Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Sodium azide was tested in a 2-year carcinogenicity study conducted by the NTP (1991). In this study, adverse effects were found after oral administration by gavage of sodium azide in male and female rats. Based on the brain necrosis, mortality which was attributed to brain necrosis, other pathological findings, body weight, food consumption and clinical and behavioral signs, a NOAEL of 5 mg/kg bw was determined. Equivocal results were observed in the 90-day oral study. In this study, a NOAEL of 10 mg/bw was determined based on mortality which is attributed to the observed brain necrosis, clinical and behavioral signs as well as other histopathological findings (pulmonary congestion and haemorrhage).

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981-1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
exposure time: 5 days/week for 2 years; only 2 dose groups; no urinalysis, hematology, blood chemistry performed
GLP compliance:
yes
Limit test:
no
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
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston NY
- Age at study initiation: 48-55 days
- Weight at study initiation: 153-156 g
- 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

ENVIRONMENTAL CONDITIONS
- 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
Vehicle:
water
Details on oral 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 wate, stoppered and shaken until throroughly mixed. The flask was then filled to volume with water, using a pipette to carefully add the last few mililiter, stoppered, mixed and transferred to the appropriate dosing bottles.


DIET PREPARATION
- Maximum storage time for feed: 120 days
Analytical verification of doses or concentrations:
yes
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)
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:
60
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.
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- 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.

FOOD CONSUMPTION: Yes

OPHTALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes, examined organs are listed in the Table 1 below.
Other examinations:
no data
Statistics:
no data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
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 examination 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).
Mortality:
mortality observed, treatment-related
Description (incidence):
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.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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. Summary values are depicted in Table 3.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
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.
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
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
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.

Brain:
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.

Lung:
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.

Liver:
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.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
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.
Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (nominal)
System:
central nervous system
Organ:
brain
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Table 2: Survival of Rats in the 2 -year gavage studies of sodium azide.

 

Vehicle control

5 mg/kg bw/day

10 mg/kg bw/day

Male

 

 

 

Animals initially in study

60

60

60

Natural deaths

16

14

27

Moribund kills

19

18

15

Accidental deathsa

1

1

9b

Animals surviving to study termination

24

27

9

% survival at end of studyc

61

47

19

Mean survival (days)d

660

662

572

Survival P valuese

0.003

0.555 N

0.002

Female

 

 

 

Animals initially in study

60

60

60

Natural deaths

11

5

22

Moribund kills

10

12

11

Accidental deathsa

2

0

5b

Missexed

0

0

1

Animals surviving to study termination

37f

43

21

% survival at end of studyc

62

72

39

Mean survival (days)d

670

704

565

Survival P valuese

0.010

0.223 N

0.015

aCensored from survival analyses.

bThe increased number of accidental deaths in this group appeared to be secondary to brain necrosis induced by the chemical.

cKaplan-Meier determinations. Survival rates adjusted for accidental deaths.

dMean of all deaths (uncensored, censored, terminal sacrifice).

eThe entry under the "control" column is the trend test result. Subsequent entries are the results of pairwise test. Negative trends are indicated by "N".

fOne of these animals was found dead on the last day of the study.

Table 3:Mean body weights of rats in the 2-year gavage study of sodium azide

Male:

 

Vehicle control

5 mg/kg bw/day

10 mg/kg bw/day

Study weeks

Mean weight [g]

Weight [% of control]

Mean weight [g]

Weight [% of control]

Mean weight [g]

Weight [% of control]

1 – 13

285

100

278

98

277

97

17 – 51

440

100

413

94

395

90

54 – 104

482

100

456

95

423

88

 

Female:

 

Vehicle control

5 mg/kg bw/day

10 mg/kg bw/day

Study weeks

Mean weight [g]

Weight [% of control]

Mean weight [g]

Weight [% of control]

Mean weight [g]

Weight [% of control]

1 – 13

175

100

272

98

169

97

17 – 51

236

100

226

96

202

86

54 – 104

321

100

298

93

249

78

 

Conclusions:
In a 2-year oral study, dose-related depression in mean body weight was observed throughout the study period. Survival of high-dose rats of each sex was significantly lower than controls. The reduced survival was attributed to brain necrosis and cardiovascular collapse induced by sodium azide. Treatment-related non-neoplastic brain lesions (necrosis of the cerebrum and thalamus) were observed at significantly increased incidences in high-dose (10 mg/kg bw/day) male and female rats. The increased incidence of lung congestion observed in this dose group was considered due to cardiovascular collapse secondary to brain necrosis. There were no treatment-related increases in incidences of neoplasms in rats. Based on these results, the NOAEL is considered to be 5 mg/kg bw/day and the LOAEL to be 10 mg/kg bw/day.
Executive summary:

