Dinitrogen tetraoxide

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

overview of available data

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

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Remarks on result:

not determinable because of methodological limitations

Results: F1 generation

Effect levels (F1)

Remarks on result:

not determinable because of methodological limitations

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

The following conclusion was reached by MAK:

There are a few studies of the toxic effects of NO₂ on fertility and development. However, they do not fulfil present-day requirements and are therefore of only limited use.

Six male rats were exposed to NO₂ concentrations of 1 ml/m³ for 21 days (7 hours per day, 5 days a week). Light microscopic examination of the testicular tissue did not reveal any differences between the exposed animals and the 5 controls. No changes were

detected in the exposed animals with regard to spermatogenesis, germ cell atrophy or Leydig cell abnormalities. The level of vitamin B12 in serum was comparable in the two groups (Kripke and Sherwin 1984).

The influence of NO₂ on the oestrus cycle was investigated in groups of 10 female rats. The duration of the oestrus cycle was determined over 24 days before the exposure to NO₂. The animals were then exposed to NO₂ concentrations of 0.13 or 2.4 mg/m³

(0.07 and 1.2 ml/m³) for 12 hours a day over 3 months. At 0.07 ml/m³ there were no effects on the oestrus cycle compared to that of the controls. After 1.2 ml/m³, however, the cycle was longer: with a cycle in the controls of 5.3 days, it was extended to up to 6.4

days after exposure for one month, 9.0 days after exposure for 2 months and 9.1 days after exposure for 3 months. In the third month of exposure the increased cycle duration was attributed to a 20 % increase in the oestrus and an 85 % increase in the oestrus

interval. After a three-month recovery period the average duration of the oestrus cycle no longer differed from the control values. Histopathological examinations at the end of exposure revealed changes in the adrenal gland, the thyroid gland and the pituitary gland

in the group exposed to 1.2 ml/m³. A reduction in the number of functional primordial follicles was detected in the ovaries and dystrophy of the glandular epithelium in the uterus. At the end of the 3-month exposure to 1.2 ml/m³, 7 of the exposed rats were

mated with untreated males. It was reported that the exposure had no influence on the number of females which became pregnant. The litter size at birth was reduced to 5.1 (after 1.2 ml/m³) compared to the control value of 8.0 pups. The weight of the newborn

pups and the body weight gains in the first 12 days of life were also significantly reduced (20–30 %) (Barlow and Sullivan 1982, Shalamberidze and Tsereteli 1971).

Applicant's summary and conclusion

Conclusions:

The evaluation of MAK (2005) concluded that available studies on fertility of nitrogen dioxide do not fulfil present-day requirements and are therefore of only limited use. The substance was not classified in a Pregnancy risk group by the MAK. This result can be read across to dinitrogen tetraoxide.