Potassium cyanate

Repeated dose toxicity: other routes

Administrative data

Endpoint:

sub-chronic toxicity: other route

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

public available literature (non Guideline, non GLP)

Data source

Reference

Reference Type:

publication

Title:

Pharmacology of cyanate. I. general Effects on experimental animals

Author:

Cerami, A.; Allen, T.A..; Graziano, J.H. deFuria, F.G.; Manning, J.M.; Gillette, P.N.

Year:

1973

Bibliographic source:

J. Pharmacol. Exp. Ther. 185: 653-666, 1973

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Public available literature only. No guideline indicated. For details on method see below.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium cyanate

EC Number:

209-676-3

EC Name:

Potassium cyanate

Cas Number:

590-28-3

Molecular formula:

KOCN

IUPAC Name:

potassium cyanate

Details on test material:

not indicated.

Test animals

Species:

mouse

Strain:

other: B6/D2 F1

Sex:

not specified

Details on test animals or test system and environmental conditions:

not indicated.

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

water

Details on exposure:

not indicated.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 months

Frequency of treatment:

daily (5 times a week)

Doses / concentrations

Remarks:

Doses / Concentrations:
- Three groups of 20 B6/D2 F1 female mice were injected i.p. once daily (five times a week) for a five-month period with either a) 0.1 ml of saline; b) 0.1 ml of 0.02 M KNCO (6.5 mg/kg); or c) 0,1 of 0.1 M KNCO (32.5 mg/kg).
- single i.p. administration of 91 mg/kg daily
- A group of 20 female B6/D2 F1 mice were injected once daily (five times a week) with 0.1 ml of 0.285 M KNCO; the injections were discontinued when the mice displayed signs of chronic toxicity

No. of animals per sex per dose:

20 females

Control animals:

yes

Details on study design:

not indicated.

Examinations

Observations and examinations performed and frequency:

- body weight
- mortality
- amount of carbamylation of the amino-terminal valine of the hemoglobin

Sacrifice and pathology:

At intervals some of the animals were sacrificed and examined for gross and histopathological lesions.

Other examinations:

not indicated.

Statistics:

not indicated.

Results and discussion

Results of examinations

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):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

Three groups of 20 B6/D2 F1 female mice were injected i.p. once daily (five times a week) for a five-month period with either a) 0.1 ml of saline; b) 0.1 ml of 0.02 M KNCO (6.5 mg/kg); or c) 0,1 of 0.1 M KNCO (32.5 mg/kg) without any apparent effects.

The hemoglobin concentration of some of the mice receiving 32 mg/kg of KNCO tends to be approximately 10 to 15% higher than that of the other two groups. The extent of carbamylation of the NH2-terminal valine of hemoglobin of the mice receiving cyanate increases linerarly and plateaus at approximately 0.15 and 0.8 to 1.0 carbamyl residues per hemoglobin tetramer for the 6.5 and 32.5 mg/kg groups, respectively. It should be pointed out that the hemoglobin molecule exists as a tetramer of 2 α- and 2 β-chains and has 4 amino-terminal valine residues; therefore, in the case of the 32.5 mg/kg group this corresponds to reacting an average of 0.8 of the 4 amino-terminal valine residues. The separation of the α- and β-chains of the hemoglobin of a mouse at a plateau value of 0.88 carbamyl group per mole of hemoglobin tetramer revealed an equal distribution of the cyanate between the NH2-terminal valine of the α- and β-chains. In addition, there was no detectable carbamylation of the ε-amino groups of lysine in the sample.

At intervals some of the animals were sacrificed and examined for gross and histopathological lesions. No pathological findings were noted in the cyanate-treated animals. Sodium cyanate has also been administered by i.p. injection to another series of mice for a comparable period of time at dose levels of 6 and 32 mg/kg without adverse effects.

Although a single i.p. administration of 91 mg/kg of KNCO does not kill a mouse, the daily administration of this amount leads to weight loss and eventually to death. A group of 20 female B6/D2 F1 mice were injected once daily (five times a week) with 0.1 ml of 0.285 M KNCO; the injections were discontinued when the mice displayed signs of chronic toxicity. As soon as the cyanate injections were discontinued the surviving animals quickly regained the lost weight.

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

> 32.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No effects up to this dose level.

Applicant's summary and conclusion

Conclusions:

Three groups of 20 B6/D2 F1 female mice were injected i.p. once daily (five times a week) for a five-month period with either a) 0.1 ml of saline; b) 0.1 ml of 0.02 M KNCO (6.5 mg/kg); or c) 0,1 of 0.1 M KNCO (32.5 mg/kg) without any apparent effects. The NOAEL is determined to be > 32.5 mg/kg bw/day.

Executive summary:

In a subchronic toxicity study potassium cyanate was administered i.p. to 20 female B6/D2 F1 mice /dose in water at dose levels of 0, 6.5 and 32.5 mg/kg bw/day for 5 months.

No apparent effects were observed.

The hemoglobin concentration of some of the mice receiving 32 mg/kg of KNCO tends to be approximately 10 to 15% higher than that of the other two groups. The extent of carbamylation of the NH2-terminal valine of hemoglobin of the mice receiving cyanate increases linearly and plateaus at approximately 0.15 and 0.8 to 1.0 carbamyl residues per hemoglobin tetramer for the 6.5 and 32.5 mg/kg groups, respectively. It should be pointed out that the hemoglobin molecule exists as a tetramer of 2 α- and 2 β-chains and has 4 amino-terminal valine residues; therefore, in the case of the 32.5 mg/kg group this corresponds to reacting an average of 0.8 of the 4 amino-terminal valine residues. The separation of the α- and β-chains of the hemoglobin of a mouse at a plateau value of 0.88 carbamyl group per mole of hemoglobin tetramer revealed an equal distribution of the cyanate between the NH2-terminal valine of the α- and β-chains. In addition, there was no detectable carbamylation of the ε-amino groups of lysine in the sample.

At intervals some of the animals were sacrificed and examined for gross and histopathological lesions. No pathological findings were noted in the cyanate-treated animals. Sodium cyanate has also been administered by i.p. injection to another series of mice for a comparable period of time at dose levels of 6 and 32 mg/kg without adverse effects.

Although a single i.p. administration of 91 mg/kg of KNCO does not kill a mouse, the daily administration of this amount leads to weight loss and eventually to death. A group of 20 female B6/D2 F1 mice were injected once daily (five times a week) with 0.1 ml of 0.285 M KNCO; the injections were discontinued when the mice displayed signs of chronic toxicity. As soon as the cyanate injections were discontinued the surviving animals quickly regained the lost weight.

The NOAEL is > 32.5 mg/kg bw/day .

This subchronic toxicity study (i.p. administration) in the mouse is acceptable as supporting study, although no guideline was followed.