2,3-dihydroxypropyl methacrylate

Endpoint summary

Description of key information

Experimental studies on toxicokinetics are not available. Based on molecular structure, molecular weight, water solubility and octanol-water partition coefficient it can be expected that 2,3 -dihydroxypropyl methacrylate is likely to be absorbed via the oral route. The potential for dermal absorption is considered to be medium to low. Systemic bioavailability is considered negligible after inhalation of vapours, but may be relevant after inhalation of aerosols. Metabolism of 2,3 -dihydroxypropyl methacrylate to methacrylic acid and glycerol will likely occur at the sites of first contact by carboxyesterases. Both metabolites are expected to be widely distributed in the organism, and, due to its log Pow, methacrylic acid is expected to be lipophilic enough to distribute into cells. Accumulation in the body is not favourable for 2,3 -dihydroxypropyl methacrylate and its metabolites. The primary metabolites are expected to enter standard physiological pathways.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of 2,3-dihydroxypropyl methacrylate (CAS 5919-74-4) has been investigated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of REACH (Regulation (EC) No. 1907/2006) and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of 2,3-dihydroxypropyl methacrylate was conducted to the extent that can be derived from relevant available information on physico-chemical and toxicological properties of the test substance itself as well as of its potential enzymatic degradation products.

 

Physico-chemical properties

2,3-dihydroxypropyl methacrylate is a light yellow liquid at 20°C with a molecular weight of 160.17 g/mol. The log Pow was estimated to be -0.12 at 23°C and pH of 6.2. Due to rapid spontaneous polymerisation, no vapour pressure could be determined. 2,3-dihydroxypropyl methacrylate was thermally unstable despite the addition of several polymerisation inhibitors. The substance is miscible with water at room temperature (23°C) and at 20°C ± 5°C at any rate. In a hydrolysis study according to OECD 111, 2,3-dihydroxypropyl methacrylate was shown to be stable at pH 4 and 7. At pH 9, the estimated half-life was approx. 7 days at 25°C. Therefore, at physiological pH of the gastro-intestinal tract, especially under acidic conditions in the stomach (approx. 2), and of the skin (approx. 5.5) hydrolysis may not play a role in the toxicokinetic behaviour of the substance.

In their publication on the “Toxicological assessment of lower alkyl methacrylate esters by a category approach” Gelbke et al. (2018) state that “all short chain methacrylate esters are hydrolysed by carboxyesterases that are widely distributed throughout the body and have a high activity within many tissues”. Among the relevant tissues, the authors name “the liver, blood, gastro-intestinal tract, nasal epithelium and skin”. This statement could be confirmed for several short-chain alkyl methacrylates (methyl methacrylate, ethyl methacrylate, i-butyl methacrylate, n-butyl methacrylate and 2-ethylhexyl methacrylate), as well as two additional methacrylates (hexyl methacrylate, octyl methacrylate) which were rapidly hydrolysed in “the olfactory and nasal respiratory tract, the blood, skin and liver of rats and humans” (Jones, 2002, as cited from Gelbke et al. 2018). It is highly probable that metabolism of 2,3-dihydroxypropyl methacrylate follows the same pathway, namely enzymatic hydrolysis, even though no experimental information on the expected half-life is available. The common metabolite for all methacrylate esters is methacrylic acid (CAS 79-41-4). The second primary metabolite is the corresponding alcohol, namely glycerol (CAS 56-81-5) in case of 2,3-dihydroxypropyl methacrylate.

The molecular weights of the primary metabolites methacrylic acid and glycerol are 86.06 and 92.094 g/mol, respectively. Both substances were demonstrated to be soluble in water, with water solubilities of 98 g/L at 20°C for methacrylic acid (ECETOC, 2012, as cited from Gelbke et al., 2018) and 1000 g/L (Episuite, WsKowwin v.1.42, 2021). As the primary metabolites are smaller in size than the parent compound and, due to their high water solubility a comparable or even greater absorption potential through biological membranes is considered to occur compared to the parent compound. In regard to the high water solubilty, passage through aqueous pores or carriage through the epithelial barrier by the bulk passage of water seems likely. The log Pow values for both substances are moderate to low at 0.93 (methacrylic acid, ECETOC, 2012, as cited from Gelbke et al., 2018) and -1.652 (glycerol, Episuite, Kowwin v1.68, 2021).

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral:

The smaller the molecule, the more easily it will be taken up. In general, substances with a molecular weight < 500 g/mol and with a log Pow between -1 and 4 are favourable for oral absorption by passive diffusion.

The low molecular weight of the parent (160.17 g/mol) and primary metabolites (86.06 and 92.094 g/mol) combined with the water solubility of parent and metabolites (approx. 100 mg/L or higher) suggest that 2,3-dihydroxypropyl methacrylate and its metabolites are favourable for absorption via the gastrointestinal (GI) tract. Due to the low size, all three compounds have the potential to pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. The log Pow of the substances (-0.12 for the parent compound and 0.93 for methacrylic acid and -1.652 for glycerol) suggest that the absorption occurs by passive diffusion.

