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EC number: 500-079-6 | CAS number: 32055-14-4
In order to better understand the toxicokinetic behaviour of MDI after inhalation exposure, biological samples from the Gledhill (2001a) experiments (urine, faeces, bile) were investigated in a separate study on the metabolism of MDI. Urine, faeces and bile were collected for the identification of metabolites at 6 (in urine and bile only), 12, 24, 36 and 48 h (and for intact animals at 24 hourly intervals until 7 days after the end of exposure). Metabolites present in bile and excreta were identified by LC/MS and/or by co-chromatography with reference standards and quantified.
Identification/quantitation of metabolites:
There was no MDA detected in any of the samples analysed for this study. With the exception of 1 minor metabolite, all low molecular weight metabolites present in urine and bile were identified or characterised as follows:
Metabolite I: N,N'-diacetyl-4,4'-diaminobenzhydrol. This was the major urinary metabolite in both intact and bile duct cannulated rats (1% and 6% of the dose respectively). It was also present in bile (1% of the dose).
Metabolite II: N,N'diacetyl-4,4'-diaminophenylmethane This metabolite was present in urine of intact and cannulated rats (0.5% and 4% of the dose respectively) and was present as the major metabolite in bile (4% of the dose).
Metabolite III: N-acetyl-4,4'diaminophenylmethane
Metabolite IV: N,N'-diacetyl-4,4'-diaminobenzophenone Metabolites III and IV were minor urinary metabolites (< 0.5% of the dose) and were not present in bile.
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 (metabolite VI). The implication of these results, made by the author, is that a proportion of the MDI dose (10%) is converted to these metabolites via intermediary formation of an amine group which is rapidly acetylated. Both formation and acetylation are most likely to occur within specific cells or compartments. It is not possible from the current data to elucidate whether this stage involves:
- MDA, although none was detected
- bound-MDA, i.e. as a bound intermediate on an enzyme involved in the formation of the metabolites,
- an amine group resulting from reversion of the expected MDI-glutathione conjugates as proposed below:
Lung: MDI + 2GSH → GSH-MDI-SHG
Tissues: GSH-MDI-SHG → GSH-MD-NCO → GSH-MD-NH2 → GSH-MD-NHCOCH3
Reversal of the second glutathione link would lead to the formation of Metabolite III, with subsequent metabolism but without free MDA having been formed at any stage.
Table 1: Quantity of each metabolite present in % radioactivity administered.
Table 2: Quantity of each metabolite present in % radioactivity administered. Samples from Gledhill study 2003.
10% of the radioactivity was excreted in urine in 0-24h, further 2% in 24-48h.
Bilary elimination accounted for approximately 14% of the dose in 0-48h after exposure and 34% was eliminated in faeces during the same time period.
MDA and MDI metabolites in urine and heamoglobin following hydrolysis:
Table 3: Amount of MDA and concentration of combined deacetylated metabolite I and IV in urine.
metabolites I and IV (ng/ml)
in brackets the values expressed [C14] nmol equiv. MDI
Radioactivity in haemoglobin:
at the end of the exposure haemoglobin contained 25 µg equiv. MDI/g mainly consisting of metabolites I and IV (as shown by GC-MS analysis after acidic hydrolysis).
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