Reaction products of acrylic acid with 2,2'-[oxybis(methylene)]bis[2-ethylpropane-1,3-diol]

Endpoint summary

Description of key information

​Based on the available weight of evidence information, the test substance is expected to have a low to moderate absorption potential through the oral route, a low absorption potential through dermal route and a moderate to high absorption potential through the inhalationroute. Based on QSAR predictions, it is likely to undergo hydrolysis of acrylic carboxylic esters followed by oxidation of free OH groups type of reactions as the first metabolic reaction. Further, based on low water solubility, log kow and thepredicted BCF values together with other WoE discussed in section 4.3.3 of the CSR, the test substance is likely to have low bioaccumulation potential.

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

ABSORPTION:

Oral absorption

Based on physicochemical properties:

According to REACH guidance document R7. C, oral absorption is maximal for substances with molecular weights below 500; molecular weights above 1,000 do not favour absorption. Also, absorption by passive diffusion is higher at moderate log Kow vales (between -1 and 4) whereas uptake via micellar solubilisation may be important at log Kow values > 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.

Based on these R7.C based indicative criteria, oral uptake of the test substance and its constituents is assessed to range from low to moderate. The test substance is an UVCB substance with several constituents and MW ranging from 304 to 1363 g/mol for all constituents (average: 720 g/mol). The test substance is a liquid with a low to high water solubility (ranging approximately from <0.1 to 281730 mg/L) and low to moderate lipophilicity (with log Kowbetween ‑0.1 and 4.14) for the different constituents. The main constituent, di- TMPTTA, present at 20 – 70%, has a molecular weight of 466 g/mol with a specific water solubility of 15 mg/Lat 25°C (low solubility) and log Kow of 4.14 (moderate). In addition, there were no significant systemic effects were noted in either the acute oral toxicity testing at 5,000 mg/kg bw or the repeated dose screening study up to 1000 mg/kg bw/day conducted in rats.

Conclusion:Overall, based on the above information, the oral uptake of the test substance and/or its constituents is assessed to range from low to moderate. However, as a conservative approach a default value of 100% (in line with the ECHA Guidance Chapter R.8) has been considered for the risk assessment.

Dermal absorption

Based on physicochemical properties:

According to REACH guidance document R7.C (ECHA, 2017), dermal absorption is maximal for substances having a MW below 100 together with log Kow values ranging between 2 and 3 and water solubility in the range of 100-10,000 mg/L. Substances with MW above 500 are considered to be too large to penetrate skin. Further, dermal uptake is likely to be low for substances with log P values <0 or <-1, as they are not likely to be sufficiently lipophilic to cross the stratum corneum (SC). Similarly, substances with water solubility below 1 mg/L are also likely to have low dermal uptake, as the substances must be sufficiently soluble in water to partition from the SC into the epidermis.

The test substance is liquid, with an MW exceeding 100 g/mol,low water solubilityand a log Kow greater than 3 (for major constituents). This suggests that the test substance is likely to have a low penetration potential through the skin. This is further supported by the absence of systemic effects in thein vivoskin sensitisation study conducted with the test substance.

Based on QSAR prediction:

The above conclusion is supported by modelling run with the DERMWIN v2.02 application of EPISuite v4.11. The calculated dermal permeability coefficient (Kp1[1]) of the individual constituents of the test substance is given in the below table:

Constituents (acronyms)	Boundary composition (% w/w)	Mole fraction Xi = (mass fraction/MW)/∑ (mass fraction/MW)	Kp (cm/hr)	Kp (cm/hr)*xi
di-TMPTTA	20-70	0.535913	2.88E-03	1.46E-03
dimer di-TMPTA + di-TMPTTA	0-15	0.079378	1.33E-03	1.00E-04
di-TMPTA	2-40	0.140966	7.22E-04	9.64E-05
di-TMPTTA + AA	0-15	0.107952	1.19E-03	1.22E-04
dimer di-TMPTA + di-TMPTA	0-12	0.035241	3.34E-04	1.11E-05
dimer di-TMPTA + di-TMPTTA + AA	0-10	0.030535	5.52E-04	1.60E-05
Trimer AA	0-10	0.022485	6.18E-04	1.32E-05
di-TMPDA	0-14	0.032446	3.37E-04	1.04E-05
dimer di-TMPTA + di-TMPDA	0-10	0.015085	1.56E-04	2.23E-06
Trimer AA + AA	0-5	0.012778	2.55E-04	3.09E-06
di-TMPTA + AA	0-5	0.023974	2.99E-04	6.79E-06
di-TMPMA	0-5	0.019105	8.46E-07	1.53E-08
Weighted average (WA)				1.84E-03 cm/hr

