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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1980
Reliability:
3 (not reliable)
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:
Effect of Increased maternal Hemoglobin Oxygen Affinity on Fetal Growth in the Rat
Author:
Hebbel, R.P.; Berger, E.M.; Eaton, J.W.
Year:
1980
Bibliographic source:
Blood, Vol. 55, No. 6 (June), 1980

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
Type of method:
in vivo

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:
not indicated.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
Pregnant Sprague-Dawley rats (age = 80 days) were purchased with date of impregnation known. They were fed standard rat chow and allowed tap water ad libitum.

Administration / exposure

Route of administration:
other: exchange transfusion
Vehicle:
other: not applicable
Details on exposure:
On ninth day of gestation, rats were exchanged transfused with either normal (control group) or carbamylated (experimental group) homogenous rat blood. Rat blood was incubated with sodium cyanate prior to exchange transfusion for 60 min at room temperature to achieve carbamylation (50 mM).
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no analytical verification of doses.
Duration of treatment / exposure:
Rat blood was incubated with sodium cyanate prior to exchange transfusion for 60 min at room temperature to achieve carbamylation (50 mM).
Blood exchanged rats were observed from day 9 to day 22 of gestation.
Frequency of treatment:
once (incubation of blood with cyanate)
Duration of test:
Throughout gestation period of the rats (maximum 22 days)
Doses / concentrations
Remarks:
Doses / Concentrations: 0, 50 mM
Basis: nominal incubation concentration in blood exchanged blood
No. of animals per sex per dose:
22 control and 18 exposed animals
Control animals:
yes
Details on study design:
On ninth day of gestation, rats were exchanged transfused with either normal (control group) or carbamylated (experimental group) homogenous rat blood. Rat blood was incubated with sodium cyanate prior to exchange transfusion for 60 min at room temperature to achieve carbamylation (50 mM).
Examinations:
Placenta and fetal carcass were weighed. Litters were examined for malformations, and uteri were examined for evidence of resorptions. Blood parameters of fetal blood were observed (P50, hemoglobin concentration, etc.).
Maternal blood parameters investigated: P50, hemoglobin, hematocrit, and reticulocyte count.
Statistics:
variance statistical analysis
Student's t-test

Results and discussion

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
50 other: mM in blood (transfusion exchanged)
Sex:
female
Basis for effect level:
other: reduced mean fetal weight

Observed effects

The pregnant experimental group manifested a significant shift in P50 so that 24 hr after exchange transfusion P50 (maternal) = P50 (fetal), indicating an efficiency of exchange transfusion of about 60%.
There was no significant effect of increase maternal haemoglobin oxygen affinity on litter size nor in the apparent number of resorptions. Only one grossly malformed, nonviable fetus was found, and this was in an unmanipulated litter. The maternal p50 was lowered. There was an approximately 10 % difference between control and experimental groups in mean fetal weight on the 21st day of gestation, fetuses from the experimental group being smaller. This decrement in fetal weight was accompanied by a concomitant placental hypertrophy, as evidenced by an increment in mean placental weight at a decrement in relative fetal weight. The mean weight of the fetoplacental unit was, nevertheless, lower for experimental litters. In contrast no effect of single exchange transfusion was apparent on fetuses examined on the 20th day of gestation.

Applicant's summary and conclusion

Conclusions:
The increase in oxygen affinity produced by exchange transfusing of pregnant rats on day 9 of gestation with blood that had been treated previously with sodium cyanate caused reduction of fetal body weight.
Executive summary:

Pregnant rats were exchange transfused with homologous blood on the ninth day of gestation, the experimental group receiving donor blood having P50 of about 15 mm Hg achieved by prior incubation with sodium cyanate (50 mM). This changed mean maternal p50 from 41.1 to 24.6 mm Hg; the normal prenatal rat has P50 = 23.7 mm Hg due to low erythrocyte 2,3-DPG content. Parameters reflecting the adequacy of fetal oxygenation were examined on the 20th and 21st days of gestation and at term (22 days). Fetuses from the experimental group were significantly smaller on the 21st day and at term, and this was accompanied by placental hypertrophy. There was no significant difference in fetal weight on the 20th day of gestation unless a second exchange transfusion was performed to further lower maternal P50. There was a trend towards erythrocytosis in the experimental group fetuses. It is concluded that a narrowing of the P50 difference between mother and fetus caused by sodium cyanate has adverse effects on fetal wellbeing in the rat.

This study is not considered relevant for the hazard assessment of cyanate as effects were noted only secondary due to hemoglobin damage of parental animals and due to the artificial test conditions.