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Diss Factsheets

Administrative data

epidemiological data
Type of information:
other: epidemiological study
Adequacy of study:
supporting study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted and documented epidemiological cohort study

Data source

Reference Type:

Materials and methods

Study type:
cohort study (prospective)
Endpoint addressed:
Test guideline
no guideline followed
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium azide
EC Number:
EC Name:
Sodium azide
Cas Number:
Molecular formula:
sodium azide


Type of population:
Ethical approval:
confirmed, but no further information available
Details on study design:
The purpose of this investigation was to determine whether chronic brain impairment may occur from chronic occupational exposure.

The exposed workers had sustained for more than 5 years 8-h shifts of constant inhalation of often more than (acknowledged by the company) the legal limit of 0.3 mg/m3 of sodium azide. All workers (exposed and unexposed) were examined yearly by a physician specialised in occupational health. The medical records of all the workers were scrutinised for any medical condition unlikely to have arisen due to exposure but likely to affect the dependent measures of the investigation.

The authors devised an individualised cumulative exposure index (milligrammes per cubic metre per month) by combining the work history of each worker and measurements of airborne sodium azide at each workstation. Each worker was required to carry an air pump and particle collector, which was calibrated at each workstation and for each measurement. Measurement of sodium azide concentrations was government controlled and accredited by the American Industrial Hygiene Association.
The authors devised a work-history questionnaire to determine the workstations of each worker, the duration, the ambient temperature and humidity and exposure to toxins in previous employment.
The authors implemented a medical-history questionnaire to assess possible neurological, psychiatric, or medical history that might influence neuropsychological performances or bias symptom self reports. These questionnaires were corroborated and completed by scrutiny of the medical records of the government public health unit responsible for the plant.
The authors created a neurobehavioral symptoms questionnaire to assess discomfort and clinical symptoms of exposure to toxic substances, with special emphasis on the known symptoms of exposure to sodium azide. The authors adapted the questionnaire in a way that would distinguish acute effects (questions about the current day) distinctly from chronic effects (questions about persistent and longstanding symptoms).
Neuropsychological testing included a simple reaction time (SRT) task, Lanthony's 15-hue color discrimination test, the grooved pegboard test of motor speed and coordination, and the digitsymbol subtest of the Wechsler adult-intelligence scale (visuo-perceptual scanning and learning). The Profile of Mood States (POMS) was also included.
All workers were seen after a 16-h weekend off work. To dissociate acute from chronic effects, we tested workers at the beginning (6:00-8:00 a.m.) of their shift or at the end (4:00-6:00 p.m.). Half of each group was tested first in the morning and the other half first in the afternoon. The workers were re-tested in the same way 1 year later and 2 years later, except that on these occasions, tests were administered only in the morning.
All workers of the plant were required to undergo blood tests and blood pressure and pulse measurements during the 1st year.
Exposure assessment:
Details on exposure:
TYPE OF EXPOSURE: sodium azide concentration at workplace

TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling /

EXPOSURE LEVELS: 0 - 0.93 mg/m3, mean value: 0.23 mg/m3

EXPOSURE PERIOD: The range of time at the plant, for the exposed workers, was 5 to 30.7 years.

Results and discussion

Neuropsycological tests
Table 1 presents the means and SDs of neurophysiological performances of the exposed and unexposed workers, before and after work shift, during the first year of investigation.

Acute-symptom self reports
Subjects were asked to rate the degree to which they were affected by symptoms having occurred only during the last 5 workdays (i.e. acute symptoms). The exposed workers had significantly more complaints, the exposed group was significantly more affected on 6 of 27 symptoms (headache, vertigo, nausea, fatigue, cardiac palpitations, irritated or red eyes).

Chronic-symptom self reports
Subjects rated chronic symptoms the same way they rated acute ones, and their judgements were processed in the same manner. The exposed workers did not have significantly more complaints. Of 40 chronic symptoms analysed individually, only two symptoms yielded significant group effects: the exposed group was significantly more affected by both (heart palpitations, hand trembling).

Dose-response correlations
Relationships between the cumulative exposure index and all the dependent variables (matching variables, psychological and neuropsychological test results, blood test measurements, cardiac physiology measurements) were more linear than curvilinear. The cumulative exposure index did not correlate significantly with any dependent variable whatsoever.

