By Mike Montemarano, Associate Editor11.02.23
Titanium Dioxide (TiO2), a popular food additive in dietary supplements, is coming under scrutiny due to controversial, preclinical evidence of potential genotoxicity.
TiO2 is used primarily in the nutraceuticals industry as a whitening or opacity agent in capsules and tablets, which can help prevent UV- and light-based degradation of internal active ingredients.
It was fully phased out of products in the EU following a ban instituted by the European Food Safety Authority (EFSA) a few years ago.
Recently, TiO2 was removed from a list of food additives that eventually were banned in California, in a bill dubbed the “California Food Safety Act,” though the reason it was spared from the ban wasn’t included in the summary of amendments.
Following this development, the Environmental Defense Fund and several other organizations called for a federal ban on titanium dioxide in foods in a Citizen Petition to FDA.
Many stakeholders in the industry, and most regulatory bodies, have posited that TiO2 is safe for use in food under normal conditions, or conditions respective to regulations.
Calls persist for more caution in the treatment of common additives which were approved decades ago, especially for those appearing in the Environmental Working Group’s “Dirty Dozen Guide,” which includes nitrates/nitrites, potassium bromate, propyl paraben, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), synthetic food dye, artificial sweeteners, and heavy metals.
In that same year, the Netherlands Food and Consumer Product Safety Authority (NVWA) issued an opinion that TiO2 nanoparticles, which make up under 50% of its constituent particles, could have potential genotoxic properties, and accumulate in the bloodstream. The authority also noted that all animal oral administration studies pointed to tumor formation risk, though the animal data could only be extrapolated to humans “to a limited degree,” and “no dose-response can be established” from present knowledge.
EFSA, in its updated opinion, also cited concerns that the minimum size a TiO2 nanoparticle would need to be to ensure no genotoxic properties couldn’t be determined, and ultimately, evidence isn’t sufficient on how nanoparticles might accumulate in the body.
FDA initially approved of the use of TiO2 in 1966 under the condition that it didn’t exceed 1% of food weight as an ingredient, which still stands today. It was last reviewed for safety in food by the agency in 1973, and, according to the petitioners, FDA’s approval was based on a consensus at that time that it can’t accumulate in the body.
Ultimately, the organizations hope the petition will force FDA to provide the public with the first update in a formal capacity since 1973.
Based on EFSA’s conclusions, “The FDA should have conducted a formal and transparent reassessment of the evidence, but it did not,” said Tom Neltner, senior director, safer chemicals for the Environmental Defense Fund. “As a result, we now submit this petition to force that review and hope the agency can meet the required 180-day deadline for a decision, as laid out in the statute.”
While FDA hasn’t yet conducted a follow-up review on titanium dioxide in recent memory, plenty of work has been done on an international level, CHPA noted. A 2022 review by the UK Food Standards Agency (FSA) concluded that there were no safety issues, noted Duffy MacKay, senior vice president of dietary supplements at CHPA. “The FSA considered that the EU conclusion was highly risk-averse and based on weak scientific evidence and instead set guidelines regarding the maximum allowable levels of TiO2 in food and dietary supplements, ensuring its safe consumption.”
Similarly, reviews by Health Canada and Food Standards Australia New Zealand (FSANZ) each concluded in 2022 that there is no evidence that TiO2 is a concern for human health. While titanium dioxide breaks down into nanoparticles, some studies used forms of titanium dioxide which weren’t acceptable for use in food, while others broke food-grade titanium dioxide down into particles that wouldn’t be typically found in real-world settings. Dietary studies suggest nanoparticles are absorbed minimally with no adverse health consequences, both agencies noted.
FDA has no apparent plans to make sudden changes around titanium dioxide. In 2021, it communicated to the Titanium Dioxide Manufacturers Association (TDMA) that it reviewed the findings informing the EFSA ban and found no data suggesting safety issues under present conditions of use.
Alternatives to titanium dioxide present plenty of their own problems. “The removal of this ingredient would require extensive reformulation and testing, which would lead to increased costs for manufacturers and potentially reduced consumer choices. Moreover, the use of alternative options may introduce their own set of safety concerns,” said MacKay.
