Poly[oxy(methyl-1,2-ethanediyl)], α-hydro-ω-hydroxy-, ether with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol (3:1), 2-propenoate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

ABSORPTION

Oral absorption

Based on physico-chemical properties

According to REACH guidance document R7.C, oral absorption is maximal for substances with molecular weights below 500. Water-soluble substances will readily dissolve into the gastrointestinal fluids. However, absorption of hydrophilic substances via passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Further, absorption by passive diffusion is higher at moderate log Kow values (between -1 and 4). If signs of systemic toxicity are seen after oral administration (other than those indicative of discomfort or lack of palatability of the test substance), then absorption has occurred.

The test substance is a UVCB with several constituents having molecular weights (MW) ranging from 192 to 1476 g/mol, with an average MW of 655-700 g/mol. It is a liquid with a low water solubility ranging from 35.6-68.6 mg/L and an experimental log Kow ranging from 3.9-5.2 (majority <4.5). Volatility was determined to be low (1.2E^-2 Pa).

Based on the R7.C indicative criteria, oral uptake of the major constituents is assessed to be low, given their high average molecular weight (exceeding 500), low water solubility and relatively high log Kow (≥4).

Based on QSAR prediction:

Human intestinal absorption (HIA) can also be predicted for the constituents of the test substance using the Multicase model v.3.45 of OECD QSAR Toolbox v.3.4. HIA is expressed as a percentage of the oral dose absorbed from the gastrointestinal tract. Substances with HIA values of 80% are considered as well absorbed and those with values of 90% values as extensively and almost completely absorbed. An HIA of 5% indicates poor absorption.

The estimated HIA values for the major constituents of the test substance were as follows:

-      TMP(PO)nDA: 87.8%

-      TMP(PO)nTA: 92.3%

-      TMP(PO)nTA-AA: 89.6%

-      Dimers TMP(PO)nDA + TMP(PO)nTA: 87.6%

These HIA values suggest that the individual constituents of the test substance may be well absorbed through the oral route.

Conclusion:The assessment of oral absorption based on physico-chemical properties is in contradiction with that based on (Q)SAR modelling, the first suggesting low absorption whereas the latter indicates high absorption. Given this inconsistency, a default value of 100% has been retained for risk assessment purposes.

 

Dermal absorption

Based on physico-chemical properties

According to REACH guidance document R7.C, dermal absorption is maximal for substances with molecular weights below 500 and log Kow values ranging between 1 and 2. The constituents of the test substance have an average molecular weight of 700 g/mol and an experimental log Kow of ≥4. This suggests that the substance may not penetrate easily through skin.

Based on QSAR prediction:

The above conclusion is supported by modelling conducted with the DERMWIN v2.01 application of EPISuite v4.1. The calculated dermal permeability coefficient (Kp1) corresponded to:

-      TMP(PO)nDA: 1.390E-04 cm/h

-      TMP(PO)nTA: 5.520E-04 cm/h

-      TMP(PO)nTA-AA: 2.290E-04 cm/h

-      Dimers TMP(PO)nDA + TMP(PO)nTA: 4.910E-05 cm/h

If Kp <10^-3cm/h (or 0.01 cm/h), low skin penetration should be assigned (Michael and Kenneth, 2007). Based on the calculations for the major constituents, the test substance is predicted to be absorbed slowly, with no significant systemic uptake via the dermal route.

Conclusion: Physico-chemical properties and QSAR predictions suggest that the test substance will not be absorbed significantly via skin. Therefore, a maximum of 10% dermal absorption has been applied for a conservative risk assessment.

 

Inhalation absorption

Based on physico-chemical properties

According to REACH guidance document R7.C, inhalation absorption is maximal for substances with a vapour pressure (VP) >25 KPa, particle size <100 μm, low water solubility and moderate log Kow values (between -1 and 4). Very hydrophilic substances may be retained within the mucus and not be available for absorption.

The test substance, because of its relatively low vapour pressure of 1.2E^-2Pa at 30°C, will not be available as vapour for inhalation under ambient conditions. Also, to the best of the available knowledge, there are no spray applications (PROC 7 or 11). Therefore, the substance will neither be available for inhalation as vapour nor as aerosols.

Conclusion: Overall, based on all the available weight of evidence, the test substance is expected to have low to moderate absorption through the inhalation route. Nevertheless, a conservative default value of 100% was considered for risk assessment.

 

METABOLISM

Based on QSAR modelling

The metabolism of the test substance was predicted using thein vivorat metabolism and rat liver S9 metabolism simulators of OECD QSAR Toolbox v.3.4. According to these simulators, all 4 major constituents (present at >5%) are expected to undergo ester hydrolysis, resulting in the formation of acrylic acid (AA) and the corresponding alcohol derivative (see below table for the reaction sites and the predicted metabolites).

 

Major constituents	Rat liver S9 metabolism simulator and in vivo rat metabolism simulator
TMP(PO)nDA	Predicted metabolites: TMP(PO)MA + AA
TMP(PO)nTA	Predicted metabolites: TMP(PO)DA + AA
TMP(PO)nTA-AA	Predicted metabolites: TMP(PO)DA-AA + AA
Dimers TMP(PO)nDA + TMP(PO)nTA	Predicted metabolites: Dimers TMP(PO)DA + TMP(PO)DA + AA

 

Bioaccumulation

Based on BCF values ranging from 2.46 to 6.12 L/kg wet wt for the main constituents of the test substance (estimated using the BCF baseline model v.03.10 of LCM), the potential for bioaccumulation is considered to be low.

Excretion

Based on the high MW and low water solubility, the test substance as such is not expected to be excreted via urine. Excretion via faeces is therefore expected. Nevertheless, there will be some urinary elimination following formation of water-soluble conjugates via Phase II reactions.