Oligomerisation products of 2,2'-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bisoxirane with acrylic acid and lauric acid

Endpoint summary

Description of key information

Based on the available weight of evidence and experimental studies, the test substance is expected to be have a low to moderate absorption potential through oral route and a low absorption potential through dermal route. Based on QSAR predictions, it is likely to undergo ester hydrolysis as the first metabolic reaction and likely excreted via both faeces and urine. Further, based on the MW and key physico-chemical properties it is likely to have low bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Oral absorption

Based on physicochemical properties:

According to REACH guidance document R7.C (May 2014), oral absorption is maximal for substances with molecular weight (MW) 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 the reaction products of epoxy acrylate based on Bisphenol A diglycidyl ether (BADGE), acrylic acid and lauric acid. It is an UVCB with mono-, di-, tri- and tetrafunctionalised BADGE with acrylic and lauric acid. The molecular weights of the constituents range from 430 to 843 g/mol. The purified form of the substance appears as a colourless liquid. The test substance has a poor water solubility, based on the experimentally determined range of 9-43 mg/L for its major constituents. The log Kow value of 73% of the constituents was determined to be 2.52-3.52, suggesting moderate lipophilicity.

Given that the MW exceeds 500 for majority of the constituents combined with low water solubility, the test substance is likely to have low to moderate absorption potential.

Therefore, based on the R7.C indicative criteria, the test substance can be expected to have a low to moderate absorption potential from the gastrointestinal tract.

Based on (Q)SAR predictions:

The “Lipinski’s rule OASIS” profiler of the OECD QSAR Toolbox v.4.4.1, which describes the molecular properties important for a drug’s pharmacokinetics in the human body, predicted the major constituents (present at > 80%) to be ‘less bioavailable’. Therefore, the test substance can be overall considered to have a low absorption and bioavailability potential.

Based on experimental data on read across substances:

No experimental toxicokinetic studies were conducted on the read-across substance BADGEDA. However, the constituent acrylic acid, ethyl acrylate and other simple esters of acrylic acid have been shown to be absorbed rapidly from the gastro-intestinal tract.

 

Conclusion: Overall, based on the available weight of evidence information, the test substance can be expected to overall have a low to moderate absorption potential through the oral route. Nevertheless, as a conservative approach, a default value of 100% 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 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 a liquid, with a MW exceeding 100 g/mol, low water solubility and moderate log Kow (3.53), suggesting a less likelihood of high absorption potential.

Based on (Q)SAR predictions:

The two well-known parameters often used to characterise percutaneous penetration potential of substances are the dermal permeability coefficient (Kp) and maximum flux (Jmax). Kp reflects the speed with which a chemical penetrates across SC and Jmax represents the rate of penetration at steady state of an amount of permeant after application over a given area of SC. Out of the two, although Kp is more widely used in percutaneous absorption studies as a measure of solute penetration into the skin. However, it is not a practical parameter because for a given solute, the value of Kp depends on the vehicle used to deliver the solute. Hence, Jmax i.e., the flux attained at the solubility of the solute in the vehicle is considered as the more useful parameter to assess dermal penetration potential as it is vehicle independent (Robert and Walters, 2007).

In the absence of experimental data, Jmax can be calculated by multiplying the estimated water solubility with the Kp values from DERMWIN v2.02 application of EPI Suite v4.11. The calculated Jmax values for the different carbon chains of the UVCB substance was determined to be range between 5.78E-7 to 0.319 g/cm2/h, leading to a weighted average value of 0.321 g/cm2/h. As per Kroes et al., 2004 and Shen et al. 2014, the default dermal absorption for substances with Jmax ≤0.1 μg/cm2/h is less than 10%. Based on the individual or weighted average Jmax values, the test substance can be considered to have moderate absorption potential through the dermal route.

Based on experimental data on read across substances:

No experimental toxicokinetic studies were conducted on the read-across substance BADGEDA.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), other toxicity studies can be helpful to get information on occurrence of absorption without any specification of the extent or amount. For example: if signs of systemic toxicity in dermal studies indicate that absorption has occurred. Also, if the substance has been identified as a skin sensitizer then, provided the challenge application was to intact skin, some uptake must have occurred although it may only have been a small fraction of the applied dose.

An acute dermal toxicity study with the read-across substance BADGEDA in rats did not show any signs of systemic toxicity throughout the observation period, although lesions consistent with local irritation properties of the substance were observed. Dermal absorption of BADGEDA is expected to be slowed due to binding to skin of the acrylate group. However, the presence of skin sensitisation response in a local lymph node assay, suggests some uptake potential for the test substance, although it may only have been a small fraction of the applied dose.

