Potassium cyanate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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 potassium 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 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

Reference 2

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

Toxicokinetic parameters and serum concentrations were evaluated during a OECD TG 421 compliant Reproduction/Developmental Toxicity Screening Test. The summary is provided below:

"Potassium cyanate showed rapid absorption and elimination in rat’s plasma and there was no significant difference between sexes. Further, plasma data after repeated administration indicate that dose levels applied did not lead to saturation of toxicokinetic processes."

 

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).

A 2022, OECD TG  443 and GLP compliant, extended one generation reproductive toxicity study (EOGRTS) was conducted via oral route to evaluate the reproductive and developmental toxicity of potassium cyanate. The dose levels in the study are 0, 20, 60 or 120 mg/kg bw/day are selected based on the results of an OECD TG 421 study conducted in rats. In this study, potassium cyanate did not adversely affect reproductive performance (gonad function, estrous cycle, mating behavior, conception, parturition, gestation and lactation) in parental male and female rats as well as the offspring’s development. Reduction of body weight and food consumption in male animals in P generation and in F1 adult animals was observed at the highest dose tested. Growth, development, sexual maturation and thyroid hormone levels of the F1 offspring (Cohort 1A and 1B) to adulthood were undisturbed. No adverse effects on clinical, macroscopic or microscopic pathological parameters were recorded in all dose groups of Cohort 1A and 1B. In the OECD TG 421 study (0, 20, 100 and 250 mg/kg bw/day), potassium cyanate caused clinical signs (male and female), severely depressed body weight development and food consumption (male and female), macroscopic and histopathology changes in stomach (male), lowered organ weight (epididymides, seminal vesicle with coagulating gland and prostate as a whole) in rats at the highest dose tested. Reduced reproductive performance, impaired impregnation rate in parental animals and reduced body weights in F1 offspring were also observed at the highest dose.

 Literature data are only available for developmental toxicity on sodium cyanate. 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.

Based on available data on toxicity to reproduction, the test item does not require classification.

Toxicokinetics from a Reproduction/Developmental Toxicity Screening Test with Potassium Cyanate in the Rat conducted according to OECD TG 421

The concentration of Potassium Cyanate was measured in samples from adult rats on treatment Day 0, on the last day of treatment and from pups sampled on post-natal Day 13 with a validated bioanalytical LC-MS/MS method (with electrospray ionization (ESI) in the positive mode)  for the quantification of Potassium Cyanate in rat plasma in the concentration range of 0.1 – 100 µg/mL [0.0519 – 51.9 µg/mL of free cyanate ion. Its isotope labelled analogue served as internal standard.

Potassium cyanate was not detectable in the plasma of vehicle control animals (male and female) indicating that there was no cross-contamination between the vehicle and test item treated animals (Day 0 and terminal).

Measured concentrations of Potassium cyanate in rat plasma showed inter individual variability in male and female animals at each dose level on Day 0 and at the terminal sampling.

There was no significant difference between the male and female animals in the toxicokinetic profiles of Potassium cyanate. The concentrations, absorption and elimination of Potassium cyanate were similar in the male and female animals. The measured concentrations were related to doses both in male and female animals (Day 0 and terminally). The highest serum concentrations were measured in 10 minutes post-dose samples except for females 100 mg/kg bw/day, where the peak concentration appeared in 30 minutes samples.

The elimination of the test item from the circulation was rapid at all investigated dose levels and showed concentration-dependency. The plasma concentration decreased significantly within 3 hours. Elimination of Potassium cyanate was relatively slower at high concentration and became faster at the lower concentration based on t½λ values.

There was no measurable concentration of the test item in samples of offspring on post-natal Day 13, collected 2 hours after the treatment of dams on post-natal day 13 indicating no or low transfer via milk can be expected

Dose-dependent exposure was detected without gender-dependence. Normalized values suggest a super-proportional characteristic for the systemic exposure.

Cmax values determined at tmax were similar or lower at the end of the study when compared to Day 0 values, indicating that there was no accumulation of the substance in the plasma and dose levels applied in this study were well within linear kinetics not leading to saturation of absorption or elimination processes.

Also in this study, potassium cyanate caused clinical signs (male and female), severely depressed body weight development and food consumption (male and female), macroscopic and histopathology changes in stomach (male), lowered organ weight (epididymides, seminal vesicle with coagulating gland and prostate as a whole) at the highest dose indicate distribution to various organs.

For additional details please refer to IUCLID section 7.8.1

Toxicokinetic analysis of Potassium Cyanate based on the inherent properties

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 toxicokinetic evaluation in the OECD 421 study, potassium cyanate was observed to be rapidly absorbed.

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 and adverse effects noted at high concentrations in the acute toxicity, repeated dose and the reproductive toxicity studies. Based on its very low BCF value potassium cyanate is not considered to bioaccumulate in the human body. This is in line with the lowered Cmax values observed in the OECD TG 421 study indicating that there was no accumulation of the substance in the plasma and also from the rapid elimination.

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 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 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 which was observed in the OECD TG 421 study. 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 CO₂ and mainly excreted via the lung (75 %) and the urine (7.0 %) within 6 hours after i.p. ingestions. Available in vivo toxicokinetic data from the OECD TG 421 study does not indicate significant sex-differences with regard to the toxicological profile or sensitivity and showed rapid absorption, elimination, distribution to various organs with no potential to bioaccumulate.

 

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