4,4'-methylenediphenyl diisocyanate

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Does not include experimental toxicological data

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Diisocyanate asthma: clinical aspects and immunopathogenesis

Author:

Redlich CA & Karol MH

Year:

2002

Bibliographic source:

Int.Immunopharmacol. 2 (2/3): 213-24

Materials and methods

Study type:

other: Review paper

Test guideline

Qualifier:

no guideline followed

Test material

Test material information

Constituent 1

Reference substance name:

m-tolylidene diisocyanate

EC Number:

247-722-4

EC Name:

m-tolylidene diisocyanate

Cas Number:

26471-62-5

IUPAC Name:

2,4-diisocyanato-1-methylbenzene, 2,6-diisocyanato-1-methylbenzene

Details on test material:

Commercial Diisocyanates.

Method

Subjects:

Not Applicable

Clinical history:

Not Applicable

Controls:

Not Applicable

Details on study design:

This review considers recent concepts in exposure, clinical aspects and pathogenesis of the disease. It concludes that the pathogenesis of diisocyanate asthma remains unclear, with evidence supporting both immunological and nonimmunological mechanisms. Recent findings of chemical interactions with biological nucleophiles are described.

Results and discussion

Results of examinations:

Diisocyanates, highly reactive chemicals used in the production of polyurethanes, are currently the most frequently reported cause of chemically induced occupational asthma and their use continues to rise. The prevalence of diisocyanate asthma among exposed workers is estimated to range from 5% to 15%. The exposure relationship of TDI and occupational asthma was reviewed extensively. It has declined extensively since the mid-1970s from 5 to 6% to less than 1% due to engineering and work practice control in the workplace. (Ott 2003) Other investigators found low prevalence of occupational asthma 3/243 (1.23%) and antibody-dependent sensitization 2/243 (.82%) to diphenylmethane diisocyanate in a plant engineered for minimal exposure to diisocyanates, thus concluding that strict control and monitoring of ambient MDI exposure was associated with a low prevalence of specific sensitization to MDI and a lower than expected prevalence of OA. Routes of exposure include the respiratory tract and skin. Workplace exposures are difficult to quantify and control, and there is no simple diagnostic test for the disease.

Other investigators found low prevalence of occupational asthma 3/243 (1.23%) and antibody-dependent sensitization 2/243 (.82%) to diphenylmethane diisocyanate in a plant engineered for minimal exposure to diisocyanates, thus concluding that strict control and monitoring of ambient MDI exposure was associated with a low prevalence of specific sensitization to MDI and a lower than expected prevalence of OA. (Bernstein et al 1992)

Any other information on results incl. tables

Clinical presentation: Although, the clinical presentation of diisocyanate asthma is variable, often complicating its recognition and diagnosis, industry experience has been that regular respiratory surveillance and early removal of workers who develop toluene diisocyanate (TDI)-associated occupational asthma can effectively protect these workers from accelerated pulmonary function decline (Conner III 43838) This study also suggested that diisocyanates are such well known occupational asthmagens that other exposures tend to be ignored when considering respiratory health problems in a workplace. For example in one industrial hygiene air monitoring program demonstrated excellent control of the polyisocyanate hazard, but poor control of a mould-release solution, which was considered the cause of health problems. Control of that exposure allowed previously restricted workers to return to their former work making polyurethane parts.

Symptoms of diisocyanate asthma typically do not manifest until after an unpredictable latency period of several months to years after initial exposure. Lower respiratory track symptoms begin insidiously and include cough, chest tightness, shortness of breath, or wheezing, which are temporally related to workplace exposure. Upper respiratory symptoms have not been reported. A study of specific nasal responses in subjects undergoing challenges by inhaling occupational agents causing asthma through the nose and mouth, failed to demonstrate significant response in terms of symptoms and increase in nasal resistance or significant changes in inflammatory cells and mediators in subjects exposed to diisocyanates, unlike high molecular weight agents (Desrosiers M et al Allergy. 1998 Sep;53(9):840-8).

Acute high diisocyanate exposures can also cause reactive airways dysfunction syndrome (RADS), an asthma-like illness that develops after a single exposure to a high concentration of an irritating substance. At least two reports have described cases of RADS that have transformed to immunological asthma. (Perfetti et al American journal of industrial medicine 44:325-328 (2003) Leroyer et al Thorax 1998).

Applicant's summary and conclusion

Conclusions:

Diisocyanate-associated asthma is the most frequent health effect resulting from exposure which is inadequately controlled. In the early years of the industry, annual incidence ranged from 1% to as high as 5-6% with corresponding high prevalence rates. Since the implementation of hazard control through engineering and work practices in the mid-1970s, , this incidence has declined to less than 1%The pathogenesis of diisocyanate asthma remains unclear, with evidence supporting both immunological and non-immunological mechanisms. The diagnosis of diisocyanate asthma is often problematic due to the variability of symptoms, the lack of simple diagnostic or screening tests, uncertainty regarding the underlying mechanisms, and the multiple other potential occupational and environmental causes of asthma. The clinical presentation and the approach to diagnosing diisocyanate asthma are similar to that of other causes of occupational asthma. Early diagnosis leads to better prognosis; therefore a well designed medical surveillance program is vitally important. Accurate diagnosis is equally important to avoid undue restrictions from the workplace.