Slags, ilmenite electrothermal smelting

Endpoint summary

Additional information

Repeated dose toxicity – oral

UGI (Upgraded Ilmenite) consists primarily of a titanate phase (solid solution) most of which is Ti in an oxidised form. Upon ingestion, a low rate of dissolution in the GI tract is assumed, based on the experimental verified inertness of the material in artificial gastric juice. Any material being released from UGI under physiological conditions will be in the form of ionic Ti, which is similarly the case for titanium dioxide: more specifically, the results from in vitro bioaccessibility testing in artificial gastric fluid demonstrate a similar dissolution pattern of UGI and titanium dioxide (see summary reported under point 7.1.1 basic toxicokinetics), thus read-across from repeated dose oral toxicity data on titanium dioxide is considered feasible without any restrictions.

Male and female F344 rats (8-weeks old, 50 animals per group) were fed a diet containing 2% corn oil and 25,000 or 50,000 ppm titanium dioxide for 103 weeks (7 days per week). Groups of male and female B6C3F1 mice (36 days old, 50 animals per group) were fed analogously. With the exception of white faeces, there was no other clinical sign that was judged to be related to titanium dioxide exposure (for detailed information please refer to the endpoint study records reported under section carcinogenicity).

In a 28 -days study male rats were exposed by oral gavage for 29 days to 24,000 mg/kg titanium dioxide particles (test items: H-27201, H-27203), or the vehicle. Under the conditions of this study, the no-observed-effect level for titanium dioxide was 24,000 mg/kg/day for male rats, based on the lack of any adverse effects at this dose.

 

Repeated dose toxicity – inhalation

UGI (Upgraded Ilmenite) consists primarily of a titanate phase (solid solution) most of which is Ti in an oxidised form. Upon inhalation, a low rate of dissolution in the respiratory tract is assumed, based on the experimental verified inertness of the material in artificial respiratory media. Any material being released from UGI under physiological conditions will be in the form of ionic Ti, which is similarly the case for titanium dioxide: more specifically, the results from in vitro bioaccessibility testing in such fluids demonstrate a similar dissolution pattern of UGI and titanium dioxide (see summary reported under point 7.1.1 basic toxicokinetics), thus read-across from repeated dose inhalation toxicity data on titanium dioxide is considered feasible without any restrictions.

Chronic Toxicity Studies with Pigment-Grade titanium dioxide

In 2-year chronic inhalation studies, male and female CD rats were exposed to titanium dioxide (pigment-grade) at concentrations of 10, 50, or 250 mg/m3 for six hours a day, five days a week (Lee et al., 1985). The majority of the titanium dioxide was of respirable size (95% of the particles were less than 10 microns and average particle diameter was about 1.5 microns for high dose group). Survival of the titanium dioxide-exposed animals was comparable to that of the control group. Additionally, these titanium dioxide-exposed animals did not have any compound-related clinical signs of toxicity. Histopathological evaluation showed a significant dose-related increase over controls in the incidence of rhinitis, squamous metaplasia, and tracheitis. The incidence of benign lung tumours and proliferative keratin cysts were significantly increased in the group of rats exposed to the high-dose level of 250 mg/m3 of titanium dioxide. Also observed were dose-related increases in pleurisy, slight collagenized fibrosis associated with cholesterol granulomas, alveoli bronchiolarization, pneumonia, and alveolar cell hyperplasia. The changes observed at the 10 mg/m3 concentration were minimal in severity in comparison to similar effects observed in the controls (except that the alveolar cell hyperplasia was not observed in controls).  The degree of pulmonary fibrosis seen at the two higher levels was slight. In subsequent experimentation (Warheit et al., 1997; summarized below) using these same dosing rates for four weeks, it was demonstrated that high dose animals had substantially increased lung clearance times and sustained inflammation under particle overload.

