“…El‐Din et al. (2019) (scoring 4 for NSC) examined the effect of exposing rats to TiO 2 NPs (0, 1,200 mg/kg bw per day) by gavage for 90 days on morphology of the heart ventricles. The authors reported histological changes in the myocardium of the treated group.…”
Section: Assessmentmentioning
confidence: 99%
“…The Panel considered that there were no adverse effects on clinical chemistry parameters in rats exposed by gavage to TiO 2 NPs at doses up to 100 mg/kg bw per day for 14 days (Vasantharaja et al., 2015). A potential adverse effect on the heart was reported after subchronic (90‐day) exposure to 1,200 mg TiO 2 NPs/kg bw per day, but due to limited reporting no conclusion could be drawn (El‐Din et al., 2019). Gavage administration of 24,000 mg TiO 2 (11% NPs)/kg bw per day for 29 days, without demonstrating of internal exposure, had no adverse effects on the endpoints required by the OECD TG 407 testing guideline (Warheit et al., 2015a).…”
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.
“…El‐Din et al. (2019) (scoring 4 for NSC) examined the effect of exposing rats to TiO 2 NPs (0, 1,200 mg/kg bw per day) by gavage for 90 days on morphology of the heart ventricles. The authors reported histological changes in the myocardium of the treated group.…”
Section: Assessmentmentioning
confidence: 99%
“…The Panel considered that there were no adverse effects on clinical chemistry parameters in rats exposed by gavage to TiO 2 NPs at doses up to 100 mg/kg bw per day for 14 days (Vasantharaja et al., 2015). A potential adverse effect on the heart was reported after subchronic (90‐day) exposure to 1,200 mg TiO 2 NPs/kg bw per day, but due to limited reporting no conclusion could be drawn (El‐Din et al., 2019). Gavage administration of 24,000 mg TiO 2 (11% NPs)/kg bw per day for 29 days, without demonstrating of internal exposure, had no adverse effects on the endpoints required by the OECD TG 407 testing guideline (Warheit et al., 2015a).…”
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.
“…Acute inflammatory responses in mice treated with 2.5, 5.0, and 10.0 mg/m 3 TiO₂ NPs [ 48 ]. Myocardial toxicity [ 35 ] and pathological lesions of the liver, spleen, kidneys, and brain [ 49 ].…”
Section: Discussionmentioning
confidence: 99%
“… Figure 2 Transmission electron microscopy (TEM) of the m-TiO 2 NPs with a particle size of <100 nm. Normal saline: 0.9% NaCl solution from a local pharmacy [ 35 ]. …”
Section: Methodsmentioning
confidence: 99%
“…They were caged separately. Saline was used as a vehicle to suspend m-TiO 2 NPs and the suspension was sonicated [ 35 ]for 15 min before the treatment. Animals were weighed before the dose administration.…”
Modified titanium dioxide (m-TiO
2
NPs) is a novel photocatalytic nanomaterial. Its level of toxicity was evaluated to be used in photodynamic treatment for cervical cancer. In the toxicity studies (Irwin test, acute and repeated doses (10 days)), female albino Swiss Webster (CFW) mice, 28 days old were used; the m-TiO
2
NPs was administered in single 300, 600 and 5,000 mg/kg of body weight (b.w) doses injected in the peritoneal zone. No adverse events or mortality were produced. Daily intraperitoneal doses of 300 and 600 mg/kg b.w every 24 h for 10 days did not produce adverse effects or mortality. There were no abnormal clinical signs or behavioral changes (neurological or physiological) in any of the mice. All organs exhibited normal architecture, and histological studies determined that m-TiO
2
NPs does not produce changes in the cells or tissues. Based on the test results, it is concluded that the m-TiO
2
NPs has not a toxic effect in doses equal to or less than 5,000 mg/kg b.w.
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