European ban of titanium dioxide in food took effect in , but it is still legal for use in food in the U.S.
Regulatory action
Titanium dioxide remains in many food products in this country because of regulatory folly by the Food and Drug Administration, which allows problematic food ingredients to remain undetected and unreviewed.
The FDA is reviewing the safety of titanium dioxide in response to an April petition from EWG and other environmental and public health groups. This is the FDA&#;s first comprehensive review of titanium dioxide since .
Earlier this year, a bill was introduced in the California legislature to ban the manufacture, sale and distribution of foods in the state containing titanium dioxide, along with four other harmful food chemicals.
A.B. 418, authored by Assemblymember Jesse Gabriel (D-San Fernando Valley), will soon receive its final votes in the state legislature. If the bill is signed into law, the Golden State would be the first in the nation to ban these toxic chemicals from bread, salad dressings, frozen pizzas and other popular food items.
Avoiding exposure
For those wishing to limit or avoid exposure to titanium dioxide in foods, there are some steps you can take.
Check food product labels and avoid those with titanium dioxide. Food companies must list titanium dioxide on packaged food ingredient labels. In some instances, it may simply be listed as &#;artificial color&#; or &#;color added.&#;
Goto Pairs Horses Chemical to know more.
Consult EWG&#;s
Food Scores
database to find products without titanium dioxide. When you&#;re on the go, use our
Healthy Living app
to find products without toxic chemicals.
Choose packaged foods that are certified organic, whenever possible. These products must meet strong standards that protect consumers from exposure to potentially harmful additives. Certified organic foods cannot contain artificial colors such as titanium dioxide.
Avoid ultra-processed foods whenever possible. Many contain
concerning ingredients
in addition to titanium dioxide.
Titanium dioxide in sunscreen
Sunscreens made with mineral active ingredients, like titanium dioxide and zinc oxide, generally score well in EWG&#;s Guide to Sunscreens. They provide strong sun protection with few health concerns and don&#;t easily break down in the sun.
They are the only two sunscreen ingredients classified by the FDA as safe and effective. And though titanium dioxide is usually used in mineral sunscreens in the form of nanoparticles, evidence suggests that few, if any, particles penetrate the skin.
But a chemical&#;s safety when it&#;s used externally is not always the same as when it&#;s ingested. Different uses of the same ingredient may cause very different health outcomes.
Contact us to discuss your requirements of titanium dioxide powder. Our experienced sales team can help you identify the options that best suit your needs.