2,4,6-triisopropyl-m-phenylene diisocyanate

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Justification for type of information:

Please refer to Read-across statement in section 13

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

2,4,6-triisopropyl-m-phenylene diisocyanate

EC Number:

218-485-4

EC Name:

2,4,6-triisopropyl-m-phenylene diisocyanate

Cas Number:

2162-73-4

Molecular formula:

C17H22N2O2

IUPAC Name:

2,4-diisocyanato-1,3,5-tris(propan-2-yl)benzene

Test material form:

liquid

Results and discussion

Signs and symptoms of toxicity:

not specified

Dermal irritation:

no effects

Remarks:

no skin irritation being found for any exposure or control group.

Absorption in different matrices:

not data on absorption in different matrices available

Total recovery:

- the recoveries were 95.7% (R.S.D 3.0%) and 97.0% (R.S.D 5.6%) for 2,6-TDA (100–500 ng/mL) and 2,4-TDA (20–100 ng/mL), respectively.
- Limit of detection (LOD): 1 ng/mL or TDAs

Conversion factor human vs. animal skin:

no data on conversion factors available

Any other information on results incl. tables

Urinary excretion

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.

Half-life

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 doses.

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.

Comparison of urinary 2,4-TDA with urinary 2,6-TDA

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.

Table 1.  Kinetic parameters of urinary TDA, mean (SE)
	2,4-TDA			2,6-TDA			Ratio (CV%)
	0.2%	1%	5%	0.2%	1%	5%	0.2%	1%	5%
	(1)	(2)	(3)	(4)	(5)	(6)	[=(1)/(4)]	[=(2)/(5)]	[=(3)/(6)]
Tmax(h)	12	12	12	12	12	12	1	1	1
	(0)	(0)	(0)	(0)	(0)	(0)	(0)	(0)	(0)
Cmax(µg/ml)	0.062	0.238	6.116	0.056	0.268	3.777	1.1	0.9	1.6
	(0.009)	(0.060)	(0.429)	(0.004)	(0.087)	(0.384)	(8.5)	(8.0)	(29.1)
AUC(µg*h/ml)	2.186	8.395	158.599	2.046	10.558	133.994	1.1	0.8	1.2
	(0.376)	(0.919)	(5.517)	(0.263)	(0.538)	(20.350)	(8.2)	(5.9)	(18.5)
Accumulative amounts(µg)	2.682	12.940	83.843	2.622	14.978	69.810
	(0.631)	(4.224)	(29.542)	(0.779)	(2.628)	(11.541)
k (h^-1)^a	0.0376	0.0341	0.0325	0.0329	0.00339	0.0264
	(0.002)	(0.003)	(0.003)	(0.0020)	(0.0027)	(0.004)
t1/2(h)^a	18.4	20.4	21.5	21.1	20.5	26.6	0.9	1.0	0.8
	(0.8)	(1.5)	(2.2)	(1.3)	(1.6)	(3.7)	(3.0)	(0.8)	(13.8)

 ^aP > 0.05 by Kruskal-Wallis ANOVA test.

Dose-response Relationship between TDI exposed and AUC/Cmax/Accumulative Amounts

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.

Applicant's summary and conclusion

Conclusions:

The study was conducted to reveal the toxicokinetic properties of TDI, applied dermally to the skin of rats and the detection of TDA in the urine after metabolisation of the test item to Toluene diamine (TDA). The validity criteria of the test system are fulfilled, since the control groups showed the expected results. The study was not conducted according to a certain guideline, but still its reliability is considered to be high (Klimisch 2). It has been demonstrated that the absorption of 2,4- and 2,6-TDI through skin contact is possible in this rat study.

Executive summary:

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.