Tetrapotassium hexacyanoferrate

Carcinogenicity

Description of key information

In a long term (two year) repeated dose toxicity study with the target's analogue sodium ferrocyanide 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 (5000 ppm in the food).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: 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 for cross-reference:

read-across source

Reason / purpose for cross-reference:

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:

no effects observed

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.

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 7% 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. 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.

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. 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 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 intenstinal 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 dose-related carcinogenicity was observed up to the highest dose level tested.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

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 dose-related carcinogenicity was observed up to the highest dose level tested.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

 Summary of tumour incidence in male rats fed sodium ferrocyanide in the diet at levels of o (control), 50, 500 or 5000 ppm for up to 105 weeks

	Control	50 ppm	500 ppm	5000 ppm
Total animals/group	48	47	48	48
Total primary tumors	17	16	29	17
Total animals with tumors	15	12	22	14
Total animals with multiple tumors	2	3	5	2
Total benign	13	14	22	10
Total malignant	4	2	7	7
Total malignant with metastasis	2	0	3	2

 

Summary of tumour incidence in female rats fed sodium ferrocyanide in the diet at levels of o (control), 50, 500 or 5000 ppm for up to 107 weeks

	Control	50 ppm	500 ppm	5000 ppm
Total animals/group	48	48	48	48
Total primary tumors	41	41	34	37
Total animals with tumors	36	33	29	27
Total animals with multiple tumors	4	8	5	7
Total benign	34	35	27	26
Total malignant	7	6	7	11
Total malignant with metastasis	1	0	4	2

 

 

Conclusions:

In a long term (two year) toxicity study with rats performed mainly according to OECD 453, supplemented with two interim studies (49-51 weeks and 80-82 weeks respectively), male and females rats (48/dose) were daily exposed to sodium ferrocyanide, which was mixed in the diet. 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 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 performed according to OECD guideline, but not according to GLP principles.

Justification for classification or non-classification

Based on the available data, the target's analogue, sodium ferrocyanide was found not to be carcinogenic. Therefore potassium ferrocyanide does not need to be classified for carcinogenicity according to CLP Regulation (No) EC 1272/2008.

Additional information

In a long term (two year) toxicity study 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 target's analogue 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 carcinogenicity via oral route endpoint:
One study available with Klimisch reliability 2.