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Link to relevant study record(s)

Reference
Endpoint:
dermal absorption
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
1. SOFTWARE
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2. MODEL (incl. version number)
screening model according to Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663-669.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CC(=C)C(=O)OCC1CCCO1
molecular weight: 170.21 g/mol
log P: 1.35

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The physicochemical parameters of MW, Log P and saturated aqueous solubility have been used in the evaluation of 56 methacrylate compounds. An output of predicted steady-state flux has been calculated from modifications of the QSPeRs available for these compounds using the principles defined in the Potts and Guy prediction model.
The “Relative Dermal Absorption” potential assigned to the predicted skin flux for methacrylate data is an arbitrary estimation of skin penetration potential, and is not a regulatory or OECD approved classification. It is based on several hundred chemicals tested in the same human skin model at the Central Toxicology Laboratory and Dermal Technology Laboratory. This database includes a wide variety of pharmaceutical, agrochemical and industrial chemicals tested over a 20 year period. The dermal absorption potential of a particular chemical substance is placed into one of six categories based on its skin permeability coefficient or its predicted (or actual) absorption rate.

5. APPLICABILITY DOMAIN
The prediction model used in this investigation for a set of methacrylate chemicals is based on an established model (Potts and Guy, 1992), using data derived with human epidermal membranes.

6. ADEQUACY OF THE RESULT
If necessary, the prediction model and ranking of the methacrylate chemicals could be challenged using the INVEST (In Vitro Epidermal Screening Test), selecting a few at the high and low end of the ranking to determine the in vitro dermal penetration characteristics of specific chemicals in this series. This model is a rapid and costeffective screen using pig skin as a surrogate for human skin that has been used to rank examples from various chemical series. It is, of course, dependent on a suitable analytical method for the test chemical.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The physicochemical parameters of MW, Log P and saturated aqueous solubility have been used in the evaluation of 56 methacrylate compounds. An output of predicted steady-state flux was calculated using the principles defined in the Potts and Guy prediction model. (Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663- 669)
GLP compliance:
no
Details on test animals and environmental conditions:
not applicable; in silico modelling
Type of coverage:
other: not applicable; in silico modelling
No. of animals per group:
not applicable; in silico modelling
Absorption in different matrices:
predicted flux: 28.461 µg/cm²/h; the relative dermal absorption is moderate

Based on a molecular weight of 170.21 g/mol and a log Kow of 1.35, the predicted flux of THFMA is 28.461 µg/cm²/h; the relative dermal absorption is moderate.

Conclusions:
The dermal absorption of THFMA is predicted to be moderate; the predicted flux is 28.461 µg/cm²/h.
Executive summary:

The dermal absorption (steady-state flux) of THFMA has been estimated by calculation using the principles defined in the Potts and Guy prediction model.

Based on a molecular weight of 170.21 g/mol and a log Kow of 1.35, the predicted flux of THFMA is 28.461 µg/cm²/h; the relative dermal absorption is moderate.

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Description of key information

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

After oral or inhalation administration, methacrylate esters are expected to be rapidly absorbed via all routes and distributed. Dermal absorption of esters is extensive only with occlusion of the site. Heylings (2013) used a QSPeR model for whole human skin based on that described by Potts and Guy (1992) to predict the dermal penetration rate of a large number of methacrylate esters, including THFMA (Heylings, 2013). For THFMA a moderate rate of dermal penetration is predicted (28.5 µg/cm2/h).

Toxicokinetics seem to be similar in man and experimental animals. MMA and other short chain alkyl-methacrylate esters are initially hydrolyzed by non-specific carboxylesterases to methacrylic acid and the structurally corresponding alcohol in several tissues, including but not limited to liver, olfactory epithelium, stratum corneum and blood. This has been shown for linear alkyl esters, several ether methacrylates, diesters as well as cycloalkyl and –aryl esters (Jones 2002, DOW 2013, McCarthy and Witz, 1997). Because of the structural similarity of THFMA to the other esters rapid hydrolysis is expected in the order of minutes.

Methacrylic acid (MAA) is subsequently cleared predominantly via the liver (valine pathway and the TCA (Tricarboxylic Acid) cycle).

