Hexamethylene diisocyanate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

In a guinea pig maximization test (GPMT) similar to OECD TG 406 1,6-hexamethylene diisocyanate (HDI) revealed a strong skin sensitizing potential. At the topical challenges (4 and 6 weeks after the first induction treatment) 16/17 or 17/17 animals reacted with erythema according to a contact allergy after application of a 0.3 or a 1.0 % HDI formulation in petrolatum (Schmidt and Bomhard, 1983). A Buehler test in guinea pigs showed a strong skin sensitizing potential of HDI (1 % induction conc., 70 % incidence of sensitization) according to EU method B.6 (Zissu et al., 1998). In a mouse local lymph node assay (LLNA) equivalent to OECD TG 429 HDI revealed a clear skin sensitizing potential (Hilton et al., 1995). In addition, HDI was found to be positive in mice using the mouse ear swelling test (MEST; Gad et al., 1986; Thorne et al., 1987). In summary, HDI was found to induce dermal sensitization in animals.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

A lung sensitization test in guinea pigs provides clear evidence that 1,6-hexamethylene diisocyanate (HDI) is a respiratory sensitizer. When animals that were sensitized intradermally (three injections, one per day) or by inhalation (5 x 3 hours per day) and were subsequently challenged by inhalation with the respective hapten of HDI no conclusive immediate-onset responses were observed. As a result of challenge with the respective conjugate of the hapten conclusive immediate-onset responses occurred. Additional evidence of a lung sensitizing potential was provided by the histopathological examination which revealed an increased eosinophilia of airways and lung associated lymph nodes as well as specific IgG1-antibody (Pauluhn, 1996). In a modified local lymph node assay (LLNA) on male mice high stimulation indices (SIs) were observed in mandibular lymph nodes (SI = 9.8) and in auricular lymph nodes (SI = 109) after 6-hour vapour inhalation of 7.5 mg/m3 for three consecutive days. HDI inhalation induced positive responses of IL-4 and IL-10 in the mandibular lymph nodes, whereas for IL-12 and IFN-gamma no dose-response in mandibular lymph nodes was found (Arts et al., 2008; De Jong et al., 2009). In summary, HDI was found to induce respiratory sensitization in animals.

In a further study 1,6-hexamethylene diisocyanate (HDI) was investigated in skin-sensitized Brown Norway (BN) rats for its concentration x time (Cxt)-response relationship on elicitation-based endpoints (Kopf, 2015a). The major goal of the study was to determine the elicitation inhalation threshold dose in sensitized, re-challenged BN rats, including the associated variables affecting the dosimetry of inhaled HDI-vapor in rats. After topical induction (2% HDI on days 0 and 7) most of the rats showed slight to moderate signs of local reactions (application site reddened with red encrustations, and inflammation), especially after the second booster administration. The local reactions waned to an appreciable extent within 1 week after the last dosing. After each challenge exposure mild and transient signs of upper respiratory tract irritation were observed in equally challenged naive and sensitized rats. Body weights were indistinguishable between the groups. Only a slight tendency of decreased body weights occurred in group 4a (124-89-74 mg/m3 for 30 min. and 72 mg/m3 for 6 min.). Delayed-type respiratory measurements did demonstrate changes in respiratory patterns after the last challenge. Two HDI-sensitized rats challenged with 68 mg/m3 x 13 min displayed unusual respiratory responses during the course of measurements. One of these rats succumbed overnight. Lung weights were minimally increased in HDI-induced / challenged rats. NO in exhaled air was mildly increased at the fourth challenge only. Neutrophilic granulocytes (PMNs) in bronchoalveolar lavage fluid (BAL) were considered as the endpoint of choice to integrate the allergic pulmonary inflammation. In summary, Cxt-dependent increased PMNs in BAL were apparent when employing both the single and repeated challenge protocol. Isolated changes in lung function delayed in onset occurred especially at the longer challenge durations. The isolated reactions seen in two rats challenged for 13 min were not complemented by any other endpoint nor was any challenge-dose related outcome apparent. BAL-PMN was amongst the most sensitive endpoints to probe for respiratory allergy. Based on this most sensitive endpoint showing a clear Cxt-dose-related increase in PMNs 68 mg HDI/m3 x 13 min is considered to be the NOAEL of the study. Hence, based on this endpoint, approx. 900 mg HDI/m3 x min is considered to be the effect threshold for elicitation in sensitized, i.e. asthmatic rats.

Justification for classification or non-classification

Skin sensitisation

According to Regulation (EC) No 1272/2008, Annex VI, classified as skin sensitising Cat.1 (H317: May cause an allergic skin reaction).

 

Respiratory sensitisation

According to Regulation (EC) No 1272/2008, Annex VI, classified as respiratory sensitising Cat.1 (H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled).