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Description of key information

In a well-conducted 2-year rat study, no signs of carcinogenic effects were found. Sodium azide is therefore considered not carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
equivalent or similar to guideline
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
: application at 5 days/week; only 2 dose groups; no hematological examination, blood chemistry, and urinalysis were performed
GLP compliance:
Specific details on test material used for the study:
- Name of test material (as cited in study report): Sodium azide
- Substance type: powder
- Physical state: solid
- Analytical purity: >99%
- Lot/batch No.: 32880
- Stability under test conditions: stable for at least two weeks at up to 60 °C
- Storage condition of test material: in the dark at room temperature
Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratories, Kingston NY
- Age at study initiation: 48-55 days
- Weight at study initiation: 153-156g
- Fasting period before study: no data
- Housing: % Animals per cage in polycarbonate cages with Hardwood chips, changes twice a week. Spun-bound polyester cage filter sheets and stainless steel racks were changed every two weeks.
- Diet (e.g. ad libitum): NIH-07 Rat and Mouse Ration (Zeigler Bros. Inc. Gardners PA), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: quarantine for 19 days before start of the study

- Temperature (°C): 68-79 °F (20-26 °C)
- Humidity (%): 10-84%
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The required amount of sodium azide for each concentration was transferred to the appropriately sized volumetric flask. The flask was filled to approximately 3/4 volume with distilled water, stoppered and shaken until throroughly mixed. The flask was then filled to volume with water, using a pipette to carefully add the last few milliliters, stoppered, mixed and transferred to the appropriate dosing bottles.

- Maximum storag time for feed: 120 days
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The study laboratory conducted periodic analyses of the sodium azide dose formulations using a titrimetric procedure. The dose formuations were analyzed at approximately 8-week intervals and were within ±10% of the target concentrations 100% of the time. Results of periodic referee analyses by the analytical chemistry laboratory agreed with the results from the study laboratory.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
5 days per week (excluding weekends)
Post exposure period:
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses selected for the 2-year studies were 5 mg/kg bw/day and 10 mg/kg bw/day. This selection was based on mortality, body weight depressions, and brain lesions observed in the 13-week studies (referenced in section 7.5.1).

Positive control:
Observations and examinations performed and frequency:
- Time schedule: twice daily

- Time schedule: weekly

- Time schedule: Body weights per cage were recorded once per week for the first 13 weeks of the studies, during weeks 17 and 19, and from weeks 21 to 31, and every 2 to 5 weeks thereafter. Mean body weights were calculated for each group.




Sacrifice and pathology:
GROSS PATHOLOGY: Yes, performed on all animals.
HISTOPATHOLOGY: Yes, performed on all animals. Examined organs and tissues are listed in the Table 1 below.
Other examinations:
no data
no data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
For more details see "details on results" section below.
Dermal irritation (if dermal study):
not examined
mortality observed, treatment-related
Description (incidence):
For more details see "details on results" section below.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For more details see "details on results" section below.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
For more details see "details on results" section below.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
For more details see "details on results" section below.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
For more details see "details on results" section below.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
For more details see "details on results" section below.
Details on results:
Of rats receiving 10 mg/kg bw/day, 49/60 males and 53/60 females became very lethargic after dosing at some time during the studies. In comparison, lethargy was observed in eight control males, eight low-dose males, four control females, and six low-dose females. Four male and four female rats receiving 10 mg/kg bw/day and one male receiving 5 mg/kg bw/day sodium azide convulsed at the time of dosing, and five high-dose males, eight high-dose females, and two low-dose females became comatose for 1 to 2 hours. Many of these animals died within 3 to 5 days following the appearance of these clinical findings. These early deaths were attributed to the brain necrosis found upon microscopic examinatoin of brain tissue sections from these animals. Additional clinical findings in high-dose rats included recumbency (males, 22/60; females, 5/60), rough hair (males, 60/60; females, 53/60), emaciation (females, 29/60), and toe-walking (males, 11/60; females, 51-60).
Survival was substantially reduced in high-dose males and females. Brain necrosis, most notably in the cerebrum and thalamus, was a major cause of mortality in high-dose male and female rats and was attributed to the toxicity of sodium azide. The lower than usual survival rate (less than 50%) of the control and low-dose male rats was probably due to the high incidence of mononuclear cell leukemia in these groups.

Mean body weights of male and female rats receiving sodium azide were consistently lower than those of controls throughout the studies. After 24 weeks, the mean body weights of high-dose male and female rats were notably lower than those of the control animals.

High-dose males consistently consumed less feed than control males. High-dose females consumed considerably less feed than control females between week 16, when feed consumption measurements were initiated, and week 56. After week 56, feed consumption by high-dose females was still below that of controls, but to a smaller margin than seen previously. Mean feed consumption values for low- and high-dose rats were lower than control values.

A high incidence of brain necrosis was observed in the high-dose males and females. The brain lesions were often of sufficient severity to result in the death of the affected animals. The high-dose animals also had an increased incidence of pulmonary congestion, sometimes with hemorrhage, which was considered to be a secondary effect of brain necrosis.

The significant treatment-related finding in the brain was necrosis of the cerebrum, thalamus, or both. This lesion was observed in a large percentage of the high-dose males and females. There was a single occurrence of cerebral necrosis in a low-dose male and a low-dose female and a single occurrence of thalamic necrosis in a low-dose male. These lesions were not observed in control animals.
The brain lesions were usually bilaterally symmetrical. Cerebral necrosis occurred at a specific subcortical site, apparently in the region of the caudate-putamen basal ganglia. Three high-dose females with cerebral necrosis also had necrosis of the hippocampus, a deep portion of the cerebral cortex. Thalamic necrosis was usually localized either in the dorsal region of the thalamus, just ventral to the hippocampus, or in the center of the thalamus. One high-dose male had necrosis in the pons, a portion of the brainstem caudal to the thalamus. The areas of necrosis varied in size, and the severity of necrosis ranged from acute to chronic.
Acute lesions consisted of necrosis of neurons that was often accompanied by necrosis of elements of the neuropil. Necrotic cells had deeply eosinophilic cytoplasm with pyknotic or karyorrhectic nuclei. Inflammatory cell infiltrate was minimal or absent from acute lesions.
Chronic lesions were characterized by the loss of neurons and neuropil, infiltration of macrophages, and proliferation of glial cells and blood vessels. Acute and chronic lesions were often seen in the same animal.

The incidence of congestion in high-dose male and female rats and of hemorrhage in high-dose male rats was higher than that in low-dose and control animals (congestion-males: control, 6/60; low-dose, 4/60; high-dose, 30/60; females: 6/60; 3/60; 21/59; hemorrhage-males: 4/60; 5/60; 17/60; females: 5/60; 5/60; 5/59). These pulmonary lesions were seen primarily in animals dying during the studies and were consistent with cardiovascular collapse and brain necrosis.

The incidence of hepatodiaphragmatic nodules in the livers of low- and high-dose female rats was higher than that in controls (controls. 1/60; low-dose, 8/60; high-dose, 11/59). Common in aging F344/N rats, these lesions consist of nodular masses of hepatic parenchyma that project from the capsular surface of the liver and protrude into the thorax at points of weakness in the skeletal muscle of the diaphragm. There was no increase in the incidence of this lesion in male rats. No other effects on skeletal muscle attributable to sodium azide administration were found in these studies, and the results of previous studies do not indicate that sodium azide has an effect on skeletal muscle. Therefore, the increased incidence of hepatodiaphragmatic nodules in the female rats was not considered to be treatment related.

A variety of neoplasms occurred randomly throughout the groups with no apparent compound related increase in incidence. Significantly decreased incidences were observed for certain neoplasms, including mononuclear cell leukaemia in male rats (control, 33/60; low-dose, 28/60; high-dose, 14/60), adrenal gland pheochromocytoma in male rats (26/55; 16/56; 6/54), mammary gland fibroadenoma in female rats (20/60; 11/60; 8/59), and pituitary gland neoplasms in female rats (37/60; 28/60; 17/59). These decreases were attributed to the reduced survival of the high-dose groups and possibly were also associated with reduced body weights.
Only a few neoplasms of the brain were found in these studies. A single glioma occurred in a high-dose male, an oligodendroglioma in one low-dose female, and a single astrocytoma in a high-dose female. A granular cell tumor, presumably of meningeal cell origin, occurred in one high-dose male. None of these neoplasms was considered to be treatment related.
Relevance of carcinogenic effects / potential:
No significant carcinogenic effects were observed.
Dose descriptor:
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
histopathology: neoplastic
Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of sodium azide for male or female F344/N rats administered 5 or 10 mg/kg bw/day.
Executive summary:

In a carcinogenicity study (similar to OECD Guideline 453) sodium azide(purity >99%)in distilled water was administered to 60F344/N rats/sex/dose via oral gavageat dose levels of 0, 5 or 10 mg/kg bw/day for 103 weeks (5 days per week).

Dose-related depression in mean body weight was observed throughout the study period. Mean food consumption values in low and high-dose groups were lower than control values. Survival of high-dose rats of each sex was significantly (P<0.05) lower than controls (males: control, 24/60; low-dose, 27/60; high-dose, 9/60; females: 37/60; 43/60; 21/59). The reduced survival was attributed to brain necrosis and cardiovascular collapse induced by sodium azide, as observed by necropsy and histopathologic examination. Clinical examinations revealed lethargy, convulsions upon dosing, recumbency, emaciation, and toe-walking.

Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of sodium azide for male or female F344/N rats administered 5 or 10 mg/kg bw/day. Therefore, the NOAEL for carcinogenicity was determined to be 10 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
10 mg/kg bw/day
Study duration:

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available data, sodium azide does not warrant classification for carcinogenicity in accordance with CLP Regulation 1272/2008.

Additional information

In a well-conducted 2 -year rat study, no signs of carcinogenic effects were found (NTP 1991). Sodium azide is therefore considered not carcinogenic.