Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine

Endpoint summary

Description of key information

There are no experimental studies available in which the toxicokinetic behavior of Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine has been assessed.

In accordance with Annex VIII, Column 1, Item 8.8.1., of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behavior of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2008).

The substance is an UVCB with a molecular weight of about 846 g/mol (structural representative). It is a solid at room temperature, with a very low water solubility. The log Pow was not determined experimentally as the substance decomposes. The log Pow was predicted to be 7.6. The vapour pressure was predicted to be very low.

The expected toxicokinetic behavior is derived from the physicochemical properties, the results from the available toxicological studies and the available literature following the information given in guidance document 7c. Please note that the real behavior may be different but can only be determined with ADME studies, which are not justified based on the very low toxicity of the substance.

ABSORPTION

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters to provide information on this potential are the molecular weight, octanol/water coefficient (log Pow) value and water solubility (ECHA, 2008). The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008). 

Based on the physicochemical properties, systemic availability of the UVCB substance may be limited but cannot be completely excluded following oral intake. Considering the very low vapor pressure, it is not expected that relevant amounts of the UVCB substance are inhalable under normal use conditions. Based on the physicochemical properties, uptake of the UVCB substance into the systemic circulation following dermal exposure is very limited. As the substance is sensitizing to the skin, some uptake must have occurred, although it may only have been a small fraction of the applied dose. Following oral intake, it is expected that the majority of the chemical is excreted with the faeces. For any amounts potentially being bioavailable, it is assumed that circulation within the blood stream and subsequent metabolism may occur. Ultimately, absorbed amounts are expected to be excreted with the faeces or, to a lesser extent, in the urine depending on the molecular size. Due to the predicted high logPow and the predicted very low water solubility, accumulation in adipose tissue cannot be ruled out.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

1)   Physicochemical Data on Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine

The UVCB substance Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine appears asa honey-likesolid at standard ambient temperature and pressure. The molecular weight of the UVCB substance depends on the degree of polymerisation and is expected to be considerably higher than 500 g/mol, the generic representative for the UVCB substance has a molecukar weight of 846 g/mol. The UVCB substance is predicted to possess a very low vapour pressure and very low water solubility. The LogPow value is predicted to be 7.6.

2)   Toxicokinetic Analysis of Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine

 

Absorption

Oral route:

In order to be absorbed into the systemic circulation, chemicals have to dissolve into the gastro-intestinal (GI) fluids and make contact with the mucosal surface. The water solubility of the substance is predicted to be very low, and is thus not expected to readily dissolve into the gastrointestinal fluids.

The molecular weight of the reaction products is expected to be considerably above 500 g/mol and thus, does not favor absorption into the systemic circulation via the GI tract. With regards to toxicological data, an acute oral systemic toxicity studies in rats (OECD 423) conducted with the UVCB substance determined the respective LD50 value to be greater than 2000 mg/kg (limit dose) with only minor signs for toxicity (Impaired general state and piloerection). Furthermore, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats (OECD 422) was conducted on the read-across substance. Local irritation at the stomach was observed. No signs of systemic toxicity were observed in the parental animals and the offspring. Thus, the NOAEL for general, reproductive and developmental toxicity was determined to be 750 mg/kgbw/day (highest tested dose).

Overall, with regard to the physicochemical properties and the absence of critical systemic effects in the toxicological investigation, it is unlikely that relevant amounts of the UVCB substance will reach the systemic circulation. Even if certain amounts become bioavailable no systemic toxicity is expected.

Dermal route:

The physicochemical properties of the UVCB substance such as molecular weight, log Pow and water solubility, will drastically limit the amount available for dermal absorption.

Some dermal uptake of the test substance must have occurred, although it may only have been a very small fraction of the applied dose, because the substance was sensitizing in a Local Lymph Node Assay (LLNA, OECD 429) assay conducted on mice. Here, immunological response was triggered.

Overall, the physicochemical properties support that absorption into the systemic circulation is expected to be very low after dermal application.

 

Inhalation route:

Considering the very low vapor pressure, the predicted log Pow of 7.6 and the low predicted water solubility, it cannot be ruled out that the substance is taken up via inhalation and could reach the deep lung.

 

Distribution

 

With regards to the physicochemical properties and the results achieved from the comprehensive toxicity testing, it appears that the bioavailability of the UVCB substance via the main entrance routes (i.e., oral, dermal and through inhalation) is limited but cannot be excluded. If any amounts of the UVCB become systemically available, they will be most likely transported within the body via the blood stream. Due to the absence of systemic effects in the oral toxicity studies, there are no hints with regard to any potential target organ.

 

Metabolism

 

Because absorption of the UVCB substance into the interior part of the body cells is considered to be limited, considerable contact of the substance with intracellular metabolizing enzymes is unlikely. However, in the event that fractions of the UVCB substance reach the systemic circulation it cannot be ruled out that they are metabolized by Phase I enzymes while undergoing functionalization reactions aiming to increase their hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the chemicals or its Phase I metabolites in order to ultimately facilitate excretion.

 

Excretion

 

As mentioned before, it is expected that the bioavailability of the UVCB substance is most likely to be limited and distribution into the body will be low. Thus, it is expected that following oral ingestion the vast majority of the chemicals is excreted with the faeces. However, even if a certain amount of the reaction product is absorbed, this will most likely be excreted via the faeces as well due to the molecular size. For smaller degradation or break down products, resulting from metabolism processes, excretion via the urine might also be possible. Moreover, with regard to the predicted substance’s LogPow value, the bioaccumulation cannot be ruled out.

 

3 Summary

 

Based on the physicochemical properties, systemic availability of the UVCB substance may be limited but cannot be completely excluded following oral intake. Considering the predicted very low vapor pressure it is not expected that relevant amounts of the UVCB substance are inhalable under normal use conditions. Based on the physicochemical properties uptake of the UVCB substance into the systemic circulation following dermal exposure is very limited. Following oral intake, it is expected that the majority of the chemical is excreted with the faeces. For any amounts potentially being bioavailable, it is assumed that circulation within the blood stream and subsequent metabolism may occur. Ultimately, absorbed amounts are expected to be excreted with the faeces or, to a lesser extent, in the urine depending on the molecular size. It cannot be ruled out that the substance has a potential for bioaccumulation.