Registration Dossier

Administrative data

Description of key information

 Besides a subacute 28-day repeated dose toxicity study, for sodium cyanate only a number of non standard public available literature studies are available. These studies, investigating the repeated dose toxicity in different species (mouse, rat, dog, monkey) for different exposure times (up to one year), together with data from human medical treatment, are summarised in a weight of evidence approach and allow a reliable evaluation of the toxic properties of both sodium cyanate. A 15 months study with dogs and monkeys showed no effects up to concentrations of 53.5 and 51 mg/kg bw/day respectively. Main adverse effects observed are neurotoxicty and development of cataracts. These effects are considered of secondary nature due to severe changes in the blood system (damage of haemoglobin, disturbance of O2 distribution). Together with several supporting studies, the NOAEL of the chronic study in dogs and monkeys represents a reliable basis as overall NOAEL (oral, long-term) to be used for risk assessment. Human medical treatment causes very similar effects as compared with the dog and monkey data. The effects were noted at about 30 mg/kg bw/day. The NOAEL(dog) of 50 mg/kg bw/day is 1.67 times higher as the NOAEL(human) almost showing the default allometric scaling factor of 1.4. Thus, in conclusion, it is scientifically justified to derive the DNELs long-term from the chronic NOAEL(dog) of 50 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1992-04-07 to 1992-07-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
84/449/EEC
Deviations:
no
Principles of method if other than guideline:
NA
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
- age at the beginning: 7 weeks (males); 6 weeks (females)
- body weight: 145 - 185 g (males); 128 - 160 g (females)
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
NA
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The method was based on the precipitation with semicarbazide hydrochloride. Subsequently the dried precipitate was weighed.
Duration of treatment / exposure:
Duration of the study was 4 weeks treatment period (substance administration up to the day before autopsy) and 6 weeks treatment-free recovery period.
Frequency of treatment:
Frequency of treatment was once daily a.m. (7 days per week).
Remarks:
Doses / Concentrations:
0 mg/mL
Basis:
nominal in water
Remarks:
Doses / Concentrations:
14.7 mg/mL
Basis:
nominal in water
Remarks:
Doses / Concentrations:
31.6 mg/mL
Basis:
nominal in water
Remarks:
Doses / Concentrations:
68.1 mg/mL
Basis:
nominal in water
No. of animals per sex per dose:
5 male and 5 female animals in groups 2 and 3 each. 10 male and 10 female animals in groups 1 and 4 each.
The last 5 animals of each sex of group 1 were used as recovery animals.
Control animals:
yes, concurrent vehicle
Details on study design:
After death of 2 male and 1 female animals in group 4 only the last 3 respectively 4 animals were used as recovery animals.
Positive control:
NA
Observations and examinations performed and frequency:
Clinical investigations:
- Mortality: Mortality was checked twice daily (a.m. and p.m., on Saturdays, Sundays, and on national and business holidays only once daily (a.m.).
- Behaviour and general condition of the animals (clinical symptoms): The animals were observed daily for the occurrence of toxicity symptoms as well as their severity and duration.
- Food consumption: Once a week, starting with pre-test period.
- Body weight: Once a week, starting with pre-est period.
- Reflexes: Pain, pinna, and corneal reflexes were tested once week, starting with pre-test period.
- Examinations of eyes, hearing, and teeth: Prior to first substance administration and in week 4 as well as in week 10 from recovery animals. The hearing was checked with a simple noise test. The teeth were inspected. Eye examination using a focussed visual light beam.
Clinical pathology:
- Blood collection: In weeks 1 and 4 a.m. as well as in week 10 from recovery animals. Blood was collected from the retro-orbital venous plexus of 1 eye under CO2 anaesthesia from all animals.
- Anticoagulants: ETDA was used as an anticoagulant for haematological parameters. The clinical chemistry was done with serum. Only for the determination of methaemoglobin and oxygenated haemoglobin heparinized capillary tubes were used.
- Urine collection: Urine was collected in metabolism cages in week 4 a.m. from all animals. Pre-treatment before sampling with tap water (10 mL/kg bw).
- Haematology: In weeks 1 and 4 as well as in week 10 from recovery animals: Erythrocytes (RBC), haematocrit (Hct), haemoglobin (Hb), leucocytes (WBC), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV) thrombocytes (Platelets).
- Clinical chemistry: In weeks 1 and 4 as well as in week 10 from recovery animals: Alanine aminotransferase (ALAT), albumin, alkaline phosphatase (AKP), asparatate aminotransferase (ASAT), blood urea, calcium (Ca), chloride (Cl), cholinesterase (CHE), creatine kinase (CK), creatinine, iron (Fe), gamma-glutamyltransferase (gamma-GT), glucose, glutamate dehydrogenase (GLDH), inorganic phosphate (P=, methaemoglobin (MetHb), oxygenated haemoglobin (O2ct, HbO2), potassium (K), serum electrophoresis, sodium (Na), total bilirubin (tot. Bili). total cholesterol (Chol), total protin (tot. Prot), triglycerides (triglyc).
- Urinalysis: in week 4: Bilirubin, glucose, haemoglobin/erythrocytes, ketones, leucocytes, nitrite, osmolality, pH-value, protein, urobilinogen.
Additionally the volume of the collected urine was determined. Microscopical examinations of the urine sediment were done in animals whose urine state showed pathological changes in haemoglobin/erythrocytes, leucocytes, or protein.
Sacrifice and pathology:
Pathology:
Sacrifice: At the end of the treatment or recovery period the surviving animals were anesthetized with CO2 and sacrificed by exsanguination.

Other examinations:
Gross Necropsy:
- Autopsy: All animals were subjected to full gross necropsy which included examination of the external surface of the body, all orifices and abdominal cavities and their contents. The following organs or tissues or a respresentative sample were preserved: all gross lesions, adrenal glands (r/l), bone marrow, bone marrow smear, brain, cecum, colon, duodenum, epididymides (r/l), heart, ileum,jejunum, kidneys (r/l), liver, lungs, ovaries (r/l), rectum, spleen, stomach, testes (r/l).
- Organs: Adrenals (r/l), brain, heart, kidneys (r/l), liver, ovaries (r/l), spleen, testes (r/l).
The organ weights were expresssed as absolute values and relative to body weight after exsanguination. No organ weights were taken from the intercurrently dead animals.

Histopathology:
- Fixation, Staining: All above mentioned organs and tissues except for bone marrow smears were fixed in a 4 % neutral buffered formaldehyde solution. The bone marrow smears were air dried. All fixed organs and tissues of group 1 animals and group 4 animals as well as of the intercurrently dead animals were trimmed, embedded in paraffin wax, sectioned at approximately 4 µm, and stained with Hematoxylin and Eosin. Additionally sections of the following organs of group 2 and 3 animals as well as of the recovery animals of group 1 and group 4 were prepared: adrenals, bone marrow smears, brain, cecum, colon, duodenum, epididymides, heart, ileum, jejunum, kidneys, liver, lungs, ovaries, rectum, spleen, stomach, and testes. Additional sections of the stomach were stained with the periodic acid Schiff reagent, with the silver impregnation technique according to Grimelius and according to the staining produre of Schiebler and Behr.
- Microscopical examination: All slides prepared were examined microscopically, except for the sections of the following organs of group 2 and 3 animals: brain, cecum, colon, duodenum, heart, ileum, jejunum, liver, lungs, ovaries, rectum.
Statistics:
Mean values of all blood parameters and - where indicated - standard deviations were calculated separately for each group and sex.
For statistical evaluation of food consumption, body weights, and organ weights the Dunnet-Test was used. For values of haematological and clinical chemistry examinations the Dunnet- Test was used in case of normal distribution, otherwise the STEEL-Test was employed. Significant differences between mean values of control group 1 and dose groups 2, 3, and 4 were marked with * or ** , respectively.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Clinical Investigations:
- Clinical signs: In the low dose group (2, 68.1 mg/kg) the behaviour and general condition of the animals was not affected in 1 rat, was recorded at the same incidence in the other dose and control groups and is therefore considered as incidental.
Of the animals of the mid dose group (3, 147 mg/kg) only 1 rat showed salivation, 1 kept her head in a tilted position, and 2 exhibited alopecia. Salivation was detected between days 10 and 21 of the treatment. Tilted head and alopecia were observed firstly in weeks 1 or 3, respectively, and lasted until the end of the treatment period.
The animals of group 4 (316/237 mg/kg) exhibited a whole number of symptoms starting on days 7 to 14. Signs were slight to moderate hypokinesia, coordination disturbances, restrained or stilted gait, salivation, piloerection, and sunken sides. Two rats exhibited reddish salivation for 1 day each. One rat showed tilted head. During the recovery period all clinical findings faded within 2 weeks. Nine days after the end of the administration in 2 males the reduced size of testes was noted. This finding remained until termination of the study. Deaths occurred only in the high dose group (316 mg/kg). After 11 to 14 days 2 males and female were found dead. To prevent further fatalities the dose was reduced to 237 mg/kg on day 15.
- Food consumption: In animals of the low and mid dose groups (2,3) a slight, respectively moderate retardation of the increase in food consumption during the treatment period was recorded. Both sexes were equally affected. The maximum differences of mean values in group 2 were about 9 % in female and 4 % in males. In group 3 the maximum mean differences were about 15 % in males and 13 % in females. In the high dose group there was a very steep reduction of food intake in week 2. The mean difference relative to the control animals reached about 45 % in males and 28 % in females. After the reduction of the dose at the end of week 2 food consumption improved slightly and the difference was about 35 % in males and 28 % in females in week 4. After termination of the treatment the food uptake reached control values within 3 weeks.
-Body weights: The body weight gain was affected by the test substance only in the mid and high dose groups. In group 3 only males showed a very slight effect. In males as well as in females of group 4 body weight remained almost constant during the treatment period. The maximum difference of means relative to control, reached in week 4, was about 33 % in males and 16 % in females. Only during the first 4 weeks of the recovery period the body weight increased steeply. Afterwards the increase of body weight slowed down in males and stopped in females. Body weight reached about 90 % of control values.
- Examinations of reflexes, eyes, hearing, and teeth: No defects were detected during examinations of eyes, teeth, and ears in week -1 and 4. In weeks 4 or 10 1 control female each exhibited mydriasis of the left eye. No changes were recorded during the weekly examination of pinna, corneal, and pain reflexes.

