Registration Dossier

Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1993

Materials and methods

Type of sensitisation studied:
respiratory
Study type:
study with volunteers
Principles of method if other than guideline:
A human sensitisation study was conducted in 96 workers (employed at 3 facilities that manufacture or use TMXDI), to evaluate the clinical (questionnaire) and immunological effects (serum antibody) of TMXDI.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
None

Method

Type of population:
occupational
Ethical approval:
not specified
Subjects:
- Number of subjects exposed: 96 workers at 3 facilities (two are laboratories and one is start-up plant) which produce TMXDI
- Sex: Male
Clinical history:
Not reported
Controls:
Controls for ELISA:
Negative control: Serum obtained from non-exposed asymptomatic individuals
Positive control: Serum from an individual with positive antibody titers to Hexamethylene diisocyanate (HDI)-HSA
Route of administration:
inhalation
Details on study design:
EXPOSURE TO TMXDI (personal monitoring):
- 31 workers were exposed to < 0.0004 ppm
- 65 workers were exposed to <0.0004 to 0.0102 ppm
- Peak exposure concentrations, due to spills, mechanical failures etc during start-up phase (1987 and 1988) of commercial production ranged from 0.3-0.5 ppm

TYPE AND DETAILS OF TEST USED
- Immunologic assays: ELISA
- Exposure period: Personal sampling (240 L) for test material was performed during routine operations, several times in 1984, 1985, and 1988; analysed by HPLC (concentrations ranged from <0.0004 to 0.0102 ppm).
- Sampling: Serum samples were collected from each of 96 workers from three facilities in 1988 or early 1989 and frozen at -20°C, until analysis.
- Method: An ELISA was conducted by blinded technicians, to estimate IgG and IgE against TMXDI-HSA (human serum albumin) in the serum of exposed workers, according to previously described protocol of Voller et al., 1976; Sepulveda et al., 1979). The endpoint was defined as the last worker serum dilution having an optical density greater than twice the mean of the negative control sera.

- Questionnaire assessment: American Thoracic Society questionnaire modified to assess relationship between symptoms and workplace exposures was used.

- Final evaluation/overall assessment: Questionnaires and serologic results (based on respiratory and ocular symptomatology were assessed individually by 2 blinded physicians from Northwestern University.

Results and discussion

Results of examinations:
Questionnaire Assessment: 39 workers had symptoms consistent with an irritant syndrome; 11 workers had only irritant eye symptoms while 3 had only irritant throat symptoms. For details refer to Table 1 under 'Any other information on results incl. tables'.

ELISA: No worker had symptoms suggestive of new onset asthma. One worker had low level IgE (1:10) against TMXDI-HSA; that worker reported no work related respiratory symptoms. Seven workers had very low level IgG (1:10) against TMXDI-HSA; All 8 of the workers with antibody worked in jobs with the higher exposure range (<0.0004 to 0.0102 ppm). For details refer to Table 1 under 'Any other information on results incl. tables'.

In cases of peak exposure (start up phase), none developed evidence of immunologically mediated respiratory disease due to TMXDI isocyanate and a small proportion developed low level antibody against TMXDI-HSA.

Final Evaluation/overall assessment: None of the 96 workers had an immunologically mediated respiratory or ocular disease from exposure to m-TMXDI , nor did non-immunologic sensitization appear to occur as none of the workers had histories compatible with new onset symptoms. For details refer to Table 1 under 'Any other information on results incl. tables'.


Any other information on results incl. tables

Table 1: Workers questionnaire, serologic result and final evaluation

  Total irritant symptoms Percentage (%) Positive antibody  Percentage (%) No immunologic respiratory disease related to m-TMXDI Percentage (%)
Group 1 (< 0.0004 ppm) 31 14 48 0 0 31 100
Group 2 (0.0004 to 0.0102 ppm) 65 25 39 8 12 65 100

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, apart from upper respiratory or occular irritant symptoms, there was low incidence of positive serology and no clinical hypersensitivity in worker population on exposure to m-TMXDI.
Executive summary:

A human sensitisation study was conducted using 96 workers employed at three facilities that manufacture or use TMXDI to evaluate the clinical (questionnaire) and immunological effects (serum antibody).

The study population was divided into three groups based upon relative exposure (31 workers at <0.0004 ppm and 65 workers at < 0.0004 to 0.0102 ppm) and duration of exposure was up to 3 years. IgE and IgG against TMXDI conjugated to HSA (TMXDI-HSA) were determined by ELISA.

There were no workers with immunologically induced disease due to TMXDI nor were there any workers whose questionnaires suggested new onset of asthma. Approximately 48% of workers experienced some irritant symptoms, mostly upper respiratory or ocular. Very low level IgG against TMXDI-HSA was present in 8% of workers, all of whom were in the highest exposure category. No immunologic respiratory disease has been identified in this worker population. Further, in cases of peak exposure (start up phase), none developed evidence of immunologically mediated respiratory disease due to TMXDI isocyanate and a small proportion developed low level antibody against TMXDI-HSA. Hence, under the conditions of the study, apart from upper respiratory or ocular irritant symptoms, there was low incidence of positive serology and no clinical hypersensitivity in worker population on exposure to m-TMXDI.