There is one acute oral toxicity study (BSL Bioservice, 2009a) and an oral repeated dose toxicity study with a reproductive and developmental toxicity screening test available for2,3-dihydroxypropyl methacrylate(Envigo CRS Limited, 2018), both of them indicating that oral absorption must have occurred. In the acute oral toxicity study (BSL Bioservice, 2009a), piloerection, apathy, recumbency and half-eyelid closure were noted at 2000 mg/kg bw within the first 2-3 hours post-dosing. The effects were fully reversible. There were no treatment-related effects on the body weight development and no macroscopical findings at scheduled necropsy. The LD50 was > 2000 mg/kg bw. In the oral repeated dose toxicity study with a reproductive and developmental toxicity screening test (Envigo CRS Limited, 2018),two females receiving 500 mg/kg bw/day were killed for welfare reasons due to poor clinical condition: the major factor contributing to the deterioration in the clinical condition of both females was aspiration pneumonia. Another female was found dead but the cause of death could not be determined. Small mean body weight losses were recorded in unpaired females during the first week of treatment at 150 or 500 mg/kg bw/day and food intake was marginally lower at 500 mg/kg bw/day. Body weight gain at 500 mg/kg bw/day was decreased during Days 14-20 of gestation to Day 4 of lactation and overall food intake during lactation was reduced. The analysis of organ weights performed after five weeks of treatment in males and on Day 14 of lactation in females revealed marginally but statistically significantly increased relative kidney weights in males and females (110% and 118% of control, respectively), liver weights in males (113% of control) and brain weights in females (106%) at 500 mg/kg bw/day (adjusted for body weight). A reduced mean number of implantations and litter size were observed at the same dose level of 500 mg/kg bw/day. The NOAEL for systemic effects as well as for reproduction and for development was 150 mg/kg bw/day.

Overall, systemic bioavailability of 2,3-dihydroxypropyl methacrylate and its primary metabolites is considered likely after oral uptake of the substance.

 

Inhalation:

2,3-dihydroxypropyl methacrylate is a liquid. Due to its thermal instability, no vapour pressure could be determined. Therefore, the potential for exposure to vapours and subsequent absorption via inhalation during normal use and handling is considered to be negligible.

Based on the results by Jones (2002, as cited from Gelbke et al. 2018), in case of exposure to an aerosol derived from 2,3-dihydroxypropyl methacrylate, it is likely that ester hydrolysis to methacrylic acid and glycerol would occur at the site of first contact (olfactory and nasal respiratory tract). With regard to exposure to methacrylic acid, local irritant effects are expected to be the predominant effects due to the substance’s corrosive properties. Local tissue destruction of the respiratory epithelium by the corrosive primary metabolite could potentially increase absorption and systemic bioavailability of 2,3-dihydroxypropyl methacrylate and its primary metabolites after aerosol exposure. The moderate log Pow values of parent and metabolites (between -1 and 4) indicate the potential for absorption directly across the respiratory tract epithelium by passive diffusion.

In summary, systemic bioavailability of 2,3-dihydroxypropyl methacrylate and its primary metabolites in humans is considered negligible after inhalation of vapours, but may be relevant after inhalation of aerosols.

 

Dermal:

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin (ECHA, 2017). Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The estimated values for water solubility (miscible) and log Pow (-0.12), as well as the moderate molecular weight (160.17 g/mol) of 2,3-dihydroxypropyl methacrylate suggest that absorption via the dermal route is possible, but may be low as its poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. The dermal permeability coefficient (Kp) for the substance can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (EpiSuite, 2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

Using the QSAR DERMWIN tool for calculations, the permeability constant Kp is 1.67E-04 cm/h (DERMWIN v2.00, 2009), predicting a high dermal absorption potential based on a flux of 167.4 µg/cm²/h and considering a water solubility of 1 x 10⁶mg/L (ranking based on Kroes et al., 2007).

Experimental studies following the dermal route of exposure, i.e. acute dermal toxicity, skin irritation and skin sensitisation, can provide further information of the potential bioavailability of the substance after dermal application. There is one acute dermal toxicity study available for 2,3-dihydroxypropyl methacrylate in which groups of male and female Wistar rats were treated with the test substance under semi-occlusive conditions at 2000 mg/kg bw (Envigo Research Limited, 2017). No mortality, clinical signs or skin irritation were reported. No or limited toxicity might not only indicate limited dermal absorption of 2,3-dihydroxypropyl methacrylate but may also be related to low dermal toxicity following acute exposure. Further, no irritating properties of 2,3-dihydroxypropyl methacrylate were observed in the skin irritation study (Manabe et al., 1990). However, in the murine local lymph node assay (LLNA) according to OECD 429 (BASF SE, 2017c), application of the undiluted test substance led to a considerable loss in body weights of the treated mice which is considered a sign of systemic toxicity indicating dermal absorption of 2,3-dihydroxypropyl methacrylate. No irritation, but a borderline increase in³H-thymidine incorporation was observed in the high-dose group.

