N,N-dimethylisopropylamine

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment (Original publication in German, English translation available)

Data source

Reference

Reference Type:

publication

Title:

Bronchiale Hyperreaktivität bei Arbeitern einer Graugiesserei [Bronchial hyperreactivity in foundry workers]

Author:

Wolf C, Pospischil M, Petzl DH and Petrak R

Year:

1988

Bibliographic source:

Zbl Arbeitsmed, 38: 279-285

Materials and methods

Study type:

other: health record from industry

Endpoint addressed:

eye irritation

respiratory irritation

Principles of method if other than guideline:

A study was carried out on 47 core shop workers in a light metal foundry. The aim of the study was to understand the effects of inhaling harmful substances on lung function and bronchial responsiveness. In addition to recording anamnestic data and lung function parameters, bronchial responsiveness was also measured which, as a sensitive parameter, can also show clinically latent bronchial motility disorders. Bronchial responsiveness can thus be used as a marker in the study of the effects of potentially toxic inhalants on the lungs.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N-dimethylisopropylamine

EC Number:

213-635-5

EC Name:

N,N-dimethylisopropylamine

Cas Number:

996-35-0

Molecular formula:

C5H13N

IUPAC Name:

dimethyl(propan-2-yl)amine

Test material form:

other: liquid

Method

Type of population:

occupational

Subjects:

The investigation was carried out at 47 people (25 men, 22 women). The age of the subjects was on average 32.3 ± 9.6 years (men 31 ± 10 years, women 33.7 ± 8.7 years). 20 people work in Hall 1, 27 people work in Hall 2. 38 people after the cold-box process, 9 people by the hot-box process.
Anamnestic data were collected following:
- Familial history of asthma and atopy.
- Number of years worked in the core shop.
- Specification of the job (cold box, hot box).
- Smoking habits (pack years).
- Respiratory distress.
- Frequency of occurrence of visual disturbance (corneal oedema).

Family history of asthma:
None of the subjects studied indicated a family history of asthma, nor suffered from atopy

Duration of exposure:
Because of skewed distribution, the number of working years is given as a median with 25 and 75 percentile. For the group as a whole the number of years worked was x (25./ 75. Perc.) = 3.0 (5.0/1.5) years. For the men it was 3.0 (10.0/1.5) years and for the women 3.0 (4.25/1.87) years. No statistically significant difference in the number of working years in the core shop could be found between men and women.

Specifications of the work station (cold-box or hot-box):
No statistically significant difference in the number of working years could be found between the different processes.

Smoking habits:
Non-smokers represented 19 of the subjects (10 men and 9 women) and smokers represented 28 (15 men and 13 women). The number of packyears for smokers was 8.8 ± 7.2 (10.3 ±8.4 for men and 7.11 ± 5.4 for women). There is no difference in the number of cigarettes smoked in men and women.

Current complaints:
36 subjects (19 men and 17 women) claimed to be free of complaints (Complaint group 1). 11 subjects (6 men and 5 women) claimed to have moderate respiratory complaints in the form of a slight cough, largely unrelated to working conditions (Complaint group 2). No subjects claimed to suffer from severe coughing and asthma (complaint groups 3 and 4 respectively).
No significant correlation could be established between respiratory complaints and bronchial responsiveness, duration of exposure or lung function parameters. Only in smokers could a connection be shown (p = 0.03), between respiratory complaints and the number of cigarettes smoked.
Breathlessness in the workplace itself was claimed by 8 subjects, 3 of which distinctly suffered from bronchial hyperreactivity. However, no significant correlation could be established regarding the type of process, the number of years worked, the PC20 or any one of the two halls.
36 subjects claimed to suffer from corneal oedema. This occurred 15 times a year (median value). Here again, no significant correlation could be shown regarding the Hall, process or responsiveness. However, a connection with the number of years worked could be shown(p=0.006).

Ethical approval:

not specified

Route of exposure:

inhalation

Reason of exposure:

unintentional, occupational

Exposure assessment:

measured

Details on exposure:

DMIPA measurements at the workplace
Hall 1: 4 measuring points: 9.7, 5.8, 4.9, 2.6 mg/m3 air.
Hall 2: 3 points: <2.0, 8.6, 12.75 mg/m3 air.

Examinations:

Lung function testing:
An open system was used for measuring lung function (Vitalograph-Compact). The following measurements were taken:
Inspiratory vital capacity (IVC), Forced vital capacity (FVC), Forced expiratory volume in one second (FEV1), as well as the mid-expiration and end-expiration flow-volume loop parameters FEF 25-75 and FEF 75-85 respectively. The European Coal and Steel Community (ECSC)'s reference values were used as the normal values and were pre-programmed into the spirometer.

