Reaction products of 1,4-cyclohexanedimethanol with propylene oxide and ammonia

Endpoint summary

Description of key information

As the test substance is an UVCB substance, not all physico-chemical properties are clearly defined but reflect the properties of a group of constituents. The below toxicokinetic assessment is thus indicative only as single constituents within the UVCB might have significant different physico-chemical properties.

For the test substance, no experimental data are available on toxicokinetics. Therefore, a qualitative assessment of the absorption, distribution/accumulation, metabolism and elimination is performed on the basis of the physico-chemical properties of the substance (as indicated in  the ECHA specific Guidance 7.c for the implementation of REACH). In addition, toxicological data on the substance are used to support this assessment.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The test substance Jeffamine RFD 270 is a UVCB with an average molecular weight of about 270. It is miscible with water in all proportions (water solubility of 100 g/L) with a log Pow in the range of 1.59 to 3.48 (using the measured peak area for each calculated partition coefficient, the weighted mean Log Kow for the test substance is 2.17) and a low vapour pressure (17 Pa at 20°C). Decomposition of the substance occurred at 137°C.

The substance is an aliphatic amine containing both rigid (cycloaliphatic) and flexible (poyetheramine) segments in the same molecule. The dissociation constant (pKa) was determined to be 10.46 using the titration method.

 

Absorption

Oral/Gastro-intestinal (GI) absorption

Mechanisms by which substances can be absorbed in the gastro-intestinal (GI) tract include the passage of small water-soluble molecules (molecular weight up to around 500) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. As the substance is miscible with water and has a mean molecular weight of 270 (within a range of 200 and 490 and a typical value of 289), this passive diffusion will be the predominant mechanism for absorption in the GI tract. In addition, moderate octanol/water partition coefficient (log P) values (between -1 and 4) are considered to be favorable for absorption by passive diffusion; as logP values between 1.59 and 3.48 were obtained, uptake of several constituents in the substance might be possible. Ionized substances do not readily diffuse across biological membranes which makes the pKa is an important parameter to indicate ionization at a GI relevant pH. For UVCB substances, the pKa can however not easily be defined. Only one pKa value of an individual component in the substance was determined (10.46) and based on this value it could be concluded that some ionization (amine groups) at the biologically relevant pH range might occur, thus hampering the uptake of these individual components. In addition, once absorbed, substances will go to the liver before entering the systemic circulation – first pass metabolism may then limit the systemic bioavailability of the parent compound. Although no information is available for the test substance related to the first pass metabolism, this could limit the systemic bioavailability. As a risk mitigation, taking into account all of the the above information, an oral absorption factor of 50% will be derived for the test substance. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor. As signs of systemic toxicity have been observed in the acute and combined repeated dose/reproductive toxicity screening test via the oral route, absorption has occurred.

 

Respiratory absorption

Given the fact that the substance decomposes at 137 °C and the vapour pressure (Vp) of 17 Pa at 20°C, the test substance is not considered a highly volatile substance (Vp > 25 KPa or boiling point < 50°C). It is therefore unlikely that the substance is inhaled as a vapour at ambient temperature.

The test substance being a water soluble liquid will readily dissolve into the mucus lining the respiratory tract. Lipophilic substances (log P > 0) would then have the potential to be absorbed directly across the respiratory tract epithelium by passive diffusion. Hydrophilic substances might be absorbed through aqueous pores (for substances with molecular weights below around 200) or to be retained in the mucus and transported out of the respiratory tract, subsequently swallowed and becoming available for oral absorption. In view of its moderate log Pow values the substance will mainly be absorbed directly across the respiratory tract epithelium. For risk assessment purposes the inhalation absorption of the substance is set at 100%.

 

Dermal absorption

The substance is a water soluble liquid and as such it is readily available for absorption through the skin. As the substance is miscible with water and has a moderate log Pow (in the range of 1.59 to 3.48) it may contain components that can cross the lipid rich environment of the stratum corneum. With a molecular mass below 500 and log Pow in the range (-1, 4), the data meet the criteria for 100% dermal absorption (as given in the ECHA specific Guidance 7.c for the implementation of REACH). However, it is generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor for the substance is set to 50%. The results of the available toxicity studies using the dermal route do not provide reason to deviate from this factor.

In addition, the substance is observed to be corrosive to the skin as observed in a primary dermal irritation study in rabbits (performed according to OECD Guideline 404).

 

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like the test substance, will diffuse through aqueous channels and pores.

Based on the high water solubility and low molecular weight it could be expected that the substance will distribute widely through the body after absorption. However, as the substance contains ionizable amine groups its diffusion across membranes could limit its distribution.

  

Accumulation

In view of the moderate log Kow and the high water solubility, the substance is not expected to accumulate in the body. Substances with log Pow values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.

 

Metabolism and Excretion

The substance is expected to undergo Phase I and Phase II metabolic reactions. Based on the high water solubility and relatively low molecular weights, the substance and its conjugation products are expected to be mainly excreted in the urine.