2-Propenoic acid, 2-methyl-, 2-hydroxyethyl ester, reaction products with phosphorus oxide

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 phys-chem properties and the available toxicological data, the absorption by oral and dermal route is expected. However, the bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Oral absorption:

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 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 type of substance having a molecular weight of ~386 g/mol (range [98-626]). It is a liquid with a tested water solubility of 11600 mg/L. Volatility was determined to be low (0.66 Pa) and has a good lipophilic character (log Kow of the all components present at >10% concentration corresponding to 3).

Based on the R7.C indicative criteria, the constituents of the test substance are assessed to be well absorbed, given their molecular weights ranging between 98 and 626, good water solubility and favourable log Kows of <0.3 – 3.7, with a value of 3 for the≥10% constituents. Systemic effects were observed at the doses equal or higher than 1000 mg/kg bw/day in the oral OECD 422 study, confirming the oral absorption of test substance. Also, given the acidic nature of the test substance, the absorption is expected to take place mostly from the intestinal tract.

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 different components of the test substance were as follows:

-      2-Propenoic acid, 2-methyl-, 2-hydroxyethyl ester, phosphate (‘Mono phosphate’): 28.3%

-      Bis(methacryloyloxyethyl) hydrogen phosphate (‘Di-phosphate’): 77.6%

-      Trimer of 2-propenoic acid, 2-methyl-, 2-hydroxyethyl ester, phosphate (‘Tri-phosphate’): 84%

-      Pyro-phosphate or Tetrabis(methacryloyloxyethyl) pyrophosphate (‘Tetra-pyrophosphate’- assumed to be worst case component): 63.1%

-      Orthophosphoric acid: 14.7%

This supports the above conclusion of good oral absorption. For the risk assessment, a worst-case value of 100% was therefore taken.

Dermal absorption

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 constituents of test substance have molecular weights of 98-626 and log Kows of <0.3 – 3.7, with a value of 3 for the ≥10% constituents. This suggests that the substance may not penetrate very easily through skin. The conclusion is supported by modelling run with the DERMWIN v2.01 application of EPISuite v4.1. The calculated dermal permeability coefficient (Kp[1]) corresponded to:

-      Mono phosphate:1.45 x 10-4cm/h

-      Di-phosphate: 1.55 x 10-4cm/h

-      Tri-phosphate: 1.66 x 10-4cm/h

-      Tetra-pyrophosphate (assumed to be worst case component): 1.43 x 10-5cm/h

-      Orthophosphoric acid: 1.36 x 10-4cm/h[2]

It has been suggested that if Kp <10^-3cm/h, low skin penetration will be assigned (Michael and Kenneth, 2007). Based on these calculations, the substance is predicted to be absorbed slowly, with no significant systemic uptake via the dermal exposure route. However, test substance is a skin sensitizer which suggests a dermal absorption. So a value of 100% dermal absorption was applied for a very conservative risk assessment.

Absorption via inhalation

Because of its low vapour pressure of 0.66 Pa at 20°C, exposure via inhalation will not be significant under ambient conditions but may occur in situations where test substance is aerosolized or volatilises during use or handling. For these occasions, the wearing of an approved respirator recommended by an industrial hygienist after an evaluation of the operation is given as a risk management measure. As a result, respiratory exposure is not expected. Please note that spray application (PROC 7 or 11) are not supported by the registrant.

Metabolism

The predicted metabolism of the constituents of test substance were evaluated usingin vivorat metabolism and rat liver S9 metabolism simulators of OECD QSAR Toolbox v.3.4. According to these simulators, all constituents undergo similar transformation reactions, i.e., ester hydrolysis resulting in the formation of methacrylic acid and 2-hydroxyethyl dihydrogenphosphate. Another possible metabolic pathway predicted by thein vivorat metabolism simulator is the phosphate hydrolysis or O-dealkylation of the methacryloyloxyethyl group. However, the results of acute, repeated dose and mutagenicity testing suggest that no toxic metabolites are formed when the constituents of test substance are broken down.

Bioaccumulation

Based on the physico-chemical information (log Kow and water solubility), it is concluded that the potential for bioaccumulation is low.

Excretion

Based on the physico-chemical information, metabolic pathways main excretion of test substance can be expected to be via urine.

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

[2] The prediction may not be very reliable for orthophosphoric acid as the training set does not include inorganic compounds