Inhalation provocation test:
The bronchial provocation test was carried out as a multi-stage test according to the protocol of the Austrian- Working Group for Clinical Respiratory Physiology (Österreichische Gesellschaft für Lungen-erkrankungen und Tuberkulose, ed. 1986). A Pari-Inhalierboy nebuliser was used for aerosol generation and 4 nebuliser heads were used for provocation. Nebulising capacity was measured by weighing the nebuliser head before and after a 2-minute operating period with 5ml of 0.9% saline solution from which aerosol nebulisation was calculated in ml/min. The average result was 0.46 ± 0.018 ml/min (± 2 standard deviations). The aerosol was inhaled for 2 minutes via tidal breathing through a mouthpiece (nose closed). After measuring the initial lung function the diluent containing the dissolved bronchoconstrictor was breathed in, followed by histamine solutions in increasing concentrations of 0.025, 0.05, 0.1, 0.25, 0.5, 1.2 and 4 mg histamine/ml. An initial concentration of 0.5 mg/ml was chosen for subjects free of complaints whereas an 0.025 mg histamine/ml was used in patients with a history of asthma or asthmoid bronchitis. An FEV1 of less than 60% of vital capacity was considered grounds for exclusion from the test. A PC20 of 1.4 mg/ml was fixed as the boundary between normally responsive and hyperresponsive (Wolf 1987).
The measurement parameter used was FEV1. Measurements were taken at 30 seconds and 90 seconds after completed inhalation. If the result at 90 seconds was lower than the result at 30 seconds, measurements continued to be taken in 2-minute intervals until they stabilized. The stop criterion was a drop in FEV1 of more than 19% of the FEV1 attained with the diluent. If the stop criterion was not reached, the inhalation was continued with the next concentration of histamine solution. Percentage drops in FEV1 were plotted on a semi-logarithmic graph against the value of the diluent inhalation and the concentration corresponding to a drop in FEV1 of 20% was calculated (PC20).

Results and discussion

Results of examinations:

Lung function test:
Table 2 shows the parameters recorded in the lung function test. With the exception of FEV1%FVC, all of the other values are given as a percentage of the ECSC reference values. No lung function parameter could distinguish between smokers and non-smokers, just as no difference could be shown between the different complaint groups. Neither could any significant difference be shown between the number of years worked and lung function parameters.

Bronchial responsiveness
The results of the bronchial responsiveness tests are given in Table 3. The values given are the PC20 for the control group that was not exposed to harmful substances as well as the PC20 for the foundry workers, both for the group as a whole (total) and for the different complaint groups. There is no significant difference in the PC20 values of the foundry workers as a whole compared to the two complaint groups. However, there is a significant statistical difference between the PC20 of the control group and the foundry workers, both in the group as a whole (p = 0.001) and in complaint group 1 (p = 0.0001). For the complaint group 2, no significant difference (p=0.4) was found between the control group and the foundry workers.
Table 4 shows the PC20 values related to the work station (cold-box or hot-box process in Hall 1 or 2). There is no significant variation in PC20 values according to the work station. Assessment of PC20 values showed no correlation between the length of time worked and bronchial responsiveness. However, a highly significant correlation was shown between PC20 values and the lung function parameters FEV1 (p=0.009), FEV1%VC (p=0.006), FEF25-75 (p = 0.0001) and FEF75-85 (p=0.0002).

Any other information on results incl. tables

Table 2: Lung function measurements for the group as a whole (total), complaint group 1 (= no permanent respiratory complaints) and complaint group 2 (= permanent presence of a slight cough).

 

Lung function parameters in core shop workers (% ECSC reference values)
	Total	Group 1	Group 2
FVC FEV1 FEV1%FVC FEF 25-75 FEF 75-85	96.6 ± 17.6 92.3 ± 16.9 81.9 ± 8.2 85.3 ± 24.6 93.9 ±31.8	99.6±16.4 94.9 ± 15.6 81.7± 8.1 85.8± 22.6 91.5 ±29.8	87.7 ± 18.7 84.2 ± 18.9 82.2+ 8.8 84.0 ± 30.6 100.5 + 37.0

Table 3: Median and percentiles of PC20 values for core shop workers and control groups. GR 1 and GR 2 = complaint group 1 and 2 respectively.

 

PC 20 (mg/ml)
	Control group			Core shop workers
	Total	GR 1	GR 2	Total	GR 1	GR 2
Median	3.9	4.7	2.3	1.7	1.7	2.0
25. Percentile	1.8	2.3	1.3	0.96	0.97	0.4
75. Percentile	6.1	6.6	5.7	4.0	3.9	4.0
n	129	75	54	47	36	11

 

Table 4: PC20-values of core workers according to the work station.

 

Bronchial responsiveness according to the
work station.
PC 20 (mg/ml)	Cold Box	Hot Box
Hall 1	1.7	***
Hall 2	1.8	1.8

Applicant's summary and conclusion

Executive summary:

47 workers of a core chop in a light-metal foundry were investigated to assess lung function and bronchial hyperreactivity. None of the persons suffered from asthma or severe respiratory symptoms, 11 persons reported mild respiratory tract complaints. 36 workers had visusal disturbances (blue haze) caused by dimethylisopropylamine (DMIPA), which induces a corneal edema. 20 persons had an increased bronchial reactivity. It was impossible to show a correlation between visual disturbances, respiratory symptoms and bronchial reactivity, but there was a strong correlation between bronchial reactivity and forced expiratory flow parameters. It was therefore concluded, that the cause of the bronchial hyperresponsiveness is an inflammation of small airways. It was hard to find the responsible substrat because many of potential toxic substances occur together. It was suggested that amines, which are used as catalysts in cold-box-procedure, could play an important role in development of bronchial hyperreactivity.