Conclusion: Overall, based on the available weight of evidence information, the test substance can be expected to overall have a low absorption potential through the dermal route. Nevertheless, as a conservative approach, a default value of 100% (same as oral) 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 (<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 liquid physical state and an estimated low vapour pressure of 0.0107 Pa at 20°C, will not be available as particles or vapours for inhalation under ambient conditions. Of the inhalable fraction, due to the droplet size and the low water solubility, only some portion of the droplets are likely to be retained in the mucus and will not be available to reach the deeper lungs. The deposited droplets in the upper respiratory tract are expected to be absorbed at a relatively slower rate compared to the deeper lungs due to differences in vascularity. Some amount of these deposited droplets is also expected to be transported to the pharynx and swallowed via the ciliary-mucosal escalator. Therefore, the systemic uptake of the test substance via respiratory route can be considered to be similar or slightly higher compared to the oral route. However, scenarios that include spraying or situations where exposure at elevated temperatures/pressure may occur are not covered in this registration.

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

METABOLISM:

Based on identified literature:

No literature was identified in the publicly available domain regarding the metabolic profile of the substance or the read-across substance BADGEDA. However, evidence from other types of acrylates suggests that hydrolysis of the ester bond is likely to occur, producing acrylic acid and the corresponding alcohol, which are subsequently metabolised through normal metabolic routes. This hydrolysis is mediated by the ubiquitous tissues and circulating carboxylesterases. Another potential route of metabolism and detoxification may involve conjugation of the vinyl group with the sulfhydryl group of GHS, with excretion as mercapturates.

Based on (Q)SAR predictions: 

Q)SAR modelling tools such as the OECD QSAR Toolbox v.4..4.1 and SMARTCyp Web Service (Rydberg, 2013) allow the identification and prioritisation of metabolic pathways, which in turn allow in relative terms an assessment of whether chemically similar substances follow similar or different metabolic pathway.

The OECD QSAR Toolbox has been used to predict the first metabolic reaction, as the two metabolic simulators, in vivo rat metabolism simulator and rat liver S9 metabolism simulator, take into account hydrolysis as a Phase I metabolic reaction, while SMARTCyp is not powered enough for this type of reaction.

The two simulators of the OECD Toolbox predicted ester hydrolysis as the first metabolic reaction for all the constituents leading to the formation of acrylic acid and the corresponding alcohol derivative.

DISTRIBUTION  

Based on physico-chemical properties:

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 that the test substance has a low to moderate permeating potential due to its non-ionic nature, combined with its physico-chemical information (i.e., high MW, moderate lipophilicity and low water solubility) suggests that test substance would be distributed to many tissues, once absorbed and bioavailable. The estimated weighted average BCF (bioaccumulation factor) values of the test substance based on regression method and Arnot Gobus method were determined to be 171.34 (log BCF = 2.23) and 22.86 (log BCF = 1.36) L/kg ww respectively, indicating an overall low bioaccumulation potential.

Based on ‘other toxicity’ studies:

According to REACH guidance document R7.C (ECHA, 2017), identification of the target organs in repeated dose studies can be indicative of the extent of distribution.

A combined repeated dose oral toxicity with reproductive/developmental screening study available with the read across substance, BADGEDA (discussed in section 5.6) did not reveal any signs of toxicity either in the macroscopic or microscopic observations. 

Conclusion: Based on all the available weight of evidence information, the test substance is expected to have a distribution potential, but it is not likely to bioaccumulate. 

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 low water solubility, MW exceeding 300 g/mol and non-ionic structure, the non-metabolised test substance is not expected to be excreted via urine. Following metabolism, however, the water-soluble metabolites would be excreted via urine. Also, as the oral absorption of the test substance is assumed to be low to moderate, the unabsorbed portion would be excreted unchanged by faeces.

Based on experimental data on read across substances:

No toxicokinetic study was conducted with the substance or the read-across substance BADGEDA.

Conclusion: Based on the available weight of evidence, excretion of the non-metabolised substance would be primarily via faeces, whereas the water-soluble metabolites are expected to be primarily excreted via urine. 

Publications not presented in reference list under Annex 1

 Kroes R et al., 2004. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem. Toxicol. 42:65-83.

European Chemicals Agency (ECHA), 2017. Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c. Endpoint specific guidance. Version 3.0. June 2017

Roberts MS and Walters KA, 2007. Dermal absorption and toxicity assessment. CRC Press; 2007 December 14.

Rydberg P et al., 2013. The contribution of atom accessibility to site of metabolism models for cytochromes P450. Molecular Pharmaceutics 10 (4):1216-1223.

Shen J et al., 2014. An in silico skin absorption model for fragrance materials. Food Chem. Toxicol. 74:164-176.