An industry-wide switch to alternative colorants would also create major supply chain issues due to the spike in demand, resulting in increased costs and material shortages.
Beyond the fact that a sizable portion of the industry would need to engage in costly reformulation, product redesign, stability studies, and new label production, companies selling products internationally would have added costs associated with new product registrations, MacKay noted.
As a result of all this, finished products would be more expensive, and loss of business would be expected, MacKay concluded.
“While EFSA’s opinion was questionable and the titanium dioxide ban is currently only applicable in the EU—the UK, for instance, has no plans to follow suit—it has undoubtedly further fueled the conversations around the safety of titanium dioxide and its place in food supplement applications across the globe,” Lamps said. “Even though TiO2 remains a permissible food additive in the U.S., consumer expectations around supplement safety are shifting. Consumers increasingly prioritize unquestionable safety, particularly as they gravitate toward clean-label supplements. This shift in consumer preference is likely to impact the perceived acceptability of TiO2 in the U.S. dietary supplement market, and beyond.”
Lamps said that it remains to be seen whether more additives like those in EWG’s “Dirty Dozen” or others might be placed in similar crosshairs soon, “It’s hugely important that brands and supplement manufacturers meet all necessary regulation requirements, and keep abreast of any changes and updates as they happen.”
One issue is that it may set a precedent in which several valuable additives are hastily banned due to small degrees of uncertainty. Several reviews and scientific studies have reaffirmed TiO2’s safety within established regulatory limits, he noted..
“There is overwhelming consensus among trusted regulatory authorities and scientific bodies that strongly disagrees with the conclusion made by EFSA. The adoption of EFSA’s precautionary approach without scientific justification would disregard the breadth of accumulated scientific research spanning several decades.”
State bans on additives could clearly interfere with FDA’s function of enforcing centralized standards, MacKay noted.
While TiO2 was off the hook in the California Food Safety Act, similar pieces of legislation are seeking to ban TiO2 and other FDA-approved additives in other states like New Jersey (A5436) and New York (SB 6055/A6424), noted Carlos Gutierrez, vice president of state and local government affairs at CHPA.
CHPA formally removed its opposition to theCalifornia Food Safety Act once TiO2 was removed from the legislation, but concerns persist that state bills will continue to target ingredients, according to Gutierrez.
“This is an issue we’ve seen former FDA officials speak on recently,” MacKay noted, pointing to an op-ed written by Frank Yiannas, former FDA deputy commissioner of food policy and response. “Without relying on a strong, science-driven federal food safety agency, our country is left with a state-by-state patchwork of different, emerging regulatory standards that would weaken our nation’s food system and food safety efforts. Our nation is better when each state can help feed the rest of the states with a uniform standard of safe, available food.”
“The most important priority is consumer and product safety,” Gutierrez continued. “Industry relies on FDA to maintain a strong, science-driven federal food safety agency. It is not sustainable for consumers or industry to follow the priorities of individuals and groups like EDF that try to ban specific foods and ingredients using weak science, by advocating for state laws and petitioning FDA. The EDF should have recognized that TiO2 had already been recently reviewed by other international regulators with similar food safety frameworks and that FDA’s limited resources could have been used more efficiently than on a duplicative scientific review.”
TiO2 is used primarily in the nutraceuticals industry as a whitening or opacity agent in capsules and tablets, which can help prevent UV- and light-based degradation of internal active ingredients.
It was fully phased out of products in the EU following a ban instituted by the European Food Safety Authority (EFSA) a few years ago.
Recently, TiO2 was removed from a list of food additives that eventually were banned in California, in a bill dubbed the “California Food Safety Act,” though the reason it was spared from the ban wasn’t included in the summary of amendments.
Following this development, the Environmental Defense Fund and several other organizations called for a federal ban on titanium dioxide in foods in a Citizen Petition to FDA.
