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4,4´-methylenedicyclohexyl diisocyanate (CAS-Nr. 5124-30-1); Information/Assumptions regarding toxicokinetics


The following remarks on the toxicokinetics of 4,4´-methylenedicyclohexyl diisocyanate are based on physicochemical properties of the compound and on toxicological data. Experimental toxicokinetic studies were not performed.


4,4´-Methylenedicyclohexyl diisocyanate is a colourless to light yellow liquid with a low vapour pressure (1.22 * 10-5hPa at 20 °C, Bayer AG 1994) under normal ambient conditions.

Due to the low vapour pressure inhalation exposure via vapour is not to be expected. Wherever aerosolisation occurs exposure is possible. Only the respiratory tract is concerned after acute and repeated inhalative aerosol exposure to rats (Pauluhn 1995 and 2008; Bernstein 1987). All clinical signs and histopathological findings in these studies could be related to the irritant properties of the substance, indicating certain reactivity due to the chemical nature of the isocyanate-groups of the molecule. There are no indications reported suggestive for an absorption or systemic availability of the substance or a metabolite. Nevertheless, absorption through the lung epithelium could not be neglected at all, e.g. after conjugation of 4,4´-methylenedicyclohexyl diisocyanate to lung fluid proteins.

Regarding oral absorption at least partial hydrolysis is assumed to occur in the gastro-intestinal tract. In fact oral toxicity was low with an LD50 (rat) of 18200 mg/kg bw (Sterner 1976). In this non-guideline study strong hyperemia for acute mortalities up to slight hyperemia for late mortalities was recorded as gross pathology observations, confirming the substance’s irritating properties at the portal of entry. Other organs were reported to be unobtrusive, therefore no indications for systemic bioavailability could be concluded from the study.

Dermal absorption of 4,4´-methylenedicyclohexyl diisocyanate could not be excluded at all, since the calculated Kow shows a high lipophilicity (6.11, Currenta 2009). In fact, systemic availability after dermal exposure could not be deduced from an acute study, where a low dermal toxicity was observed (LD50 (rat) > 7000 mg/kg bw, Muermann 1985) and from acute dermal irritation/corrosion studies, where no signs of systemic toxicity were observed (Wakefield 1996, Kroetlinger 1994). Nevertheless, 4,4´-methylenedicyclohexyl diisocyanate has shown skin sensitizing properties (Sterner 1983), thus indicating that a dermal uptake, even though small, can occur. Deducing from that the substance has the property to react with nucleophilic groups of proteins or peptides and form hapten-protein complexes or conjugate-antigens.

Based on the results of several in vitro genotoxicity tests (Wirnitzer 2005, Herbold 2004 and 2007, all performed with and without metabolic activation) it is concluded that DNA-reactive metabolites of 4,4´-methylenedicyclohexyl diisocyanate will most probably not be generated in mammals in the course of hepatic biotransformation.