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Key value for chemical safety assessment

Additional information

Oral exposure:

No information is available on the toxicokinetics of MDI following oral exposure in animals.

Dermal exposure:

Two studies on the dermal absorbtion and distribution of radioactive labelled MDI in rats are available. Both studies appear to be reliable, although they show contradictory results. From the study of Vock and Lutz (1997) it must be concluded that absorption through the skin is not negligible. Following unoccluded application of 14C-MDI 10% of the administered radioactivity was recovered in the epidermis, 20-30% in faeces and 1% in urine. In the GLP-study of Leibold et al. (1999) the largest proportion of radioactivity was recovered from the application site (32/61% for high dose/low dose) and the dressing (69/42%). Dermal absorption was rather limited following semiocclusive application. Only 0.9% of the applied radioactivity was absorbed at the most. Absorbed radioactivity was excreted via urine and faeces, with the faecal route of excretion becoming more relevant during prolonged observation time.

Although addressed in the study report, contamination from grooming probably explains high levels of absorption found by Vock and Lutz, whereas the high amount of competitive extraction of 14C-MDI to the dressing may contribute to low levels of absorption detected by Leibold et al. (1999).

An in vitro study (Clowes et al., 1999) confirmed the low levels of 14C-MDI absorption obtained by Leibold et al. (1999). No radioactivity was absorbed through human skin during a 54h continuous exposure, and only small amounts (maximally 0.23% of applied dose) were absorbed through rat and guinea pig skin. The majority of applied MDI equivalents were found to be associated with the skin.

Consequently, a dermal uptake of 1% (Leibold et al., 1999) is used to calculate the body burden in the dermal exposure assessment.

Inhalation exposure:

With respect to inhalation exposure, there is good and reliable data regarding distribution/excretion in experimental animals. In a two part full inhalation metabolism/toxicokinetics/distribution study performed by Gledhill (2003a,b), approximately 5% of the dose was excreted in urine and 79% in faeces of rats. Bile duct cannulated animals excreted approximately 12% of the dose in urine, 14% in bile and 34% of the dose in faeces. In conclusion, most of the systemically available dose was excreted via bile, and a slightly lower amount via urine. No radioactivity was recovered in exhaled air.

Similar results were obtained in an older study by Centre d'Etudes Nucleaires de Saclay (1977) were the faecal elimination of MDI and its metabolites was greater than the urinary elimination.

In both studies radioactivity was widely distributed with the respiratory and excretory organs containing the highest concentrations. The highest concentration of radioactivity was present in the respiratory nasal tissue (Gledhill 2003a).

Due to grooming and respiratory clearance a combined oral/inhaled exposure existed in the study of Gledhill (2003a). 25-32 % of the applied dose was systemically available. The data does not allow to discriminate between absorption in the respiratory tract on the one hand, and gastro-intestinal tract on the other hand. However, taking into account the low urinary excretion in the study of Vock and Lutz (1997), together with the likelihood of oral intake due to grooming, and based on mechanistic in-vitro studies described below, the respiratory tract may be regarded as the main entry for systemically available MDI.

A detailed summary on urinary, plasma and in vitro metabolite studies is provided at the end of this Endpoint Summary. Taken together, all available studies provide convincing evidence that MDI-haemoglobin adduct and MDI-metabolite formation proceeds:

1) via formation of a labile isocyanate GSH-adduct:

2) then transfer to a more stable adduct with larger proteins, and

3) without formation of free MDA. MDA reported as a metabolite is actually formed by analytical workup procedures (strong acid or base hydrolysis) and is not an identified metabolite in urine or blood.

Other routes of exposure:

After intradermal administration of 14C-MDI to rats about 26% of the radioactivity was absorbed. Excretion was mainly via faeces (Leibold et al., 1999). Following intramuscular injection of 14C-MDI less than 25% of the applied dose was recovered in the excreta 120h after application. The amount of faecal elimination was larger if compared to urinary elimination, indicating that for absorbed MDI biliary transport is a significant route of excretion. The remaining radioactivity was found in the carcass.

