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The following remarks on toxicokinetics are based on the physico-chemical properties of tris(p-isocyanatophenyl)thiophosphate and on toxicological data. Experimental studies on toxicokinetics were not performed.

Tris(p-isocyanatophenyl) thiophosphate is marketed and handled as solution in ethyl acetate containing approximately 27% of tris(p-isocyanatophenyl) thiophosphate. The trade name of the solution is Desmodur RFE. Removal of the solvent from Desmodur RFE does invariably lead to generation of higher molecular weight species. This is due to the inherent reactivity of the isocyanate moieties and the process can thus be monitored via the decrease of the isocyanate content (see IUCLID section 1.4: analytical material balances before/after solvent removal). Therefore, the trade product Desmodur RFE (27% active ingredient in ethyl acetate) was employed as test substance for all toxicological tests as this was believed to best represent the substance to be registered. In toxicological studies with inhalative exposure to Desmodur RFE the solvent evaporated during the exposure procedure so that the samples taken from the breathing zone were nearly solvent free. Thus, in the inhalation studies the exposure can be considered as exposure to the neat active ingredient tris(p-isocyanatophenyl)thiophosphate.

Tris(p-isocyanatophenyl)thiophosphate is a white organic solid with a very low vapour pressure under normal ambient conditions (0.0002 Pa at 20°C; see section 4.6 in IUCLID), therefore inhalation exposure to the vapour is expected to be negligible. Tris(p-isocyanatophenyl) thiophosphate is highly insoluble in water (see section 4.8 in IUCLID). This property, together with the quite high molecular weight (> 465 g/mole) and the bulky structure of tris(p-isocyanatophenyl) thiophosphate do not favour absorption. Furthermore, in aqueous media tris(p-isocyanatophenyl)thiophosphate rapidly hydrolyses to mainly insoluble oligomeric and polymeric ureas (see section 5.1 in IUCLID). Due to hydrolytic instability of tris(p-isocyanatophenyl) thiophosphate in aqueous solutions the QSAR predicted log Pow of about 8.2 is of little relevance (see IUCLID section 4.7).

Under physiological conditions it is assumed that tris(p-isocyanatophenyl) thiophosphate also rapidly hydrolyses to insoluble oligomeric and polymeric ureas. Therefore intestinal absorption of tris(p-isocyanatophenyl)thiophosphate subsequent to oral ingestion is supposed to be low. This assumption is confirmed by the data on acute oral toxicity in rats with Desmodur RFE (LD50 ≥ 2500 mg/kg bw). In this study a dose of 2000 mg/kg bw was tolerated without mortalities, clinical signs, effects on weight gain or gross pathological findings (Krötlinger, 2002). Since removal of the solvent from Desmodur RFE is not possible without altering the test article an acute oral toxicity study with the neat tris(p-isocyanatophenyl) thiophosphate cannot be performed. Therefore, taking into account the content of the active ingredient in the trade product (27%) an oral LD50 of > 625 mg/kg bw was calculated for tris(p-isocyanatophenyl) thiophosphate. The available data do not indicate that tris(p-isocyanatophenyl) thiophosphate is systemically available after oral uptake.

Acute inhalation studies in rats proved a low acute toxicity for tris(p-isocyanatophenyl) thiophosphate and no macroscopic findings in tissues other than the lung were recorded. The NOAEL was 1554 mg/m³ air in this study (Pauluhn, 2011a). At high concentrations of ≥ 3622 mg/m³ concomitant with mortality and signs of respiratory irritation distinct test article deposits were observed in the respiratory tract. In a subacute (4-week) inhalation study on rats with tris(p-isocyanatophenyl) no signs of systemic toxicity became obvious. As far as alterations from normal were observed in the lungs they appear to follow a particle-overload-like phenomenon (Pauluhn, 2012). Taking together the observations from single and repeated inhalative exposure there are no indications that tris(p-isocyanatophenyl) thiophosphate is systemically available after inhalative exposure.

An acute skin irritation study on rabbits revealed no systemic intolerance reactions after application of 0.5 ml Desmodur RFE (Leuschner, 2012). In this study slight dermal irritation was seen. Desmodur RFE proved to be no skin sensitizer in a Buehler patch test in guinea pigs (Vohr, 2003). Therefore, based on the available data there is no indication that tris(p-isocyanatophenyl) thiophosphate is systemically available after dermal exposure.

Three in vitro genotoxicity tests were performed with Desmodur RFE (Ames Test, Herbold, 2002; HPRT test, Wollny, 2012; Chromosome aberration test, Sutter, 2012) with and without metabolic activation. In all these tests Desmodur RFE was maximally dosed up to cytotoxic and/or precipitating concentrations, thus, the results are considered relevant for the neat tris(p-isocyanatophenyl) thiophosphate. The results show that DNA-reactive metabolites of tris(p-isocyanatophenyl) thiophosphate will most probably not be generated in mammals in the course of hepatic biotransformation.