Clinical Pathology
- Haematology:
After 2 days of administration the examination of cellular blood constituents did not reveal any toxicologically significant differences in treated animals. Although there is a statistical significant increase of the absolute numbers of lymphocytes in group 4 males, the value is still within the normal range. Therefore the finding is considered as incidental. During the second investigation in week 4 changes were detected predominantly in red blood cells. The number of red cells (erythrocytes), haemoglobin content, hematocrit, mean corpuscular volume (females only), and the number of reticulocytes (females only) was significantly increased in males and females of groups 3 and 4. The changes (hematocrit, mean corpuscular volume, mean corpuscular hemoglobin) were dose dependent and could be detected also in group 2, although they mostly were not significant in this group. The high value of mean corpuscular hemoglobin in group 2 is within the normal range, does not show a correlation to the dose, and is therefore considered as incidental. Among the white blood cells the numbers of lymphocytes, absolute as well as relative, were reduced reaching significant levels with significant differences only in group 4. At the end of the recovery period (week 10) all changed parameters had returned to normal values. The only exceptions were mean corpuscular volume, which had been increased in females and now was above control in males, too, and mean corpuscular hemoglobin, which also was high in males and females.
- Clinical chemistry: The clinical chemistry examination performed in parallel to the haematology in weeks 1, 4, and 10 showed changes in a whole number of parameters. In week 1 males of group 4 exhibited increases in oxygenated hemoglobin concentration, blood urea, and cholesterol. Slight decreases were noticed in the activities of cholinesterase and glutamate dehydrogenase. While in group 3 animals levels of oxygenated hemoglobin, cholinesterase, and glutamate dehydrogenase still were altered, animals of group 2 did not show significant changes. The low potassium concentration in males of group 3 is not dose dependent and therefore considered as incidental. In females the values for creatine kinase and alanine aminotransferase activities, total protein, alpha1- und beta-globulins, and potassium were low. Only the concentration of iron was increased. Changes were mostly observed in groups 3 and/or 4, but group 2 also showed slight, insignificant effects (iron, creatine kinase): At the end of the treatment period (week 4) animals of both sexes showed considerable increases in the concentrations of oxygenated hemoglobin and iron in groups 3 and 4. In group 2 slight increases of oxygenated hemoglobin were noted, although these were not statistically significant. The concentration of iron also was increased. Also in rats of both sexes (groups 3 and/or 4) the concentrations or activities of glucose, total protein, cholineesterase, glutamate dehydrogenase, albumin (minimally), potassium (minimally), alpha1-globulins /absolute and relative), and alpha2-globulins (absolute) were significantly reduced. Additionally alanine aminotransferase (only in group 3), alkaline phosphatase, and triglycerides (only in group 4) appeared decreased in females of these groups but were still in the control range and are considered as incidental findings. Males of groups 3 and 4 showed reductions in gamma-glutamyltransferase (only group 4) and alpha2-globulins (relative) and at the same time minimal increases in cholesterol, and beta- globulins (relative). The small alterations in chloride, creatinine, calcium, albumin (relative) are all within the normal range, not dose dependent and therefore are considered as incidental findings. At the end of the recovery period all parameters had returned to normal except for a remaining, slightly high iron concentration in female rats. There are some slight statistically significant changes in methaemoglobin, aspartate aminotransferase, creatinine, total protein, albumin (absolute), alpha1-globulins (absolute, in females) and blood urea and alpha2-globulins, but they are well within the normal range. They possess no toxicological importance and are judged as incidental findings.
- Urinalysis: No test substance related findings were detected during the examination of urine.

Pathology:
- Gross Necropsy: The macroscopical inspection of the rats during section revealed changes in stomachs and male genital organs. The mucous membranes of the glandular stomachs were thickened in male and female animals of the high dose group (group 4). The organs of the male genital tract were small.
- Organ Weights: At necropsy absolute organ weights were significantly altered only in male rats of group 4. Relative organ weights were changed in females of groups 3 and 4 and males of group 4. The organs affected were brain, heart, liver, kidneys, spleen, and testes with respect to absolute weights and brain, heart, kidneys, and adrenals with respect to relative weights. In females absolute organ weights appeared normal, but relative weights of brain, liver, kidneys, and spleen were increased. The alterations probably were due to direct effects of the test substance only spleen, adrenals, and testes. Absolute weights were decreased for spleens in males of group 4, while the relative weights were unchanged. In group 4 females the absolute weights seemed to be normal (although body weights were decreased) and therefore the relative weights appeared high. Adrenals only showed slightly increased relative weights in males of group 4. Testes were grossly reduced in size and their absolute weights were reduced by 40 to 50 %. The relative weight was only very slightly lowered. All findings are considered as secondary effects due to the severely reduced body weight.

Histopathology:
Treatment related changes were seen in stomach, spleen, adrenals, testes, epididymides, prostate, and seminal vesicles.
-Stomach: Treatment related changes of the stomach consisted of a diffuse hyperplasia of the mucosa and of diffuse mixed inflammatory cell infiltrates. The hyperplasia of the mucosa was restricted to the glandular stomach and was more pronounced in the fundic than in the pyloric area. In sections stained with the PAS reagent it was possible to identify chief cells, parietal cells, and mucous neck cells in the hyperplastic mucosa. The neck region of the gastric glands, characterized by the occurrence of mucous neck cells, seemed to be enlarged. The same results were obtained from sections stained according to the procedure of Shiebler and Behr. No hyperplasia of endocrine cells was observed in sections stained with the silver impregnation technique according to Grimelius. Diffuse mucosal hyperplasia of the glandular stomach was observed in all treated animals. There was no obvious tendency towards a dose related increase in the severity of this change. The finding was graded slight to moderate with the exception of each 1/5 female of the low dose and high dose groups.Incidence and severity of mucosal hyperplasia showed a tendency towards regression during the recovery period. The finding was graded slight to moderate with the exception of each 1/5 female of low dose and high dose groups. Incidence and severity of mucosal hyperplasia showed a tendency towards regression during the recovery period. The finding was observed in 1/3 males and 2/4 females of the high dose group, graded as minimal. The microscopic finding of diffuse mucosal hyperplasia correlated with the macroscopic observation of a thickened mucosa in each 1/5 male and 1/5 female of the high dose group. Diffuse mixed inflammatory cell infiltrates occurred in the lamina propria mucosa of the glandular stomach, predominantly in the fundic area. It was always associated with diffuse hyperplasia of the mucosa. Mixed inflammatory cell infiltrates were observed in 3/5, 4/5, and 5/5 males and in 4/5, 5/5, and 5/5 females of groups 2, 3, and 4, respectively. It was graded minimal to slight in the low dose group and slight to moderate in the mid and high dose groups. The inflammatory changes showed nearly complete regression during the recovery period. Only 1/4 females had minimal diffuse mixed inflammatory cell infiltrates. A focal submucosal edema, graded as moderate, was observed in 1/5 high dose group female. This finding is presumably treatment related, although the same change was found in 1/5 female control rat of the recovery group.
-Spleen: The spleen was changed by a treatment related reduction of the marginal zone and a treatment related increase in the extramedullary haematopoiesis. A reduced marginal zone was observed only in males. One/5 animals of the mid and 3/5 of the high dose groups had this finding. It was graded minimal in the case of the group 3 animal and minimal to moderate in the group 4 rats. The finding showed complete regression during the recovery period. An increased extramedullary haematopoiesis was observed in animals of all groups. In both males and females the finding showed a minimal dose related increase in incidence and/or severity. In males, 1/5, 2/5, 4/5, and 3/5 animals of groups 1, 2, 3, and 4, respectively, had this finding. It was graded minimal to moderate without a clear tendency towards a dose related increase of severity. Three/5, 2/5, 4/5, and 5/5 females of groups 1, 2, 3, and 4, respectively, had an increased extramedullary haematopoiesis, graded as minimal to moderate. The mean severity of this finding increased dose related from 1.3 in the control group to 2.0, 2.0, and 2.2 in groups 2, 3, and 4, respectively (explanation of codes for the grading: 1=minimal, 2=slight, 3=moderate, 4=marked, 5=massive). The finding showed strong tendency towards regression during the recovery period. 4/5 group 1 and 3/3 group 4 recovery males had an increased extramedullary haematopoiesis, with a mean severity of 1.0 in group 1 and 1.3 in group 4. In females the change was observed in 3/5 controls and 2/4 high dose group rats, with a mean severity of 2.0 in group 1 and 1.5 in group 4.
- Treatment related changes of the adrenals consisted of an increased cortical vacuolization. The vacuolization was most pronounced in the zona glomerulosa and fasciculata. The zona reticularis was less intensely affected. In both males and females the finding showed a dose related increase in incidence and severity. Two/5, 2/5, and 5/5 males of groups 2, 3, and 4, respectively, had an increased cortical vacuolization. The mean severity of the finding increased from 1.0 in group 2 to 1.5 in group 3, and 2.0 in group 4. In females, the finding was observed in 3/5 group 2 and each 5/5 group 3 and 4 animals. The mean severity was 1.0 in group 2, 1.6 in group 3, and 1.8 in group 4. In the recovery groups the finding occurred in group 4 animals as well as in control rats. Three/5 group 1 and 2/3 group 1 and 2/3 group 4 males had this finding. In females the change occurred in 3/5 controls and 3/4 high dose group animals. The mean severity was 2.0 and 2.5 in group 1 and group 4 males, respectively, and 2.3 in each controls and high dose group females.

