2023/12/19 by Hartwig, Andrea, MAK Commission
#2 #4-Toluene diisocyanate #4-Toluylendiisocyanat #571.95 Toxicology #571.95 Toxikologie #6-Toluene diisocyanate #6-Toluylendiisocyanat #616.9803 Betriebs- und Arbeitsmedizin #616.9803 Industrial and occupational medicine #Atemwegssensibilisierung #Entwicklungstoxizität #Gemisch #Hautsensibilisierung #Kanzerogenität #Luft #Lungenfunktion #MAK value #MAK-Wert #Reizwirkung #Spitzenbegrenzung #Toluene diisocyanates #Toluylendiisocyanate #air #airway sensitization #carcinogenicity #developmental toxicity #irritation #lung function #maximale Arbeitsplatzkonzentration #maximum workplace concentration #mixture #peak limitation #skin sensitization
paper · doi:10.34865/mb58484isme8_4ad
The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re-evaluated toluene diisocyanates (2,4-toluene diisocyanate [584-84-9], 2,6-toluene diisocyanate [91-08-7] and the isomer mixture [26471-62-5]) to derive a maximum concentration at the workplace (MAK value) and to review its carcinogenicity classification. The critical effects are sensory irritation and sensitization in humans and animals. A concentration that protects from sensitization cannot be derived. Neither irritation nor loss of lung function in humans was described at a concentration of 1 μl/m3. In some studies, however, lung function decrements were observed at a mean concentration of 1 μl/m3; these were most likely caused by peak concentrations of 20 μl/m3 or above. A LOAEC of 50 μl/m3 was derived for chronic and necrotic rhinitis from a two-year inhalation study in rats and mice. A benchmark dose lower confidence limit of 10 μl/m3 was calculated from the rat data for a 5% increase (BMDL05) in chronic rhinitis. A BMDL for mice could not be calculated. Based on the BMDL05, a MAK value of 1 μl/m3 has been set taking into account the extrapolation to humans (1:3), the higher sensitivity of mice, the experience at the workplace and the “Preferred Value Approach”. Toluene diisocyanates are not genotoxic after inhalation and genotoxic doses such as after oral exposure are not achieved due to the irritant effect. Toluene diisocyanates were not carcinogenic in an inhalation study in rats and mice and it was estimated that the carcinogenic toluenediamine is formed only in very low amounts from toluene diisocyanates during exposure at the level of the MAK value of 1 μl/m3. As the critical effect is sensory irritation, Peak Limitation Category I has been assigned. Toluene diisocyanates are potent sensitizers; therefore, in analogy to other diisocyanates, an excursion factor of 1 is set. Irritation of the respiratory tract at a mean concentration of 5 μl/m3 is caused by exposure peaks; therefore, a momentary value of 5 μl/m3 is derived to avoid very high short-term concentrations. Toluene diisocyanates are assigned to Pregnancy Risk Group C because the margin between the NOAEC for developmental toxicity in rats and the MAK value is sufficient and no teratogenicity was observed. Due to the skin and respiratory sensitizing effects, the designations with “Sa” and “Sh” are confirmed. The systemic availability of the substance or its active metabolite toluenediamine after dermal exposure seems to be considerably reduced by the high reactivity of toluene diisocyanates and their affinity with structural components of the skin. There is no indication of systemic effects after dermal exposure. Therefore, toluene diisocyanates are not expected to be taken up via the skin in toxicologically relevant amounts.