Dinitrogen oxide

Carcinogenicity

Description of key information

In the available carcinogenicity study on mice exposed to nitrous oxide no increase of tumour incidences was observed.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

303 male and female Swiss Webster mice were treated with nitrous oxide concentrations of 100000 or 400000 ml/m3, 4 hours per day, 5 days per
week. After 78 weeks of exposure, there was a 5-week period without treatment following which surviving mice were killed and examined for non-neoplastic and neoplastic lesions.

GLP compliance:

no

Species:

mouse

Strain:

Swiss Webster

Sex:

male/female

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Duration of treatment / exposure:

4 h/d, 5d/w

Frequency of treatment:

78 weeks

Post exposure period:

5 weeks

Dose / conc.:

100 000 ppm

Remarks:

(10%)

Dose / conc.:

400 000 ppm

Remarks:

(40%)

No. of animals per sex per dose:

10% N2O: 75M; 77F
40% N2O: 76M; 75F
Control: 91M; 88F

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
HAEMATOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Mortality:

mortality observed, non-treatment-related

Description (incidence):

In the 10% N2O group 18/75 male and 14/77 female animals died, and in the 40% N2O group 36/76 males and 18/75 females died. However, in the control goup 23/91 males and20/88 females died during the course of the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights for male and female mice in the 10% N2O group were the same as those in the air control group throughout the study, whereas they were 5% less in the 40% N2O group.

Haematological findings:

no effects observed

Description (incidence and severity):

No morphological or functional effects on the mouse hematopoietic system were observed.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Mean organ weights for N2O-treated mice were not statistically different from those of control mice.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Gross examination of tissues revealed a variety of lesions; however, their presence was unrelated to treatment.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination of tissues revealed a variety of non-neoplastic lesions; however, their presence was unrelated to treatment.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination of tissues revealed a variety of neoplastic lesions; however, their presence was unrelated to treatment.

Dose descriptor:

NOAEC

Effect level:

100 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEC

Effect level:

400 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

Key result

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

727 273 mg/m³

Study duration:

chronic

Species:

mouse

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The criteria for classification for carcinogenicity according to Regulation (EC) No 1272/2008, as amended for fifteenth time in Regulation (EU) No 2020/1182, are not met.

Additional information

Carcinogenicity: via inhalation route

A carcinogen bioassay of nitrous oxide was performed in groups of male and female Swiss-Webster mice exposed to either air (n = 179), 10% N₂O (n = 152), or 40% N₂O (n = 151) for 4 h per day, 5 days per week. After 78 weeks of exposure, there was a 5-week period without treatment following which surviving mice were killed. Mice killed at this time or dying in extremis at other times were subjected to complete autopsy unless advanced autolysis or cannibalism precluded examination. Mean body weights for male and female mice in the 10% group were the same as those in the air control group throughout the study, whereas they were 5% less in the 40% group. No morphological or functional effects on the mouse hematopoietic system were observed. Mean organ weights for treated mice were not statistically different from those of control mice. Gross and microscopic examination of tissues revealed a variety of neoplastic and non-neoplastic lesions; however, their presence was unrelated to treatment (Baden et al. 1986).

Other studies of the carcinogenic effect of nitrous oxide also produced negative results. However, either the exposure period was too short (Eger et al. 1978) or the concentration used was too low (Coate et al. 1979b) so that these studies cannot be included in the evaluation of carcinogenicity. Some epidemiological studies have demonstrated an increased tumour incidence (above all of leukaemia and lymphomas) in persons occupationally exposed to anaesthetics (mainly nitrous oxide). However, tumour types and locations were inconsistent among the epidemiological studies which are therefore not considered in the assessment of carcinogenicity of nitrous oxide (MAK value documentation (1993).

General remark

1 mL/m³ (ppm) = 1.83 mg/m³