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Description of key information

In a long term (two year) repeated dose toxicity study with rats, supplemented with two interim studies (49-51 weeks and 80-82 weeks respectively), the NOAEL was determined to be ≥ 630 and ≥ 450 mg/kg bw/day for females and males, respectively, based on the absence of effects seen at the highest concentration of the read across substance sodium ferrocyanide (5000 ppm in the food).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Based on identical metal-cyanide complex species, the source substance sodium ferrocyanide and the target substance potassium ferrocyanide can be regarded as analogues, which implies that data from sodium ferrocyanide can be read-across to the target substance potassium ferrocyanide based on this information. The complete rationale can be found in the read-across report in section 13.
Reason / purpose:
read-across source
Reason / purpose:
assessment report
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Description (incidence and severity):
not required
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Description (incidence and severity):
no adverse effects were observed on weight, macroscopically or microscopically of/on organs nor on urinalysis, therefore adverse effects on clinical chemistry are not expected
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Description (incidence and severity):
not required
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Findings were generally similar in both the control and treated groups. The percentage mortality of the control rats for both sexes was higher that that of the three treatment groups at the end of the study. Female rats showed a statistically significant dose related decrease in mortality rate for the cumulative mortality levels for each group in every week. However, this was not statistically significant in the heterogeneity of death rates between the groups. Survival in each group is no less than 50% at 24 months for all groups, except for the control group males with a survival just below this value, 48%.

BODY WEIGHT AND WEIGHT GAIN
Body weight of male and female rats in the control and treatment groups were similar throughout the course of the 2-y study. Female rats given 5000 ppm had a slightly lower mean body weight compared to control rats during the latter of the study, resulting in statistically significance during some weeks, 41-49 and 57-61 and week 92, but the weights were all within 8% of the control values for these periods. This is not considered to be toxicologically relevant.
Interim I and II study: Comparable trends

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption differed during the study, sometimes being less compared to controls, sometimes being more compared to controls. In some weeks this was statistically significant, but these differences were not considered to be related to treatment.
Interim I and II study: comparable trends.

The calculated intake (mg/kg bw/d) over the whole study period expressed for m/f:
2-y study; Interim I; Interim II;
50 ppm 4.4/6.2; 5.4/6.8; 4.7/6.8
500 ppm 45.0/62.5; 51.8/69.8; 46.8/63.8
5000 ppm 450.7/630.1; 519.5/692.5; 461.8/672.5

WATER CONSUMPTION
The pattern of water consumption by male and female rats in the control and 50 and 500 ppm treatement groups was similar throughout the study. Male and female rats administered 5000 ppm drank more than control animals during the first nine months of the study (up to twice the volume of the control animals, strong week-to-week variation). During the last year of the study water quantities were comparable between 5000 ppm group and controls. While the difference seen in the first year of the study must be attributed to treament with sodium ferrocyanide there is no indication that this is an adverse effect (see also Urinalysis results).
Interim I and II study: Comparable trends, however, the high water intakes seen in rats given 5000 ppm substance during the earlier part of the 2-y study were not repeated in the corresponding periods of the interim studies.

HAEMATOLOGY
Changes observed in treated animals were not dose-related or common to both sexes on any single occasion, and were not found consistently on different occasions. Therefore none of the effects seen are considered to be a consequence of treatment.

CLINICAL CHEMISTRY
Although clinical chemistry parameters were not included in this study, as no adverse effects on organs nor on haematology and urinalysis, this is not considered to have affected the outcome of the study.

URINALYSIS
Some differences were seen between the results of renal function tests for treated rats compared with control rats. No permanent disturbance of the renal system was apparent. In the first 26 weeks of exposure a dose-dependent, significant increase in the numbers of cells excreted via the urine per hour was observed, both in male and female rats. This effect became less clear over time, and was absent at the last time point (104 weeks). Overall, kidney functions were normal during the study, therefore, the increased water intake of 5000 ppm treated male and female rats in the first part of the 2-y study (which correlates with increased urine volume) is not expected to be an adverse effect of the substance.
A trend of increased protein excretion in the urine of both control and treated rats was found. This is a characteristic of ageing rats, which severity or onset was not accelerated by the substance.