Metabolites identified in vivo and in vitro:

The results of the inhalation study performed by Gledhill (2003b) indicate that a proportion of the 4,4´-MDI dose (approx. 10%) is converted to metabolites via the intermediary formation of an amine group which is rapidly acetylated. In urine and bile 4 main metabolites were identified (N,N´-diacetyl-4,4´-diaminobenzhydrol, N,N´-diacetyl-4,4´-diaminophenylmethane, N-acetyl-4,4´-diaminophenylmethane and N,N´-diacetyl-4,4´-diaminobenzophenone) which may all relate to the same metabolic pathway. None of these specified low molecular weight metabolites were found in faeces. The solvent extract of faeces and the major radioactive component in bile (9% of the dose) was thought to consist of mixed molecular weight polyurea oligomers derived from MDI. This assumption is supported by mechanistic in-vitro studies described below.

In recent studies relevant amounts of GSH-metabolites were only detected in the urine of rats following intratracheal instillation of a di-GSH conjugate of pMDI but not following an inhalation exposure to a pMDI aerosol (Bartels et al., 2009). The few data available on the toxicokinetics of MDI in humans (see biomonitoring) indicate that it is possible to detect exposure to MDI by analyzing urinary metabolites. In another report the half-life of MDA in hydrolysed urine was determined to be 70-80 hours, the half-life in serum was 21 days.

MDI-adducts to haemoglobin or other plasma proteins may be of some use for biological monitoring, since the amount of adducts would be indicative of an integrated exposure. But the total amount of MDA retrievable from Hb-adducts and urinary precursors accounts for less than 0.5 % of the applied dose of MDI (Pauluhn et al, 2006). Taking into account false-positive results observed in animal studies, an extrapolation from the yield of biomarkers in urine or blood towards inhalative MDI exposure remains uncertain.

Following hydrolytic work-up, the corresponding amines were detected in the bronchioalveolar lavage, blood, and urine in a repeated dose inhalation study with pMDI. If compared to a dermal application study and a control experiment with MDA, the author suggests, that kind and yield of biomarkers determined (AcMDA/4,4´-MDA ratios in haemoglobin and 4,4´-MDA/3-oligomeric MDA in urine) are dependent on the route of exposure and differ markedly for MDI and MDA (Pauluhn and Lewalter, 2002). In addition, the intratracheal instillation of MDI-bis-glutathione adduct, rats show a similar pattern of biomarkers as after inhalation exposure. In this respect a poor acetylator (dog) does not show differences to the good acetylator (rat) (Pauluhn et al, 2006).

Further mechanistic insight into the fate of inhaled MDI is provided by in-vitro studies. MDI added to buffered solutions (pH = 5.0 to 7.4) containing N-Acetylcysteine as a surrogate for GSH did not show the production of detectable amounts of MDA, even if MDI was added in abundance (Mormann and Lucas-Vaquero, 2002a). Upon hydrolysis, neither MDI-GSH-bis-adduct (Reisser et al, 2002) nor the MDI-acetylcysteine-bis-adduct (Mormann and Lucas-Vaquero, 2002b) liberate detecable amounts of MDA. The initially formed amino-group is highly reactive against remaining thiocarbamate, and as a result of the bifunctionality of the MDI and its thiocarbamate, a polymerisation to insoluble polyurea results. A surplus of GSH retards this hydrolysis and subsequent polymerisation (Reisser et al, 2002). The thiocarbamate formed by the reaction between an NCO-group of MDI and a thiol is easily and rapidly transferred to other SH-groups, less fast to aliphatic amino-groups and almost not transfered to aliphatic OH-groups in aqueous buffered solutions. These transfer reactions are rather a bimolecular process (Mormann and Lucas-Vaquero, 2004) than a unimolecular process with the intermittent release of a free isocyanate-group (Day et al, 1997).

Discussion on bioaccumulation potential result:

For basic toxicokinetics endpoint summary refer to the 7.1 Toxicokinetics, metabolism and distribution endpoint summary.

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