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Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Both the target and the source substance show similar behaviour in aqueous medium (dissociate quickly to cyante and K+ or Na+, respectivley). Both potassioum and sodium are present in cells and body fluids (e.g. essential electrolytres), therefore the toxicity of potassium cyanate and sodium cyanate is only due to the cyanate ion.
Reason / purpose for cross-reference:
read-across source
Details on absorption:
not observed
Details on distribution in tissues:
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 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.
Details on excretion:
Evolved as CO2: 72.2 %
Urine: 7.0 %
Metabolites identified:
yes
Details on metabolites:
CO2

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

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: see 'Remark'
Remarks:
public available literature only (non GLP, non guideline) Read across to sodium cyanate was done. In aqueous solution cyanate salts dissociate very quickly to cyanate ion and the respective alkali metal ion. It is not expected that Na+ or K+ contribute to the toxicity of cyanates as both represent basic metal ions present in the human body in high concentrations.
Reason / purpose for cross-reference:
reference to other study
Objective of study:
distribution
excretion
Qualifier:
no guideline followed
GLP compliance:
not specified
Radiolabelling:
yes
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)
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.
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
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 order to determine whether the 14CO2 came from breakdown of cyanate in an acidified urine or directly as CO2 from the lungs, a 200 g 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.
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 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.
Details on excretion:
Evolved as CO2: 72.2 %
Urine: 7.0 %
Metabolites identified:
yes
Details on metabolites:
CO2

Distribution of 14C cyanate in a mouse after the injection i.p. of 10 µmol of 14C 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

Conclusions:
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 order to determine whether the 14CO2 came from breakdown of cyanate in an acidified urine or directly as CO2 from the lungs, a 200g 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.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

General


Potassium cyanate is produced at different EU manufacturing sites. The substance is used as basic industrial chemical for the synthesis of pharmaceuticals and for steel hardening purposes.


Toxicological profile of Potassium Cyanate


Studies with potassium cyanate are not available for every toxicological endpoint to be addressed where required and applicable. Read across to sodium cyanate was performed instead. In aqueous solution cyanate salts dissociate very quickly to cyanate ion and the respective alkali metal ion. It is not expected that Na+ or K+ contribute to the toxicity of cyanates as both represent basic metal ions present in the human body in high concentrations.


An acute oral toxicity study with rats revealed a LD50-value of 567 mg/kg bw for females and 936 mg/kg bw for males. In an acute dermal toxicity study with rats a LD50 of > 2000 mg/kg bw was determined. In a skin irritation study no skin irritating or corrosive effects were observed in rabbits. An eye irritation test showed that potassium cyanate is irritating to the rabbit’s eye. A LLNA assay with mice showed that sodium cyanate (Read across) is not a skin sensitizer.


Potassium cyanate was not mutagenic in a bacterial mutagenicity test (a reverse mutation test - Ames test) without metabolic activation. Two new state of the art tests with mammalian cells (Chromosome aberration test and HPRT test) showed that potassium cyanate is not clastogenic or mutagenic with and without metabolic activation.


Only limited toxicity data after repeated dose application are available for potassium cyanate. Cerami et al. (1973) showed no adverse effects in mice after i.p. injection for 5 months at a concentration 32.5 mg/kg bw/day. In a review article a TDLo (lowest published toxic dose) of 3360 mg/kg/150 days (equivalent to 22.4 mg/kg bw/day) is given for mice treated i.p. for 150 days.


In contrast, a broad spectrum of repeated dose data is available for sodium cyanate, which can be considered to be a reliable basis for read across. The available studies are mainly public available literature data from 1973-1988 with non-standard tests. Cerami et al. (1973) report no adverse effects after 15 months oral application of 53.5 mg/kg bw/day to dogs. Kern et al. (1977) showed the occurrence of cataracts in dogs when sodium cyanate is administered in a dose of >= 90 mg/kg bw/day for up to 38 months orally. In a 4-week oral toxicity guideline and GLP compliant study with rats, Berthold (1993) reported a NOAEL of 68.1 mg/kg bw/day. Sodium cyanate, if ingested at high doses, is able to damage a number of organs. The main target organs are the red blood cells, spleen, liver, adrenals and testes from the male genital system. Local effects can occur in the stomach. The study also shows that all effects are in principle reversible, although complete recovery can take rather long time.


