Registration Dossier

Diss Factsheets

Toxicological information

Sensitisation data (human)

Currently viewing:

Administrative data

sensitisation data (humans)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Falling short of highest standards concerning aspects of protocol or reporting.

Data source

Reference Type:

Materials and methods

Type of sensitisation studied:
Study type:
study with volunteers

Test material

Constituent 1
Reference substance name:
EC Number:
Cas Number:
Details on test material:
Commercial diisocyanates.


Type of population:
Ethical approval:
confirmed and informed consent free of coercion received
139 anonymous blood donors recruited through Biological Specialty Corp (Colmar, PA). All the participants provided written informed consent before entry into the study.
Clinical history:
150 donors had blood samples collected at medical centers in Pennsylvania and Florida and completed a brief 13-item questionnaire. Questionnaire items captured the demographic profile of the study group (age and sex), characterization of possible work- and hobby-related exposure to products containing diisocyanates, smoking history, allergy and asthma status, respiratory symptoms, and recent respiratory tract infections. Questionnaire responses were used to identify individuals with no known isocyanate exposure and those with possible work- or hobby-related exposure to diisocyanates.
Reference control serum samples were obtained from 8 individuals with no known exposure to diisocyanates and were preselected for negativity (optical density [OD] <0.1) compared with the known positive control (OD >0.6).
Route of administration:
other: not applicable
Details on study design:
Diisocyanate specific IgE and IgG antibodies were assayed in triplicate by means of indirect ELISA detection of the immunocomplexes with a labeled immunoglobulin, as previously described. The IgE antibodies were also assayed using a biotinstreptavidin ELISA procedure. Competitive inhibition assays were performed for all the sera exhibiting positive binding to any diisocyanate-HSA antigen with an OD of at least 0.2.

Results and discussion

Results of examinations:
One hundred fifty donors provided serum samples and completed the aforementioned questionnaire. A review of the responses identified 4 persons who had worked in facilities using diisocyanates and 7 who had reported contact with diisocyanate-containing products through other work or home activities. Results of these 11 persons considered to have had previous diisocyanate exposure are summarized and discussed separately.

In the remaining donors, IgG reactive with HDI-HSA, diphenylmethane diisocyanate–HSA, and TDI-HSA were detected in 18 (13%), 0, and 7 donors (5%), respectively. Inhibition (>50%) was demonstrated in 6 of 9 participants with elevated HDI-HSA levels and in 2 of 7 with elevated TDI-HSA levels. We detected IgE reactive with the same antigens in 3 donors (2%); however, none were confirmed to be positive using the biotin-streptavidin IgE assay.

The numbers and percentages of positive immunoassay results among the 139 donors are given in Table 2 by antibody class and conjugate. Positive samples were defined as having OD values of at least 0.10 that exceeded the mean +3 SDs of the 8 negative referent samples on 3 separate ELISA runs. The 29 positive test results were detected in 24 different donors. The ELISA inhibition tests were performed on 19 samples that had demonstrated a level of binding of OD of 0.2 or greater.

Any other information on results incl. tables

Table 2. Positive Binding by Antibody Class and Conjugate in 139 Donors With No Known or Likely Diisocyanate Exposure

Antibody class and conjugate

Positive Results*

Inhibition test, No. positive/No. tested


% (95% Cl)

IgE class




HDI conjugate


0.7 (0.0 - 3.9)


MDI conjugate


0.7 (0.0 - 3.9)


TDI conjugate


1.4(1.7 - 5.1)


IgG class




HDI conjugate


12.9 (7.9 -19.7)


MDI conjugate


0 (0.0 - 2.6)


TDI conjugate


5.0 (2.1 - 10.1)


Abbreviations: CI, confidence interval; HDI, hexamethylene diisocyanate; MDI, diphenylmethane diisocyanate; TDI, toluene diisocyanate. * Positive readings on 3 enzyme-linked immunosorbent assays (3 separate runs) at 1:10 dilution of test sera.

Applicant's summary and conclusion

The detection and characterization of diisocyanate-induced respiratory disease presents many challenges to clinicians and researchers, alike. The importance of early diagnosis as well as the lack of reliable and accurate markers of the disease has been demonstrated in the reported papers. Specific inhalation challenges ( SIC) testing is not readily available due to its complexity. Use of peak expiratory flows to monitor work-related bronchoconstriction represents a more accessible option, but it requires rather extensive monitoring and expertise in its evaluation, and is problematic if the individual has been removed from the exposure. Antibody testing is appealing due to its accessibility and relatively low cost, as well as the absence of potential side effects for the patient, but unlike high molecular weight (HMW) agents , these serologic markers are insensitive and non-specific for disease detection.

A stepwise algorithmic approach has been recommended for the diagnosis of diisocyanate asthma, while the worker is still in the workplace. Serial measurements of lung function, performed during active exposure to diisocyanates, are relied upon to confirm a diagnosis of OA. This approach emphasizes the need to first define whether asthma is present or absent, while the worker is being exposed to a suspect agent. To confirm diisocyanate asthma, it is essential to demonstrate work-related decrements in lung function by prolonged serial measurements of PEFR or FEVI . This step-wise approach is complex, therefore a physician should be consulted who is experience in the evaluation of occupational lung disorders.