Tripotassium hexacyanoferrate

Endpoint summary

Description of key information

In a long term (two year) repeated dose toxicity study with rats, the NOAEL of sodium ferrocyanide 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. This result is read across to potassium ferricyanide.

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 presence of identical metal-cyanide complex species, sodium ferrocyanide and potassium ferricyanide can be regarded as analogues, which implies that data from sodium ferrocyanide can be read-across to potassium ferricyanide. The read across hypothesis is attached in 'Attached justification'.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Description (incidence):

Findings were generally similar in both the control and treated groups. The percentage mortality of the control rats for both sexes was higher than 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 changes:

no effects observed

Description (incidence and severity):

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):

no effects observed

Description (incidence and severity):

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

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

The pattern of water consumption by male and female rats in the control and 50 and 500 ppm treatment 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 treatment 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.

Ophthalmological findings:

not examined

Description (incidence and severity):

not required

Haematological findings:

no effects observed

Description (incidence and severity):

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 biochemistry findings:

not examined

Description (incidence and severity):

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 findings:

no effects observed

Description (incidence and severity):

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.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

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.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

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 of sodium ferrocyanide was determined to be ≥ 630 and ≥ 450 mg/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 is 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/sex) 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). This result is read across to 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:

A reliable study was used (Klimisch 2).

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/sex) 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).

This result is read across to potasium ferricyanide, the read across hypothesis is attached in IUCLID Section 13.

Justification for classification or non-classification

Based on the available data, potassium ferricyanide is not classified for repeated dose toxicity according to CLP Regulation (No) EC 1272/2008.