Several studies with animals but also human data show distinct neurotoxicological effects of sodium cyanate at high doses. Effects observed are demyelination in the pyramidal tracts of the spinal cord, spastic quadriplegia, seizure in EEG and polyneuropathy. These effects are probably secondary to the sodium cyanate intake and attributed to a carbamylation of haemoglobin (Gerald, 1976; Tellez, 1979; Shaw, 1974; Peterson, 1974 and Charache, 1975).


No standard data on reproduction toxicity is available for potassium and sodium cyanate. Literature data are only available for developmental toxicity. No adverse effects on developmental toxicity were observed in two non state of the art studies. In the key study (i.p. administration) no adverse effects on reproduction and maternal toxicity were observed at all up to a concentration of 25 mg/kg bw/day (highest concentration investigated). In the supporting study also no effects on developmental toxicity were observed. However, it was observed that the female rats were not able to get pregnant again as long as they were maintained at very high doses (on 1 % cyanate diet = 1500 mg/kg bw/day). In two additional studies, some effects on development (body and liver weight reduction in pups) were noted after exchange transfusion of the maternal blood. As these studies were not conducted according a widely accepted guideline at all, the results are more than questionable and not taken into account for risk assessment.


 


Toxicokinetic analysis of Potassium Cyanate


 


Potassium cyanate is a white solid at room temperature with a molecular weight of 81.12 g/mol. The substance (salt) is very well soluble in water (750 g/L). The logPow of the structural analogue sodium cyanate was measured to be < 0.3. Based on this log Pow a BCF of 3.162 can be calculated. As solid substance potassium cyanate has a very low vapour pressure of 2.91 x 10-7 Pa (calculated). Potassium cyanate consists of relatively large particles. A range of 500 to 125 µm covers 80 % of the particle size distribution. No particles with a diameter below 10 µm were found.


In aqueous systems, potassium cyanate is hydrolyzed to ammonia and potassium bicarbonate. The hydrolysis rate of potassium cyanate was found to be 47 % at pH 9 after 5 days at 50 °C. Hydrolysis rates at pH 4 and pH 7 were approximately 100 % under these test conditions.


Oral absorption is favoured for molecular weights below 500 g/mol. Based on the high water solubility and the low logPow value potassium cyanate is expected to be readily absorbed via the GI tract. As the substance is water soluble and the molecular weight is low (less than 200) potassium cyanate may pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. As the substance is believed to dissociate quickly in water, the species taken up are potassium and cyanate ions. Potassium cyanate showed toxic effects when administered orally in acute toxicity tests (LD50 females 567 mg/kg bw). Together with the observed target organs , it can be assumed that potassium cyanate is well absorbed after oral administration and widely distributed into the body.


Based on the very low vapour pressure and the relatively big particle sizes inhalation exposure can practically excluded.


Similarly, based on physical – chemical properties of potassium cyanate (low Pow, high water solubility) is not likely to penetrate skin to a large extent. Dry particles will have to dissolve into the surface moisture of the skin before uptake can begin. Nevertheless, if dissolved the low molecular weight (below 100 g/mol) favours dermal uptake. However, based on the very low log Pow (< 0.3) a dermal absorption is not very likely as the substance is too hydrophilic to pass the skin. Furthermore, application of potassium cyanate to skin of rats, rabbits and mice did not cause irritation/corrosion, sensitisation nor systemic effects (mortality).


When reaching the body potassium cyanate will be widely distributed due to low molecular weight and high water solubility. This is in line with target organs noted at high concentrations. Based on its very low BCF value potassium cyanate is not considered to bioaccumulate in the human body.


