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Description of key information

Key value for chemical safety assessment

Additional information

Data availability:

There are extensive data available for the methyl ester (MMA) and this has been reviewed in the EU Risk Assessment (2002). Sufficient data is available to confirm applicability of this data across all members of the category, including MAA, and this has been reviewed in the OECD SIAR (2009). Data on MAA, the common metabolite, has been reviewed in the EU Risk Assessment (2002). The following text relies on these reviews with any addition to the original documents is italicised. Due to the very short half-life of the parent ester in the body and ester hydrolysis being the first step in metabolism, several endpoints in the later parts of the assessment are satisfied by read-across to methyl methacrylate.

Trends/Results

Taken from the EU Risk Assessment on MAA: “Deposition of methacrylic acid vapours in the surgically isolated upper respiratory tract (URT) of anaesthetised rats was studied after inhalation of 450 μg/l (133 ppm) using a unidirectional respiratory flow technique (cyclic flow studies were not possible due to vapour absorption on the cyclic flow pump) for 60 min (Morris and Frederick, 1995). Deposition of methacrylic acid was measured throughout exposure determining the difference in vapour concentration of methacrylic acid in the inspired and the URT expiring air. Deposition rates (from 30 to 60 min of exposure) of about 95% were observed under 200 ml/min unidirectional flow conditions. However, the degree of penetration to underlying cells could not be derived from this experiment.”

 

Further from the EU Risk Assessment on MAA: “After a single oral administration of the sodium salt of methacrylic acid to Wistar rats (540 mg/kg bw) methacrylic acid was detected in the blood serum by means of HPCL. The maximum concentration was found after 10 min, whereas after 60 min no more methacrylic acid was detectable (Bereznowski et al., 1994).

There are no studies which specifically address the metabolism of exogenously applied methacrylic acid. However it is generally accepted that methacrylic acid-coenzyme-A is a naturally occurring intermediate of the valine pathway. Methacrylic acid-CoA is rapidly converted into (S)-3-hydroxyisobutyryl-CoA by the enzyme enoyl-CoA-hydratase. This pathway joins the citrate cycle, carbon dioxide, and water being the final products (Rawn, 1983; Shimomura et al., 1994; Boehringer, 1992).”

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 (McCarthy & Witz, 1991). For MAA, by analogy with acrylic acid and its esters, it can be predicted that the free carboxyl group will reduce the already low reactivity of methacrylates with GSH even further, so that GSH conjugation will only play an insignificant role in MAA metabolism, and then possibly only when very high tissue concentrations are achieved. Morris (1992) did not find any effect on GHS concentrations in URT tissues up to inhaled MAA concentrations of 410 ppm, a concentration which causes tissue damage in the URT in inhalation experiments.

 

Table: Summary of the results for the peak rates of absorption of MAA & alkyl methacrylate esters through rat & human epidermis

 

Rat epidermis

Human epidermis

Ester

Peak rate of absorption (μg cm-2hr-1) ±SEM

Period of peak absorption rate (hours)

% age of applied dose absorbed over x hours

Peak rate of absorption (μg cm-2hr-1) ±SEM

Period of peak absorption rate (hours)

% age of applied dose absorbed over x hours

MAA

23825±2839

0.5-4

93% / 24h

812

-

-

MMA

5888±223

2-8

46% / 16h

453±44.5

4-24

10% / 24h

EMA

4421

-

-

253

-

-

i-BMA

1418

-

-

80

-

-

n-BMA

1540±69

0-6

18% / 24h

76.7±9.8

0-24

2% / 24h

HMA

147

-

-

25

-

-

2EHMA

234±4.8

0-30

7.8% / 30h

22.7.7±3.7

3-24

0.6% / 24h

OMA

159±15

0-24

-

7.8

-

-

 Key: The values in normal type were obtained experimentally, whilst those in italics, are predicted values based on statistical analysis (single exponential fit) of the experimental data

 

Studies completed after the EU ESR on MAA indicate rapid absorption through skin and subsequent clearance from blood. Topically applied MAA absorbs rapidly through intact rat epidermis and viable whole skin in-vitro (Jones, 2002). In another study intravenous injection of MAA in rats demonstrated very rapid clearance from the blood (half-life <5mins), suggestive of rapid subsequent metabolism (Jones, 2002).

A comparison of measured blood concentration data after i.v. administration of 10 and 20 mg/kg MAA and a simulation based on a one-compartment model shows good agreement. 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 to 1.7 min.

Conclusions

MAA is readily absorbed by all routes and rapidly cleared from blood and, as indicated by studies with MMA, this metabolism is by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.

Local effects may be observed at the site of contact, because of the irritating/corrosive properties of MAA.

References quoted from the EU ESR on MAA, but not copied into the IUCLID dataset:

Boehringer (1992). Biochemical Pathways,.

Rawn DJ (1983). Biochemistry, catabolism of amino acids, succinyl-CoA family. Harper and Row Pub., 843-845.

Shimomura Y, Murakami T, Fujitsuka N, Nakai N, Sato Y, Sugiyama S, Shimomura N, Irwin J, Hawes JW, Harris RA (1994). Purification and partial characterization of 3-Hydroxyisobutyryl-Coenzyme-A hydrolase of rat-liver, J. Biol. Chem., 269, 14248-14253.