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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:
1981
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: public available study (non GLP, non guideline) Read across to sodium cyanate. For justification of read across see endpoint summary.

Data source

Reference
Reference Type:
publication
Title:
High oxygen affinity of maternal blood reduced fetal weight in rats
Author:
Bauer, C.; Jelkmann, W. and Moll, W.
Year:
1981
Bibliographic source:
Respiration Physiology (1981) 43, 169-178

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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Source: Merck, Darmstadt, Germany

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Rats of the Sprague-Dawley strain weighing about 250 g were obtained from an animal breeding farm (Dr. Ivanovas, Kislegg, Germany). The rats were kept in animal house of the University under standard conditions (12 h light-dark cycle starting at 7 a.m., food: Altromin-R10 standard pellets and tap water ad libitum).

Administration / exposure

Route of administration:
other: exchange transfusion
Vehicle:
water
Details on exposure:
On day 19 of gestation pregnant animals were anesthetized and the blood was exchanged from female rats previously treated with sodium cyanate (exchange transfusion).
Female rats which served as blood donors for the exchange transfusion experiments received drinking water that contained either 0.5 g/dL sodium cyanate or water with the equivalent concentration of sodium as sodium chlorite for a period of 14 days.
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:
Female rats which served as blood donors for the exchange transfusion experiments received drinking water that contained either 0.5 g/dL sodium cyanate or water with the equivalent concentration of sodium as sodium chlorite for a period of 14 days. Three days before the blood was drawn, the animals were allowed to drink normal tap water again.
On day 19 of gestation pregnant animals were anesthetized and the blood was exchanged from female rats previously treated with sodium cyanate (exchange transfusion). On day 21 of gestation the animals were sacrificed.
Frequency of treatment:
blood donors: continuously via the drinking water
Duration of test:
blood donors: 14 days
maternal animals: 21 days of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5 mg/L
Basis:
nominal in water
No. of animals per sex per dose:
not indicated.
Control animals:
yes
Details on study design:
Mating:
Virgin female rats were made pregnant by mating them between 8 a.m. and 10 a.m. in a ratio of one female to one male rat. This procedure yielded only a relative small percentage of pregnant animals (about 30 %) but has the advantage that the error in estimating the gestational age is only +/- 1h or less, which is important in view of the fast growth rate of rat fetuses. The day of mating was considered day zero of gestation.

Examinations:
On day 21 of gestation the animals were sacrificed. The abdomen was quickly opened and the weights of the fetus and the placenta after removing the umbilical vessels, of the fetal brain and the fetal liver were measured. The hematocrit of fetal blood was determined after puncturing the fetal heart. The oxygen concentration, oxygen capacity and P50 of the blood was determined. In addition hemoglobin and total protein concentration of the blood were measured.
Statistics:
Mean values were tested for significant difference using Student's t-test. It was ascertained that all single values were within the limit of mean +/- 3 SD which indicated normal distribution. Differences were considered significant at a level of p =< 0.01.

Results and discussion

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
5 mg/L drinking water
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Fetus body weight

Observed effects

Blood exchange with cyanate led to an immediate fall in oxygen half saturation pressures (P50) from 36.4 Torr to 26.2 Torr. Two days later, P50 was not significantly different from the value obtained immediately after the transfusion, which indicated that the oxygen affinity remained unchanged during this time period. At none of the dates investigated significant differences in haemoglobin concentration were found. It should be noted that the cyanate treatment did not lead to an alteration of oxygen binding capacity of haemoglobin. Furthermore the total protein concentration was not significantly different in cyanate blood.
Exchange transfusion per se did not affect the fetuses: in the animals where exchange transfusion was done with normal blood, non of the fetus parameters measured differed significantly from those in the unmanipulated animals. However, exchange transfusion with cyanate blood led to a significant reduction of fetal body weight and liver weight whilst the weight of the fetal brain and the weight of the placenta were not changed. It should be noted that both in the cyanate and the control group, all fetuses were found alive at the time of the operation on day 21. Therefore, fetal survival in utero was not affected by the acute rise in oxygen affinity of the maternal blood.

Applicant's summary and conclusion

Conclusions:
The increase in oxygen affinity produced by exchange transfusing of pregnant rats on day 19 of gestation with blood that had been treated previously with sodium cyanate caused reduction of fetal body and liver weight.
Executive summary:

The effects of an acute increase of the oxygen affinity of maternal blood in pregnant rats on fetal weight, fetal brain and liver weights, placental weight and the hematocrit of the fetal blood were examined. The increase in oxygen affinity was produced by exchange transfusing of pregnant rats on day 19 of gestation with blood that had been treated and modified previously with sodium cyanate. As a result of the exchange transfusion, the difference in oxygen affinity between maternal and fetal blood essentially disappeared causing an artificial situation. Pregnant rats exchanged with normal blood served as controls. On day 21 of gestation, the fetal body weight and the fetal liver weight were significantly smaller by 18% and 25% respectively, in the group where the oxygen affinity of the maternal blood was acutely raised when compared to the controls causing a lower support of the pups with oxygen. Also, the hematocrit of the fetal blood was significantly higher in the group where mothers had the high blood oxygen affinity. Placental weight and fetal brain weight were not significantly altered. The authors infer, that the reduction of fetal weight is due to fetal hypoxia which is caused by the abolishment of the difference in oxygen affinity between maternal and fetal blood, cause by sodium cyanate.

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.