Unlike in Europe, the FDA has been reluctant to give nanomaterials a single, overarching definition. Explaining FDA’s approach to regulating nanotech products last month in a guest column for Science, Commissioner Margaret A. Hamburg, M.D., Ph.D., reiterated, “although one definition for nanomaterial may offer meaningful guidance in one context, that definition may be too narrow or broad in another. For this reason, FDA is not at this time adopting a regulatory definition of nanotechnology.” FDA issued a draft guidance on the subject last year.
The EU doesn’t share Dr. Hamburg’s reluctance, however. In October the EC published a recommended definition of nanomaterials that alarmed many. The commission defines nanomaterials as materials that meet any of three criteria:
- At least 50% of the particles have one external dimension between 1 nm and 100 nm;
- The material has a surface area by volume greater than 60 m2 / cm3.
- The substance appears on a list that captures materials that would otherwise fall outside the definition.
The dimension standard echoes FDA’s draft guidance for nanomaterials published last year, under which “at least one dimension” must be between 1 nm and 100 nm. The U.S. agency would also check whether nanomaterials exhibit physical or chemical properties or biological effects attributable to its dimensions, even if they fall outside the nanoscale range, going up to one micrometer.
“Implementing the proposed definition will add unnecessary burden for companies, leading to added costs and less efficient use of resources,” Cefic, the European Chemical Industry Council, said in a statement. Cefic criticized the EC’s definition as “too broad in scope and therefore difficult to integrate into existing legislation in a meaningful way.”
Not necessarily, Jeremy Warren, CEO of NanoSight, told GEN. Because nanotech numbers require precision to be enforceable, a count-based threshold like the 50% standard in relation to the size fits the bill better than a percentage by weight, since chemical reactivity increases per mass dose for smaller particles.
“We welcome this definition as a starting point to deliver regulation on potential toxicity,” Warren said. “There is much research work to be done, and having this definition, this building block in place, will surely enable government investment in research to go the next steps, from simple physical parameters to the far more complex challenges of bio-availability and bio-interaction at the heart of toxicology.”
Warren acknowledges that he has an interest in the commission adopting a number-based standard since NanoSight applies characterization technology in its nanoparticle measurement instruments like the NTA (Nanoparticle Tracking Analysis) in combination with occasional electron microscopy to inform the bottom end of the 1–100 nm range.
EC’s decree has been criticized by the Nanotechnology Industries Association (NIA), saying that it would undermine the European free market. “Instead of a business development possibility, it is much more a threat of costly product compliance,” Steffi Friedrichs, D.Phil., NIA’s director general, told GEN.
“And that means, obviously, you have some companies that are only making a very small margin on moving from regular materials to nanomaterials that cannot afford now to market product,” Dr. Friedrichs said. “What we estimate, as a rule of thumb, is half of the companies that are now affected by this would not have been thinking of their material as a nanomaterial before.” NIA noted that several drugs contain fluorine atoms to increase bioactivity of the API.
The additional cost of the EC’s definition has yet to be quantified. It depends on two key future decisions: Will the commission ultimately allow member states to implement nanoparticle policies or seek to do so itself across Europe? And more importantly, will nanomaterials need to be authorized and registered separately from their larger chemical counterparts as the commission moves to implementation?
Industry, Dr. Friedrichs said, would prefer a nanoparticle standard that uses weight percent, because current equipment is calibrated to measure such weight and because fewer materials would be defined as nanomaterials than under a simpler number-of-particles threshold.
“So far we have mostly seen a marginal increase of nanomaterials being brought onto the market where their larger counterparts have been used before, for no cost increase at all, but a high efficiency and a high functionality increase. Now this sort of thing would obviously not be possible if you then tell the companies that are doing enough that they have to spend extra money for an entirely new safety approval for their materials,” Dr. Friedrichs explained.
The EC defended the number standard by saying it “should cover for the fact that nanomaterials most typically consist of many particles present in different sizes in a particular distribution. Without specifying the number-size distribution, it would be difficult to determine if a specific material complies with the definition where some particles are below 100 nm while others are not,” the commission concluded, citing findings by its Scientific Committee on Emerging and Newly Identified Health Risks.
The commission also wisely warned against using its definition to inhibit nanomaterial use in medicines: “Given the special circumstances prevailing in the pharmaceutical sector and the specialized nano-structured systems already in use, the definition in this recommendation should not prejudice the use of the term nano when defining certain pharmaceuticals and medical devices.”
That, in turn, could touch off further study by the EC about how to account for differences between industries in future regs. FDA, Dr. Hamburg said, doesn’t view nano products as “intrinsically benign or harmful” but expects new nanotechnologies to develop in an “unpredictable, rapid, and unevenly distributed” fashion.
Much, though not all, of the EC definition was quickly adopted by France. As of the first week of May no other European nation had followed France in enacting new nanomaterial laws. The U.K.’s national innovation agency, the Technology Strategy Board, posted on its blog in March that it was developing a U.K. government response on the French decree as well as proposed data requirements for a national nanomaterial reporting initiative.
France made a key change from the EC’s definition by applying its regulations to users of “nanoparticle” substances “in an amount of at least 100 grams per year.” While industry generally prefers a weight standard to a quantity standard for defining nanoparticles—contrary to NanoSight’s Warren—the 100 grams used by France is lighter than what businesses had hoped for.
Warren of NanoSight said the EC’s definition will have a long-term positive effect on corporate giants since it reduces risk as they invest more resources into the segment and because they’re in a better position to deal with new regulations than smaller and medium-sized businesses.
“Because it comes from the European government and because the number of scientists and the scientific committees working on this have consulted so widely and are so eminent and have thought this through, its provenance gives it a lot of weight,” Warren said. He believes that if industry and regulators can get this right, then instead of putting ‘contains nanomaterial’ in the smallest permissible font on a label, industry might put ‘contains nano’ in a bright splash of color, “implying progressiveness, advanced, and useful technology, and above all, trustworthiness.”
For that to happen, however, the commission, and ultimately member nations, must come to a consensus on nanomaterial standards—the industry is unlikely to thrive in a region where one country defines nanomaterials by number and another by weight. Ideally, a single pan-European standard should emerge, as drug reviews have come under the umbrella of the EMA, for example. Regulators should also revisit regulation of naturally occurring nanomaterials to avoid imposing new burdens on industry at a time when Europe’s economies are already struggling to produce.