The Kp values of the constituents were predicted to range between 8.46E-07 to 2.88E-03 cm/hr, leading to a weighted average value of 1.84E-03 cm/hr.It has been suggested that if Kp <10-3cm/h (or 0.01 cm/h), low skin penetration will be assigned (Michael and Kenneth, 2007). Based on these calculations for the major constituents, the test substance is predicted to be absorbed slowly, with no significant systemic uptake via the dermal exposure route.

Conclusion: Overall, based on all the available weight of evidence information, the test substance can be expected to have a low absorption potential through the dermal route. However, as a conservative approach a default value of 100% (in line with the ECHA Guidance Chapter R.8) has been considered for the risk assessment.

Inhalation absorption

Based on physicochemical properties:

According to REACH guidance document R7.C (ECHA, 2017), inhalation absorption is maximal for substances with VP >25 KPa, particle size (<100μm), low water solubility and moderate log Kow values (between -1 and 4). Very hydrophilic substances may be retained within the mucus and are not available for absorption.

The test substance, because of its liquid physical state and relatively low vapour pressure, will not be available as particles or vapours for inhalation under ambient conditions. Should there be inhalation exposure during normal handling and use conditions, only coarse droplets would be an exposure potential resulting in very low respiratory fraction. Of the inhalable fraction, due to the low water solubility, the test substance will not be retained in the mucus and hence is more likely to reach the deeper lungs for absorption, where absorption via passive diffusion will be favoured given its high log Kow. On the other hand, the larger deposited droplets from the upper respiratory tract will be subsequently transported to the pharynx and swallowed via the ciliary-mucosal escalator. The absorption potential of this fraction of the test substance can be considered to be similar to the oral route.  

Conclusion: Based on the above information, if exposure occurs, the test substance can be expected to have moderate to high absorption through the inhalation route. Therefore, as a conservative approach, a default value of 100% (in line with the ECHA Guidance Chapter R.8) 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 simulator and the rat liver S9 metabolism simulator of the OECD QSAR Toolbox v.3.4. According to these simulators, the main constituents (present at >5%) are primarily predicted to undergo ester hydrolysis as first metabolic reaction. For those constituents, which contain a free OH group (di-TMPTA and dimer di-TMPTA + di-TMPTTA + AA), thein vivorat metabolism simulator has predicted oxidation; it should be noted that oxidation is expected to occur immediately after the ester hydrolysis reaction. See the table in CSR for the reaction sites.

Conclusion:According to the simulators from OECD QSAR Toolbox, the main constituents (present at >5%) are primarily predicted to undergo ester hydrolysis and oxidation as first metabolic reactions.

DISTRIBUTION     

According to REACH guidance document R7.C (ECHA, 2017), the smaller the molecule, the wider the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores, although the rate of diffusion for very hydrophilic molecules will be limited. Further, if the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. 

Considering the physico-chemical information (i.e., MW, moderate lipophilicity and low water solubility) suggests that test substance could be distributed to highly perfused organs/tissues (i.e., liver, kidney), once absorbed and bioavailable. 

However, based on the log Kow <4.5 and predicted BCF values using BCFBAF v3.02 of EPI Suite^TMv.4.11 and BCF base-line model v.05.12 of LMC, the bioaccumulation potential of the substance is expected to be low. 

Conclusion:Based on all the available weight of evidence information, the test substance is likely to be distributed if absorbed, but with a low bioaccumulation potential.  

EXCRETION:     

Based on physicochemical properties:   

According to REACH guidance document R7.C (ECHA, 2017), the characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine (4.5 to 8). 

Given the physicochemical properties and MW, the test substance is likely to be excreted via faeces. However, there will also be urinary elimination following formation of water-soluble conjugates or metabolites via Phase II reactions. 

Conclusion:Based on all the available weight of evidence information, the test substance is expected to be excreted via both urine and faeces.    

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