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Carcinogenicity

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Description of key information

Inhalation exposure is the most appropriate route for assessing occupational risk in humans. Effects from chronic exposure of animals to TDI are limited to effects on the respiratory tract caused by local irritation, no signs of tumor formation or systemic toxicity were observed. 
The oral and dermal route of exposure are not relevant for assessment (see repeated dose toxicity).

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
1.086 mg/m³

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008 the classification of 2,4-/2,6-TDI (CAS No 26471-62-5) was considered for the classification of TDI Biuret since TDI Biuret contains >= 50 % of 2,4-/2,6-TDI.

Carcinogenicity 

2,4-/2,6-TDI is classified under Annex I of Directive 67/548/EEC with R40 (Carc Cat 3: limited evidence of a carcinogenic effect). This classification corresponds to Category 2 (suspected of causing cancer) according to Annex VI-1 of CLP Regulation (EC) No 1272/2008.

Additional information

Since no data on carcinogenicity are available for TDI Biuret, such data have been 'read across' from TDI(justification of read-across see below).

The most relevant assessment of carcinogenicity in animals comes from a 2-year chronic inhalation toxicity and carcinogenicity study with TDI in rats and mice (Owen, 1980 + 1986; Loeser, 1983). The animals were whole body exposed to 0, 0.05 and 0.15 ppm of TDI (80/20) vapour for 6 hours/day, 5 days/week. No evidence of any increase in treatment-related tumors in either species was observed. An MTD was achieved in rats and mice as characterized by decreased body weights and moderate to severe rhinitis. Therefore, the NOAEC for carcinogenicity after long-term inhalation of TDI vapour is 0.15 ppm (1.086 mg/m3) for both species.

 

In contrast, an increase in the number of tumors in various organs was observed in rats and mice after oral long-term administration of TDI over 2 years (NTP, 1986; Dieter et al., 1990). Doses of 0, 30 and 60 mg/kg bw/day (male rats), 0, 60 and 120 mg/kg bw/day (female rats and mice) or 0, 120 and 240 mg/kg bw/day (male mice) were applied. In rats increased tumor incidences were seen in subcutaneous tissue and in the pancreas (both sexes). In addition, female rats showed nodular changes in the liver and mammary gland tumors. In female mice the incidences of hemangiomas, hemangiosarcomas and adenomas of the liver were increased. No increased incidence of compound-related tumors was observed in the male mouse.

 

The results of the studies using oral administration are compromised by severe deficiencies in test substance handling that led to the fact that the sample administered also contained other unidentified breakdown and reaction products of TDI, possibly including TDA. Hydrolysis of TDI to form the genotoxic and animal carcinogen TDA is the most plausible explanation for the observed tumors following oral administration of TDI. Therefore, these studies are considered "invalid" by Klimisch criteria. In addition the addition of TDI directly into the acidic environment of the stomach, bypassing the oral cavity, is an unrealistic exposure scenario which leads to generation of the diamine which would not occur in normal handling and use.

 

Overall Assessment: 

1.  Valid animal inhalation studies showed no carcinogenic effect from TDI exposure.

2.  An oral chronic exposure study with TDI is considered invalid due to mishandling of test material and the inappropriate exposure route.

3.  Human studies show no evidence of carcinogenic hazard (see summary in .10.2, Collins 2009).

4.  Based on these evidence there is a strong case that TDI should not be classified as a carcinogen.

Justification of read-across from supporting substance (2,4-/2,6-TDI to TDI Biuret)

The 80:20 mixture of 2,4-/2,6-TDI (CAS No. 26471-62-5) is the monomeric component of the oligomeric TDI Biuret. The examination of the material balance of Desmodur VP.PU 60WF14 (TDI Biuret) yielded amounts of 42 % 2,4-TDI, 13.7 % 2,6-TDI and ca. 44 % TDI Biuret (Currenta, 2009). Thus, TDI Biuret contains ca. 56 % of a 80:20 mixture of 2,4-/2,6-TDI.

 

With regard to the toxicological comparability of TDI Biuret and 2,4-/2,6-TDI acute inhalation toxicity studies in rats revealed 4-hour LC50 values (aerosol) of 112 mg/m3 for TDI Biuret (based on sum of TDI isomers) and 107 mg/m3 for 2,4-/2,6-TDI (Folkerts, 2010). All qualitative cornerstones of TDI-induced respiratory tract injury were essentially identical. This included the typical delayed-onset mortality, likely as a result of a bronchiolitis obliterans. Of note is the over-proportional presence of TDI vapor relative to the TDI Biuret after inhalation exposure. This is consistent with the higher vapor pressure of TDI. In summary, the similarities of LC50s in the presence of TDI Biuret up to analytically verified breathing zone concentrations of 112 mg TDI Biuret/m3 demonstrates that the inhalation toxicity of TDI per se isnot affected to any appreciable extent by the presence of TDI Biuret aerosol. This means, modulating factors due to physicochemical interactions (partitioning of the vapor phase with the liquid aerosol phase) were not apparent as this would have lead to a more immediate onset of mortality (immediate acute lung edema rather that delayed bronchiolitis obliterans). Overall, these data demonstrate that the acute inhalation toxicity of TDI Biuret is negligible relative to TDI and any dependence of acute hazards on specific use patterns (vapor vs. aerosol) cannot be envisaged(expert opinion of Prof. J. Pauluhn: Desmodur VP.PU 60 WF14 (TDI Biuret): Comparison of acute inhalation toxicities of TDI Biuret and TDI, dated Sep. 3, 2010; complete expert opinion attached in IUCLID chapter 7 “Endpoint summary: Toxicological information”).

In addition, the toxicity profiles of TDI Biuret and 2,4-/2,6-TDI also show a high degree of consistency regarding the endpoints acute oral toxicity, skin irritation, eye irritation, skin sensitization and genotoxicity in vitro.

Therefore, based on all available data the test results obtained for 2,4-/2,6-TDI can be transferred to TDI Biuret and based on such a read-across further testing of TDI Biuret is not required. This approach is in accordance with Annex XI, section 1.5 of the REACH Regulation (EC) No 1907/2006.