Many stakeholders in the industry, and most regulatory bodies, have posited that TiO2 is safe for use in food under normal conditions, or conditions respective to regulations.
Calls persist for more caution in the treatment of common additives which were approved decades ago, especially for those appearing in the Environmental Working Group’s “Dirty Dozen Guide,” which includes nitrates/nitrites, potassium bromate, propyl paraben, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), synthetic food dye, artificial sweeteners, and heavy metals.
EFSA Ban
EFSA, through its food additives panel, concluded that TiO2 was safe in a 2016 review. Per the request of the European Commission, the agency conducted a follow-up review to address data gaps in 2019.In that same year, the Netherlands Food and Consumer Product Safety Authority (NVWA) issued an opinion that TiO2 nanoparticles, which make up under 50% of its constituent particles, could have potential genotoxic properties, and accumulate in the bloodstream. The authority also noted that all animal oral administration studies pointed to tumor formation risk, though the animal data could only be extrapolated to humans “to a limited degree,” and “no dose-response can be established” from present knowledge.
EFSA, in its updated opinion, also cited concerns that the minimum size a TiO2 nanoparticle would need to be to ensure no genotoxic properties couldn’t be determined, and ultimately, evidence isn’t sufficient on how nanoparticles might accumulate in the body.
Call for a Federal Ban
Earlier this year, a coalition of five public health advocacy organizations comprised of the Environmental Working Group, Environmental Defense Fund, Center for Science in the Public Interest, Center for Food Safety, and Center for Environmental Health petitioned FDA to revoke its approval of TiO2 in food.FDA initially approved of the use of TiO2 in 1966 under the condition that it didn’t exceed 1% of food weight as an ingredient, which still stands today. It was last reviewed for safety in food by the agency in 1973, and, according to the petitioners, FDA’s approval was based on a consensus at that time that it can’t accumulate in the body.
Ultimately, the organizations hope the petition will force FDA to provide the public with the first update in a formal capacity since 1973.
Based on EFSA’s conclusions, “The FDA should have conducted a formal and transparent reassessment of the evidence, but it did not,” said Tom Neltner, senior director, safer chemicals for the Environmental Defense Fund. “As a result, we now submit this petition to force that review and hope the agency can meet the required 180-day deadline for a decision, as laid out in the statute.”
Counterpoints
In comments submitted in response to the petition to ban titanium dioxide, the Consumer Healthcare Products Association (CHPA) said that evidence supporting the safety of TiO2 is substantial, while evidence to the contrary is of relatively low quality.While FDA hasn’t yet conducted a follow-up review on titanium dioxide in recent memory, plenty of work has been done on an international level, CHPA noted. A 2022 review by the UK Food Standards Agency (FSA) concluded that there were no safety issues, noted Duffy MacKay, senior vice president of dietary supplements at CHPA. “The FSA considered that the EU conclusion was highly risk-averse and based on weak scientific evidence and instead set guidelines regarding the maximum allowable levels of TiO2 in food and dietary supplements, ensuring its safe consumption.”
Similarly, reviews by Health Canada and Food Standards Australia New Zealand (FSANZ) each concluded in 2022 that there is no evidence that TiO2 is a concern for human health. While titanium dioxide breaks down into nanoparticles, some studies used forms of titanium dioxide which weren’t acceptable for use in food, while others broke food-grade titanium dioxide down into particles that wouldn’t be typically found in real-world settings. Dietary studies suggest nanoparticles are absorbed minimally with no adverse health consequences, both agencies noted.
FDA has no apparent plans to make sudden changes around titanium dioxide. In 2021, it communicated to the Titanium Dioxide Manufacturers Association (TDMA) that it reviewed the findings informing the EFSA ban and found no data suggesting safety issues under present conditions of use.
What’s at Stake?
Advocates for the use of titanium dioxide in supplements, such as CHPA and others, claim that it is irreplaceable from both a cost and performance standpoint, and banning it would result in products with altered appearance and reduced stability.Alternatives to titanium dioxide present plenty of their own problems. “The removal of this ingredient would require extensive reformulation and testing, which would lead to increased costs for manufacturers and potentially reduced consumer choices. Moreover, the use of alternative options may introduce their own set of safety concerns,” said MacKay.
