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 witha low water solubility (ranging approximately from >0.1 to 100 mg/L) and low to moderate lipophilicity (with log Kowbetween ‑0.1 and 4.14). The mainconstituent, di- TMPTTA, present at 20 – 70%, has a molecular weight of 466 g/mol with a specific water solubility of 15 mg/Lat25°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 an 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	1.54E-03
dimer di-TMPTA + di-TMPTTA	0-15	0.079378	1.33E-03	1.06E-04
di-TMPTA	2-40	0.140966	7.22E-04	1.02E-04
di-TMPTTA + AA	0-15	0.107952	1.19E-03	1.28E-04
dimer di-TMPTA + di-TMPTA	0-12	0.035241	3.34E-04	1.18E-05
dimer di-TMPTA + di-TMPTTA + AA	0-10	0.030535	5.52E-04	1.69E-05
Trimer AA	0-10	0.022485	6.18E-04	1.39E-05
di-TMPDA	0-14	0.032446	3.37E-04	1.09E-05
dimer di-TMPTA + di-TMPDA	0-10	0.015085	1.56E-04	2.35E-06
Trimer AA + AA	0-5	0.012778	2.55E-04	3.26E-06
di-TMPTA + AA	0-5	0.023974	2.99E-04	7.17E-06
di-TMPMA	0-5	0.019105	8.46E-07	1.62E-08
Weighted average (WA)				1.94E-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 1.94E-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.

Based on predicted vapour pressure values for the individual constituents using EPISuite (v.4.11) and T.E.S.T (v.4.2) QSAR models, the test substance is considered to have low volatility under ambient conditions. However, should there be inhalation exposure during its handling and use conditions, considering the poor water solubility of the substance, the test substance not expected to be retained in the mucus and almost the entire test substance amount is likely to reach the lower respiratory tract followed by absorption into the blood stream.

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.

BIOACCUMULATION:

Based on low water solubility, log kow and the predicted BCF values together with other WoE discussed in section 4.3.3 of the CSR, both uptake and bioaccumulation potential are expected to be low.

EXCRETION:

Based on predicted metabolism and physico-chemical information, the main excretion pathway of the test substance is expected to be via urine.

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

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