2-hydroxy-3-(prop-2-enoyloxy)propyl 2-methyl-2-propylhexanoate

Endpoint summary

Description of key information

There were no studies available in which the toxicokinetic properties of the test substance were investigated. However, as per REACH guidance document R7. C (2014), information on absorption, distribution, metabolism and excretion may be deduced from the physicochemical properties. Based on the physico-chemical properties, QSAR predictions/modelling as well as the available toxicological data, the test substance is expected to have higher absorption potential via the oral and inhalation route compared to the dermal route. It is likely to be metabolised predominantly via ester hydrolysis resulting in the formation of acrylic acid and the corresponding alcohol derivative. Overall, the substance is expected have low bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

ABSORPTION:

Oral absorption

Based on physico-chemical properties:

According to REACH guidance document R7.C (May 2014), 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 vales (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, with molecular weight (MW) ranging from 244-400.6 g/mol and a MW of 300.4 g/mol for the major constituents (present >95%). It is a liquid with a moderate water solubility ranging from 142 mg/L and an experimental log Kow ranging from 4.11-4.19. Volatility was determined to be low (based on vapour pressure of 0.0277 Pa at 45°C).

Based on the R7.C indicative criteria, oral uptake of the constituents of the test substance is assessed to be moderately absorbed, given the molecular weight not exceeding 500, moderate water solubility and the borderline log Kow values of the major constituents. This is supported by the presence of systemic effects in a combined oral repeated dose and reproductive and development toxicity screening study in rats at the higher highest dose.

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 the 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 with 90% values are extensively and almost completely absorbed. For those compounds for which the absorption was reported as being poor, the value is 5%. The estimated HIA values for the major constituents of the test substance were as follows:

-         Cardura acrylate isomers: 89.3%

-         Neo undecanoic acid, 1-ester with 1,2,3-propanetriol mono-2-propenoate: 89.6%

-         Cardura diester: 92.2%

Based on the above data, the individual constituents of the test substance are expected to be absorbed through the oral route.

Conclusion: Based on all the available weight of evidence information, the test substance can be overall expected to have good absorption through the oral route. Therefore, as a conservative approach a value of 100% has been considered for the risk assessment.

Dermal absorption

Based on physico-chemical properties:

According to REACH guidance document R7.C (May 2014), dermal absorption is maximal for substances with molecular weights below 500 and log Kow values ranging between 1 and 2. The test substance has a MW weight of 300.4 g/mol for the major constituents (present >95%) and an experimental log Kow greater than 4. This suggests that due to low MW, the substance may have some penetration potential through the skin.

Based on QSAR prediction:

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

-         Cardura acrylate isomers: 7.16E-03 cm/h

-         Neo undecanoic acid, 1-ester with 1,2,3-propanetriol mono-2-propenoate: 1.27E-02 cm/h

-         Cardura diester: 2.51E-01 cm/h

However, it has been observed that the predicted Kp data from the usual QSAR programs are not suitable for lipophilic substances (CONCAWE, 2010). Therefore, the maximum flux (Jmax) or a dermal absorbed dose per event (DAD-event; mg/cm2)), which provide better estimates for dermal penetration, have been used for predicting the dermal absorption potential for the substances in the current assessment. Jmax is the theoretically achieved dose, based on Fick’s first law of diffusion, when a material is maintained in a saturated solution or at steady state equilibrium whose flux describes the amount of permeant per unit time and area (i.e., μg/cm2/h).

In absence of experimental data, it can be calculated by multiplying the water solubility with the predicted Kp values from DERMWIN model.

-      Cardura acrylate isomers:0.274μg/cm2/h

-      Neo undecanoic acid, 1-ester with 1,2,3-propanetriol mono-2-propenoate:0.153 μg/cm2/h

-      Cardura diester:4.69E-03 μg/cm2/h

 

As per Shen et al. 2014[2], the default dermal absorption for substances with Jmax is >0.1 μg/cm2/h but ≤10 μg/cm2/h, may not exceed 40%. Based on these calculations, the test substance is predicted to be moderately absorbed via the dermal exposure route. 

Conclusion: Based on all the available weight of evidence information, the test substance can be overall expected to have low to moderate absorption through the dermal route. Therefore, a value of 50% dermal absorption has been applied for a conservative risk assessment.

 

Inhalation absorption

Based on physico-chemical properties:

According to REACH guidance document R7.C (May 2014), inhalation absorption is maximal for substances with 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 available for absorption.

The test substance, because of its relatively low vapour pressure of0.0277 Pa at 45°C, will not be available as vapours for inhalation underambient conditions. Therefore, the substance will neither be available for inhalation as vapours nor as aerosols. Further, if at all there is any inhalation exposure, considering the moderate water solubility of the substance it is expected to be retained in the mucus and only very little may reach the lower respiratory tract. The absorption fate of the deposited material thereafter is expected to be similar to the oral route/gastrointestinal tract.

Conclusion:Overall if inhaled, based on all the available weight of evidence information, the test substance can be expected to have moderate to good absorption through the inhalation route. Therefore, a default value of 100% has been considered for the risk assessment.

METABOLISM:

Based on QSAR modelling:

The predicted metabolism of the test substance was evaluated using thein vivorat metabolism and rat liver S9 metabolism simulators of the OECD QSAR Toolbox v.3.4. According to these simulators, the major constituents (present at >95%) are primarily predicted to undergo ester hydrolysis resulting in the formation of acrylic acid (AA) and the corresponding alcohol derivative. Only the minor constituent, cardura diester, present at <2% is predicted to undergo either hydroxylation of the terminal carbon (as per thein vivorat metabolism and rat liver S9 simulator) or oxidation of the OH group (as per the in vitro rat liver S9) as first reactions. The probability of this constituent undergoing ester hydrolysis has been predicted at the second and third level by the respective simulators. See the table in the CSR for the reaction sites and predicted metabolites.

BIOACCUMULATION:

Based on the MW and physico-chemical information (log Kow and water solubility) and metabolism data, the bioaccumulation potential of the substance is expected to be low.

EXCRETION:

Based on the high MW and moderate water solubility, the test substance as such is expected to be excreted via urine.

[1]Log Kp = -2.80 + 0.66 log kow – 0.0056 MW

[2]http://fragrancematerialsafetyresource.elsevier.com/sites/default/files/Shen-An_0.pdf