An industry-wide switch to alternative colorants would also create major supply chain issues due to the spike in demand, resulting in increased costs and material shortages.
Beyond the fact that a sizable portion of the industry would need to engage in costly reformulation, product redesign, stability studies, and new label production, companies selling products internationally would have added costs associated with new product registrations, MacKay noted.
As a result of all this, finished products would be more expensive, and loss of business would be expected, MacKay concluded.
Alternative Dosage Forms
Meanwhile, Lonza proactively launched TiO2-free dosage forms in 2019 ahead of the EFSA ban, including a semi-opaque plant-based capsule which uses calcium carbonate as a TiO2 alternative, and a white hard gelatin capsule which uses crystalized salts as a novel opacifying technology. The viability of each product was determined in internal head-to-head comparison studies, “offering bright white color that consumers expect, without compromising on safety or functionality,” said Julien Lamps, associate director of global product management at Lonza Capsules & Health Ingredients.“While EFSA’s opinion was questionable and the titanium dioxide ban is currently only applicable in the EU—the UK, for instance, has no plans to follow suit—it has undoubtedly further fueled the conversations around the safety of titanium dioxide and its place in food supplement applications across the globe,” Lamps said. “Even though TiO2 remains a permissible food additive in the U.S., consumer expectations around supplement safety are shifting. Consumers increasingly prioritize unquestionable safety, particularly as they gravitate toward clean-label supplements. This shift in consumer preference is likely to impact the perceived acceptability of TiO2 in the U.S. dietary supplement market, and beyond.”
Lamps said that it remains to be seen whether more additives like those in EWG’s “Dirty Dozen” or others might be placed in similar crosshairs soon, “It’s hugely important that brands and supplement manufacturers meet all necessary regulation requirements, and keep abreast of any changes and updates as they happen.”
Will State Bills Undermine FDA?
MacKay noted there is more at stake than meets the eye with activist organizations pushing for bans on food additives.One issue is that it may set a precedent in which several valuable additives are hastily banned due to small degrees of uncertainty. Several reviews and scientific studies have reaffirmed TiO2’s safety within established regulatory limits, he noted..
“There is overwhelming consensus among trusted regulatory authorities and scientific bodies that strongly disagrees with the conclusion made by EFSA. The adoption of EFSA’s precautionary approach without scientific justification would disregard the breadth of accumulated scientific research spanning several decades.”
State bans on additives could clearly interfere with FDA’s function of enforcing centralized standards, MacKay noted.
While TiO2 was off the hook in the California Food Safety Act, similar pieces of legislation are seeking to ban TiO2 and other FDA-approved additives in other states like New Jersey (A5436) and New York (SB 6055/A6424), noted Carlos Gutierrez, vice president of state and local government affairs at CHPA.
CHPA formally removed its opposition to theCalifornia Food Safety Act once TiO2 was removed from the legislation, but concerns persist that state bills will continue to target ingredients, according to Gutierrez.
“This is an issue we’ve seen former FDA officials speak on recently,” MacKay noted, pointing to an op-ed written by Frank Yiannas, former FDA deputy commissioner of food policy and response. “Without relying on a strong, science-driven federal food safety agency, our country is left with a state-by-state patchwork of different, emerging regulatory standards that would weaken our nation’s food system and food safety efforts. Our nation is better when each state can help feed the rest of the states with a uniform standard of safe, available food.”
“The most important priority is consumer and product safety,” Gutierrez continued. “Industry relies on FDA to maintain a strong, science-driven federal food safety agency. It is not sustainable for consumers or industry to follow the priorities of individuals and groups like EDF that try to ban specific foods and ingredients using weak science, by advocating for state laws and petitioning FDA. The EDF should have recognized that TiO2 had already been recently reviewed by other international regulators with similar food safety frameworks and that FDA’s limited resources could have been used more efficiently than on a duplicative scientific review.”
