1-isocyanato-2(or 4)-(4-isocyanatobenzyl)benzene and their reaction products with [(methylethylene)bis(oxy)]dipropanol and butane-1,3-diol and propylene glycol

Endpoint summary

Description of key information

Carcinogenicity:

Three cancer mortality studies have been conducted that focused on assessing the potential long-term health effects of diisocyanate exposure. These studies were conducted in polyurethane foam production facilities in the US, Sweden and the UK, respectively Schnorr et al. (1996), and Hagmar (1993a; 1993b) (updated by Mikoczy et al. (2004)), and Sorahan and Pope (1993) updated by Sorahan and Nichols (2002). In summary, cohorts of workers with potential exposure to TDI, MDI and other chemicals from these three studies when combined represent the long-term mortality experience of over 17,000 polyurethane foam production workers. In two of the cohorts, cancer incidence as well as mortality incidence was studied. Among the various cancer sites examined, suggestive findings across studies were reported only in regard to lung cancer among women employees.

Two of the three studies reported a statistically significant increased standardized mortality ratio (SMR) for lung cancer for female workers (SMR 1.81 Sorahan and Nichols (2002), SMR 3.52 Mikoczy et al. (2004)), and the third reported a non-statistically significant increased SMR (1.73 (Schnorr et al. (1996)) for female and a non- statistically significant decreased SMR (0.79 (Schnorr et al. (1996)) for male workers. However, no dose-response relation was found in either study and the authors of both studies with statistical findings concluded that the excess rates were unlikely to be attributable to the occupational exposures present in the plants under investigation. Evidence was presented from other epidemiologic research that the percentage of smokers in female polyurethane foam production workers in the UK was higher than in non-exposed controls and also higher than in women of the general UK population. The excess of pancreatic cancers reported by Sorahan and Nichols (2002) was interpreted by him not to be related to the working conditions in the factories. This interpretation is further supported by the fact that in the other two cohort studies no excess was found. On the contrary, Mikoczy et al. (2004) reported a deficit in pancreatic cancer in the Swedish cohort.

 

Sensitization:

There are clinical case reports of occupational diisocyanate asthma after initial exposure to presumably high concentrations of unspecified MDI substances. Occupational challenge tests or specific inhalation challenges have demonstrated asthmatic responses to low levels of MDI substances in sensitized individuals. Although antibody testing is appealing as a diagnostic tool, unlike high molecular weight agents, these serologic markers are insensitive and non-specific for disease detection (Ott et al., 2007).

An epidemiological study reported a reduction of absolute number of diisocyanate asthma cases more recently, compared to previous data in Canada (30 occupational asthma (OA) claims due to isocyanates (ISO)/year during 1980 to 1993 as compared to 7.4 ISO claims/year in 1998 to 2002) (Buyantseva et al., 2011).

A recent study in France has shown a significant decrease of work-related asthma over the period 2001–2009 for cases related with isocyanate exposures (Paris et al., 2012). In addition, a majority of diisocyanate asthma cases reported at least an improvement in respiratory symptoms at their last assessment; and 46 % reported clearing of all of their symptoms (Buyantseva et al., 2011). The isocyanate-related asthma incidence in Europe was reviewed by Poole (2013), who concluded that there was some indication of a downward trend in isocyanate associated occupational asthma in some countries, (i.e. France and Belgium), the number of cases in other countries remain steady, or possibly rising (Czech Republic). While tests are available to identify specific agents responsible for inducing the hypersensitive state, such testing is not applied in the majority of cases, with diagnosis relying on clinical examination and labour anamnesis. There is some indication that isocyanate occupational asthma might be associated with certain occupations/jobs using spray applications, but information is sparse. A cross-sectional study was performed with 243 employees exposed to MDI substances in a polyurethane processing facility. The 8-hour time weighted average exposures did not exceed 5 ppb, and all three cases diagnosed for work-related asthma appeared to have been induced as a result of intermittent high exposures during non-routine work activities (Bernstein et al., 1993). Overall, various recent data on isocyanate related asthma incidence indicates a reduction in cases in the last decade. Where controls and current exposure standards are met, new asthma cases can be minimized.

CLP regulation notes that evidence for chemical-induced respiratory sensitisation (asthma/rhinitis/conjunctivitis/alveolitis) will normally be based on human experience. This data can include “consumer experience and comments, preferably followed up by professionals (e.g. bronchial provocation tests, skin prick tests and measurements of specific IgE serum levels); records of workers’ experience, accidents, and exposure studies including medical surveillance; case reports in the general scientific and medical literature; consumer tests (monitoring by questionnaire and/or medical surveillance); epidemiological studies.” (ECHA, 2017a) As such, there is a large human dataset available that includes both case studies and epidemiological reports (Table 60). 

Major findings include:

• MDI substances cause both immediate (seconds to minutes) and delayed-onset (up to several hours) type respiratory hypersensitivity in humans;


• Humans exposed to MDI may suffer from a broad spectrum of respiratory effects not all related to respiratory sensitization, including respiratory irritation, aggravation of asthma and pathological changes of the airways;


• Reported results suggest that relatively high peak concentrations can induce sensitisation, and that prevention of such concentrations will prevent workers from developing respiratory allergy;


• There are clinical case reports of occupational diisocyanate asthma after initial exposure to presumably high concentrations of MDI substances. Occupational challenge tests or specific inhalation challenges have demonstrated asthmatic responses to low levels of MDI substances in sensitized individuals;


• Epidemiological studies demonstrate that annual incidence of isocyanate-related occupational asthma has decreased concomitant with decreasing exposure levels, which is primarily driven by better industrial hygiene practices avoiding peak exposures;


• In addition, a majority of diisocyanate asthma cases reported at least an improvement in respiratory symptoms at their last assessment; and 46% reported clearing of all their symptoms (Buyantseva et al., 2011).