Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyltrimethoxysilane

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Statement, no study available

Details on absorption:

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. Absorption of highly lipophilic substances with log Pow > 4 may be limited by the inability of the substance to dissolve in the fluids of the gastrointestinal tract and hence make contact with the mucosa. However, highly lipophilic substances, particularly those that are poorly soluble in water (1 mg/L or less) may form micelles and be absorbed into the lymphatic system to some extent. Therefore, from the physicochemical properties of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane is can be assumed that the oral bioavailability of the parent substance will be low. However, the parent substance undergoes rapid hydrolysis which might indicate that the parent compound may only be present in the GI-tract for a limited period of time and the resulting hydrolysis products, which are more hydrophilic than the parent compound, dissolve rapidly in the GI-fluids. The predicted hydrolysis products of the target substance are presented in Table 1, showing higher water solubility and log Pow values between 4.16 and 0.97. The results of a repeated dose toxicity study where clinical signs have been observed and changes in pancreas at 1000 mg/kg bw/day in male and female rats and at 300 mg/kg bw/day in female rats indicate that oral absorption of the hydrolysis products must have been occurred.

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of 3.93E-4 Pa at 20°C and 5.9E-4 Pa at 25°C Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane is unlikely to be available as a vapor to a large extent and exposure and uptake via inhalation is considered as negligible. As the substance is a liquid no generation of dust is possible.

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. Therefore, for Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane low dermal absorption is predicted because of its low water solubility, a molecular weight above 500 g/mol and an estimated log Pow value of 7.11. In cases were the molecular weight is above 500 and log Pow outside the range of -1 to 4 are observed a maximum worst case value of 10% skin absorption can be assumed for risk assessment purposes.
This assumption is supported by the results of an acute dermal toxicity study where neither systemic toxicity nor behavioral changes were noted in male and female rats up to the highest applied dose of 2000 mg/kg bw. The test item caused dermal irritation symptoms as well defined and slight erythema, dry skin and desquamation. As the substance is identified as skin sensitizer, some dermal uptake of the applied substance must have been occurred.

Details on distribution in tissues:

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. If the molecule is lipophilic (log Pow >0), it is likely that the substance distributes into cells and the intracellular concentration may be higher than its extracellular concentration particular in fatty tissues. Therefore, for Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane a slow distribution into the body water is expected. However, as the substance shows rapid hydrolysis to more hydrophilic compounds it is expected that the hydrolysis products are distributed through-out the body water to reach various tissues. As target tissue the pancreas (enlargement, pale color; increased amount of zymogen granules and flattened and basophilic acinar cells) was reported in a 14-day repeated dose toxicity study after oral application. Daily exposure to a substance with a log Pow of around 4 or higher could result in a built up of the substance in the body. As the substance hydrolyzes rapidly, no bioaccumulation of the parent compound in fatty tissue is expected after repeated exposure. For the hydrolysis products a low potential of bioaccumulation is expected since they are more hydrophilic and only one hydrolysis product has a predicted log Pow slightly above 4.

Details on excretion:

In general, urinary excretion is favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances with a molecular weight above 300 are likely to be excreted via bile and may undergo hepatic circulation. Molecules having strong polarity and high molecular weight are less likely to re-circulate.
Therefore, the parent compound Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane and its metabolites are expected to be excreted mostly via the bile into faeces. A low potential for enterohepatic circulation is expected due to the high lipophilicity of the parent substance and high molecular weight of the hydrolysis products. Highly lipophilic substances like the target substance with a log Pow between 4 and 6 that come into contact with the skin will penetrate the lipid rich stratum corneum and persist in this layer until its sloughed off.

Metabolites identified:

yes

Details on metabolites:

The aqueous hydrolysis half-life of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane was calculated using HYDROWIN v 2.00 as part of EPISuite v4.11 from US Environmental Protection Agency. The hydrolysis half-life of the test item was calculated to be <10 min even at low pH indicating fast formation of hydrolysis products.
A further compound of the target substance is trimethoxysilane, which is reported to hydrolyze very rapidly to produce methanol and silanetriol. Depending on the pH and concentration of the substance, the silanetriols may condense to form oligomers and polymers [2]. Methanol is metabolized mainly via alcohol dehydogenases and further via aldehyde hydrogenases to form CO2 and H2O.
In general, from the in vitro genotoxicity tests no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9 Mix could be detected, which might indicate that no metabolic activation of the substance occurs in vitro and probably also in vivo.

Description of key information

Based on physico-chemical properties, oral and dermal absorption is expected to be low for the parent compound. Since hydrolysis of the parent compound occurs very rapidly oral and dermal absorption is expected for these hydrolysis products. These assumptions are supported by the results of repeated dose toxicity studies in vivo where clinical signs have been observed. Absorption via the inhalation route is, due to physico-chemical properties of the test item, not expected. Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane hydrolyzes rapidly and therefore, no bioaccumulation of the parent substance is expected after continuous exposure. The test substance and/or its metabolites are expected to be excreted mostly via faeces and only partially via urine.

