2-propenoic acid, 2-methyl-, 4-benzoylphenyl ester

Endpoint summary

Description of key information

No experimental data on absorption, distribution, metabolism and excretion of BPMA are available.

Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the physico-chemical properties of the compound as well as data obtained in a basic data set.

 

Absorption

Based on physico-chemical properties, oral absorption by passive diffusion is plausible. Based on physico-chemical properties, dermal absorption is plausible. Based on low vapour pressure, inhalatory absorption is considered as not relevant due to low exposure.

 

Distribution

Physico-chemical properties of B

NMA indicates a moderate distribution in the body.

 

Bioaccumulation

Due to the well-known metabolism of methacrylate esters the bioaccumulation potential is considered as negliable.

 

Metabolism of Methacrylic esters

Ester hydrolysis by carboxylesterases has been established as the primary step in the metabolism of methacrylate esters. Methacrylic acid as one primary metabolite of BNMA is subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively).

 

Excretion

The majority of the methacrylic metabolite MAA is exhaled as CO2. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic Statement of 4-Benzoylphenyl methacrylate (BPMA)

 

General

No experimental data on absorption, distribution, metabolism and excretion of BPMA are available.

According to REACH, the human health hazard assessment shall consider the toxicokinetic profile (Annex I). However, generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACH Annex VIII, 8.8.1).

Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the physico-chemical properties of the compound as well as data obtained in a basic data set.

 

Absorption

The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information. Relevant acute oral toxicity, skin sensitisation and irritation as well as toxicity after repeated oral dosing was not observed with BPMA. No information on acute dermal or inhalatory toxicity is available. Thus, data from existing toxicity studies do not give any indication for the extend of absorption.

To be absorbed, the substance has to cross biological membranes, either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, and water solubility. In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log P values of - 1 to + 4) are favourable for membrane penetration and thus absorption. The molecular weight of BNMA is relatively moderate with 266 g/mol, favouring oral absorption of the compound; in addition, the substance is moderately lipophilic (log of 3.6) and water solubility is given (4 mg/L) indicating that absorption by passive diffusion is plausible (ECHA Guidance R.7c, 2017; Chapter R7.12.2.1). As a consequence for rsik assessment and DNEL calculation, the default rate of 50% for oral absorption is considered as plausible (ECHA Guidance R.8, 2012; Chapter R.8.4.2).

Dermal uptake is expected to be moderate at this molecular weight level (< 100: dermal uptake high; > 500: no dermal uptake). For dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. Therefore, at the water solubility level of 1-100 mg/L, dermal uptake is anticipated to be low to moderate. On the other hand the log P of 3.6 allows dermal absorption. As a conclusion, based on the discussed physico-chemical parameters, dermal absorption is considered as plausible and a default value of 50% skin absorption rate can be used for risk assessment (ECHA references see above).

For respiratory uptake it can be considered that generally liquids would readily diffuse/dissolve into the mucus lining. Thereby, lipophilic substances with moderate log P values (between - 1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. This is given for BPMA with a log P value of 3.6. However, the calculated vapour pressure is low (0.0056 Pa) so that inhalative exposure is not considered as relevant exposure route when compared with oral and dermal exposure. Although respiratory absorption is considered as not plausible, the default value of 100% respiratory absorption rate can be used for risk assessment as a worst case approach (ECHA references see above).

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. The molecular weight of 266 g/mol, the moderate water solubility of BNMA indicates a moderate distribution in the body. Through its lipophilic properties (log P > 0), BNMA is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissue.

The results of the toxicity studies identified no target organ toxicity (ECHA Guidance R.7c, 2017; Chapter R7.12.2.1).

 

Bioaccumulation

While the log P of BNMA is between 3 and 4 and thus not indicative for accumulation in fatty tissue ((ECHA Guidance R.7c, 2017; Chapter R7.12.2.1), it can be concluded from the well-known metabolism of methacrylate esters that the bioaccumulation potential is considered as negliable due to the assumed rapid hydrolysis by ubiquitous carboxylesterase enzymes (see below).