These assumptions are further supported by a distribution/excretion study (Cerami, 1973) with the structural analogue sodium cyanate. In this study 14C sodium cyanate was administered to female mice in single and multiple doses i.p. 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 (exhaled) during the first six hours and another 8-10% is found in the urine. In order to determine whether the 14COcame 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 COand 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 COfrom the lungs. 7.5 % of the injected dose reacted specifically with amino-terminal valine of haemoglobin; this amount is significantly higher than in many of the other organs or tissues of the body and explains the toxic effects noted on the blood cells at high doses. 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, the ovaries and the brain.


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.


 


Mode of action of potassium cyanate is a carbamylation of protein residues in haemoglobin. This reaction is attributed to the cyanate ion and also reported in detail for sodium cyanate. Toxic effects like neurotoxicity or developmental effects after exchange transfusion of blood of pregnant rats are probably secondary to the cyanate intake and attributed to a carbamylation of haemoglobin leading to a dysfunction of the oxygen transport and metabolism in the human body (Gerald, 1976; Tellez, 1979; Shaw, 1974; Peterson, 1974 and Charache, 1975). These effects are however only noted at high doses, when a significant damage to hemoglobines has taken place.


 


Summary:


Based on physical-chemical characteristics, particularly water solubility, octanol-water partition coefficient and vapour pressure, no or only limited absorption and bioavailability by the dermal and inhalation routes is expected, which is further supported by the dermal acute toxicity study result. For the oral route rapid uptake of potassium cyanate and distribution via the blood is expected. Bioaccumulation of potassium cyanate is not likely to occur based on the physical-chemical properties and the limited data available for sodium cyanate. The cyanate ion reacts with protein residues like haemoglobin via carbamylation and can cause secondary toxic effects like neurotoxic and developmental toxicity. Potassium cyanate is broken down to COand mainly excreted via the lung (75 %) and the urine (7.0 %) within 6 hours after i.p. ingestions. Available data does not indicate significant sex-differences with regard to the toxicological profile or sensitivity.


 


References


Berthold, K. (1993); 4-week oral toxicity study after repeated administration in rats and a subsequent 6- week recovery period; unpublished report


 Charache, S.; Duffy, T.P.; Jander, N.; Scott, J.C.; Bedine, M.; Morell, R. (1975); Toxic-Therapeutic Ratio of Sodium Cyanate; Arch Intern - Vol 135, Aug 1975


Cerami, A.; Allen, T.A..; Graziano, J.H. deFuria, F.G.; Manning, J.M.; Gillette, P.N. (1973); Pharmacology of cyanate. General Effects on experimental animals; J. Pharmacol. Exp. Ther. 185: 653-666, 1973


ECHA (2008),Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance


Gerald, M.C., Gupta, T.K. (1976); Effect of sodium cyanate on the seizure susceptibility of mice; Toxicology and applied Pharmacology, 1976, 37 (3), 473-479


Kern, H.L.; Bellhorn, R.W.; Peterson; C.M. (1977); Sodium cyanate-induced ocular lesions in the beagle; The Journal of Pharmacology and Experimental Therapeutics, Vol.200, No.1 (1977)


Marquardt H., et al., (1999). Toxicology. Academic Press,,, 1999


Mutschler E., et al., (2001). Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft,, 2001


Peterson, C.M.; Tsairis, P.; Ohinishi, A.; Lu, Y.S.; Grady, R., Cerami, A.; Dyck, P.J. (1974); Sodium Cyanate Induced Polyneuropathy in Patients with Sickle-Cell Disease; Annals of Internal Medicine 81: 152-158 (1974)


Shaw, C.M. et al.(1974); Neuropathology of cyanate toxicity in Rhesus monkeys; Pharmacology, 1974, 12 (3), 166-176


Tellez,et al. (1979); Neurotoxicity of sodium cyanate; Acta Neuropathologica, 1979, 47 (1), 75-79