Male genital system:
- Testes: The testes of treated animals were changed by a degeneration of the germinal epithelium and a hyperplasia of Leydig cells. The degeneration of the germinal epithelium was in most cases diffuse. The severity of the change differed between the tubules of one testis and between both testes of the same animal. Tubules with marked degeneration were lined only by Sertoli cells, while less intensely affected tubules had spermatogonia and reduced numbers of spermatocytes and spermatides. In these tubules also multinucleated giant cells or necrotic spermatocytes, spermatides and spermatozoa occurred. Degeneration of the germinal epithelium was observed in all animals of the high dose group. Diffuse degeneration occurred in 1/5 group 2 rat, graded as minimal, and in 4/5 group 4 animals, graded as moderate to massive. One/5 group 4 male had slight focal degeneration of the germinal epithelium. No group 3 animal had degeneration of the germinal epithelium. The degeneration of the germinal epithelium showed a minimal tendency towards regression during the recovery period. In affected organs, intact tubules were observed next to tubules lined only by Sertoli Cells, suggesting that only less intensely changed tubules showed regeneration. Two/3 high dose group rats had marked diffuse degeneration of the germinal epithelium, 1/3 had moderate focal degeneration. Diffuse hyperplasia of Leydig cells occurred in 2/5 high dose group males, graded minimal and slight. This finding showed tendency towards progression during the recovery period. Two/3 group 4 recovery males were affected, graded slight to moderate.
- Epididymides: As a result of the testicular degeneration of the germinal epithelium, the epididymides had a treatment related reduction of spermatosoma. The finding was diagnosed in 5/5 high dose group animals, graded slight to marked. During the recovery period the finding showed minimal tendency towards regression. Two/3 high dose group rats had severe reduction of spermatosoma. The animal with focal testicular degeneration of the germinal epithelium had no absence of spermatozoa in the epididymides.
- Prostate and seminal vesicles: Prostate and seminal vesicles of the one examined high dose group male had diffuse atrophy. This microscopical finding correlated to the macroscopical observation of a small prostate and seminal vesicles. All other findings noted are regarded as incidental (e.g. mononuclear infiltrates liver, kidneys, heart, brain, lung) or caused by the sacrifice procedure and not to be treatment related. Two/7 high dose group males and 1/6 high dose group females died intercurrently. In these animals, autolytic changes occurred, predominantly in the digestive tract. In organs without dominant autolysis, the same treatment related findings occurred as in animals terminally sacrificed. Additional findings which occurred in the three animals with intercurrent death were regarded as agonal changes.
Key result
Dose descriptor:
LOAEL
Effect level:
147 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
food consumption and compound intake
haematology
Key result
Dose descriptor:
NOEL
Effect level:
68.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
147 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
blood
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
147 mg/kg bw/day (nominal)
System:
male reproductive system
Organ:
adrenal glands
other: testes
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
147 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The data of the present study show that sodium cyanate, if ingested, is able to damage a number of organs. The main target organs are the red blood cells, spleen, testes and male genital system, liver and adrenals. 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. The no observed effect level cannot be determined exactly from these data. The NOEL is expected slightly below 68.1 mg/kg, because there were only slight, mostly statistically insignificant effects in this dose group (hyperplasia and inflammatory infiltrates in the stomach, cortical vacuolization in the adrenals, diffuse degeneration of the germinal epithelium in the testes, extramedullary haematopoiesis in the spleen, increase of oxygenated haemoglobin iron, reduced food intake).
Executive summary:

In this subacute toxicity study sodium cyanate (90 %) was administered to 5 Wistar rats/sex/dose in water by gavage at dose levels of 0, 68.1, 147, 316 (reduced to 237 mg/kg/day after 2 weeks) mg/kg bw/day.

The results of this 4-week oral toxicity study in Wistar rats indicate that sodium cyanate can affect the general condition and behaviour of the animals. Clinically the main findings were a considerable retardation of body weight gain, accompanied by reduced locomotive activity, impaired coordination, and clonic seizures at 147 and 316 mg/kg bw/day. Additionally there were signs of bad general condition, e. g. piloerection and sunken sides. These findings were recorded predominantly at the high dose (316/237 mg/kg). Changes in blood parameters indicate a negative influence of sodium cyanate on the function of the red blood cells and hence a decrease of the availability of oxygen to the tissue. The increase in red blood cell count, haematocrit, mean corpuscular volume, and reticulocytes can be understood as an attempt to increase the oxygen pressure in the tissue. This also correlates to the increased extramedullary haematopoiesis in the spleen and the elevated iron concentration in plasma. The reduction of the activities of almost all liver enzymes in serum indicates an effect of the test substance on the liver, which is not clearly a damage to the liver cells (no histological correlate), but seems to reduce protein synthesis and/or secretion of proteins into the blood. This is emphasized also by the decrease in albumin and globulin proteins. Similar effects of sodium cyanate on protein synthesis and secretion are described in the literature. The macroscopical changes in the size of the male genital tract are correlated with a microscopically observed degeneration of germinal epithelium in the testes. Whether this degeneration is the consequence of a direct action of the test substance on the germinal epithelium or due to hypoxia within the tissue caused by impaired oxygen delivery from the blood, cannot be conclusively determined from the data available but is likely. Nevertheless, the other changes in the male genital system (size of organs, proliferation of Leydig cells) are most likely secondary to the damage of the testes. The slight increased cortical vacuolization in the adrenals and the decrease of the number of lymphocytes has to be considered as a substance related effect, although the mechanisms involved are not clear. The diffuse hyperplasia of the mucosa in the glandular part of the stomach accompanied by an also diffuse mixed inflammatory cell infiltration appears to be due to a slight local irritation of the relatively high concentration of the test substance. The finding correlates to the macroscopically detected thickening of the mucous membrane. Except for the effects on the male genital system and the adrenals all changes were almost fully reversible within the 6-week recovery period. The vacuolization of the adrenals remained unchanged. The germinal epithelium also showed a tendency to recovery, but recovery is expected to take quite long periods of time to be complete in this tissue.

The data of the present study show that sodium cyanate, if ingested, is able to damage a number of organs. The main target organs are the red blood cells, which then might cause secondary toxicity to spleen, testes and male genital system, liver and adrenals. 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. The no observed effect level cannot be determined exactly from these data. The NOEL is expected slightly below 68.1 mg/kg, because there were only slight, mostly statistically insignificant effects in this dose group (hyperplasia and inflammatory infiltrates in the stomach, cortical vacuolization in the adrenals, diffuse degeneration of the germinal epithelium in the testes, extramedullary haematopoiesis in the spleen, increase of oxygenated hemoglobin iron, reduced food intake).

