2-Propenoic acid, reaction products with dipentaerythritol

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 and dermal routes and primarily excreted via urine. Based on QSAR predictions, it is likely to undergo aliphatic hydroxylation as the first metabolic reaction. 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 DPHA is the reaction products of dipentaerythritol with acrylic acid. It is an UVCB with dimeric and trimeric esters of pentaerythritol with acrylic acid along with Michael adducts. The molecular weights of the constituents range from 470 to 1174 g/mol (weighted average = 271.6 g/mol). The purified form of the substance appears as a yellowish liquid. The test substance has a low water solubility, based on the experimentally determined range of 6-80 mg/L for its major constituents. The log Kow value of 75% of the constituents was determined to be ≤3.44.

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 constituents with C8-C14 alkyl chains (present at ca. 80%) to be ‘bioavailable’ and the constituents with C16-C18 and C18-unsatd. alkyl chains (present at ca. 20%) to be ‘less bioavailable’. Therefore, the test substance can be overall considered to have a moderate absorption and bioavailability potential.

Based on experimental data on read across substances:

No experimental toxicokinetic studies were conducted on the read-across substance PETIA, however, weight of evidence from studies with the constituent alcohol and acid (pentaerythritol and acrylic acid) provide information about the toxicokinetic behaviour.

Pentaerythritol alone has been shown to be taken up and eliminated rapidly in testing with animals and humans. In dogs, 69% of 14C pentaerythritol administered orally was excreted unchanged in 24 h urine, the rest in feces. A later review identified the kinetics as first order and apparently dose-independent. Feeding studies in humans revealed that about 85% of pentaerythritol fed was eliminated unchanged in urine. Elimination was essentially complete within 30 h. Acrylic acid, ethyl acrylate and other simple esters of acrylic acid have also been shown to be absorbed rapidly from the gastro-intestinal tract.

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 are present in acute or repeated dose studies, then absorption has occurred. Also coloured urine and/or internal organs can provide evidence that a coloured substance has been absorbed.

An OECD Guideline 422 repeated dose and reproductive/development toxicity screening study conducted with the read across substance PETIA in rats, showed signs of systemic toxicity at doses >75 mg/kg bw/day, suggesting a likelihood of absorption to a certain extent.

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. Therefore, as a conservative approach, a 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 solid, with a MW exceeding 100 g/mol, low to moderate water solubility and moderate log Kow (3.44), 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; Log Kp = -2.80 + 0.66 log kow – 0.0056 MW) 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 0.044 to 66.3 μg/cm2/h, leading to a weighted average value of 5.54 μg/cm2/h. As per Kroes et al., 2004 and Shen et al. 2014, the default dermal absorption for substances with Jmax between >0.1 to ≤10 μg/cm2/h can be considered to be less than 40%. Based on the weighted average Jmax value, 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 PETIA.

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 and a 14-week dermal repeated dose toxicity study conducted with the read-across substance PETIA 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 PETIA is expected to be slowed due to binding to skin of the acrylate group. This is supported by the observations made for acrylic acid, ethyl acrylate and other simple esters of acrylic acid.

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 dermal route. Therefore, as a conservative approach, a 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 predicted low vapour pressure of 1.34E-4 Pa at 20 °C, will not be available as particles or vapours for inhalation under ambient conditions. Therefore, the substance will neither be available for inhalation as vapours nor as aerosols. 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. Therefore, 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 DPHA or the read-across substance PETIA. 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 Toolbox v 4.4.1 and FAME/FAME 2/ FAME 3 (Kirchmair et al., 2013; Sicho et al., 2017; Sicho et al., 2019) allow the identification and prioritisation of Phase I metabolic pathways, which in turn allow in relative terms an assessment whether chemically similar substances follow similar or different metabolic pathways.

The OECD Toolbox was used to predict the first metabolic reaction, as two metabolic simulators (in vivo rat metabolism simulator and rat liver S9 metabolism simulator) take into account amide hydrolysis as a Phase I metabolic reaction. The results were compared with the output generated from FAME 3 model, which represents the third generation of the FAst MEtabolizer program. FAME (FAst MEtabolizer) is a fast and accurate predictor of sites of metabolism (SoM) which is based on a collection of random forest models trained on diverse chemical data sets of more than 20000 molecules annotated with their experimentally determined SoMs. It is not limited to a specific enzyme family or species. Besides a global model, dedicated models are available for human, rat, and dog metabolism; specific prediction of phase I and II metabolism is also supported (Kirchmair et al., 2013). FAME3 allows the prediction of both phase 1 and phase 2 SoMs (Sicho et al., 2019).

Based on predictions from the two simulators of the OECD Toolbox, FAME and expert judgement, ω and ω-1 aliphatic hydroxylation was predicted to be the first metabolic reactions for the representative structure of the test substance (see below Table). Hydrolysis of the amide bond to release the free alkanolamine does not seem to be a preferred metabolism path.

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, high lipophilicity and low water solubility) suggests that test substance would be distributed to many tissues, once absorbed and bioavailable. However, based on the predicted BCF values, which ranges from 3.16-836 L/kg ww (weighted average = 138.44 L/kg ww) using the BCFBAF v3.01 program of EPI Suite^TM v.4.1, the bioaccumulation potential of the substance is expected to be low.

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, PETIA (discussed in section 5.6) showed histopathologic alterations in the non-glandular stomach (as a result of local irritation), hypertrophy of the zona fasciculata of the adrenal cortex and lymphoid depletion in both high dose males and females (Stump, 2011). 

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 DPHA 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 DPHA or the read-across substance PETIA.

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