Registration Dossier

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:
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

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
yes

Test animals

Species:
mouse
Strain:
other: B6/D2 F1
Sex:
female
Details on test animals 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:
Test 1: 1 mouse
Test 2: no data
Control animals:
not specified
Positive control:
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 as14CO2

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.