Fig. 1: see attachment

The carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin. Those organs and tissues that play an important role and/or contribute substantially to the primary metabolism of the short-chain, volatile, alkyl-methacrylate esters are the tissues at the primary point of exposure, namely the nasal epithelia and the skin, and systemically, the liver and blood.

Fig. 2: see attachment

For tetrahydrofurfuryl alcohol the following subsequent metabolism has been established (Zarnt et al. 1997 and 2001):

Fig. 3: see attachment

THF-alcohol -> THF-aldehyde -> THF-carboxylic acid

The resulting tetrahydrofuroic acid is either excreted directly via the kidneys, or – by analogy to the structurally similar furfuryl alcohol (Nomeir et al. 1992)– in the form of glycine and lysine conjugates.

Alternative(minor) pathway: GSH Conjugation

Methacrylate esters can conjugate with glutathione (GSH) in vitro, although they show a low reactivity, since the addition of a nucleophile at the double bond is hindered by the alpha-methyl side-group (Cronin2012, Freidig et al. 1999). Hence, ester hydrolysis is considered to be the major metabolic pathway for alkyl-methacrylate esters, with GSH conjugation only playing a minor role in their metabolism, and then possibly only when very high tissue concentrations are achieved.

References:

Abbott P.J et al. (2001) WHO Food Additives Series no. 46: Furfuryl Alcohol and Related Substances

Freidig AP, Verhaar HJM, Hermens JLM. 1999.Quantitative structure-property relationships for the chemical reactivity of acrylates and methacrylates. Environmental Toxicology and Chemistry 18(6), 1133 -1139.

Cronin M. 2012. QSAR prediction of Glutathione/Protein Binding Reactivity of Methacrylic Monomers. Unpublished Report on behalf of Higher Methacrylate REACH Task Force. Testing laboratory: Liverpool, John Moores University.

DOW. 2013. Methacrylate Esters: In Vitro Metabolism in Rat Blood and Liver Microsomes. Testing laboratory: Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674. Report no.: 120171. Study on behalf of Higher Methacrylate REACH Task Force, 17260 Vannes Court, Hamilton, VA 20158, USA.

Heylings JR (2012). Dermal technology laboratory Ltd. Med IC4, Keeke University Science and Business Park, Keele, Staffordshire, ST5 5NL UK. Unpublished report on behalf of Higher Methacrylates REACH Task Force. Testing laboratory: Dermal technology laboratory Ltd. Med IC4, Keeke University Science and Business Park, Keele, Staffordshire, ST5 5NL UK. Report no.: PV2206.

Jones, R. D .O. 2002. Using physiologically based pharmacokinetic modeling to predict the pharmacokinetics and toxicity of methacrylate esters. Thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medicine, Dentistry, Nursing and Pharmacy

McCarthy TJ, Witz G (1997). Structure-activity relationships in the hydrolysis of acrylate and methacrylate esters by carboxyesterase in vitro. Toxicology 116: 153-158.

Nomeir A A, D M Silveira, M F McComish and M Chadwick. 1992. Comparative metabolism and disposition of furfural and furfuryl alcohol in rats. Drug Metabol Disposition 20 (2) 198-204

Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663-669.

Summitt, C. B., Johnson, L. C., Jonsson, T. J., Parsonage, D., Holmes, R. P., Lowther, W. T. 2015. Proline dehydrogenase 2 (PRODH2) is a hydroxyproline dehydrogenase (HYPDH) and molecular target for treating primary hyperoxaluria. Biochem. J. 466: 273-281.

Zarnt, G., T. Schräder, and J. R. Andreesen. 1997. Degradation of tetrahydrofurfuryl alcohol by Ralstonia eutropha is initiated by an inducible pyrroloquinoline quinone-dependent alcohol dehydrogenase. Appl. Environ. Microbiol. 63:4891–4898.

Zarnt G., T. Schräder, J. R. Andreesen. 2001. Catalytic and molecular properties of the quinohemoprotein tetrahydrofurfurylalcohol dehydrogenase from Ralstonia eutropha strain Bo. J. Bacteriol. 183: 1954-1960.