Dinitrogen tetraoxide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Substance evaluation by reknown scientific organization, contains a comprehensive overview and analysis of available information; acceptable for risk assessment purposes.

Justification for type of information:

It is understood that there is an equilibrium existing between NO2 and N2O4. Hence, it would seem inevitable that any toxicity studies conducted with these oxides will share common toxicities. It also seems plausible that the prevalent oxide of nitrogen would be Nitrogen Dioxide.

Cross-reference

Reason / purpose for cross-reference:

read-across source

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Dinitrogen tetraoxide

EC Number:

234-126-4

EC Name:

Dinitrogen tetraoxide

Cas Number:

10544-72-6

Molecular formula:

N2O4

IUPAC Name:

Dinitrogen tetraoxide

Test material form:

gas

Test animals

Species:

other: Not specified

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Remarks on result:

not determinable because of methodological limitations

Results (fetuses)

Effect levels (fetuses)

Remarks on result:

not determinable because of methodological limitations

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The following conclusion was reached by the MAK:

None of the studies fulfil present-day requirements and most have grave limitations (in particular the lack of methodological data and the inadequate representation of data). These studies are therefore of only very limited use.

One author carried out studies with mice of the effects on prenatal development (Singh 1984) and postnatal development of the offspring (Singh 1988) after exposure of the dams to NO₂. Exposure to NO₂ on days 7 to 18 and 8 to 18 of gestation was very

high (22 and 45 ml/m³ air). The concentration of 22 ml/m³ caused haematomas, reduced body weights and increased mortality in the foetuses, while 45 ml/m³ led to delays in postnatal development of the pups (Singh 1984, 1988). Lower concentrations were not

investigated.

In rats exposed over the whole gestation period to NO₂ concentrations of 0.045 or 0.43 ml/m³, increased “intrauterine mortality” was reported even at the low concentration. At the higher concentration reduced maternal and foetal body and liver weights,

and stillbirths were observed (Gofmekler et al. 1977). Comparable effects were described by the working group of Tabacova et al. (see below) only after 10-fold higher concentrations of 0.53 and 5.3 ml/m³.

The toxic effects of NO₂ on prenatal development in rats were investigated by another working group; the results, however, are only available as an abstract. This study reported that daily exposure to NO₂ concentrations of 1 or 10 mg/m³ (0.53 or 5.3 ml/m³)

for 6 hours during the gestation period resulted in lipid peroxidation in the placenta, a small, dark placenta and postimplantation losses, reduced foetal weights, delayed ossification and hydrocephalus (Tabacova and Balabaeva 1986, 1988).

There is only one published study of the toxic effects of NO2 on postnatal development (Tabacova et al. 1985). Wistar rats were exposed to concentrations of 0.05, 0.1, 1.0 or 10 mg/m³ (0.027, 0.053, 0.53, 5.3 ml/m³) for 6 hours a day during the whole gestation period. After NO₂ concentrations of 0.053 ml/m³ air and more, changes were observed in posture and gait in 9-day-old and 14-day-old pups, which were no longer visible after the animals were weaned. Evidence of biochemical changes (e.g. lipid peroxidation) was not observed in this exposure group. After NO₂ concentrations of 0.53 ml/m³, lipid peroxidation in the liver and delays in postnatal development were observed in the pups. At the high concentration of 5.3 ml/m³ the viability and body weight gains of the pups, determined on day 21 after birth, were reduced; after 2 and 3 months these differences were no longer found (Tabacova et al. 1985).

In a follow-up study, no morphological or biochemical changes were observed apart from early transient behavioural changes in newborn rats whose mothers were exposed to NO₂ concentrations of 0.1 mg/m³ (0.053 ml/m³) for 6 hours a day during the whole

gestation period. Increased MetHb, lipid peroxidation, the inhibition of liver enzymes and further biochemical changes were reported after the offspring were exposed at the age of 2 years to NO₂ concentrations of 0.05 ml/m³ air for 6 hours a day for 30 days. The

authors of this study, available only as an abstract, attributed this to the increased sensitivity of the ageing organism (Tabacova et al. 1987). The studies do not exclude the possibility that toxic effects on development can occur after maternal exposure to NO₂

concentrations in the range of 0.5 ml/m³. These studies, as a result of their limitations, do not allow a decisive evaluation to be made; prenatal and postnatal studies carried out according to present-day standards are urgently needed.

Applicant's summary and conclusion

Conclusions:

The evaluation of MAK (2005) concluded that currently available studies on developmental toxicity of nitrogen dioxide are not sufficient for a decisive evaluation as a result of their limitations. The substance is not classified in a Pregnancy risk group by the MAK. This result can be read across to dinitrogen tetraoxide.