 

Metabolism of Methacrylic esters

Ester hydrolysis by carboxylesterases has been established as the primary step in the metabolism of methacrylate esters. For MMA and other short-chain alkyl-methacrylate mono esters extensive toxicokinetic data are available, for example in the EU Risk Assessment for MMA (2002) as well as the OECD SIAR for short-chain alkyl-methacrylate esters (EMA, n-BMA, i-BMA and 2-EHMA, 2009) which will serve as supportive information for BNMA with a more complex alcohol moiety.

Taken from the OECD SIAR: “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 (Satoh & Hosokawa, 1998; Junge & Krish, 1975; Bogdanffy et al., 1987; Frederick et al., 1994). 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.”

Taken from the EU Risk Assessment on MMA; “Activities of local tissue esterases of the nasal epithelial cells appear to be lower in man than in rodents (Green, 1996 later published as Mainwaring, 2001). Toxicokinetics seem to be similar in man and experimental animal. After arthroplasty using methyl methacrylate-based cements, exhalation of unchanged ester occurs to a greater extent than after i.v., i.p. or oral administration. After oral or parenteral administration methyl methacrylate is further metabolised by physiological pathways with the majority of the administered dose being exhaled as CO2 (Bratt and Hathway, 1977; ICI, 1977a). Conjugation with GSH or NPSH plays a minor role in methyl methacrylate metabolism and only occurs at high tissueconcentrations (McCarthy and Witz, 1991; Elovaara et al., 1983)”.

Taken from the OECD SIAR: “Other short chain alkyl-methacrylate esters, like MMA, are initially hydrolyzed by non-specific carboxylesterases to methacrylic acid and the structurally corresponding alcohol in several tissues (ECETOC 1995, 1996b).

Studies completed after the MMA RA have confirmed that all lower alkyl-methacrylate esters are rapidly hydrolysed by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. For example, no parent ester can be measured systemically following skin exposure to EMA and larger esters, as the lower rate of absorption for these esters is within the metabolic capacity of the skin (Jones, 2002). Parent ester will also be effectively hydrolysed within the G.I. tract and within the tissues of the upper respiratory tract (particularly the olfactory tissue). Systemically absorbed parent ester will be effectively removed during the first pass through the liver resulting in their relatively rapid elimination from the body.

Subsequent metabolism of the primary metabolites within the body

Again, taken from the OECD SIAR for methacrylate esters with smaller alkyl alcohol moieties: “Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively).”

In terms of MAA, the common metabolite for these esters a comparison of measured blood concentration data after i. v. administration of 10 and 20 mg/kg MAA was made and a simulation based on a one-compartment model shows good agreement (Jones, 2002). Based on that information, the following kinetic parameters were determined from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination (Vss = 0.039 L/SRW; Vmax = 19.8 mg/hr x SRW; Km = 20.3 mg/L; SRW: standard rat weight = 250 g) the half-life of MAA in blood was calculated as 1.7 min.

 

Excretion

The majority of the methacrylic metabolite MAA is exhaled as CO2. 

 

Literature

Bogdanffy MS, Randall HW, Morgan KT (1987). Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicology and Applied Pharmacology 88: 183-194.

Bratt H, Hathway DE (1977). Fate of methyl methacrylate in rats. Brit. J. Cancer 36, 114-119.

ECHA (2017). Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance v3.0, European Chemicals Agency, ECHA-17-G-11-EN, June 2017.

ECHA (2012). Guidance on Information Requirements and Chemical Safety Assessment Chapter R.8: Characterisation of dose [concentration]-response for human health v2.1, European Chemicals Agency, ECHA-2010-G-19-EN, Nov 2012.

Elovaara E, Kivistoe H, Vainio H (1983). Effects of methyl methacrylate on non-protein thiols and drug metabolizing enzymes in rat liver and kidneys. Arch. Toxicol. 52, 109-121.

European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methyl methacrylate. European Union - Risk Assessment Report, Vol. 22.

Frederick C. B., Udinsky J. R., Finch L (1994). The regional hydrolysis of ethyl acrylate to acrylic acid in the rat nasal cavity. Toxicology letters, 70: 49-56.

Jones O (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.