Overall, taking all available information into account, dermal absorption potential of 2,3-dihydroxypropyl methacrylate is considered possible with medium to high dermal penetration rates.

 

Distribution and accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues (ECHA, 2017).

As discussed before, 2,3-dihydroxypropyl methacrylate is expected to be rapidly hydrolysed in “the olfactory and nasal respiratory tract, the blood, skin and liver of rats and humans” (Jones, 2002, as cited from Gelbke et al. 2018) by carboxyesterases to the primary metabolites methacrylic acid (CAS 79-41-4) and glycerol (CAS 56-81-5). Based on their good water solubility, low molecular weight (86.06 and 92.094 g/mol), and moderate to low logPow values (0.93 and -1.652), the primary metabolites are expected to readily diffuse through aqueous channels and pores and that they will distribute widely through the body after absorption has occurred. Substances absorbed from the GI tract will be transported via the portal vein to the liver, where further metabolism can take place. Substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before they are transported to the liver where metabolism will take place.

Furthermore, the log Pow of 0.93 of methacrylic acid indicates that it is lipophilic enough to distribute into cells and the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues.

Substances with log P values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance (ECHA, 2017). Based on the prediction of enzymatic hydrolysis of the parent 2,3-dihydroxypropyl methacrylate at the site of first contact to the primary metabolites methacrylic acid and glycerol, accumulation in the body is considered unlikely. Methacrylic acid will be further metabolised by standard physiological pathways to the final products carbon dioxide and water (EU Risk Assessment Report, 2002). Glycerol is considered one of the end products of lipid metabolism and one of the degradation products of glucose metabolism. It is a building block for lipid synthesis (Lehninger, 1970).

 

Metabolism

Biotransformation is one of the main factors, which influence the fate of a substance in the body, its toxicity, and its rate and route of elimination.

In their publication on the “Toxicological assessment of lower alkyl methacrylate esters by a category approach” Gelbke et al. (2018) state that “all short chain methacrylate esters are hydrolysed by carboxyesterases that are widely distributed throughout the body and have a high activity within many tissues”. Among the relevant tissues, the authors name “the liver, blood, gastro-intestinal tract, nasal epithelium and skin”. This statement could be confirmed for several short-chain alkyl methacrylates (methyl methacrylate, ethyl methacrylate, i-butyl methacrylate, n-butyl methacrylate and 2-ethylhexyl methacrylate), as well as two additional methacrylates (hexyl methacrylate, octyl methacrylate) which were rapidly hydrolysed in “the olfactory and nasal respiratory tract, the blood, skin and liver of rats and humans” (Jones, 2002, as cited from Gelbke et al. 2018). It is highly probable that metabolism of 2,3-dihydroxypropyl methacrylate follows the same pathway, even though no experimental information on the expected half-life is available. The common metabolite for all methacrylate esters is methacrylic acid (CAS 79-41-4). The second primary metabolite is the corresponding alcohol which is glycerol (CAS 56-81-5) in case of 2,3-dihydroxypropyl methacrylate.

This prediction of the main potential metabolites following enzymatic transformation and breakdown was further substantiated using the QSAR OECD toolbox v4.4 (2020). This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the GI tract. The simulation was performed with the “Hydrolysis simulator (acidic)” and the “in vivo Rat metabolism simulator”.

 

Excretion

The low molecular weight (< 300 g/mol) and good water solubility of 2,3-dihydroxypropyl methacrylate suggest excretion by the kidneys into the urine. The primary metabolites methacrylic acid and glycerol are expected to enter standard physiological pathways either leading to complete breakdown (methacrylic acid) or recirculation as building block (glycerol).

 

 

 

References

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.

 

EU Risk Assessment Report (2002). Methacrylic acid. Volume 25, 2002; online available athttps://op.europa.eu/en/publication-detail/-/publication/daa6fcca-a7e7-11e7-837e-01aa75ed71a1/language-en/format-PDF/source-215941333

 

Gelbke H-P, Ellis-Hutchings R, Müllerschön H, Murphy S, Pemberton M (2018). Toxicological assessment of lower alkyl methacrylate esters by a category approach. Regulatory Toxicology and Pharmacology 92: 104-127 

 

Jones RDO (2002). Using physiologically based pharmacokinetic modelling to predict the pharmacokinetics and toxicity of methacrylate esters. A thesis submitted to Univ. of Manchester for the degree of Doctor of Philosophy.

 

Kroes et al. (2007). Food Chem Toxicol 45: 2533-2562

 

Lehninger AL (1970). Biochemistry: The molecular basis of cell structure and function. Worth Publishers, Inc, NY.

 

OECD (2020). (Q)SAR Toolbox v4.4. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Prediction performed August 2021. http://toolbox.oasis-lmc.org/?section=overview

 

US EPA (2021). EPISuite Estimation Programs Interface Suite^TMfor Microsoft Windows.