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When the mutagenicity of isomers and homologues of MDI (4,4f-MDI,
2,4f-MDI, a mixture of monomeric MDI isomers, and PMDI) was determined
in the Salmonella/microsome test using DMSO and ethyleneglycol dimethyl ether (EGDE) as
solvents, positive results were obtained for DMSO solutions of all four
diisocyanates in the presence of S9 mix containing 30% S9 fraction. Uniformly
negative results were found when the diisocyanates were dissolved in EGDE
(Andersen et al., 1980; Herbold, 1980a,b; Woolrich, 1982; Shimizu et al.,
1985; Zeiger, 1987; Herbold et al., 1998). MDI is not stable in DMSO, there being many products generated
within minutes (Herbold, 1990; Gahlmann, 1993). Thus, it seems that positive
test results in any in vitro test system are caused by the degradation products of MDI in DMSO, rather
than by MDI itself. One of the degradation products of MDI is MDA, which
is known to be genotoxic and whose formation was detected when MDI was
dissolved in DMSO (Herbold et al., 1998). No MDA could be detected in solutions of MDI in EGDE. It is therefore
concluded that the positive results obtained with diisocyanates in DMSO
solutions are due to the formation of MDA. The stability of MDI in a model
and a real-test environment was studied (Seel et al., 1999). When MDI was dissolved in DMSO, more than 99% of the MDI was degraded
before the start of incubation with test ingredients of the Salmonella mutagenicity assay, and MDA was detected at 2.1-2.8% of the MDI concentration
within 45 s of incubation. Tests assessing the mutagenic potential of MDI
in vitro and in vivo show
no convincing evidence of mutagenic activity.
Female Wistar rats were treated topically (on the back) with
14C-MDI (labelled in the ring) in acetone to investigate the possibility
of systemic circulation and DNA-binding potency of MDI (Vock & Lutz,
1997). About 10% of the radioactivity was retained at the site of application.
DNA radioactivity in the liver was at the limit of detection. In a second
experiment using topical administration, 32P-postlabelling analysis did not reveal isocyanate-DNA adducts in the skin
(Vock & Lutz, 1997).
Tissues obtained from female Wistar rats exposed to a 0.9-Κm
aerosol of MDI for 17 h per day, 5 days per week, for 1 year, at levels
of 0, 0.3, 0.7, or 2.0 mg/m3, were analysed for DNA adducts using a
32P-postlabelling method (Vock et al., 1996). In the lung, neither isocyanate adducts nor the arylamine adduct
was detectable. The same negative result was seen in the liver, bladder,
kidney, respiratory epithelium, and peripheral lymphocytes. In the olfactory
epithelium, on the other hand, the arylamine-derived DNA adduct nucleotides
were detected at very low levels (5-10 adducts per 1010 nucleotides).
References
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