13 Weeks toxicity study with TK analysis in the rat/SiMn slag/OECD 408/GLP

Summary
The objective of this study was to make an assessment of the sub-chronic systemic toxic potential of granulated silico-manganese slag (a by-product of the production of manganese alloys) when administered orally, by gavage, to Sprague-Dawley rats for 13-weeks.
Three groups, each comprising 10 males and 10 females, received doses of 10, 100 or 1000 mg/kg/day. A similarly constituted control group received the vehicle only (corn oil). Dose volumes of 5, 1, 5 and 5 mL/kg bodyweight were used for animals receiving silico-manganese slag at 0, 10, 100 and 1000 mg/kg/day, respectively. During the study, clinical condition, detailed physical and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, ophthalmoscopy, haematology (peripheral blood), blood chemistry, organ weight, macropathology and histopathology investigations were undertaken.
Results
The plasma samples taken in Week 7 for proof of absorption analysis were analysed and manganese, aluminium, barium and silicon concentrations were found to be less than the limit of quantification in all dose groups indicating that no quantifiable absorption had occurred.
The appearance and behaviour of the animals were unaffected by treatment, there were no sensory reactivity, grip strength and motor activity findings that were attributable to treatment and there was no effect on body weight and food consumption. There were no treatment-related ophthalmic findings. The haematology and biochemical examinations performed in Week 13 did not reveal any findings that were attributable to treatment. Organ weights were not affected by treatment with SiMn slag.

Macroscopic examination revealed mucosal depressions in the stomach of one female given 100 mg/kg/day and one male given 1000 mg/kg/day. There were no other macroscopic findings.

Histopathological changes occurred in the glandular and non-glandular stomach of one female given 100 mg/kg/day and four males given 1000 mg/kg/day. These changes included ulceration with inflammation and oedema in the non-glandular region and foveolar
hyperplasia, associated with eosinophilic globules, and inflammatory cell infiltrate in the glandular region.

Conclusion
It was concluded that oral (gavage) administration of granulated silico-manganese slag to Sprague-Dawley rats at doses up to 1000 mg/kg/day for 13 weeks did not cause any evidence of systemic toxicity. The analysis of plasma manganese, aluminium, barium and silicon indicated that no quantifiable absorption had occurred. Gastric irritation occurred in a few animals (one female given 100 mg/kg/day and four males given 1000 mg/kg/day) and was attributed to the physical properties of the silico-manganese slag, since it was a hard, granular
material which was considered to have caused physical irritation leading to localised damage to the gastric mucosa in these animals. The no-observed-adverse-effect level (NOAEL) for systemic toxicity in this study was considered to be 1000 mg/kg/day.

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