Variation in the toxicity of inhaled cerium dioxide nanoparticles cannot be explained simply, according to analysis by scientists at BASF and the Dutch National Institute for Public Health and the Environment (RIVM). The results highlight some of the considerations facing German competent authority Baua, which is currently evaluating the substance under REACH.
Six experimental studies published between 2012 and 2017 found adverse effects in rats and mice, following inhalation of the particles. However, the effects found by the most recent of these studies, published in 2017, were markedly less severe.
The studies used nanoforms of cerium dioxide that differed across several parameters, including size, shape and chemical composition. They also used different model species: some used rats, others mice.
The aim of the current analysis, led by Susan Dekkers at RIVM – who also led the 2017 study – was to find relationships between the parameters, or the model species used, and the variations in effects observed in the six studies.
BASF scientists supplied data from additional experimental studies to enable proper comparison of the data in the existing six studies. They conducted the studies for the EU’s NanoMile project, but they are not yet published in peer-reviewed journals.
The scientists found that the variations could not be explained solely in terms of the external exposure, the particle size and the chemical composition.
"Particle size is highly important," they say in a paper published late last year in Inhalation Toxicology, but other physico-chemical properties, such as surface reactivity and surface shape, may influence toxicity.
They also found that rats were more sensitive to the effects than mice.
"This research does indicate that there are differences in toxicity between the different nanoforms of cerium dioxide," Dr Dekkers told Chemical Watch. "However, [these] depend on the dose metrics and post exposure period, which makes it impossible to confirm that one nanoform is more toxic than the others based on the current dataset."
A further study, in which exposure doses were adjusted to control precisely how many particles were deposited in the lungs, and where, would be needed to "confirm absolute differences in toxicity", she adds.
Regulatory context
The European Commission is currently considering how to implement the category 2 carcinogenicity classification that Echa’s Risk Assessment Committee recommended for titanium dioxide. The classification – which covers all forms of the compound – has faced strong opposition from some sectors, including titanium dioxide manufacturers.
According to Rac, the mechanism of toxicity behind it is potentially common to all poorly soluble particles, raising concerns that a wide range of similar compounds, including cerium dioxide, might face similar regulatory action.
The issue – in relation to cerium dioxide, at least – might be cleared up definitively by a large-scale experimental study that BASF is currently conducting, partially funded by the German government. The study involves high numbers of rats and much longer exposure periods compared with others.
However, the multimillion Euro project has been delayed several years. When launched in 2012, the expectation was that the finals results would be available in 2016. In 2017, BASF told Chemical Watch that it expected publication in the second quarter of 2018.
Birgit Lau from the company told Chemical Watch today that investigations were complete, the final report was being reviewed and its completion due "within the next months".
"Such a comprehensive long-term inhalation study has not been performed before," she added, regarding the timing of the report. "Several tens of thousands of histological slides had to be examined. The evaluation is correspondingly time-consuming."
