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Description of key information

No NOAEL was identified in the available studies.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat

Additional information

General information

Water soluble zirconium salts like zirconium(tetra)nitrate, zirconium(di)acetate oxide or zirconium sulfate once in aqueous media dissociate very quickly at pH values of 4 to 9.5 forming the conjugate acid and hydrated forms of the insoluble ZrO2 (the most stable form of zirconium in water) (Daunderer, M.; Lehrbuch Klinische Toxikologie, 89. Erg. Lfg.; 11/94).

Due to the similar dissociation pattern it is concluded, that read across to other soluble zirconium salts is valid for the assessment of toxicological and ecotoxicological endpoints of zirconium(tetra)nitrate.

Tests with zirconium metal can be regarded as worst case scenario as dissociation of zirconium(tetra) nitrate will not lead to free zirconium metal in aqueous media.

 

Oral repeated toxicity

In a chronic (life time) toxicity study, zirconium sulfate and metal zirconium was administered in small doses to Long-Evans rats in diet (2.66 µg/g) and water (5 ppm) from weaning to natural death (Schroeder et al., 1969).

Clinical observations were performed daily. Body weight was determined weekly during weaning period and monthly thereafter. Haematology and clinical chemistry were conducted monthly with half of the animals being fasted. The examined parameters were serum glucose and cholesterol. Urinalysis was also conducted examining the glucose value and the whole protein in the urine. After natural death, necropsy and histopathology was conducted with all animals.

Zirconium had no effects on the growth or mature weights of the animals. Survival and longevity were similar to the control group. Female rats fed with zirconium showed higher serum glucose levels at 30, 150, 540 days of age. Furthermore glucose in urine was significantly increased in the animals at 18 months of age. 23% of the control animals were also affected. No significant effects were seen regarding the whole protein content in urine. Serum cholesterol of fasted animals was significantly higher in males treated with zirconium. The test substance was not tumorigenic and accumulation of zirconium in rat tissue was very poor.Additionally no treatment related effects were seen regarding clinical signs, necropsy and histopathology.No NOAEL was identified.

In a subchronic toxicity study a suspension of zirconium metal was administered to 12 rats in water by gavage at a dose level of 1000 mg/kg bw every three days (Mogilevskaya et al., 1968).Animals were treated for a period of one and a half to two months. The test animals did not show any substance related findings regarding weight, behavior and general condition.Furthermore no microscopic alterations were determined during necropsy. No NOAEL was identified in the publication.

 

Inhalation toxicity

In this chronic toxicity study a suspension (in physiological saline) of zirconium (50 mg) was administered intratracheal to 26 rats once at the beginning of the test. 90 % of the particles in saline were smaller than 2 µm. One half of the animals were then observed for a period of 4 months. The other half was observed for 8 months.

The test animals did not show any substance related findings regarding weight, behavior and general condition. Furthermore no gross internal lesions were observed during necropsy.

The lungs of each animal (pathology after 4 months) were examined microscopically and cellular accumulations around the dust particles were observed. Furthermore the thickening of the interalveolar septa was seen due to the proliferation of histiocytes and fibroblasts. Throughout the entire lung large amounts of dust were observed.

After eight months the process of cellular accumulation had progressed slowly with increasing number of connecting tissue fibers in the foci and in the thickening of the interalveolar septa. Proliferation of connective tissue cells and fibrosis around vessels and bronchi of all kinds was also observed. Furthermore areas of emphysema, and thickening and swelling of the blood vessels was seen. In the bronchial glands large amounts of dust were found.

 

Conclusion

The chronic toxicity study (Schroeder et al., 1969) shows that when administered in very low doses (2.66 µg/g diet; 5 mg/kg water), the read across substance zirconium sulfate does not cause any treatment related adverse effects. In order to derive a distinct classification higher doses should also be investigated. Therefore no classification can be determined based on these results.

The subchronic toxicity studies in the rat (Mogilevskaya, 1968) are unacceptable for classification due to major defiencies in study design. For oral application only 12 animals were tested. One dose level was applied to the test animals every three days. For inhalation application one dose of 50 mg zirconium suspended in saline was administered by trachea. Furthermore only limited documentation of the oral and inhalation results were presented in the publication. However the findings indicate that zirconium as such does not exhibit any treatment related effects when administered to rats. The results published in the paper can be used as supporting information.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available information is not considered suitable for classification purposes under 67/548/EEC. As a result a decision on classification and labelling is not possible for repeated dose toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available information is not considered suitable for classification purposes under Regulation 1272/2008. As a result, a decision on classification and labelling is not possible for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation EC No 605/2014.