In a chronic  toxicity study (similar to OECD Guideline 453) sodium azide (purity >99%) in distilled water was administered to 60 F344/N rats/sex/dose via oral gavage at dose levels of 0, 5 or 10 mg/kg bw/day for 103 weeks (5 days per week). Treatment-related depression in mean body weight was observed throughout the study period. Mean feed consumption values in low- and high-dose groups (5 and 10 mg/kg bw/day, respectively) were lower than control values. Survival of high-dose rats of each sex was significantly 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 in high-dose animals. Treatment-related non-neoplastic brain lesions (necrosis of the cerebrum and thalamus) were observed at significantly increased incidences in high-dose male and female rats. The increased incidence of lung congestion observed in this dose group was considered due to cardiovascular collapse secondary to brain necrosis. The incidence of hepatodiaphragmatic nodules in the livers of low- and high-dose female rats was higher than that in control. This finding common in aging F344/N rats were not considered to be treatment related.There were no treatment-related increases in incidences of neoplasms in rats.


Based on these results, the NOAEL is considered to be 5 mg/kg bw/day and the LOAEL to be 10 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Study conducted equivalent to guideline
System:
central nervous system
Organ:
brain

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Suitable data were available to assess the toxicity of the target substance sodium azide after repeated dose exposure. Therefore, the available data from repeated dose toxicity studies conducted with sodium azide were used in a weight of evidence approach to assess the specific target organ toxicity of the target substance.

Sodium azide was nominated by the National Cancer Institute for evaluation of its carcinogenic activity because of the high potential for human exposure and the lack of adequate carcinogenicity testing. Sodium azide (>99% pure) was administered to rats orally by gavage at doses of 0, 5 and 10 mg/kg bw/day. Studied parameters included regular cage-side and clinical examinations, body weight measurements, gross necropsy and histopathologic examination of all animals. Clinical chemistry, hematology, urinalysis, and neurobehavioral tests were not performed.

Two-year studies were conducted by administering 0, 5, or 10 mg/kg bw/day sodium azide to groups of 60 male and 60 female Fischer F344 rats. 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 in high-dose animals.

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. The NOAEL (2 -year, rat) was 5 mg/kg bw/day.

In a 13 -week study conducted by the NTP, rats were administered sodium azide (>99% purity) by gavage at doses of 0, 1.25, 2.5, 5, 10 and 20 mg/kg bw. Studied parameters included regular cage-side and clinical examinations, body weight measurements, gross necropsy and histopathologic examination of all animals. Clinical chemistry, hematology, urinalysis, and neurobehavioral tests were not performed. In comparison to the 2 -year study, organ weights for brain, heart, liver, lungs, right kidney and thymus were determined, but histopathology was carried out on less organs than in the 2 -year study.

In this study, 7 out of 9 male and all 10 female rats receiving 20 mg/kg bw/day sodium azide died, and no death occurred in the lower dose groups. There were no significant differences in the mean body weight among the various dose groups.

Clinical findings (labored breathing and hunched position) and histopathologic lesions (brain necrosis and pulmonary congestion and hemorrhage) were seen in the rats administered 20 mg/kg bw/day sodium azide. Deaths in the 20 mg/kg bw/day dose groups were attributed to brain necrosis. No histopathologic lesions were observed in the lower dose groups.

The results of these studies demonstrate a steep dose response for compound-related toxic effects of sodium azide in F344/N rats. A NOAEL of 10 mg/kg bw/day and a LOAEL of 20 mg/kg bw/day was obtained. Significant increase in liver weights were observed in female rats but considered to be not relevant for LOAEL derivation as neither a clear dose response nor histopathological changes in liver tissue were observed.

In conclusion, a NOAEL of 5 mg/kg bw/day could be determined in a chronic study, which is equal to the subchronic NOAEL of 10 mg/kg bw/day by converting the chronic NOAEL to a subchronic (90 -day study) according to a pragmatic approach described in the Guidance on the Application of the CLP Criteria, Version 5.0 July 2017.

Justification for classification or non-classification

Significant brain necrosis was observed in the high dose group of the NTP study (1991) at 20 mg/kg bw/day (90 -day study) and 10 mg/kg bw/day (2 -year study). According to CLP table 3.9.2.9.7, the guidance value for classification as STOT RE 2 is a LOAEL between 10 and 100 mg/kg bw/day reported in a 90d study (or 30 -300 mg/kg bw/day based on a sub-acute study). Converting these values to a chronic (2 -year, 103 -week study) according to a pragmatic approach described in the Guidance on the Application of the CLP Criteria, Version 5.0 July 2017, these values will be extrapolated to 1.3 and 12.5 mg/kg bw. Therefore, the organ specific adverse effects at 10 mg/kg bw/day reported in the 2 -year study as well as in the 90 -day study does warrant classification for specific target organ toxicity (brain), STOT RE 2 (H373) in accordance with CLP regulation (EC) No 1272/2008.