The 3-year follow up
The measurements in the present investigation were obtained once a year over a period of 3 years. As a few workers left the plant, only those workers were retained for these particular analyses who completed all three assessments. Repeated measurement ANOVAs were executed to determine the eventuality of group main effects or interactions of the group effect with the time effect. None of these reached significance. The authors maintained the same statistical approach to symptom self-report analysis as in the previous sections. All significant differences were to the effect of more complaints in the exposed group. Group comparisons of chronic symptoms revealed that all significant differences were to the effect of more complaints in the exposed group. Whether for acute symptoms or for chronic symptoms, the incidence of complaints decreased from the 1st to the 2nd year, and particularly from the 2nd to the 3rd year.

Creatinine levels
In the cohort exposed to sodium azide, markedly reduced creatinine concentrations were measured. In the exposed and unexposed cohorts, creatinine levels were unrelated to any of the matching variables such as cigarette or alcohol intake, age, height, weight, education. Plasma creatinine was unrelated to the cumulative exposure index. In the exposed cohort, morning measurements of neuropsychological performance were unrelated to creatinine levels. However, at the end of the work shift five of the POMS subscales and the POMS global score were significantly correlated with creatinine levels.

Confounding factors:
Partial correlation analyses was used to eliminate possible confounding effects of age, education, and body weight, height, cigarette or alcohol consumption, on the cumulative exposure index.

Any other information on results incl. tables

Table 1: Means and SDs of neuropsychological performances of the exposed and unexposed workers, before their work shift and after, during the 1st year of the investigation

Neuropsychological test

Exposed workers

(n = 41)

Unexposed workers

(n = 42)





Reaction time (ms)

228 (35)

224 (37)

219 (29)

220 (29)

Digit-symbol (symbols)

55.9 (7.7)

56.8 (8.3)

56.4 (10.3)

57.4 (9.9)

Grooved pegboard-dominant hand (s)

63.7 (9.7)

61.0 (8.1)

65.8 (8.8)

62.1 (8.4)

Grooved pegboard-non-dominant hand (s)

66.2 (8.1)

64.5 (9.1)

68.8 (10.9)

67.3 (10.6)

Lanthony 15-hue (right eye) (errors)

1.29 (0.22)

1.37 (0.32)

1.25 (0.17)

1.30 (0.26)

Lanthony 15-hue (left eye) (errors)

1.33 (0.26)

1.36 (0.27)

1.25 (0.19)

1.32 (0.20)

POMS (total)

6.0 (21)

13 (25)

9.7 (17)

13 (21)

POMS tension/anxiety

40.5 (6.4)

41.2 (7.5)

41.5 (5.8)

41.3 (6.7)

POMS depression

40.5 (4.5)

41.6 (5.3)

41.1 (3.7)

41.0 (4.8)

POMS hostility/anger

42.7 (6.6)

45.0 (9.1)

44.2 (7.0)

44.1 (5.6)

POMS vigour/activity

52.6 (6.5)

50.5 (7.1)

51.0 (6.5)

50.7 (5.6)

POMS fatigue/inertia

41.3 (6.6)

43.1 (7.5)

41.4 (5.4)

41.6 (5.6)

POMS confusion/disorientation

37.0 (6.5)

38.7 (6.6)

37.7 (5.1)

37.9 (6.4)

PMOS: Profile of Mood States

Applicant's summary and conclusion

Exposed workers presented significantly more acute symptoms of exposure than unexposed workers. Symptoms reported included headache, vertigo, nausea, fatigue, cardiac palpitations, irritated or red eyes. The only reccuring chronic symptom was trembling of the hands. No psychological or neuropsychological tests differentiated the exposed from the unexposed group.
Executive summary:

The occupational neuropsychotoxicology of sodium azide was investigated. Neuropsychological and psychological tests, a symptom self-report questionnaire and haematological and cardiac measurements were gathered from 41 exposed workers and 42 unexposed workers in a chemical production plant yearly for 3 years. The exposed workers presented significantly more acute symptoms of exposure (headache, vertigo, nausea, fatigue, cardiac palpitations, irritated or red eyes) than did the unexposed workers. However, only one chronic symptom was repeatedly and more significantly reported, namely trembling of the hands. No psychological or neuropsychological tests (reaction time, psychomotor, cognitive, chromatopsia, Profile of Mood States) differentiated the two groups. However, acute effects of exposure on plasma creatinine and on systolic pressure were noted. Low creatinine levels in the plasma of exposed workers correlated significantly with impairment of mood on the Profile of Mood States test, but not with any other measure. The authors recommend that workers exposed to sodium azide be assessed with tremometry, clinically and in a future field study.