Hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate

Endpoint summary

Description of key information

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the test 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 properties. The target substance hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate(CAS No. 162492-01-5) is expected to be hydrolysed within the human body and the hydrolysis products readily absorbed via the oral route. Only low absorption via the dermal and inhalation route is expected. The smaller molecule size of the hydrolysis products facilitates the absorption. Any fraction of the parent molecule that is absorbed will be hydrolysed mainly in the liver. The absorbed hydrolysis products are readily distributed throughout the organism, with limited distribution in adipose tissue. However,bioaccumulation potential is assumed for the absorbed test substance.Most of the hydrolysis products are expected to be rapidly conjugated and excreted via the urine or enter oxidation pathways. The predicted metabolite CO₂will be excreted via the exhaled air.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - dermal (%):

10

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate(CAS No. 162492-01-5) was investigated. In accordance with Annex VIII, Column 1, 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, 2017), an assessment of the toxicokinetic behaviour of hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate was 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 physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

Physico-chemical properties

Hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate is a multi-constituent substance which meets the definition of an UVCB substance. The substance has a molecular weight of 852.9249 g/mol.

It is a liquid at 20 °C with a water solubility of < 0.54 mg/L at 20 °C. The log Pow is 4.23 and the vapour pressure was calculated (by extrapolation) to be 8.1E-6 Pa at 20 °C. 

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2017).

The low water solubility (< 0.54 mg/L) and the high log Pow value (4.23) of the substance indicate that absorption may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption.

The available data on acute oral toxicity indicate the substance has low acute toxicity. In the acute oral toxicity study performed with hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate no mortality was observed in 6 female rats administered 2000 mg/kg bw by gavage. No clinical signs of toxicity were observed during the 14-day observation period, no effects on body weight were noted, and the gross necropsy showed no treatment-related macroscopic changes (Holalagoudar, 2016). The LD50 value was > 2000 mg/kg bw.

Data of an oral repeated dose toxicity study combined with a reproductive/developmental toxicity screening test do not indicate that oral absorption of the test substance might occur since no treatment related effects were observed. The test substance was administered orally via gavage to male and female rats at doses of 0 (vehicle only), 100, 300 or 1000 mg/kg bw/day before and during mating as well as after mating (altogether for 54 – 57 days for males and females). Reversibility of any effects observed was assessed following a 14 day recovery period in additional animals of the control and high dose group. No treatment-related changes in any of the parameters were observed at any dose. Therefore, oral absorption of the test substance is not indicated.

The potential of a substance to be absorbed in the GI tract may be influenced by chemical changes taking place in GI fluids as a result of metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply or apply to a lesser extent (ECHA, 2017).The ester bonds may be hydrolysed in the GI tract by esterases to form the corresponding alcohol and acid moieties. The rate of hydrolysis is unknown. The smaller molecules of the alcohol and acid moieties are likely to be absorbed faster than the parent molecule. 

In conclusion, based on the available information, hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate is not assumed to be readily absorbed. However, the substance is predicted to undergo enzymatic hydrolysis in the GI tract and absorption of the hydrolysis products rather than (or in addition to) the parent substance is likely. The absorption rate of the hydrolysis products is expected to be high.  

 

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if the water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The target substance hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate is sparsely water soluble (< 0.54 mg/L) indicating a low potential for dermal absorption. Furthermore, the log Pow is above 4 and the molecular weight is above 500 g/mol indicating dermal absorption is limited. The available data on acute dermal toxicity support that the substance has low acute toxicity.

An acute dermal toxicity studies was performed with hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate. No mortality and no clinical signs were observed in 5 male and 5 female rats treated with 2000 mg/kg bw under semi-occlusive conditions. Signs of slight local irritation (erythema grade 1 in 4/5 females and desquamation in 1/5 female) were reversible within 3 days. No treatment-related effects on body weight or body weight gain were noted, and the gross necropsy showed no treatment-related macroscopic changes (Holalagoudar, 2016). The LD50 value was > 2000 mg/kg bw.

 

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

QSAR calculations regarding the molecular weight, log Kow and water solubility, estimated the following dermal absorption rates (calculated with DERMWIN, v.2.01, 2011, modified considering the Fick´s first law): 1.64 × 10^-5cm/h. Considering the water solubility (< 0.54 mg/L corresponding to < 0.00054 mg/cm³; 0.00054 mg/cm³ applied), the dermal flux is estimated to be 0.00001 µg/cm²/h. This indicates a very low dermal absorption potential.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. There is no in vivo data on the effects of acute or long-term dermal exposure to the target substance. The available in vitro skin corrosion and skin irritation data on the target substance showed no cytotoxic effects on the viability of a reconstituted three-dimensional human epidermis model (EPISKIN-SMTM) consisting of normal human epidermal keratinocytes (Lehmeier 2016). In the acute dermal toxicity study signs of slight local irritation were observed which were reversible within 3 days. Additionally, discrete erythema (score 1 or 2) were developed on the skin of guinea pigs in the skin sensitisation study (GPMT; Weisz, 2016). The test substance has been identified as Skin Sensitizer Category 1A according to Regulation (EC) No 1272/2008 (Weisz, 2016). Thus, some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017).