In a study reported by Muhle et al. (1991), titanium dioxide was used as a negative control dust in a two-year inhalation study with toner particles. Male and female F-344 rats were exposed (6 hr/day, 5 days/week) to 5 mg/m3 titanium dioxide (rutile form) of 1.1 µm MMAD with a respirable fraction of 78%. Bronchoalveolar hyperplasia of Type II pneumocytes was a rare finding in control animals but occurred in 9% of titanium dioxide-exposed animals (Muhle et al., 1995). The principal non-neoplastic lung lesion in titanium dioxide-exposed rats was a minimal to mild fibrosis.

 

Chronic Toxicity Studies with Sub-pigmentary titanium dioxide

Heinrich et al. (1995) exposed female Wistar rats by whole body inhalation to sub-pigmentary titanium dioxide (80% anatase: 20% rutile) at an average concentration of 10 mg/m3 for 24 months followed by 6 months without exposure. The particle size of the titanium dioxide used ranged from 15 to 40 nm with a MMAD of 0.8 mm (agglomerates of sub-pigmentary particles). The mean lifetime of rats were significantly shortened with 90% mortality at the end of the 130-week experiment. At the end of 2-year exposures, body weights of exposed animals were significantly lower than controls. Wet lung weights increased substantially during exposure, progressing with study duration. This was reflected in retained test material in the lungs, which increased from 5 mg/lung to 39 mg/lung from 3 months to 24 months of exposure. Alveolar lung clearance rates were significantly compromised after 3 months of exposure and a 3-month recovery period following 18 months of exposure showed no reversibility of the damage. Bronchioalveolar hyperplasia of moderate to severe grade and slight to moderate interstitial fibrosis of the lungs was present after 2 years of exposure in rats. Exposure of female NMRI mice to sub-pigmentary titanium dioxide under the same conditions as for rats resulted in a significantly decreased lifespan at an inhalation concentration of approximately 10 mg/m3 (Heinrich et al., 1995). Lung wet weights and particle lung burdens increased as for rats. Retained test material in mouse lung was 26 mg/lung after 1 year of exposure as compared with 29 mg/lung for similarly exposed rats. No other pathology related findings were reported for titanium dioxide in this study.

 

Subchronic Inhalation Studies in Other Rodent Species

Subchronic inhalation exposures of rats, mice, and hamsters to either pigmentary or sub-pigmentary titanium dioxide particles at concentrations likely to induce particle overload produced a more severe and persistent pulmonary inflammatory response in rats, as compared with either mice or hamsters. Rats were unique among these three species in the development of progressive fibroproliferative lesions and alveolar epithelial metaplasia (Bermudez et al., 2002 and 2004). Thus, female rats, mice or hamsters were exposed to 10, 50 or 250 mg/m3 concentrations of pigmentary (rutile type) titanium dioxide particles for 6 hours/day, 5 days/week for 13 weeks followed by 4, 13, 26 or 52 weeks of postexposure (46 weeks for hamsters)(Bermudez et al., 2002). Lung and associated lymph node loads of titanium dioxide increased in a concentration-related manner. Retained lung burdens were greatest in mice following exposure, with rats and hamsters displaying similar lung burdens immediately following exposure. Particle retention data indicate that particle overload in the lungs was reached in both rats and mice at the 50 and 250 mg/m3 concentrations. Inflammation was observed in all three species at the two highest concentrations. This inflammation persisted in rats and mice throughout the postexposure recovery period at the highest exposure concentration. In hamsters, inflammatory responses were eventually resolved due to the more rapid clearance of particles from the lung. In rats exposed to the highest concentration (250 mg/m3), pulmonary lesions consisted of epithelial proliferative changes manifested by increased alveolar epithelial cell labelling indices, as evidenced by the results of cell proliferation studies. Associated with these proliferative changes in the rat were increased interstitial particle accumulations and alveolar septal fibrosis. Although rats exposed to 50 mg/m3 developed minimal alveolar cell hypertrophy, accumulation of particle-laden macrophages, and inflammation, no alveolar septal fibrosis or relevant cell turnover at alveolar sites were observed at this lower exposure concentration. Similar changes to those seen in rats were not observed in either mice or hamsters.

