The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO
2
nanoparticles (
NP
s) and data from an extended one‐generation reproductive toxicity (
EOGRT
) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO
2
NP
s < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO
2
particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO
2
NP
s (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the
EOGRT
study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO
2
NP
s, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO
2
particles have the potential to induce
DNA
strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico‐chemical properties of TiO
2
particles and the outcome of either
in vitro
or
in vivo
genotoxicity assays. A concern for genotoxicity of TiO
2
particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO
2
particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut‐off value for TiO
2
particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO
2
NP
s. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.
To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers in this symposium presented their research results on different neurotoxic chemicals as they relate to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to methylmercury and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-to-moderate dose human equivalent gestational lead exposure produced late-onset obesity, and motor and coordination dysfunction only in male mice. Didima de Groot discussed the role of caloric restriction and/or high fat diets during gestation and/or postnatal development in mediating the metabolic and neurotoxic effects of developmental methylmercury exposure in rats. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following 24 hour exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment.
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