ORGAN WEIGHTS
Although there was some suggestion of increased caecum weight in male rats given 5000 ppm substance in the interim studies, this increase was not seen in the corresponding group in the 2-y study. Other differences were seen (increased spleen weight, decreased intestinal weight both at 50 ppm in male rats, increased pituitary glands in female rats at 50 ppm), but never consistent over sexes or dose dependent. It was thus concluded that the increased organ weights were not a toxicological relevant adverse effect.

HISTOPATHOLOGY: NON-NEOPLASTIC
Occasionally a single histopathological finding was found with a higher prevalence in one or more groups (lung, liver). However, no clear dose trend is found, no consistent pattern is seen in the male and female groups, therefore it is unlikely that these differences can be attributed to the treatment. In addition, periartritis was seen, but not statistically significant, and this is commonly found in old rats. An increased number of fibrous polyps was seen in the uteri of high dose females, however this is commonly found in old female rats. Since no clear dose response is seen, this was considered not to be related to treatment.

HISTOPATHOLOGY: NEOPLASTIC
No dose related effect was seen in tumours of the pituitary, pancreas and thyroid, which are relatively common in aged rats. Basal cell carcinoma, lipoma, sarcoma, fiborsarcoma and squamous cell carcinoma were found either in the skin or subcutaneous tissues of several animals. However, these kind of tumours have frequently been reported in control rats and therefore, it is unlikely they result from treatment.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 630 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effects were observed up to the highest dose level tested
Key result
Dose descriptor:
NOAEL
Effect level:
>= 450 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse effects were observed up to the highest dose level tested.
Critical effects observed:
not specified
Conclusions:
In a long term (two year) repeated dose toxicity study with rats performed mainly according to OECD 453, supplemented with two interim studies (49-51 weeks and 80-82 weeks respectively), the NOAEL was determined to be ≥ 630 and ≥ 450mg/kg/day for females and males, respectively, based on the absence of effects seen at the highest concentration (5000 ppm in the food).
This result can be read across to potassium ferrocyanide.
Executive summary:

In a long term (two year) toxicity study with rats, supplemented with two interim studies (49-51 weeks and 80-82 weeks respectively), male and females rats (48/sexe) were daily exposed to sodium ferrocyanide, which was mixed in the food. During the studies, body weight and food and water intake was monitored at regular intervals. Furthermore, blood and urine samples were examined for several relevant parameters. At the end of the study, rats were killed and organs and tissues were examined macro- and microscopically. Rats exposed to the highest concentration (5000 ppm in food) showed elevated water consumption in the first nine months. The sodium ferrocyanide in the diet did not adversely affect growth or general health of the rats in the three treatment groups. No dose-related variations were found in the haematology or urine analyses. Neither were dose-related differences found in the weight of the organs, or in the (non-neoplastic and neoplastic) histopathology of organs or tissues between the exposed groups or differences with the non-exposed groups. From these data, the NOAEL was determined to be ≥ 630 and ≥ 450 mg/kg bw/day for females and males, respectively, based on the absence of effects seen at the highest concentration (5000 ppm in the food).

The results can be read across to the target substance, potassium ferrocyanide.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
450 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Study was performed according to OECD guideline 453, but not according to GLP principles.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a long term (two year) toxicity study with rats, supplemented with two interim studies (49-51 weeks and 80-82 weeks respectively), male and females rats (48/sexe) were daily exposed to the targets' source substance sodium ferrocyanide, which was mixed in the food. During the studies, body weight and food and water intake was monitored at regular intervals. Furthermore, blood and urine samples were examined for several relevant parameters. At the end of the study, rats were killed and organs and tissues were examined macro- and microscopically. Rats exposed to the highest concentration (5000 ppm in food) showed elevated water consumption in the first nine months. The sodium ferrocyanide in the diet did not adversely affect growth or general health of the rats in the three treatment groups. No dose-related variations were found in the haematology or urine analyses. Neither were dose-related differences found in the weight of the organs, or in the (non-neoplastic and neoplastic) histopathology of organs or tissues between the exposed groups or differences with the non-exposed groups. From these data, the NOAEL was determined to be ≥ 630 and ≥ 450 mg/kg bw/day for females and males, respectively, based on the absence of effects seen at the highest concentration (5000 ppm in the food).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
One study available with Klimisch reliability 2.

Justification for classification or non-classification

Based on the available data, the target's analogue, sodium ferrocyanide showed no repeated dose toxicity. Therefore potassium ferrocyanide is not classified for repeated dose toxicity according to CLP Regulation (No) EC 1272/2008.