This subacute toxicity study in the rat is acceptable and satisfies the guidelines requirement for a subacute oral study (EU B.7 and OECD 407) in rats.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: public available literature non GLP, non Guideline) Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Limit test:
no
Species:
monkey
Strain:
other: Rhesus
Sex:
not specified
Details on test animals and environmental conditions:
body weight: 5-7 kg
Source: Drs. Ashley Brinson and Carolyn Ristau
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Each rhesus monkey received 0.5 g of cyanate sprinkled on a banana or an apple.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
15 months
Frequency of treatment:
daily 5 times a week
Remarks:
Doses / Concentrations:
0.5 g per monkey/day = 51 mg/kg bw /day
Basis:
actual ingested
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
- amount of carbamylation of the aminoterminal valine residue of the hemoglobin molecule
- oxygen affinity of the blood
- standard blood parameters
- general behaviour
Sacrifice and pathology:
monkeys were sacrificed after 12 months for routine gross and microscopic pathological survey.
Other examinations:
no data
Statistics:
no data
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:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
After 15 months of exposure of monkeys no long-term effects were observed. The animals appear healthy and alert and have maintained their weight during this period.
During the period of cyanate administration, a number of physiological measurements were determined bimonthly in the monkeys. The following analyses of the serum from the cyanate-treated group of monkeys were found to be the same as the values observed for control groups of animals during this period: bilirubin, glucose, albumin, calcium, blood urea nitrogen, lactic acid dehydrogenase, alkaline phosphatase, glutamic oxaloacetic transaminase and cholesterol.
The hematocrits, hemoglobin concentrations and white cell differential and counts were the same in the cyanate and control groups of monkeys.
The amount of carbamylation in treated monkeys levelled off after several weeks at 0.8 to 1.2 carbamyl groups per hemoglobin tetramer and remained in that range for the entire year. The electrophoretic pattern of the sera of dogs and monkeys receiving cyanate was indistinguishable from the pattern observed for control sera. Whole blood CO2 was not significantly different between cyanate and control groups.
After 12 months of cyanate administration, two of the monkeys, as well as control monkeys, were sacrificed for routine gross and microscopic pathological surveys. These surveys did not detect any significant lesions in these animals.
Key result
Dose descriptor:
NOAEL
Effect level:
51 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Worst case approach: The NOAEL was calculated based on a body weight of 7 kg and corrected for exposure frequency (5 times per week).
Key result
Critical effects observed:
no
Conclusions:
After 15 months of exposure of monkeys (51 mg/kg bw/day) no long-term effects were observed.
Executive summary:

In a chronic toxicity study sodium cyanate was administered to 6 rhesus monkeys/dose in diet at dose levels of 0 and 51 mg/kg bw/day for 15 months.

After 15 months of exposure of monkeys no long-term effects were observed. The animals appear healthy and alert and have maintained their weight during this period. No indication for neurotoxic effects were noted.

During the period of cyanate administration, a number of physiological measurements were determined bimonthly in the monkeys. The following analyses of the serum from the cyanate-treated group of monkeys were found to be the same as the values observed for control groups of animals during this period: bilirubin, glucose, albumin, calcium, blood urea nitrogen, lactic acid dehydrogenase, alkaline phosphatase, glutamic oxaloacetic transaminase and cholesterol.

The hematocrits, hemoglobin concentrations and white cell differential and counts were the same in the cyanate and control groups of monkeys.

The amount of carbamylation in treated monkeys levelled off after several weeks at 0.8 to 1.2 carbamyl groups per hemoglobin tetramer and remained in that range for the entire year. The electrophoretic pattern of the sera of dogs and monkeys receiving cyanate was indistinguishable from the pattern observed for control sera. Whole blood CO2 was not significantly different between cyanate and control groups.

After 12 months of cyanate administration, two of the monkeys, as well as control monkeys, were sacrificed for routine gross and microscopic pathological surveys. These surveys did not detect any significant lesions in these animals. The NOAEL is 51 mg/kg bw´/day (Worst case approach: The NOAEL was calculated based on a body weight of 7 kg and corrected for exposure frequency (5 times per week)). No LOAEL can be determined.

This chronic study in the monkey is acceptable as supporting study.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: public available literature non GLP, non Guideline) Read across to sodium cyanate. For justification of read across see endpoint summary.
Reason / purpose:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
mouse
Strain:
other: B6/D2 F1
Sex:
female
Details on test animals and environmental conditions:
body weight: 20 g
Source: Jackson Laboratories (Bar Harbor, Maine, USA)
Route of administration:
oral: feed
Vehicle:
other: food
Details on oral exposure:
Three groups of female mice were fed one of the following diets:
a) Purina mouse chow
b) Purina mouse chow containing 0.2% sodium cyanate
c) Purina mouse chow containing 1% sodium cyanate
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
15 months
Frequency of treatment:
continuous
Remarks:
Doses / Concentrations:
0, 0.2 and 1 % = 0, 300 and 1500 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
- carbamylation of hemoglobin
- body weight
- organ weight
Sacrifice and pathology:
After 13 months of receiving the 1 % cyanate diet, representative animals were sacrificed for pathological examination.
Other examinations:
no data
Statistics:
no data
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
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:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
The mice have been receiving cyanate diets (0.2 and 1%) for 15 months without any apparent irreversible ill effects. The only effects noted in the group receiving a 1 % cyanate diet have been a slight reduction in weight, a failure to remove food and debris from the hair coat and a reversible inhibition of reproductive capacity. This effect was considered not relevant (see reproduction toxicity endpoint). After several months mice fed 0.2 and 1 % cyanate plateaued at approximately 1.0 carbamyl groups per hemoglobin tetramer. Organ weights were all within the normal range, and no gross or histopathological lesions were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Body weight loss
Key result
Critical effects observed:
no
Conclusions:
The mice have been receiving cyanate diets (0.2 and 1%) for 15 months without any apparent irreversible ill effects.
Executive summary:

In a chronic toxicity study sodium cyanate was administered to 50 B6/D2 F1 female mice/dose in diet, at dose levels of 0, 0.2, 1.0 % in the diet for 15 months.

The mice have been receiving cyanate diets (0.2 and 1%) for 15 months without any apparent irreversible ill effects. The only effects noted in the group receiving a 1 % cyanate diet have been a slight reduction in weight, a failure to remove food and debris from the hair coat and a reversible inhibition of reproductive capacity. This effect was considered not relevant (see reproduction toxicity endpoint). After several months mice fed 0.2 and 1 % cyanate plateaued at approximately 1.0 carbamyl groups per hemoglobin tetramer. Organ weights were all within the normal range, and no gross or histopathological lesions were observed.

NOAEL = 300 mg/kg bw/day

LOAEL = 1500 mg/kg bw/day (based on body weight loss)

This chronic study in the mouse is acceptable as supporting study.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: public available literature non GLP, non Guideline) Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
dog
Strain:
Beagle
Sex:
not specified
Details on test animals and environmental conditions:
body weight: 6-8 kg
Source: Marshall Laboratories (North Rose, N.Y.)
Route of administration:
oral: capsule
Vehicle:
other: capsule
Details on oral exposure:
Each beagle was given a 600 mg capsule daily (5 times a week) of sodium cyanate one to two hours after feeding.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
15 months
Frequency of treatment:
daily 5 times a week
Remarks:
Doses / Concentrations:
one 600 mg capsule per dog/day = 53.5 mg/kg bw /day
Basis:
actual ingested
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
- amount of carbamylation of the aminoterminal valine residue of the hemoglobin molecule
- oxygen affinity of the blood
- standard blood parameters
Sacrifice and pathology:
two dogs were sacrificed after 12 months for routine gross and microscopic pathological survey.
Other examinations:
no data
Statistics:
no data
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:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
After 15 months of exposure of dogs no long-term effects were observed. The animals appear healthy and alert and have maintained their weight during this period.
The only toxic reaction occurred suddenly without prior weight loss after six months of cyanate administration to the dogs. The acute toxic episode was characterized by muscular tremors and apparent muscular weakness in all the dogs receiving cyanate. One dog experienced a particularly severe toxic reaction. The dog was recumbent and unable to rise for a period of several days. During the first day, the dog had intermittent grand mal seizures. The clinical signs in the less severely affected dogs disappeared a few days after the administration of the drug was discontinued. The severely affected dog took longer to recover but by 14 days had a complete clinical recovery with no residual neurological deficits.
An investigation into the possible explanation for this acute reaction revealed that for a four-day period preceding this episode, thy cyanate capsules had been administered to the dogs by a new animal attendant three hours before feeding rather than the usual one hour after feeding. The pre-prandial administration probably resulted in increased absorption and precipitated the observed reaction. One week after this episode, five of the dogs were returned to the regimen and since then have had no problems.
During the period of cyanate administration, a number of physiological measurements were determined bimonthly in the dogs. The following analyses of the serum from the cyanate-treated group of dogs were found to be the same as the values observed for control groups of animals during this period: bilirubin, glucose, albumin, calcium, blood urea nitrogen, lactic acid dehydrogenase, alkaline phosphatase, glutamic oxaloacetic transaminase and cholesterol.
The functioning of the liver was assessed in the dogs at 0, 3 and 12 months by the Bromsulphalein clearance test and was found to be in the normal range.
The two groups of dogs had similar white cell counts and differentials. However, several of the dogs in both the control and cyanate groups displayed a 10 to 15% increase in hematocrit and hemoglobin concentration when compared to the rest of the dogs. The amount of carbamylation in treated dogs levelled off after several weeks at 0.8 to 1.2 carbamyl groups per hemoglobin tetramer and remained in that range for the entire year. The electrophoretic pattern of the sera of dogs receiving cyanate was indistinguishable from the pattern observed for control sera. Whole blood CO2 was not significantly different between cyanate and control groups.
After 12 months of cyanate administration, two of the dogs, as well as control dogs, were sacrificed for routine gross and microscopic pathological surveys. These surveys did not detect any significant lesions in these animals.
Key result
Dose descriptor:
NOAEL
Effect level:
53.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Worst case approach: The NOAEL was calculated based on a body weight of 8 kg and corrected for exposure frequency (5 times per week).
Key result
Critical effects observed:
no
Conclusions:
After 15 months of exposure of dogs no (53.5 mg/kg bw/day) long-term effects were observed.
Executive summary:

In a 15-month dog study sodium cyanate was administered to 6 beagle/dose in by capsule at dose levels of 0 and 53.5 mg/kg bw/day.

