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EC number: 218-485-4
CAS number: 2162-73-4
The peak urinary excretion of TDA (Cmax)
occurred during the first 12 h collection interval among three doses of
TDI. The Cmax of 2,4-TDA was found to be 0.062 ± 0.009, 0.238 ± 0.060
and 6.116 ± 0.429 μg/mL for low (0.2%), moderate (1%) and high (5%) TDI
dose group, respectively.
Skin-absorbed 2,4-TDA was not completely
eliminated by urinary excretion over 6 days in the high exposure group.
The elimination pattern of 2,6-TDA was
similar to 2,4 -TDA. The Cmax was reached at 12 h after the end of
exposure and found to be 0.056 ± 0.004, 0.268 ± 0.087 and 3.777 ± 0.384
μg/mL for low, moderate and high exposure groups, respectively.
The decrease trend slowed after 60 h for the
moderate and high dose groups. However, the U-TDA concentration
measurements were below the detection limit from 120 h, 72 h for the
moderate and low exposure groups, respectively.
The accumulative amount profiles across 144
h for 2,4- and 2,6-TDA were similar. Excretory urinary TDA amount
increased abruptly within 24 h since the end of exposure, the
elimination amounts were becoming slow within 24– 60 h. The elimination
amounts reached a plateau after 60 h.
Apparent half-lives (t1/2) of excretory TDA
were about 20.1 h (SD = 1.9) and 22.7 h (SD = 3.4) for 2,4- and 2,6-
forms among three exposure groups with relatively narrow ranges.
An increasing t1/2 following by an increase
of dose was found consistently for both 2,4- and 2,6-forms. The data
indicating slower elimination and longer retention could occur at higher
When the first-order kinetic linearity was
tested, highly satisfactory coefficients of correlation (r = 0.930 ±
0.959 P < 0.05 for 2,4-TDA; r = 0.902 ±
0.953 P < 0.05 for 2,6- TDA) were obtained
for U-TDA measurements since the exposure termination (time after tmax).
These results suggested the elimination pattern of excretory TDA
concentration profiles in 6-day consecutive urine samples were
first-order kinetics. However, a non-linear saturation was found for
high exposure at 60 h after tmax. The possible explanation for this
observation could be: in lower doses, the TDA elimination process in the
kidney could connect with the distribution process in highly perfused
tissues with hardly any time lag. On the other hand, at a high dose, the
TDA elimination process could not be immediately completed because of
overwhelming residual TDA following the TDA distribution process in
highly perfused tissues.
The rat skins were originally exposed to a
mixture of 2,4- and 2,6-TDI at a ratio of 80%:20% (m:m). The average
ratios of 2,4-/2,6-TDA were found, however, to be 1.1, 0.9 and 1.6 in
the low, moderate and high exposure groups for Cmax, respectively. For
AUC results, the average ratios were 1.1, 0.8 and 1.2, respectively
(Table 1). The overall ratios for both 2,4- and 2,6-form were close to
unity, rather than 4:1, as expected from the exposure composition. The
discrepancy between skin exposure application and urinary concentration
might be attributed to the greater reactivity of 2,4-TDI, possibly
related to higher self-polymerization to form polyurea polymers.
aP > 0.05 by Kruskal-Wallis
A linear increasing logarithm AUC trend for
both forms of U-TDA with increasing TDI exposure was found (r = 0.968
for 2,4-TDA; r = 0.973 for 2,6-TDA) (Fig. 4a). A similar fashion for
Cmax (r = 0.973 for 2,4-TDA; r = 0.984 for 2,6-TDA) and accumulative
amounts (r = 0.998 for 2,4-TDA; r = 0.999 for 2,6-TDA) to AUC was also
obtained. The above-mentioned findings suggested a clear dose-dependent
fashion of skin absorption for 2,4- and 2,6-TDI.
The toxicokinetics of the substance of
interest Toluene diisocyanate (TDI) were investigated by Yeh et al.
(2008) after dermal application in rats (dorsum, area approximately 3 *
5 cm). The exposure duration was 5 h, after which the substance was
carefully washed of the skin, using a cleasing agent. It has been
demonstrated that the absorption of 2,4- and 2,6-TDI through skin
contact is possible in this rat study. A clear dose-dependent skin
absorption for 2,4- and 2,6-TDI was demonstrated by the findings of AUC,
Cmax and accumulative amounts (r ≥ 0.968). Excretory 2,4- and 2,6- TDA
concentration profiles in 6-day consecutive urine samples were shown to
fit in first-order kinetics, although higher order kinetics could not be
excluded for high doses. The apparent half-lives for excretory urinary
TDA were about 20 h at various skin exposures, similar to that from the
inhalation exposure in the previous animal experiment. The overall yield
ratios for 2,4- to 2,6-TDA in urine were found to be close to unity,
apparently lower than the expectancy of 4:1, possibly due to the higher
self-polymerization reactivity of 2,4- than 2,6-TDI.
It is concluded that skin absorption of TDI
was confirmed in a rat model and a clear dose-dependent skin absorption
relationship for 2,4- and 2,6-TDI was demonstrated. The findings in this
study clearly demonstrate the skin absorption capability of topical TDI
exposure based on the observation of the internal dose concentration
profile of U-TDA across 6 days.
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