Additional information

Absorption

Absorption is a property of a substance to diffuse across biological membranes.Generally, oral absorption is favored for molecular weights below 500 g/mol andlog Pow values between -1 and 4.Absorption of highly lipophilic substances with log Pow > 4 may be limited by the inability of the substance to dissolve in the fluids of the gastrointestinal tract and hence make contact with the mucosa. However, highly lipophilic substances, particularly those that are poorly soluble in water (1 mg/L or less) may form micelles and be absorbed into the lymphatic system to some extent. Therefore, from the physicochemical properties of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilaneis can be assumed that the oral bioavailability of the parent substance will be low. However, the parent substance undergoes rapid hydrolysis which might indicate that the parent compound may only be present in the GI-tract for a limited period of time and the resulting hydrolysis products, which are more hydrophilic than the parent compound, dissolve rapidly in the GI-fluids. The predicted hydrolysis products of the target substance are presented in Table 1, showing higher water solubility and log Pow values between 4.16 and 0.97.The results ofa repeated dose toxicity study where clinical signs have been observed and changes in pancreas at 1000 mg/kg bw/day in male and female rats and at 300 mg/kg bw/day in female rats indicate that oral absorption of the hydrolysis products must have been occurred.

 

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of 3.93E-4 Pa at 20°C and 5.9E-4 Pa at 25°C Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane is unlikely to be available as a vapor to a large extent and exposure and uptake via inhalation is considered as negligible. As the substance is a liquid no generation of dust is possible.

 

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. Therefore, for Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane low dermal absorption is predicted because of its low water solubility, a molecular weight above 500 g/mol and an estimated log Pow value of 7.11. In cases were the molecular weight is above 500 and log Pow outside the range of -1 to 4 are observed a maximum worst case value of 10% skin absorption can be assumed for risk assessment purposes.

This assumption is supported by the results of an acute dermal toxicity study where neither systemic toxicity norbehavioral changes were noted in male and female rats up to the highest applied dose of 2000 mg/kg bw. The test item caused dermal irritation symptoms as well defined and slight erythema,dry skin and desquamation. As the substance is identified as skin sensitizer, some dermal uptake of the applied substance must have been occurred.

 

Distribution

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. If the molecule is lipophilic (log Pow >0), it is likely that the substance distributes into cells and the intracellular concentration may be higher than its extracellular concentration particular in fatty tissues. Therefore,for Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane a slow distribution into the body water is expected. However, as the substance shows rapid hydrolysis to more hydrophilic compounds it is expected that the hydrolysis products are distributed through-out the body water to reach various tissues. As target tissue the pancreas (enlargement, pale color; increased amount of zymogen granules and flattened and basophilic acinar cells) was reported in a 14-day repeated dose toxicity study after oral application. Daily exposure to a substance with a log Pow of around 4 or higher could result in a built up of the substance in the body. As the substance hydrolyzes rapidly, no bioaccumulation of the parent compound in fatty tissue is expected after repeated exposure. For the hydrolysis products a low potential of bioaccumulation is expected since they are more hydrophilic and only one hydrolysis product has a predicted log Pow slightly above 4.

 

Metabolism

The aqueous hydrolysis half-life of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane was calculated using HYDROWIN v 2.00 as part of EPISuite v4.11 from US Environmental Protection Agency. The hydrolysis half-life of the test item was calculated to be <10 min even at low pH indicating fast formation of hydrolysis products.

A further compound of the target substance is trimethoxysilane, which is reported to hydrolyze very rapidly to produce methanol and silanetriol. Depending on the pH and concentration of the substance, the silanetriols may condense to form oligomers and polymers [2]. Methanol is metabolized mainly via alcohol dehydogenases and further via aldehyde hydrogenases to form CO2and H2O.

In general, from the in vitro genotoxicity tests no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9 Mix could be detected, which might indicate that no metabolic activation of the substance occurs in vitro and probably also in vivo.

 

Excretion

In general, urinary excretion is favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances with a molecular weight above 300 are likely to be excreted via bile and may undergo hepatic circulation. Molecules having strong polarity and high molecular weight are less likely to re-circulate.

Therefore, the parent compound Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane and its metabolites are expected to be excreted mostly via the bile into faeces. A low potential for enterohepatic circulation is expected due to the high lipophilicity of the parent substance and high molecular weight of the hydrolysis products. Highly lipophilic substances like the target substance with a log Pow between 4 and 6 that come into contact with the skin will penetrate the lipid rich stratum corneum and persist in this layer until its sloughed off.

 

References

 [1] ECHA (2017), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017

[2] OECD SIDS Initial Assessment profile, CAS No. 2487-90-3, Trimethoxysilane, SIAM 24, 19-24 April 2007