After 15 months of exposure of dogs no long-term effects were observed. The animals appear healthy and alert and did maintained their weight during this period.

The only toxic reaction occurred suddenly without prior weight loss after six months of cyanate administration to the dogs. The acute toxic episode was characterized by muscular tremors and apparent muscular weakness in all the dogs receiving cyanate. One dog experienced a particularly severe toxic reaction. The dog was recumbent and unable to rise for a period of several days. During the first day, the dog had intermittent grand mal seizures. The clinical signs in the less severely affected dogs disappeared a few days after the administration of the drug was discontinued. The severely affected dog took longer to recover but by 14 days had a complete clinical recovery with no residual neurological deficits.

An investigation into the possible explanation for this acute reaction revealed that for a four-day period preceding this episode, thy cyanate capsules had been administered to the dogs by a new animal attendant three hours before feeding rather than the usual one hour after feeding. The pre-prandial administration probably resulted in increased absorption and precipitated the observed reaction. One week after this episode, five of the dogs were returned to the regimen and since then have had no problems.

During the period of cyanate administration, a number of physiological measurements were determined bimonthly in the dogs. The following analyses of the serum from the cyanate-treated group of dogs were found to be the same as the values observed for control groups of animals during this period: bilirubin, glucose, albumin, calcium, blood urea nitrogen, lactic acid dehydrogenase, alkaline phosphatase, glutamic oxaloacetic transaminase and cholesterol.

The functioning of the liver was assessed in the dogs at 0, 3 and 12 months by the Bromsulphalein clearance test and was found to be in the normal range.

The two groups of dogs had similar white cell counts and differentials. However, several of the dogs in both the control and cyanate groups displayed a 10 to 15% increase in hematocrit and hemoglobin concentration when compared to the rest of the dogs. The amount of carbamylation in treated dogs levelled off after several weeks at 0.8 to 1.2 carbamyl groups per hemoglobin tetramer and remained in that range for the entire year. The electrophoretic pattern of the sera of dogs receiving cyanate was indistinguishable from the pattern observed for control sera. Whole blood CO2 was not significantly different between cyanate and control groups.

After 12 months of cyanate administration, two of the dogs, as well as control dogs, were sacrificed for routine gross and microscopic pathological surveys. These surveys did not detect any significant lesions in these animals.

The NOAEL is 53.5 mg/kg bw/day (Worst case approach: The NOAEL was calculated based on a body weight of 8 kg and corrected for exposure frequency (5 times per week)). No LOAEL can be determined.

This study in dogs is acceptable as key study, together with the data of the monkey study (also Cerami et al., 1973) as supporting information.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1988
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Review data only Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not indicated.
Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
not indicated.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
8 days
Frequency of treatment:
not indicated.
No. of animals per sex per dose:
not indicated.
Control animals:
not specified
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
not indicated.
Sacrifice and pathology:
not indicated.
Other examinations:
not indicated.
Statistics:
not indicated.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
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:
not specified
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:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
not indicated.
Key result
Dose descriptor:
other: TDLo - lowest published toxic dose
Effect level:
400 other: mg/kg/8d
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Behavioural - somnolence (general depressed activity) equivalent to 50 mg/kg bw/day
Key result
Critical effects observed:
no
Conclusions:
TDLo (rat, oral) = 400 mg/kg/8d equivalent to 50 mg/kg bw/day (intermittent).
Executive summary:

In a subacute toxicity study sodium cyanate was administered to rats orally for 8 days.

Effects: Behavioural - somnolence (general depressed activity)

The TDLo (lowest published toxic dose) = 400 mg/kg/8d equivalent to 50 mg/kg bw/day (intermittent).

This subacute study in the rat is acceptable, as supporting study.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1988
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Review data only Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
mouse
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not indicated.
Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
not indicated.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
10 days
Frequency of treatment:
not indicated.
No. of animals per sex per dose:
not indicated.
Control animals:
not specified
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
not indicated.
Sacrifice and pathology:
not indicated.
Other examinations:
not indicated.
Statistics:
not indicated.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
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:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
not indicated.
Key result
Dose descriptor:
other: TDLo - lowest published toxic dose
Effect level:
2 000 other: mg/kg/10 D
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Peripheral Nerve and Sensation - flaccid paralysis without anaesthesia (usually neuromuscular blockage) Behavioural - somnolence (general depressed activity) Related to Chronic Data - death equivalent to 200 mg/kg bw/day
Key result
Critical effects observed:
no
Conclusions:
TDLo (mouse, oral) = 400 mg/kg/8d equivalent to 50 mg/kg bw/day (intermittent).
Executive summary:

In a subacute toxicity study sodium cyanate was administered to mice orally for 10 days.

Effects:

Peripheral Nerve and Sensation - flaccid paralysis without anaesthesia (usually neuromuscular blockage)

Behavioural - somnolence (general depressed activity)

Chronic Data - death

The TDLo (lowest published toxic dose) = 2000 mg/kg/10 d equivalent to 200 mg/kg bw/day (intermittent).

This subacute study in the rat is acceptable, as supporting study.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1988
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Review data only Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
mouse
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not indicated.
Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
not indicated.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
3 days
Frequency of treatment:
not indicated.
No. of animals per sex per dose:
not indicated.
Control animals:
not specified
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
not indicated.
Sacrifice and pathology:
not indicated.
Other examinations:
not indicated.
Statistics:
not indicated.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
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:
not specified
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:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
not indicated.
Key result
Dose descriptor:
other: TDLo - lowest published toxic dose
Effect level:
1 200 other: mg/kg/3D
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Related to Chronic Data - death equivalent to 400 mg/kg bw/day
Key result
Critical effects observed:
no
Conclusions:
TDLo (mouse, oral) = 400 mg/kg/8d equivalent to 50 mg/kg bw/day (intermittent).
Executive summary:

In a subacute toxicity study sodium cyanate was administered to mice orally for 3 days.

Effects: Chronic data - death

The TDLo (lowest published toxic dose) = 1200 mg/kg/3d equivalent to 400 mg/kg bw/day (intermittent).

This subacute study in the rat is acceptable, as supporting study.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1988
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Review data only
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not indicated.
Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
not indicated.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
3 days
Frequency of treatment:
not indicated.
No. of animals per sex per dose:
not indicated.
Control animals:
not specified
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
not indicated.
Sacrifice and pathology:
not indicated.
Other examinations:
not indicated.
Statistics:
not indicated.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
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:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Peripheral Nerve and Sensation - flaccid paralysis with appropriate anesthesia
Behavioural - somnolence (general depressed activity)
Liver - other changes
Key result
Dose descriptor:
other: TDLo - lowest published toxic dose
Effect level:
300 other: mg/kg/3d
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Peripheral Nerve and Sensation - flaccid paralysis with appropriate anesthesia Behavioural - somnolence (general depressed activity) Liver - other changes equivalent to 100 mg/kg bw/day
Key result
Critical effects observed:
no
Conclusions:
TDLo (guinea pig, oral) = 300 mg/kg/3d equivalent to 100 mg/kg bw/day (intermittent).
Executive summary:

In a subacute toxicity study sodium cyanate was administered to guinea pigs orally for 3 days.

Peripheral Nerve and Sensation - flaccid paralysis with appropriate aanesthesia

Behavioural - somnolence (general depressed activity)

Liver - other changes

The TDLo (lowest published toxic dose) = 300 mg/kg/3d equivalent to 100 mg/kg bw/day (intermittent).

This subacute study is acceptable, as supporting study.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1988
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Review data only
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
dog
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
not indicated.
Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
not indicated.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
1 year
Frequency of treatment:
not indicated.
No. of animals per sex per dose:
not indicated.
Control animals:
not specified
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
not indicated.
Sacrifice and pathology:
not indicated.
Other examinations:
not indicated.
Statistics:
not indicated.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not specified
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:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Brain and Coverings - other degenerative changes
Gastrointestinal - other changes
Nutritional and Gross Metabolic - weight loss or decreased weight gain
Key result
Dose descriptor:
other: TDLo - lowest published toxic dose
Effect level:
10 950 other: mg/kg/1 year
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: Brain and Coverings - other degenerative changes Gastrointestinal - other changes Nutritional and Gross Metabolic - weight loss or decreased weight gain equivalent to 30 mg/kg bw/day
Key result
Critical effects observed:
no
Conclusions:
TDLo (dog, oral) = 10950 mg/kg/1 year equivalent to 30 mg/kg bw/day (intermittent).
Executive summary:

In a chronic toxicity study sodium cyanate was administered to dogs orally for 1 year.

