Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Based on the results obtained in the 28 day repeated dose toxicity study by gavage, the NOAEL was determined to be 500 mg/kg/bw for male and female rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

In a GLP compliant repeated dose toxicity study, performed according to OECD guideline No. 407, Sprague Dawley rats of both sexes were treated with potassium ferrite (15, 150, and 500 mg/kg bw/d) by repeated oral gavage, for a period of 28 days (Huntingdon Life Sciences, 1997).

Dosages were chosen based on the results of a preliminary range-finding study, where three groups of three male and three female CD rats received Potassium ferrite daily at concentrations of 100, 300 or 1,000 mg/kg bw/d orally, by gavage, for seven days. In this study, no animals died; however, bodyweight gain, food consumption and food conversion efficiency were lower than expected in animals receiving 1,000 mg/kg bw/d. Macroscopic examination revealed thickened wall in the glandular mucosa and depressed areas on keratinized mucosa in the stomach of animals in the high dose group, indicating an irritant potential of the substance at high concentrations. Therefore, the doses for the main study were chosen to be 15, 150, and 500 mg/kg bw/d.

The main study was comprised of four groups, each containing five male and five female rats. No deaths were recorded throughout the study. Bodyweight, food consumption and food conversion efficiency have been unaffected by treatment. During the open field observations in Weeks 2, 3 and 4, abnormalities of gait (unsteady or slow and/or deliberate) were seen in two females receiving 500 mg/kg bw/d. One male animal receiving 500 mg/kg bw/d showed dark faeces during both Week 2 and Week 3. One male receiving 15 mg/kg bw/d showed blood stained faeces during both Week 3 and Week 4. These finding were considered to relate to the dark colour and the irritant nature of the test material.

Macroscopic examination revealed depressed areas on keratinized mucosa in the stomach of two male animals receiving 500 mg/kg bw/d and abnormal contents of the gastro-intestinal tract in two females receiving 500 mg/kg bw/d, comprising dark content of the caecum in one of these animals and dark content in the ileum, caecum and colon of the other animal. During microscopic pathology, a number of findings were seen in the stomach of animals receiving 500 mg/kg bw/d (mainly composed of mucosal edema in keratinized regions) that were attributed to the irritant nature of Potassium ferrite.

Sensory reactivity tests, grip strength and motor activity were unaffected by treatment with Potassium Ferrite. Examination of the blood and bone marrow revealed no toxicologically significant findings. After four weeks of treatment no effect on organ weights was observed. Macroscopic examination after four weeks of treatment revealed depressed areas on keratinized mucosa in the stomach of two males that received 500 mg/kg bw/d and abnormal contents of the gastro-intestinal tract in two females that received 500 mg/kg bw/d. There were no histopathological changes that could have been attributed to treatment.

In conclusion, oral administration of Potassium ferrite up to 500 mg/kg bw/d for four weeks was generally well tolerated. The observed gait abnormalities in two females and some changes in the gastro-intestinal tract were attributed to the irritant nature of the test material. The gait abnormalities were neither detected in any other animal given 500 mg/kg bw/d, nor in the two affected animals at clinical observations. Since all other neurological function tests were unaffected, the presence of gait abnormalities in the two female animals was not considered to indicate any evidence that potassium ferrite shows neurotoxic effects. The primary toxicological effect was local irritation of the GI tract and no evidence of systemic toxicity was observed. Therefore the NOAEL was considered to be 500 mg/kg bw/d.

Additionally, in a GLP-compliant one-generation study, where male animals were exposed orally with potassium ferrite (highest dose tested 500 mg/kg bw/d) for up to 126 days and female animals for up to 77 days, the NOAEL was also considered to be 500 mg/kg bw/d.

Experimental data on the hydrolysis of Potassium ferrite revealed that hydrolysis proceeds to a minor degree and results in small amounts of potassium hydroxide (a 10 % w/v solution of Potassium ferrite revealed a pH of 12.9; for details please refer to IUCLID chapter 7.2.3) and the remaining insoluble iron oxides (confirmed by a water solubility test where the mean measured water solubility in the form of iron was <1.0 mg/L). As this is also expected to happen if the substance is swallowed or inhaled, potassium hydroxide as well as the remaining iron oxides can be investigated separately for their toxic properties.

There is a 14d inhalation toxicity study with three different iron oxides available, where, in summary, histopathological evaluation of rat lungs revealed findings consistent with a 'poorly soluble particle' effect after the 2 -week exposure period, including the 3 -month postexposure period. Furthermore, conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs was not observed. No marked qualitative and quantitative toxicologically significant differences were observed in the responses after administration of the three iron oxides.

Further inhalation toxicity tests (4 weeks and 13 weeks) with one representative of the iron oxides group (Fe3O4), where rats were subchronically exposed to three different concentrations of Fe3O4, also revealed findings clearly consistent with and typical for a poorly soluble particle. The retention kinetics of inhaled Fe3O4 particles revealed neither analytical nor toxicological evidence that free, biosoluble iron was liberated from the inhaled dust to any appreciable extend. Also in this study no evidence of extrapulmonary toxicity could be detected. The results of the 13 weeks inhalation toxicity study support the view, that the NOAEL of Fe3O4 is 4.7 mg/m³.

Regarding these experimental data, it is concluded, that the primary toxic effect of Potassium ferrite is local irritation due to the release of KOH. The remaining insoluble iron oxides are hardly bioavailable. In view of the corrosive nature of the substance (10 % w/v solution; pH 12.9; for details please refer to IUCLID chapter 7.2.3), and the data already available, further testing regarding repeated dose toxicity should be avoided for animal welfare reasons.

Justification for classification or non-classification

Based on the findings of the repeated dose toxicity study, the test substance does not need to be classified according to the Directive 67/548/EEC and the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.