Dinitrogen oxide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Effect on the chronic administration of nitrous oxide 0.5% to gravid rats

Author:

Vieira, E.

Year:

1979

Bibliographic source:

Br. J. Anaesth, 51; pp 283-287

Reference 2

Reference Type:

publication

Title:

Intermittent exposure of gravid rats to 1 % nitrous oxide and the effect on the postnatal growth of their offspring

Author:

Vieira, E., Cleaton-Jones, P. Austin, P.L.

Year:

1978

Bibliographic source:

S.Afr Med J., 53(3); pp 106-108

Reference 3

Reference Type:

publication

Title:

Effects of low concentrations of nitrous oxide on rat fetuses

Author:

Vieira, E., Cleaton-Jones, P., Austin, J.C., Moyes, D.G. & Shaw, R.

Year:

1980

Bibliographic source:

Anesth Analg 79: 175–177

Reference 4

Reference Type:

publication

Title:

Effects of low intermittent concentrations of nitrous oxide on the developing rat fetus

Author:

Vieira E, Cleaton-Jones P, Moyes D.

Year:

1983

Bibliographic source:

Brit J Anaesth 55: 67–69

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

single dose level used

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dinitrogen oxide

EC Number:

233-032-0

EC Name:

Dinitrogen oxide

Cas Number:

10024-97-2

Molecular formula:

N2O

IUPAC Name:

Dinitrogen Oxide

Test material form:

gas under pressure: liquefied gas

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

Gravid rats used

Duration of treatment / exposure:

exposure from GD1 to GD19

Frequency of treatment:

continuous treatment

Duration of test:

19 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.5%
Basis:
nominal conc.

No. of animals per sex per dose:

12 gravid rats/gp

Control animals:

yes, concurrent no treatment

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

LOAEC

Remarks:

Viera (1979)

Effect level:

ca. 5 000 ppm

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEC

Remarks:

Vieira et al (1980)

Effect level:

ca. 500 ppm

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

NOAEC

Remarks:

Vieira et al., (1978)

Basis for effect level:

other: developmental toxicity

Remarks on result:

not determinable

Remarks:

no NOAEC identified

4

Dose descriptor:

NOAEC

Remarks:

Vieira et al (1983)

Effect level:

ca. 1 000 ppm

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Increased foetal loss and resorption was seen in the N2O treated group. Fetal weights and crown-rump length were also decreased in N2O exposed fetuses. Skeletal abnormalities were not seen in the controls but were observed in 9% of foetuses exposed to N2O. These were not described in detail although it is commented that the incidence was greater in females than males. No abnormalities of the internal organs were recorded (Vieira, 1979).

 

A further study by Vieira et al (1980) continually exposed 12 pregnant Wistar rats from the day after mating until GD 19 to N2O in air at concentrations of 0, 250, 500 and 1000 ppm. At the highest dose tested mean litter size and crown-rump length were significantly reduced compared to the control; other exposure levels showed no difference from the control in these respects. Skeletal abnormalities were only observed in the high dose gp, with soft part abnormalities not reported for any group. The high dose gp contained 4 resorptionsvs. zero in the control gp.

 

The effects of N2O exposure during different periods of gestation on pup development were investigated. Groups of rats exposed to air containing N2O (10000 ppm) for 6 h/d, 5 d/wk for wk 1 of gestation, the first 2 wks of gestation of for the whole 3 wks of gestation. All rats were allowed to deliver their litters and litters were monitored for 8 wks post partum. The litter size of all the groups exposed to N2O was significantly lower than control and body weight of those pups was lower than that of controls throughout the 8-wks post partum monitoring. Pups from mothers exposed during the 1^st wk of gestation only were light than all others on all occasions. Tail length and body length were reduced for all N2O treated groups throughout the 8 wk post-partum period, compared with controls, although the differences were not always statistically significant (Vieira et al., 1978).

 

Finally, in a further report by Vieira et al (1983) where gps of pregnant Wistar rats (12/gp) were exposed for 6 h/d, 5 d/wk to 0, 250, 500, 1000 or 5000 ppm in air throughout gestation. Dams were killed on GD 19and the urterine contents were examined. Litter size and mean crown-rump length of the fetus was reduced in the group exposed to 0.5% N2O. There were no malformations or resorptions in any of the groups.

 

Results from continuous exposure to N2O throughout gestation resulted in significantly more effects than intermittent exposure at similar levels.

Applicant's summary and conclusion

Executive summary:

Groups of 12 gravid rats were exposed to a constant level of 0.5% N2) (5000 ppm) from GD 1 through to GD 19. A control group were exposed to air alone (12/gp). Dams were killed on GD 19 and uterine contents examined. Detailed examination of the uterus, ovaries and fetuses were undertaken. Fetuses were fixed, cleared and stained with alizarin red, examined for skeletal anomalies and their crown-rump lengths measured.

 

Increased foetal loss and resorption was seen in the N2O treated group. Fetal weights and crown-rump length were also decreased in N2O exposed fetuses. Skeletal abnormalities were not seen in the controls but were observed in 9% of foetuses exposed to N2O. These were not described in detail although it is commented that the incidence was greater in females than males. No abnormalities of the internal organs were recorded (Vieira, 1979).

 

A further study by Vieira et al (1980) continually exposed 12 pregnant Wistar rats from the day after mating until GD 19 to N2O in air at concentrations of 0, 250, 500 and 1000 ppm. At the highest dose tested mean litter size and crown-rump length were significantly reduced compared to the control; other exposure levels showed no difference from the control in these respects. Skeletal abnormalities were only observed in the high dose gp, with soft part abnormalities not reported for any group. The high dose gp contained 4 resorptionsvs. zero in the control gp.

 

The effects of N2O exposure during different periods of gestation on pup development were investigated. Groups of rats exposed to air containing N2O (10000 ppm) for 6 h/d, 5 d/wk for wk 1 of gestation, the first 2 wks of gestation of for the whole 3 wks of gestation. All rats were allowed to deliver their litters and litters were monitored for 8 wks post partum. The litter size of all the groups exposed to N2O was significantly lower than control and body weight of those pups was lower than that of controls throughout the 8-wks post partum monitoring. Pups from mothers exposed during the 1^stwk of gestation only were light than all others on all occasions. Tail length and body length were reduced for all N2O treated groups throughout the 8 wk post-partum period, compared with controls, although the differences were not always statistically significant (Vieira et al., 1978).

 

Finally, in a further report by Vieira et al (1983) where gps of pregnant Wistar rats (12/gp) were exposed for 6 h/d, 5 d/wk to 0, 250, 500, 1000 or 5000 ppm in air throughout gestation. Dams were killed on GD 19and the urterine contents were examined. Litter size and mean crown-rump length of the fetus was reduced in the group exposed to 0.5% N2O. There were no malformations or resorptions in any of the groups.