Effects:

Brain and Coverings - other degenerative changes

Gastrointestinal - other changes

Nutritional and Gross Metabolic - weight loss or decreased weight gain

TDLo (lowest published toxic dose) = 10950 mg/kg/1 year equivalent to 30 mg/kg bw/day (intermittent).

This chronic study in the dogs is acceptable, as supporting study.

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1977
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: public available literature (non GLP, non guideline). Only very limited reliability due to different exposure times and small number of dogs used per exposure time. Read across to sodium cyanate. For justification of read across see endpoint summary.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
prior to admisson into study, the dogs were examined and checked for parasites. All animals were given distemper vaccine.
Route of administration:
oral: capsule
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Nineteen beagle dogs were housed and fed at Rockefeller University and 15 were administered 300 mg sodium cyanate capsules. The doses varied from 0 to 170 mg/kg bw/day depending on whether the dogs were exhibiting toxic effects or not.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no details on analytical verification of doses.
Duration of treatment / exposure:
The mean period of cyanate dosage for the animals was 28 months (12-39 months).
Frequency of treatment:
Dosing was done 5 days per week.
Remarks:
Doses / Concentrations:
0 to 170 mg/kg bw/day depending on whether the dogs were exhibiting toxic effects or not.
Basis:
actual ingested
No. of animals per sex per dose:
15 exposed dogs ( 11 females and 4 males)
4 control dogs (sex not specified)
Control animals:
yes, concurrent no treatment
Details on study design:
no further details given.
Positive control:
no positive control.
Observations and examinations performed and frequency:
The dogs were examined and weighed monthly and blood was obtained for complete blood count, serum bilirubin, calcium, cholesterol, glucose, lactate dehydrogenase, albumin, total protein, phosphorus, blood urinary nitrogen, glutamic oxaloacetic transaminase and uric acid, all of which were performed by standard clinical chemical methods and found to be normal.
The carbamylation was measured as hydantoin residues and results were expressed per hemoglobin tetramer. Direct ophtalmoscopic and slit lamp biomicroscopic examinations were performed on all 19 beagles.
Sacrifice and pathology:
Eight cataractous and four normal dogs were sacrificed and the eyes were enucleated and placed immediately in ice for further study. The lenses were excised and biochemical parameters were measured (cation concentrations, lactate, reduced glutathione, lens water, cation fluxes)
Other examinations:
no other examinations.
Statistics:
Statistical comparison was made using the Student's t-test.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Clinical blood parameters were found to be normal.
The control beagles were not found to have lenticular changes. Changes were found in 14 cyanate-treated dogs. Lenticular lesions ranged from minimal posterior subcapsular sclerosis of the sutur lines to large sclerotic areas covering the entire posterior surface of the lens and extending onto the anterior surface. Of note was that in animals which had been exposed to an intermittent high dose of cyanate sclerotic areas which had moved centrally were observed, indicating a previous toxic injury, while new lens formation appeared normal when the dose was below 30 mg/kg bw/day. The beagle receiving 30 mg/kg bw/day did not developed lenticular damage.
Animals which were begun on cyanate at an early age seemed to develop more severe lenticular lesions after a shorter period of time. All animals with cataracts evidenced other manifestations of toxicity during the study including weight loss in all but one puppy and signs of nervous system or gastrointestinal involvement in most of the animals.
The mean period of cyanate dosage for the animals with lenticular changes was 28 months and the mean carbamylation achieved was 0.69 residue of cyanate per haemoglobin tetramer. Corneal lesions occurred in five of the cataractous animals. The beagles with corneal lesions had received sodium cyanate for a longer period of time than the cataractous group as a whole (36 vs. 28 months) but the difference was not statistically significant. The mean carbamylation achieved was 0.78 residue of cyanate per mol of haemoglobin in the dogs with corneal lesions as opposed to 0.69 in the cataractous group as a whole. This difference was highly significant. There was no difference in the maximum dose received between the groups (113 +/- 22 vs. 119 +/-23 mg/kg bw/day).
Lens weight appeared comparable between cyanate treated and control dogs. Intracellular sodium concentration increased in the cataractous group. Potassium concentrations were decreased (not significant). Reduced glutathione concentrations were decreased significantly from control levels. Lactate leakage was increased and again the degree of impairment appeared to parallel the extent of morphological changes seen. Rubidium uptake was significantly increased in the cataractous lenses. This increase and the increased glycolytic activity would appear to be of a compensatory nature for the changes involved since the higher rubidium uptakes and lactate formation were seen in the most severely lesioned lenses. Extracellular space was increased in the cataractous lenses. This increase may be related to the altered transport of cations and also parallels the degree of structural change noted.
Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no ocular lesions observed.
Key result
Dose descriptor:
LOAEL
Effect level:
90 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: ocular lesions (cataracts)
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
90 mg/kg bw/day (nominal)
System:
eye
Organ:
other: eyes
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
Ocular lesions secondary to sodium cyanate administration in the beagle are described.
Executive summary:

Fifteen dogs were given sodium cyanate at doses of 30 to 170 mg/kg bw/day, 5 days per week. Fourteen dogs developed cataracts which were generally posterior and subcapsular. Five animals developed corneal lesions. Control beagles and cyanate treated rats and monkeys did not develop lesions. The one drug-treated beagle without ocular lesions received a maximum dose of 30 mg/kg bw/day of sodium cyanate for 19 months and achieved a mean carbamylation of 0.39 residue of cyanate per mol of haemoglobin. Animals developing cataracts received a maximum dose of 119 +/- 23 mg/kg bw/day for 28 +/- 10 months and achieved a mean carbamylation of 0.69 +/- 0.13 residue/mol. Animals developing corneal lesions received a maximum dose of 113 +/- 22 mg/kg bw/day for 36 +/- 7 months and achieved a mean carbamylation of 0.78 +/- 0.09 residue/mol.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1977
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: public available literature (non GLP, non Guideline)
Qualifier:
no guideline followed
Principles of method if other than guideline:
Public available literature. No guideline indicated. For details on method see materials and methods section.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
not specified
Details on test animals and environmental conditions:
Age at beginning of study: 2-3 months
Route of administration:
oral: feed
Vehicle:
other: diet
Details on oral exposure:
rats were given a cyanate-rich diet (0.3 % in the daily diet).
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not indicated.
Duration of treatment / exposure:
18 months
Frequency of treatment:
continuous (diet)
Remarks:
Doses / Concentrations:
0.3 % (equivalent to 150 mg/kg bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
one dose: 15 animals
control: 6 animals
Control animals:
yes, plain diet
Details on study design:
not indicated.
Positive control:
not indicated.
Observations and examinations performed and frequency:
Rats were examined and weighed bi-weekly.
Sacrifice and pathology:
Twelve cyanate-treated and six controls were sacrificed after 18 months when a fully developed paralysis had been established (Method: perfusion-fixation).
The brain, spinal cord, dorsal and ventral spinal roots, sciatic, peroneal, tibial and plantar nerves were post-fixed in Dalton's fixative and embedded in epoxy-resin.
Other examinations:
not indicated.
Statistics:
not indicated.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
The rats on cyanate diet failed to gain as much weight as the controls. No clear cut neurological abnormalities were noticed during the first 12-15 months of the study. After 18 months on cyanate-diet the rats showed marked weakness of the hind limbs. Within a month all of the animals showed symptoms. The motor deficit was greater in the hind extremities but it progressed to involve the upper extremities as well. At this time the animals were sacrificed for pathological and ultrastructural study.
Examination of brain, cerebellum and brain stem failed to disclose abnormalities. In the spinal cord, anterior horn cells occasionally exhibited small vacuoles at the periphery of the perikaryon, but all had a normal distribution of Nissl granules, and a well preserved morphological appearance. The fiber tracts of the spinal cord, including the fasciculus gracilis and cuneatus at their terminations in the medulla were normal. Cervical and lumbar dorsal root ganglia were normal.
Pathological changes occurred in peripheral nerves, especially in the lumbar roots.
Key result
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
body weight and weight gain
gross pathology
neuropathology
Key result
Critical effects observed:
no
Conclusions:
Clear cut motor deficits became apparent at a stage of advanced structural damage in the peripheral nervous system.
Executive summary:

In a subchronic toxicity study sodium cyanate was administered to 15 rats in diet at a single dose levels of 0.3 % in diet equal to 150 mg/kg bw/day.

This study indicated that the development of toxic neuropathy by cyanate in the rat required a long period of exposure to relatively high doses of the drug and suggests that there is a slow, progressive, subclinical period during which there might be a cumulative effect of chemical and structural changes. Clear cut motor deficits became apparent at a stage of advanced structural damage in the peripheral nervous system. This subchronic study in the rat is acceptable as supporting study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
chronic
Species:
dog
Quality of whole database:
Beside a subacute 28-day repeated dose toxicity study, for sodium cyanate only a number of non standard public available literature studies are available.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral / i.p. administration:

Beside a subacute 28-day repeated dose toxicity study, for sodium cyanate only a number of non-standard public available literature studies are available. These studies, investigating the repeated dose toxicity in different species (mouse, rat, dog, monkey) for different exposure times (up to one year), together with data from human medical treatment, are summarised in a weight of evidence approach and allow a reliable evaluation of the toxic properties of both sodium and potassium cyanate after repeated application, as well a reliable deduction of DNELs for the final risk assessment.

