potassium ferrite

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

   

In a GLP compliant one-generation study performed according to OECD guideline No. 415 (Safepharm, 2005), 28 male Sprague Dawley (SD) rats per dose group were exposed to Potassium ferrite (0, 15, 150 and 500 mg/kg bw/d) by gavage for 10 weeks prior to mating. 28 female SD rats per dose group were dosed at the same dose levels for 2 weeks prior to pairing. Males and females were paired on a one male : one female basis within their dose groups for a maximum of 21 days. Each day tray liners were checked for copulation plugs and a vaginal smear was taken to assess the stage of oestrus. Presence of sperm in the vaginal smear was taken a positive evidence of mating. Smearing was then discontinued, the male was returned to his original group cage and the female was moved to a solid bottom cage and was provided with wood shavings. Females were allowed to give birth and maintain their offspring until day 21 post partum. Clinical signs, bodyweight development as well as food and water consumption were monitored daily during the course of the study. During lactation offspring were monitored daily for signs of ill health, growth and development. On day 21 post partum surviving females and offspring were killed and subjected to a macroscopic examination. Selected tissues were weighed and retained for histopathological examination. Male animals were killed and similarly examined upon confirmation of successful mating.

Throughout the course of the study, group mean bodyweight and bodyweight gain were comparable to control values. At 500 mg/kg bw/d there was a slight decrease in food consumption for females during week 10 of the study, not considered to be treatment-related.

No intergroup differences in absolute or relative organ weights for test and control group animals were observed.

One female in the high dose group showed sloughing and thickening of the glandular gastric epithelium. At 150 mg/kg bw/d, one male animal showed sloughing of the glandular region of the stomach. These findings most probably refer to the irritant nature of Potassium ferrite. However, as this is a one-generation study, tissue of the GI tract was not subjected to histopathological examinations, and therefore, some effects regarding irritation of the GI tract may have been missed. 

There were eleven mortalities throughout the course of the study. One male (day 84) and seven females (day 61, 67, 74, 77, 98 (two animals), 116) dosed at 500 mg/kg bw/d, two females (day 103, 108) dosed at 150 mg/kg bw/d and one control female (day 83). The cause of death was either misadministration of the test material (6/11 animals; control group, 150 mg/kg bw/d dose group and high dose group), physical injury due to a wound on the flank (1/11 animals; high dose group) or unclear, because animals were partially cannibalized (2/11 female animals in the high dose group).

The remaining two females (high dose group) which were killed in extremis around the expected time of parturition had dead fetuses in utero. During pathological examinations, Myometritis was observed in both animals. One of both females additionally suffered from Pyometria and had a reduction of bodyweight. These findings most likely account for the difficulties during parturition. Additionally, another female of the same dose group was found to have 2 dead fetuses in utero at the terminal kill. This animal also exhibited a uterus tumor, most likely accounting for the difficulties during parturition.

The results did not indicate any effects on male or female sexual function; there were no intergroup differences in litter size or offspring viability throughout lactation. Group mean litter weights and mean offspring weights were comparable to controls for all dose levels. There were no intergroup differences in the time of completion of physical landmarks of development or the percentage of offspring passing reflexological response assessments. Considering litter observations, there were no treatment-related macroscopic abnormalities detected at terminal kill. Additionally, no treatment-related differences in the number of corpora lutea or implantation sites were observed, and there were also no treatment-related differences in pre or post implantation losses.

Therefore, the NOAEL for fertility is considered to be > 500 mg/kg bw/day. The NOAEL for development is set at 500 mg/kg bw/d. This NOAEL is based on the assumption that the effects seen in the high-dose groups (parturition problems; death before termination in all dose groups) are due to the rude treatment of the animals and are, thus, not substance-related. Difficulties during parturition (and concurrently dead fetuses in utero) are sometimes seen in reproduction toxicity tests and not necessarily related to treatment. Additionally, the affected animals suffered either from Myometritis or a uterus tumor, most probably accounting for the difficulties during parturition.

In addition to this one-generation toxicity study, read-across to KOH as well as the remaining insoluble iron oxides (proved by the amount of iron measured during a water solubility test of Potassium ferrite: < 1 mg iron/L) can be used to assess the toxicological behavior of Potassium ferrite, as hydrolysis of Potassium ferrite proceeds to a minor degree and results in minimal amounts of potassium hydroxide, as well as the remaining insoluble iron oxides.

Potassium hydroxide is not expected to be systemically available in the body under normal handling and use conditions and for this reason it can be stated that the substance will neither reach the fetus nor male and female reproductive organs in effective toxic concentrations (OECD SIDS, 2002).

Due to the lack of systemic availability of iron oxides (as they are insoluble in aqueous and organic solvents) effects on reproductive organs are not expected. In addition, Iron is an essential element for humans.

Even if some iron would be systemically available, it is concluded that there would be no toxic effects on reproduction and development, as proven by a reproduction and developmental study on rats with iron dichloride, which is soluble in water (NOAEL at 500 mg/kg bw; highest dose tested; OECD SIDS for iron dichloride, 2004).

Therefore, it can be concluded that further studies to determine the effects on fertility and development are not necessary.

Short description of key information:
The NOAEL based on a one generation study in rats exposed by oral gavage was determined to be 500 mg/kg bw/day

Justification for classification or non-classification

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