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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic information given

Data source

Reference Type:
Effect of Maternally Administered Sodium Nitrite on Hepatic Erythropoiesis in Fetal CD-1 Mice.
Globus, M., Samuel, D.
Bibliographic source:
Teratology 18, 367 - 378

Materials and methods

Principles of method if other than guideline:
The study was performed to investigate the possible embryotoxic effects of NaNO2 ingested by mammals during pregnancy, and in particular, the influence of NaNO2 on fetal hematopoiesis.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium nitrite
EC Number:
EC Name:
Sodium nitrite
Cas Number:
Molecular formula:
sodium nitrate
Details on test material:
sodium nitrite

Test animals

Details on test animals or test system and environmental conditions:
The animals were maintained on standard rat cubes supplied by Maple Leaf Mills Ltd., Ontario, and tap water ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Details on mating procedure:
Four- to five-month-old males were mated with 8- to 10-week old females (weighing approximately 22-28 grams) when the latter were found to be in the estrus phase, on the basis of vaginal smears. The day when a vaginal plug appeared was designated day 1 of gestation.
Duration of treatment / exposure:
beginning from the 1st day of pregnancy until days 14; 16 or 18 of gestation
Frequency of treatment:
one dose/day
Duration of test:
until day 19 of gestation
Doses / concentrations
Doses / Concentrations:
0.5 mg NaNO2/mouse/day (about 17 mg NaNO2/kg b.w./day)
actual ingested
No. of animals per sex per dose:
Twenty-three control and 23 treated litters were sacrificed for examination on gestation day 14; 12 control and 9 treated litters were examined on day 16; and four control and four treated litters were evaluated on gestation day 18.
Control animals:
yes, concurrent vehicle
Details on study design:
Duration of test: 14; 16 or 18 days


Fetal examinations:
Litter size, the number of resorption sites and dead implants, and embryo/fetal weights were recorded at the time of sacrifice. Embryos/fetuses were examined for gross anatomical defects, and, following removal of the livers for analysis, their carcasses were prepared for skeletal examinations. Parameters of erythropoiesis were determined for hepatic tissues, as the liver is the main site of erythrocyte production between gestation days 12 and 19 in
the mouse.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
No differences were found between treated and control animals, at any of the time points evaluated, for litter size, mean litter weight, mean embryo weight, mean number of resorption sites, or percentages of dead implants. There were no statistically significant differences between treated (n=42) and control (n=37) animals in the frequencies of skeletal abnormalities or variations, but the authors noted a tendency toward talipomanus and talipes in the nitrite-treated group. No data were provided to support this tendency. Hepatic hematopoeisis was evaluated as percentages of total hepatic erythroblasts which were at various distinct stages of maturation. The overall frequency of red blood cells was significantly increased in treated animals at 14 and 16 days of gestation, but not at 18 days. The percentage of mature erythrocytes in hepatic tissue was reduced in treated animals on gestation days 14 and 16, but not on gestationday 18. The percentages of pro- and basophilic erythroblasts were significantly decreased in treated animals of 14 and 16 days gestation age, but not on gestation day 18. Polychromatophilic erythroblasts were significantly more frequent in treated than control animals on gestation day 14, and significantly less frequent on gestation day 16, with no difference between treated and control animals on gestation day 18. Orthochromatophilic erythroblasts were also found at a higher percentage in treated than control animals on gestation day 14, and to be unchanged from controls on gestation day 18. This cell type, however, was found to be more frequent in treated than in control animals on gestation day 16. The overall frequency of white blood cells was slightly, but not significantly, reduced at all three time points. The proportion of neutrophil granulocytes was significantly increased in treated animals at day 18, but was unchanged from control values at the other time points.The authors interpreted their results as indicating a treatment-dependent increase in embryonic hepatic production of erythroid cells. The lack of a sustained increase in mature red blood cells in the livers of day 18 fetuses was considered to be due to a normal developmental shift in the main site of erythropoesis from the liver to the bone marrow and spleen. The authors acknowledge, however, that no increase in red blood cell counts could be demonstrated in the peripheral circulation. Hence the functional significance of their findings remains unclear.

Effect levels (maternal animals)

Dose descriptor:
Basis for effect level:
other: developmental toxicity
Remarks on result:
not determinable
no NOAEL identified

Results (fetuses)

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Fetal Effects
No significant differences between groups for: litter size, weight, resorptions, fetal death, or skeletal abnormalities or variations.
Significant changes in hepatic erythropoiesis.
No sustained increase in hepatic mature red blood cells on day 18.