Studies in Rats:

- In a subacute toxicity study (Berthold, 1993), sodium cyanate (90 %) was administered to 5 Wistar rats/sex/dose in water by gavage at dose levels of 0, 68.1, 147, 316 (reduced to 237 mg/kg/day after 2 weeks) mg/kg bw/day. The results of this 4-week oral toxicity study in Wistar rats indicate that sodium cyanate can affect the general condition and behaviour of the animals. Clinically the main findings were a considerable retardation of body weight gain, accompanied by reduced locomotive activity, impaired coordination, and clonic seizures at 147 and 316 mg/kg bw/day. Additionally there were signs of bad general condition, e. g. piloerection and sunken sides. These findings were recorded predominantly at the high dose (316/237 mg/kg). Changes in blood parameters indicate a negative influence of sodium cyanate on the function of the red blood cells and hence a decrease of the availability of oxygen to the tissue. The increase in red blood cell count, hematocrit, mean corpuscular volume, and reticulocytes can be understood as an attempt to increase the oxygen pressure in the tissue. This also correlates to the increased extramedullary hematopoiesis in the spleen and the elevated iron concentration in plasma. The reduction of the activities of almost all liver enzymes in serum indicates an effect of the test substance on the liver, which is not clearly a damage to the liver cells (no histological correlate), but seems to reduce protein synthesis and/or secretion of proteins into the blood. This is emphasized also by the decrease in albumin and globulin proteins. Similar effects of sodium cyanate on protein synthesis and secretion are described in the literature. The macroscopical changes in the size of the male genital tract are correlated with a microscopically observed degeneration of germinal epithelium in the testes. Whether this degeneration is the consequence of a direct action of the test substance on the germinal epithelium or due to hypoxia within the tissue caused by impaired oxygen delivery from the blood, cannot be conclusively determined from the data available but is likely. Nevertheless, the other changes in the male genital system (size of organs, proliferation of Leydig cells) are most likely secondary to the damage of the testes. The slight increased cortical vacuolization in the adrenals and the decrease of the number of lymphocytes has to be considered as a substance related effect, although the mechanisms involved are not clear. The diffuse hyperplasia of the mucosa in the glandular part of the stomach accompanied by an also diffuse mixed inflammatory cell infiltration appears to be due to a slight local irritation of the relatively high concentration of the test substance. The finding correlates to the macroscopically detected thickening of the mucous membrane. Except for the effects on the male genital system and the adrenals all changes were almost fully reversible within the 6-week recovery period. The vacuolization of the adrenals remained unchanged. The germinal epithelium also showed a tendency to recovery, but recovery is expected to take quite long periods of time to be complete in this tissue. The data of the present study show that sodium cyanate, if ingested, is able to damage a number of organs. The main target organs are the red blood cells, which then might cause secondary toxicity to spleen, testes and male genital system, liver and adrenals. 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. The no observed effect level cannot be determined exactly from these data. The NOEL is expected slightly below 68.1 mg/kg, because there were only slight, mostly statistically insignificant effects in this dose group (hyperplasia and inflammatory infiltrates in the stomach, cortical vacuolization in the adrenals, diffuse degeneration of the germinal epithelium in the testes, extramedullary hematopoiesis in the spleen, increase of oxygenated hemoglobin iron, reduced food intake). This subacute toxicity study in the rat is acceptable and satisfies the guidelines requirement for a subacute oral study (EU B.7 and OECD 407) in rats.

- In a subchronic toxicity study sodium cyanate was administered to 15 rats in diet at a single dose level of 0.3 % in diet (Tellez-Nagel, 1977). This study indicated that the development of toxic neuropathy by cyanate in the rat required a long period of exposure to relatively high doses of the drug and suggests that there is a slow, progressive, subclinical period during which there might be a cumulative effect of chemical and structural changes. Clear cut motor deficits became apparent at a stage of advanced structural damage in the peripheral nervous system. This subchronic study in the rat is acceptable as supporting study.

- In a subacute toxicity study sodium cyanate was administered to rats orally for 8 days (Filov, 1988). Effects: Behavioural - somnolence (general depressed activity). The TDLo (lowest published toxic dose) = 400 mg/kg/8 days equivalent to 50 mg/kg bw/day (intermittent).

- In a subchronic toxicity study potassium cyanate was administered i.p. to mice for 150 days (Filov, 1988). Toxic effects: Blood - changes in cell count (unspecified). The TDLo (Lowest published toxic dose) was determined to be 3360 mg/kg/ 150 days equivalent to 22.4 mg/kg bw/day.

Summary of data in Rats:

Data from the 28-day toxicity study show that several organs are affected. Most critical parameter as seen in humans and dogs (eye effects –cataracts) and trigger NOELs were not seen in rats. Neurotoxicity in rodents was observed in rats at doses clearly exceeding the doses causing cataracts in dogs and are most likely of secondary nature as blood effects are also noted at comparable doses, which will cause secondary toxicity. The i.p. administration of potassium cyanate represents a worst case scenario for rodents leading to a TDLo of 3360 mg/kg/150 d (equivalent to 22.4 mg/kg bw/day). The route of application is however of questionable relevance for the assessment of sodium cyanate.

Studies in Mice:

- In a chronic toxicity study sodium cyanate was administered to 50 B6/D2 F1 female mice/dose in diet, at dose levels of 0, 0.2, 1.0 % in the diet for 15 months (Cerami, 1973). The mice have been receiving cyanate diets (0.2 and 1%) for 15 months without any apparent irreversible effects. The only effects noted in the group receiving a 1 % cyanate diet have been a slight reduction in weight, a failure to remove food and debris from the hair coat and a reversible inhibition of reproductive capacity. This effect was considered not relevant (see reproduction toxicity endpoint). After several months mice fed 0.2 and 1 % cyanate plateaued at approximately 1.0 carbamyl groups per hemoglobin tetramer. Organ weights were all within the normal range, and no gross or histopathological lesions were observed. NOAEL = 300 mg/kg bw/day

LOAEL = 1500 mg/kg bw/day (based on body weight loss)

- In a subacute toxicity study sodium cyanate was administered to mice orally for 10 days (Filov, 1988). Effects: Peripheral Nerve and Sensation - flaccid paralysis without anaesthesia (usually neuromuscular blockage); Behavioural - somnolence (general depressed activity); Chronic Data – death. The TDLo (lowest published toxic dose) = 2000 mg/kg/10 days equivalent to 200 mg/kg bw/day (intermittent).

- In a subacute toxicity study sodium cyanate was administered to mice orally for 3 days (Filov, 1988). Effects: Chronic data – death. The TDLo (lowest published toxic dose) = 1200 mg/kg/3 days equivalent to 400 mg/kg bw/day (intermittent).

Summary of data in Mice:

Studies in mice with sodium cyanate, reveale NOAELs of 200-400 mg/kg bw/day if the substance is administered orally. Comparable organ effects as seen in rat studies were also observed in the studies in mice.

Study in Guinea Pigs:

- In a subacute toxicity study sodium cyanate was administered to guinea pigs orally for 3 days (Filov, 1988). Peripheral Nerve and Sensation - flaccid paralysis with appropriate anaesthesia; Behavioural - somnolence (general depressed activity); Liver - other changes. The TDLo (lowest published toxic dose) = 300 mg/kg/3 days equivalent to 100 mg/kg bw/day (intermittent).

Studies in Dogs:

- In a 15-month dog study (Cerami, 1973) sodium cyanate was administered to 6 beagle/dose in by capsule at dose levels of 0 and 53.5 mg/kg bw/day. After 15 months of exposure of dogs no long-term ill effects were observed. The animals appear healthy and alert and have maintained their weight during this period. The only toxic reaction occurred suddenly without prior weight loss after six months of cyanate administration to the dogs. The acute toxic episode was characterized by muscular tremors and apparent muscular weakness in all the dogs receiving cyanate. One dog experienced a particularly severe toxic reaction. The dog was recumbent and unable to rise for a period of several days. During the first day, the dog had intermittent grand mal seizures. The clinical signs in the less severely affected dogs disappeared a few days after the administration of the drug was discontinued. The severely affected dog took longer to recover but by 14 days had a complete clinical recovery with no residual neurological deficits. An investigation into the possible explanation for this acute reaction revealed that for a four-day period preceding this episode, the cyanate capsules had been administered to the dogs by a new animal attendant three hours before feeding rather than the usual one hour after feeding. The pre-prandial administration probably resulted in increased absorption and precipitated the observed reaction. One week after this episode, five of the dogs were returned to the regimen and since then have had no problems. During the period of cyanate administration, a number of physiological measurements were determined bimonthly in the dogs. The following analyses of the serum from the cyanate-treated group of dogs were found to be the same as the values observed for control groups of animals during this period: bilirubin, glucose, albumin, calcium, blood urea nitrogen, lactic acid dehydrogenase, alkaline phosphatase, glutamic oxaloacetic transaminase and cholesterol. The functioning of the liver was assessed in the dogs at 0, 3 and 12 months by the Bromsulphalein clearance test and was found to be in the normal range. The two groups of dogs had similar white cell counts and differentials. However, several of the dogs in both the control and cyanate groups displayed a 10 to 15% increase in hematocrit and hemoglobin concentration when compared to the rest of the dogs. The amount of carbamylation in treated dogs levelled off after several weeks at 0.8 to 1.2 carbamyl groups per hemoglobin tetramer and remained in that range for the entire year. The electrophoretic pattern of the sera of dogs receiving cyanate was indistinguishable from the pattern observed for control sera. Whole blood CO2 was not significantly different between cyanate and control groups. After 12 months of cyanate administration, two of the dogs, as well as control dogs, were sacrificed for routine gross and microscopic pathological surveys. These surveys did not detect any significant lesions in these animals. The NOAEL is 53.5 mg/kg bw/day (Worst case approach: The NOAEL was calculated based on a body weight of 8 kg and corrected for exposure frequency (5 times per week)). No LOAEL can be determined.

