Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

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.

Data source

Reference
Reference Type:
publication
Title:
Pharmacology of cyanate. I. general Effects on experimental animals
Author:
Cerami, A.; Allen, T.A..; Graziano, J.H. deFuria, F.G.; Manning, J.M.; Gillette, P.N.
Year:
1973
Bibliographic source:
J. Pharmacol. Exp. Ther. 185: 653-666, 1973

Materials and methods

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
Limit test:
no

Test material

Constituent 1
Chemical structure
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:
no details given

Test animals

Species:
monkey
Strain:
other: Rhesus
Sex:
not specified
Details on test animals or test system and environmental conditions:
body weight: 5-7 kg
Source: Drs. Ashley Brinson and Carolyn Ristau

Administration / exposure

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
Doses / concentrations
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.

Examinations

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

Results and discussion

Results of examinations

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.

Effect levels

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).

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

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.

Categories Display