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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Type of information:
experimental study
Adequacy of study:
supporting study
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. II. Effects on the endocrine system
Author:
Graziano, J.H.; Thornton; Y. S.; Leong, J. K.; Cerami, A.
Year:
1973
Bibliographic source:
Journal of pharmacology and experimental therapeutics, Vol. 185, No. 3, page 667-675

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:
mouse
Strain:
other: C57 BL/6J
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: The Jackson Laboratory (Bar Harbour, Maine, USA)

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: feed
Details on exposure:
Adult mice were placed on a diet containing 1% sodium cyanate by weight either on the day of cohabitation, the day of vaginal plug (day 0), or days 7 to 14 after vaginal plug. Control mice received the same diet with sodium cyanate.
Details on mating procedure:
no data
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
Minimum 14 days for males. No exact exposure duration given.
Frequency of treatment:
continuous
Details on study schedule:
minimum 14 days. No exact duration of the test given
Doses / concentrations
Remarks:
Doses / Concentrations:
0 and 1 % = 1500 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
6 females per treatment group
Control animals:
yes, plain diet
Details on study design:
no further detail given
Positive control:
no data

Examinations

Parental animals: Observations and examinations:
- number of matings
- vaginal smears
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
- number of young born per litter
- birth weights of the litter
Postmortem examinations (parental animals):
- gross pathology of ovaries and testes
Postmortem examinations (offspring):
- gross pathology
Statistics:
mean and standard deviation
Reproductive indices:
not given
Offspring viability indices:
not given

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

The feeding of a 1% cyanate diet to paired mice immediately before or at various times during pregnancy did not affect the number of successful mating, the number of young born per litter or the birth weights of the litter.
The cyanate fed females did not have further pregnancies; in fact, the mice did not have further pregnancies as long as they were maintained on the 1 % cyanate diet. This block in reproductive capacity was reversible since normal pregnancies and litters were observed when the animals were switched to a regular diet. Daily examination of vaginal smears revealed that in contrast to the control mice which had a four day estrus cycle, mice receiving a 1% sodium cyanate diet had prolonged periods of anestrus and came into estrus only occasionally and sporadically.
Histopathological examination revealed no lesions in the ovaries or testes of the animals receiving the 1 % cyanate diet.

Effect levels (P0)

Key result
Dose descriptor:
LOAEL
Effect level:
1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: number of young, no second pregnancies

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Details on results (F1)

There were no gross abnormalities of the young. The number of young weaned per litter was reduced in those mice which had receiving cyanate for 14 days or more before parturition.

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
The feeding of a 1% cyanate diet to paired mice immediately before or at various times during pregnancy did not affect the number of successful mating, the number of young born per litter or the birth weights of the litter.
The cyanate fed females did not have further pregnancies; in fact, the mice did not have further pregnancies as long as they were maintained on the 1 % cyanate diet. This block in reproductive capacity was reversible since normal pregnancies and litters were observed when the animals were switched to a regular diet. Daily examination of vaginal smears revealed that in contrast to the control mice which had a four day estrus cycle, mice receiving a 1% sodium cyanate diet had prolonged periods of anestrus and came into estrus only occasionally and sporadically.
Histopathological examination revealed no lesions in the ovaries or testes of the animals receiving the 1 % cyanate diet.
Executive summary:

In a fertility toxicity study sodium cyanate was administered to 6 females C57 BL/6J mice/dose in diet at dose levels of 0 and 1 % corresponding to 0 and 1500 mg/kg bw/day.

The feeding of a 1 % cyanate diet to paired mice immediately before or at various times during pregnancy did not affect the number of successful mating, the number of young born per litter or the birth weights of the litter. The cyanate fed females did not have further pregnancies; in fact, the mice did not have further pregnancies as long as they were maintained on the 1 % cyanate diet. This block in reproductive capacity was reversible since normal pregnancies and litters were observed when the animals were switched to a regular diet. Daily examination of vaginal smears revealed that in contrast to the control mice which had a four day estrus cycle, mice receiving a 1% sodium cyanate diet had prolonged periods of anestrus and came into estrus only occasionally and sporadically. Histopathological examination revealed no lesions in the ovaries or testes of the animals receiving the 1 % cyanate diet. The maternal LOAEL is 1500 mg/kg bw/day. The maternal NOAEL could not be derived as effects occurred in the single dose tested.

There were no gross abnormalities of the young. The number of young weaned per litter was reduced in those mice which had receiving cyanate for 14 days or more before parturition. The developmental LOAEL is 1500 mg/kg bw/day, based on reduced number of pups. The maternal NOAEL could not be derived as effects occurred in the single dose tested.

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