- Fifteen dogs were given sodium cyanate at doses of 30 to 170 mg/kg bw/day, 5 days per week (Kern et al., 1977) for 12-39 months. Fourteen dogs developed cataracts which were generally posterior and subcapsular. Five animals developed corneal lesions. Control beagles did not develop lesions. The one drug-treated beagle without ocular lesions received a maximum dose of 30 mg/kg bw/day of sodium cyanate for 19 months and achieved a mean carbamylation of 0.39 residue of cyanate per mol of haemoglobin. Animals developing cataracts received a maximum dose of 119 +/- 23 mg/kg bw/day for 28 +/- 10 months and achieved a mean carbamylation of 0.69 +/- 0.13 residue/mol. Animals developing corneal lesions received a maximum dose of 113 +/- 22 mg/kg bw/day for 36 +/- 7 months and achieved a mean carbamylation of 0.78 +/- 0.09 residue/mol. The study is of limited reliability due to different exposure times and small number of dogs used per exposure time.

- In a chronic toxicity study sodium cyanate was administered to dogs orally for 1 year (Filov, 1988). Effects: Brain and Coverings - other degenerative changes; Gastrointestinal - other changes; Nutritional and Gross Metabolic - weight loss or decreased weight gain. TDLo (lowest published toxic dose) = 10950 mg/kg/ 1 year equivalent to 30 mg/kg bw/day (intermittent).

Summary of data in Dogs:

Three chronic toxicity studies (1 year or longer) in dogs were available for sodium cyanate after oral administration. Most sensitive effect was the development of cataracts. A NOAEL of 53.3 mg/kg bw/day is derived for dogs from the most reliable study.

Studies in Monkeys:

- In a chronic toxicity study sodium cyanate was administered to 6 rhesus monkeys/dose in diet at dose levels of 0 and 51 mg/kg bw/day for 15 months (Cerami, 1973). After 15 months of exposure of monkeys no long-term effects were observed. The animals appear healthy and alert and have maintained their weight during this period. During the period of cyanate administration, a number of physiological measurements were determined bimonthly in the monkeys. The following analyses of the serum from the cyanate-treated group of monkeys were found to be the same as the values observed for control groups of animals during this period: bilirubin, glucose, albumin, calcium, blood urea nitrogen, lactic acid dehydrogenase, alkaline phosphatase, glutamic oxaloacetic transaminase and cholesterol. The hematocrits, hemoglobin concentrations and white cell differential and counts were the same in the cyanate and control groups of monkeys. The amount of carbamylation in treated monkeys leveled off after several weeks at 0.8 to 1.2 carbamyl groups per hemoglobin tetramer and remained in that range for the entire year. The electrophoretic pattern of the sera of dogs and monkeys receiving cyanate was indistinguishable from the pattern observed for control sera. Whole blood CO2 was not significantly different between cyanate and control groups. After 12 months of cyanate administration, two of the monkeys, as well as control monkeys, were sacrificed for routine gross and microscopic pathological surveys. These surveys did not detect any significant lesions in these animals. The NOAEL is 51 mg/kg bw/day (Worst case approach: The NOAEL was calculated based on a body weight of 7 kg and corrected for exposure frequency (5 times per week)). No LOAEL can be determined.

- In a subacute toxicity study sodium cyanate was administered to monkeys subcutaneous for 60 days (Filov, 1988). Effects: Spinal Cord - meningeal changes. The TDLo (lowest published toxic dose) = 1500 mg/kg/60 days equivalent to 25 mg/kg bw/day (intermittent).

Summary of data in Monkeys:

The data from studies in monkeys confirm the NOAEL derived in the dog studies.

Studies in Humans:

- Two young patients developed bilateral posterior subcapsular cataracts while receiving oral sodium cyanate (up to 30 mg/kg bw/day) for treatment of sickle cell hemoglobinopathy (Nicholson, 1976). In one of the patients, lens opacities regressed spontaneously after cyanate therapy was discontinued. Weight loss was observed in both patients.

- Two patients (Peterson, 1974) with sickle-cell disease who were receiving sodium cyanate for 440 and 600 days, respectively, in doses of up to 44 and 41 mg/kg bw/day, respectively had polyneuropathy confirmed by physical examination, quantitative sensory evaluation, nerve conduction test, electromyography (EMG) and sural nerve biopsy. The polyneuropathy clinically improved with no specific treatment after cessation of cyanate administration. Nerve conduction studies were done in 27 patients and needle EMG on 2 patients maintained on sodium cyanate for various periods. Mean duration of treatment of 16 patients with nerve conduction abnormalities was 478 days as opposed to a mean of 278 days for 11 patients without conduction abnormalities. Mean maximum dose of cyanate for the group with conduction abnormalities was 38 mg/kg bw as opposed to 33 mg/kg bw/day for those without. Patients with nerve conduction abnormalities achieved a higher carbamylation of their hemoglobin than those without and showed a mean weight loss of 9 % as opposed to minimal weight change in patients without conduction abnormalities.

- Six patients (Charache, 1975) with sickle cell anemia were treated with sodium cyanate (30 mg/kg bw/day). In four, treatment was stopped because of definite or suspected toxicity, and no Improvement was seen in the other two.

- In a 26 weeks human study sodium cyanate was administered most probably oral (Filov, 1988). Effects observed: Sense Organs and Special Senses (Eye) - effect, not otherwise specified. TDLo - Lowest published toxic dose = 5475 mg/kg/ 26 weeks equivalent to 30 mg/kg bw/day (intermittent)

Summary of human data:

The data from medical treatment of humans confirm the data from the dog studies. The patients developed cataracts and also showed neurotoxicity (secondary to changes in blood parameters). The effects were noted in concentrations slightly below the NOAELs in dog and monkey studies (30-38 mg/kg bw/day)

Dermal administration:

In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after dermal (required in section 8.6) does not need to be conducted as repeated dose toxicity studies for oral application are available. Potassium cyanate is not irritating and not sensitizing to the skin. No dermal effects are expected for repeated dose application to the skin and a low dermal absorption is expected due to the physico-chemical properties of the substance.

Inhalation administration:

In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after inhalation (required in section 8.6) does not need to be conducted as repeated dose toxicity studies for oral application are available. Inhalation exposure is regarded negligible as practically no particles below 50 µm were detected in particle size analysis (see IUCLID5 section 4.5).

Conclusion for risk assessment:

Several, mainly public available literature studies are available for sodium cyanate (read across). A subacute 28-day GLP-study with rats showed a NOAEL of 68.1 mg/kg bw/day. For subchronic to chronic exposure several literature data is available. A 15 months study with dogs and monkeys showed no reversible effects up to concentrations of 53.5 and 51 mg/kg bw/day respectively. Adverse effects observed at high doses are neurotoxicity and development of cataracts. These effects are considered of secondary nature due to severe changes in the blood system (damage of haemoglobin, disturbance of O2 distribution). Together with several supporting studies, the NOAEL of the chronic study in dogs and monkeys represents a reliable basis as overall NOAEL (oral, long-term) to be used for risk assessment. Human medical treatment causes very similar effects as compared with the dog and monkey data. The effects were notes at about 30 mg/kg bw/day. The NOAEL(dog) of 50 mg/kg bw/day is 1.67 times higher as the NOAEL(human) almost showing the default allometric scaling factor of 1.4.

Thus, in conclusion, it is scientifically justified to derive the DNELs long-term from the chronic NOAEL(dog) of 50 mg/kg bw/day representing a worst case assumption.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Together with several supporting studies, the NOAEL of the chronic study in dogs and monkeys represents a reliable basis as overall NOAEL (oral, long-term) to be used for risk assessment.

Justification for classification or non-classification

Based on the available data no specific target organ after repeated dose exposure could be detected. In accordance with annex VI of CLP (1272/2008/EC) sodium cyanate has not to be classified regarding STOT RE laying down the principles of GHS.

The test item is therefore not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.