Sodium cyanate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Public available literature only (non GLP, non guideline).

Cross-reference

Reason / purpose for cross-reference:

reference to other study

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

Objective of study:

distribution

excretion

Test guideline

Qualifier:

no guideline followed

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sodium cyanate

EC Number:

213-030-6

EC Name:

Sodium cyanate

Cas Number:

917-61-3

Molecular formula:

CNO.Na

IUPAC Name:

sodium cyanate

Radiolabelling:

yes

Test animals

Species:

mouse

Strain:

other: B6/D2 F1

Sex:

female

Details on test animals or test system and environmental conditions:

Source: The Jackson Laboratory (Bar Harbor, Maine, USA)

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

water

Details on exposure:

not indicated.

Duration and frequency of treatment / exposure:

Test 1: single exposure
Test 2: 156 injections (26 weeks), after 78 injections (13 weeks) injection in some mice were stopped and the distribution of 14C was observed for 130 days without further injections.

Doses / concentrations

Remarks:

Doses / Concentrations:
Test 1: Mice were given a single dose of 10 µmol 14C-sodium cyanate i.p.
Test 2: Mice were injected daily (six times per week) with 0.1 ml of 0.1 M NaN14CO

No. of animals per sex per dose / concentration:

Test 1: 1 mouse
Test 2: no data

Control animals:

not specified

Positive control reference chemical:

no

Details on study design:

Test 1: single exposure to one mouse, determination of 14C concentration in blood, urine and organs.
Test 2: Female mice were injected daily (six times per week) with 0.1 ml of 0.1 M NaN14CO. At intervals the animals were sacrificed and the distribution of 14C radioactivity within various organs were determined. After 78 injections (13 weeks) injection in some mice were stopped and the distribution of 14C was observed at intervals for maximal 130 days without further injections.

Details on dosing and sampling:

no details given

Statistics:

no details given

Results and discussion

Preliminary studies:

Test 1: Approximately 75% of the injected dose is broken down to form 14CO2 during the first six hours and another 8-10% is found in the urine. In oder to determine wether the 14CO2 came from breakdown of cyanate in an acidified urine or directly as CO2 from the lungs, a rat with an exteriorized bladder was anesthetized and injected with 10 µmol of 14C-cyanate. The cranial half of the animal was placed in a tight-fitting plastic bag with inlet and outlet openings; the expired air was then drawn by vacuum through an acid trap and then ethanolamine trap. The urine was also collected into ethanolamine and the radioactivity of both the exired CO2 and the urine was determined in a liquid scintillation counter. This experiment revealed the same distribution of radioactivity from the administered cyanate and pointed to a direct release as CO2 from the lungs.
7.5 % of the injected dose reacted specifically with amino-terminal valine of hemoglobin; this amount is significantly higher than in many of the other organs or tissues of the body. The muscle and the bones are the only parts with substantial amounts of radioactivity. Less than 3 % of the injected dose reacted with tissues other than red blood cells, bones and muscle. Negligible amounts of radioactivity were found in pituitary, adrenal and thyriod glands and in the ovaries.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not observed

Details on distribution in tissues:

Test 2: It is apparent from the data (distribution see table below) that the amount of radioactivity in the different organs plateaus after a different number of injections and probably refects a steady state of proteins being labeled with cyanate equaling the rate of labeled proteins being catabolized. The loss of radioactivity from the various organs after stopping the injections follows different rates and in fact might estimate the turnover of these proteins.

Details on excretion:

Evolved as CO2: 72.2 %
Urine: 7.0 %

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

CO2

Any other information on results incl. tables

Distribution of¹⁴C cyanate in a mouse after the injection i.p. of 10 µmol of¹⁴C cyanate

 

Organ/route of excretion	% of injected dose
Evolved as^14CO2	72.2
Urine	7.0
Erythrocytes	7.5
Bones	3.3
Muscle	2.1
Skin	0.8
Liver	0.7
Serum proteins	0.5
Intestine	0.4
Brain	0.17
Heart	0.08
Stomach	0.06
Kidney	0.05
Lungs	0.05
Spleen	0.01
Other: ovary, uterus, thymus, fat	0.01
Total recovery	94.9

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Approximately 75% of the injected dose is broken down to form 14CO2 during the first six hours and another 8-10% is found in the urine.

Executive summary:

In a distribution/excretion study 14C sodium cyanate was administered to female mice in single and multiple doses i.p. at dose levels of 10 µmol and 0.1 ml of 0.1 M solution. After 78 injections (13 weeks) injection in some mice were stopped and the distribution of 14C was observed at intervals for maximal 130 days without further injections.

Single dosing:

Approximately 75% of the injected dose is broken down to form 14CO2 during the first six hours and another 8-10% is found in the urine. In oder to determine whether the 14CO2 came from breakdown of cyanate in an acidified urine or directly as CO2 from the lungs, a rat with an exteriorized bladder was anesthetized and injected with 10 µmol of 14C-cyanate. The cranial half of the animal was placed in a tight-fitting plastic bag with inlet and outlet openings; the expired air was then drawn by vacuum through an acid trap and then ethanolamine trap. The urine was also collected into ethanolamine and the radioactivity of both the expired CO2 and the urine was determined in a liquid scintillation counter. This experiment revealed the same distribution of radioactivity from the administered cyanate and pointed to a direct release as CO2 from the lungs. 7.5 % of the injected dose reacted specifically with amino-terminal valine of hemoglobin; this amount is significantly higher than in many of the other organs or tissues of the body. The muscle and the bones are the only parts with substantial amounts of radioactivity. Less than 3 % of the injected dose reacted with tissues other than red blood cells, bones and muscle. Negligible amounts of radioactivity were found in pituitary, adrenal and thyroid glands and in the ovaries.

Multiple dosing:

It is apparent from the data that the amount of radioactivity in the different organs plateaus after a different number of injections and probably reflects a steady state of proteins being labelled with cyanate equalling the rate of labelled proteins being catabolized. The loss of radioactivity from the various organs after stopping the injections follows different rates and in fact might estimate the turnover of these proteins.

This distribution/excretion study in the mouse is classified acceptable.