Potassium cyanate

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1971-1974

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.

Data source

Reference

Reference Type:

publication

Title:

Sodium Cyanate Induced Polyneuropathy in Patients with Sickle-Cell Disease

Author:

Peterson, C.M.; Tsairis, P.; Ohinishi, A.; Lu, Y.S.; Grady, R., Cerami, A.; Dyck, P.J.

Year:

1974

Bibliographic source:

Annals of Internal Medicine 81: 152-158 (1974)

Materials and methods

Study type:

clinical case study

Endpoint addressed:

repeated dose toxicity: oral

neurotoxicity

Test 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

Test material

Test material information

Constituent 1

Reference substance name:

Sodium cyanate

EC Number:

213-030-6

EC Name:

Sodium cyanate

Cas Number:

917-61-3

Molecular formula:

CNO.Na

IUPAC Name:

sodium cyanate

Details on test material:

not indicated.

Method

Type of population:

general

Subjects:

a) Case reports: two right-handed black women (26 and 29 year old) with known sickle cell disease who received cyanate as drug.

b) Nerve conduction studies: 27 patients (sickle cell disease) who received cyanate as drug and 9 control patients with sickle cell disease who did not receive cyanate

Ethical approval:

not specified

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

not specified

Details on exposure:

Case 1: 20-26 mg/kg bw/day since 1972 (well tolerated), increased dose of 30-39 mg/kg bw/day from January 1973
Case 2: 20-30 mg/kg bw/day since 1971 (well tolerated), increased dose of 35.7 mg/kg bw/day from March 1973
Nerve conduction study: different doses of up to 44 mg/kg bw/day for up to 600 days.

Examinations:

Investigations of polyneuropathy measured/observed by physical examinations, quantitative sensory evaluation, nerve conduction test, electromyography (EMG) and sural nerve biopsy.

Medical treatment:

Treatment of sickle-cell disease with sodium cyanate.

Results and discussion

Clinical signs:

Case reports:
- body weight loss
- weakness of upper and lower extremities
- decrease in touch pressure
- decreased tendon reflexes
- elevated hemoglobin carbamylation
- polyneuropathy indicated in nerve conduction studies
Three months after cessation of cyanate treatment most of the adverse effects were diminished or had disappeared.

Results of examinations:

Nerve conduction studies:
16 patients were found to have nerve conduction abnormalities, and 11 patients had normal nerve conduction results. Those patients with nerve conduction abnormalities tended to have been on drug therapy for a longer period (mean 478 days versus mean 278 days) and to have been exposed to a higher dose (mean 38 mg/kg bw/day versus mean 33 mg/kg bw/day).Polyneuropathy, shown by physical examination and nerve conduction studies, occurred in one patient after only 47 days at a maximum dose of 44 mg/kg bw/day, suggesting that maximum dose is more important than duration. The higher dose of cyanate in the patients with nerve conduction abnormalities was associated with a greater degree of carbamylation of hemoglobin. The signs and symptoms of polyneuropathy were relatively subtle. None of the patients complained of painful paresthesias, although numbness or tingling in the hand or the feet was reported by 5 of the 16 patients with nerve conduction abnormalities. Ten of the 16 patients with conduction abnormalities had physical findings consistent with a polyneuropathy. 12 of the patients showing nerve conduction abnormalities had preceding weight loss, a toxic effect previously ascribed to sodium cyanate administration. In conclusion, long-term exposure to doses >= 30 mg/kg bw/day can cause polyneuropathy in humans.

Effectivity of medical treatment:

Treatment of sickle-cell disease with sodium cyanate induce polyneuropathy.

Outcome of incidence:

Treatment of sickle-cell disease with sodium cyanate induce polyneuropathy.

Applicant's summary and conclusion

Conclusions:

Treatment of sickle-cell disease with sodium cyanate induce polyneuropathy (38 mg/kg bw/day). No effects were observed at 33 mg/kg bw/day.

Executive summary:

Two patients 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. In conclusion, long-term exposure to doses >= 30 mg/kg bw/day can cause polyneuropathy in humans.