 

Hydrolysis of the ester bonds may take place in the skin, although at a lower rate than via the oral route due to the lower amount of enzymes present in the skin. For the fraction of ester that is absorbed into the skin, the ester bond will be hydrolysed and the hydrolysis products may enter the blood circulation.

Taking all the available information into account, the dermal absorption potential of the target substance is considered to be low. According to the ECHA Guidance on Toxicokinetics a dermal absorption value of 10% is chosen in the case molecular mass is > 500 g/mol and log Pow is outside the range (< -1 or > 4). Thus, with a molecular weight of 852.9249 g/mol and a log Pow of 4.23 a dermal absorption of 10% is applied for hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate.

 

Inhalation

Hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate is a liquid with low vapour pressure (8.1 x 10⁻⁶Pa at 20 °C), and therefore very low volatility. Consequently, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapour, gases or mists is not significant (ECHA, 2017). However, the substance may be available for absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract. Particles deposited in the nasopharyngeal/ thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed. The low water solubility (< 0.54 mg/L) and the high log Pow value (4.23) of the substance indicate that absorption may be limited. However, micellular solubilisation may enhance absorption. Additionally, the high molecular weight may have a limiting effect on the absorption rate. There is no experimental data on the effects of acute or long-term inhalation exposure to the target substance.

Taking all the available information into account, absorption of the target substance via inhalation is considered to be low.

 

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).

Thus, due to the lipophilic character the distribution into cells and the intracellular concentration may be higher than the extracellular concentration particular in fatty tissue. Lipophilic substances will tend to concentrate in adipose tissue and depending on the conditions of exposure may accumulate. If the interval between exposures is less than 4 times the whole body half-life of the substance then there is the potential for the substance to accumulate. It is generally the case that substances with high log Pow values have long biological half-lives. On this basis, daily exposure to a substance with a log Pow value of around 4 or higher could result in a build-up of that substance within the body. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance. If fat reserves are mobilized more rapidly than normal, e.g. if an individual or animal is under stress or during lactation there is the potential for large quantities of the parent compound to be released into the blood (ECHA, 2017). Since no experimental data are available a bioaccumulation potential is assumed.

The sensitising effects observed in the guinea pig maximisation test indicate that some uptake must have occurred although it may only have been a small fraction of the applied dose. However, no clinical signs or any other effects were observed in the acute oral toxicity studies.

As discussed under oral absorption, hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate is expected to undergo enzymatic hydrolysis in the GI tract prior to absorption. After being absorbed, the hydrolysis products are expected to be widely distributed due to the relatively small size and the functional groups, which are characteristics that increase the water solubility. The substances absorbed from the GI tract will be transported via the portal vein to the liver, where further metabolism can take place. Substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before transport to the liver where metabolism will take place. These substances are not expected to accumulate in adipose tissue due to the lack of lipophilic groups. 

 

Metabolism

No data are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v3.3.0.152, OECD, 2014). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract.

12 hepatic and 1 dermal metabolites were predicted for the test substance, respectively. The metabolites are mainly the result of hydrolysis of the ester bonds and of a hydroxyl group being added. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The smaller molecules resulting from hydrolysis of the ester bond are also expected to have higher water solubility. In contrast to the liver only one metabolite was predicted to be formed in the skin due to the lower level of enzymes in the skin. The skin metabolite and any absorbed parent substance will enter the blood circulation and have the same fate as the hepatic metabolites. Up to 57 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule. Not all of these reactions are expected to take place in the human GI-tract. The hydrolysis products may be conjugated (e.g. glucuronidation) to form a polar molecule suitable for excretion or metabolism.

Available genotoxicity data of the test substance do not show any genotoxic properties. In particular, an Ames test, an in vitro micronucleus test in Chinese hamster lung fibroblasts and an in vitro gene mutation assay (thymidine kinase locus) in mouse lymphoma L5178Y cells were consistently negative and therefore no indication of genotoxic reactivity is indicated.

The result of the skin sensitisation study (LLNA) using the source substance was positive, showing the target substance is likely to be metabolised to a reactive molecule, leading ultimately to skin sensitisation (Weisz, 2016).

  

Excretion

The hydrolysis products of hexamethylene diisocyanate, trimers, reaction products with 2-hydroxyethyl acrylate will be conjugated with e.g. glutathione to form more water-soluble molecules and excreted via the urine or metabolised.

The fraction of the target substance that is not absorbed in the GI tract will be excreted via the faeces. If microbial metabolism occurs (as predicted in the OECD QSAR Toolbox, see above under ‘Metabolism’), then the smaller metabolites may be absorbed; thereby entering the systemic circulation. The metabolites are expected to be conjugated as described above and excreted via the urine. The formation of CO₂as metabolite is also predicted. This metabolite will be excreted via the exhaled air.

  

References

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

OECD (2014). (Q)SAR Toolbox v3.3. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Prediction performed 21 June 2016.http://toolbox.oasis-lmc.org/?section=overview

US EPA (2014).Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA.Downloaded from: http://www.epa.gov/oppt/exposure/pubs/episuite.htm