In a study with sub-pigmentary titanium dioxide (80% anatase: 20% rutile; average primary particle size = 21 nm), female rats, mice or hamsters were exposed to aerosol concentrations of 0.5, 2.0 or 10 mg/m3 titanium dioxide for 6 hours/day, 5 days/week for 13 weeks followed by 4, 13, 26 or 52 weeks of postexposure (49 weeks for hamsters)(Bermudez et al., 2004). Retained lung burdens increased in a concentration-related manner in all three species. Mice and rats had similar lung burdens at the end of exposures but hamsters were significantly lower. Retardation of particle clearance in rats and mice at the highest exposure concentration (10 mg/m3) indicated that pulmonary particle overload had been achieved. Lesions of the lungs in rats consisted of foci of alveolar epithelial proliferation of metaplastic epithelial cells (alveolar bronchiolization) concomitant with circumscribed areas of heavy, particle-laden macrophages. In rats these changes were manifested by increased alveolar epithelial cell labelling indices, as evidenced by cell proliferation studies. Associated with these foci were areas of interstitial particle accumulation and alveolar septal fibrosis. These lesions observed in the rat became more pronounced with time. Mice developed a less severe inflammatory response without the progressive epithelial and fibroproliferative changes.

Repeated dose toxicity – dermal

According to the data requirements as outlined in Annexes VIII-IX, 8.6 of Regulation (EC) 1907/2006 a repeated dose toxicity study shall be via the most appropriate route of administration, having regard to the likely route of human exposure. The inhalation route is considered as the most appropriate route of exposure.

Justification for classification or non-classification

Repeated dose toxicity, oral

The reference National Cancer Institute (1979) is considered as the key study for repeated dose toxicity via oral application and will be used for classification. Rats were dosed at 3500 mg/kg bw/day orally via feed. Based on the lack of any adverse effects, the no observed adverse effect level (NOAEL) via oral application for titanium dioxide was established at 3500 mg/kg bw/day

(for detailed information please refer to the endpoint study records reported under section carcinogenicity).

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and the no observed adverse effect level (NOAEL) via oral application is above the guidance value for a Category 1 classification of 10 mg/kg bw/day and above the guidance value for a Category 2 classification of 100 mg/kg bw/day. For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, oral is required.

 

Repeated dose toxicity, dermal

Titanium dioxide was tested in various percutaneous absorption tests which have been reviewed by the Scientific Committee on cosmetic products and non-food products (SCCNFP/0005/98, 2000) and which concluded “extensive tests for percutaneous absorption, mostly in vitro, indicate that absorption does not occur, either with coated or uncoated material; one experiment found some evidence that a little of the material could be found in the openings of the follicles. [...] The toxicological profile of this material does not give rise to concern in human use, since the substance is not absorbed through the skin. In view, also, of the lack of percutaneous absorption, a calculation of the margin of safety has not been carried out.”

For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, dermal is required.

 

Repeated dose toxicity, inhalation

The rat is uniquely sensitive to lung damage when exposed under conditions of particle overload to poorly soluble low-toxicity particles such as titanium dioxide or others (Levy, 1995). Although particle overload is observed in other experimental species such as the mouse, it is only in the rat that a sequence of events is initiated that leads to fibroproliferative disease, septal fibrosis, hyperplasia and eventually lung tumours. However, similar pathological changes are not observed in other common laboratory rodents, non-human primates or in exposed humans. Detailed epidemiological investigations have shown no causative link between titanium dioxide exposure and the risk of non-malignant respiratory disease in humans.

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

The following observations have been made in experimental animals and in human epidemiological studies:

(i) No systemic toxicity was shown to result from chronic inhalation exposure in rats to high concentrations of pigment grade titanium dioxide

(ii) Particle overload is observed for insoluble particles such as titanium dioxide (Levy, 1995), whereby the rat is the most sensitive species studied, and species-specific differences are demonstrated in various mechanistic animal studies (Oberdörster, 1996). It has been demonstrated with reasonable certainty that lung overload conditions are not relevant for human health and, therefore, results based on these data do not justify classification.

(iii) It has also been clearly demonstrated through epidemiological studies of titanium dioxide -exposed workers that there is no causal link between titanium dioxide exposure and the risk of non-malignant respiratory disease in humans

For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, inhalation is required.