Methacrylic acid

Endpoint summary

Description of key information

MAA is expected to be readily absorbed by all routes. It will be rapidly cleared from blood and, after reaction with CoA, enters the standard physiological pathway of Valine catabolism, 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, more likely in rodents than in humans.

Additional information

Absorption

According to Jones (2002), the peak rate of dermal absorption occurred between 0.5 and 4 hrs, with 81% of the dose absorbed within this time period, when Methacrylic Acid (MAA) is applied onto the surface of rat epidermal membranes, with a calculated rate of diffusion of 23825 μg cm-2 hr-1. When applied to the whole rat skin, a peak rate of 4584 µg cm-2 hr-1 was determined for MAA between 5 and 8 hrs, with 36.5% of the dose absorbed within the first 8 hrs and almost 70% after 24 hrs. The rate of absorption is thus considered as extremely high. Based on the mentioned data from rat epidermis, the author calculated a predicted peak rate for human epidermis of 812 µg cm-2 hr-1 and for whole human skin of 327 µg cm-2 hr-1, respectively.

In order to understand interspecies differences in the local absorption of MAA after inhalative exposure and the respective potential for adverse local effects in different species, a hybrid computational fluid dynamics and physiologically based pharmacokinetic inhalation model was constructed based on modifications of a CFD-PBPK model for acrylic acid (Rohm & Haas 1998). This CFD-PBPK model predicted that whole-nose uptake of MAA would be 95% of the 20 ppm inhaled vapor concentration at a unidirectional flow rate of 200 ml/min. Simulated exposure of the human nasal cavity at a unidirectional flow rate of 18.9 and 35.0 L/min resulted in predicted whole nose uptake values of 78% and 74%, respectively, of the inhaled vapor concentration. A rapid inhalative absorption is concluded from the predicted whole-nose uptake of MAA.

The extensive uptake of MAA in the respiratory tract was also shown in an in vivo study in rats by Morris (1992; published as Morris & Frederick, 1995) that identified deposition rates (from 30 to 60 min of exposure) of about 95% under 200 mL/min unidirectional flow conditions in the surgically isolated upper respiratory tract (URT) of anaesthetised rats. The determination of the absorption of MAA to underlying cells could however not be determined with this study set-up, as stated in the EU Risk Assessment for MAA (2002).

Comparisons of predicted olfactory tissue concentrations of MAA following simulated exposure of rat, mouse, and human nasal cavities in the Rohm & Haas study (1998) indicated that under identical exposure conditions human olfactory tissue would have a 2-3 fold lower concentration of MAA than comparable rodent tissue. Conducting the same comparison except using human physiology associated with light physical activity resulted in a range of values based on the extent to which human oral breathing is included in the evaluation. At a reported average of 40% oral breathing at this workload, the human olfactory tissue concentration would be approximately one-half of the concentration of the comparable rat tissue, indicating a lower risk for adverse respiratory effects in humans.

Metabolism & Excretion

There are no specific metabolism studies available with exogenously applied MAA. However, it is generally accepted that the reaction product of MAA and the ubiquitous Coenzyme-A, Methacrylyl-CoA, is a naturally occurring intermediate in the valine pathway. Methacrylyl-CoA represents the third intermediate of this pathway and is rapidly converted into (S)-3-hydroxyisobutyryl-CoA by the enzyme enoyl-CoA-hydratase. Further metabolic intermediates are, below others, Propionyl-CoA, Methylmalonyl-CoA and Succinyl-CoA that joins the citrate cycle, with carbon dioxide and water being the final products (Rawn, 1983; Shimomura et al., 1994; Boehringer, 1992).

The toxicokinetic behaviour of MAA after single i.v. application to rats was studied by Jones (2002) with the purpose of validation of a PBPK model for MAA and its alkyl esters. He showed rapid clearance of MAA in the blood, indicated by concentrations below detection limits reached after 12 min (when dosed with 10 mg/kg bw) or 22 min (20 mg/kg bw). Jones calculated a systemic half-live of MAA in the rat of <5 min (namely, 2.9 minutes with a dose of 10 mg/kg bw and 4.1 minutes with 20 mg/kg bw) on the basis of the in vivo data. A simulation based on a one-compartment PBPK model shows good agreement with the in vivo data. 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; ( whereas SRW = standard rat weight = 250 g) and a calculated  t1/2 of MAA in blood to 1.7 min on the basis of the model.

This rapid clearance after MAA administration was supported by Bereznowski and coworkers (1994) that applied a single oral dose of 540 mg/kg bw sodium salt of MAA to Wistar rats (540 mg/kg bw). The maximum concentration of MAA was found in blood serum after 10 min by HPLC, whereas after 60 min no more MAA was detectable.

The understanding on the metabolic processes of MAA is supported by various metabolism studies with Methyl Methacrylate (MMA), the methanolic ester of MAA and, from a metabolism perspective, the metabolic precursor of MAA after rapid hydrolysis:

After oral administration of radiolabeled MMA to Wistar rats, 65% of the dose was exhaled as CO2 within 2 hr, 76-88% within 10 days, indicating a rapid clearance. Excreted metabolites, quantified as <2% of the dose,  in the urine were methacrylic acid, methyl malonic acid, and succinic acid. Metabolism and excretion of radiolabeled MMA were qualitatively the same after a single i.v. or i.p. administration to rats as after oral administration (Bratt and Hathway, 1977; ICI, 1977a; Crout et al., 1982). The rapid hydrolysis of MMA was documented by Jones 2002 in rats, with a systemic half-life of 4.4 min, and Crout et al. 1979 in humans, below others. This rapid hydrolysis justifies the use of MMA as read-across source substance for MAA, especially for the investigation of systemic effects, thereby bypassing potential severe local effects of the corrosive acid.

On a rather weak data basis, there are no indications that the conjugation with glutathione (GSH) is an important metabolic pathway for MAA. Morris (1992) did not find any effects on non-protein sulfhydryl (NPSH) levels in URT tissues up to inhaled MAA concentrations of 410 ppm, a concentration which causes tissue damage in the URT in inhalation experiments. NPSH levels were understood here as a sum parameter indicating direct reactivity of toxicants with reduced sulfhydryl compounds including GSH. For current QSAR models like the OECD Toolbox model v.4.1 of June 2021, it is “not possible to classify according to these [implemented] rules (GSH)” (Röhm 2021, personal communication) and in vitro information is not available (in contrast to its esters, where a comparatively low reactivity was documented, e.g. by McCarthy & Witz, 1991).

 

Distribution

Based on the aforementioned in vivo toxicokinetic data, Jones (2002) stated that “The concentration time profiles of the in vivo data show that MAA is distributed and cleared according to mono-exponential kinetics [reference to figures]. This implies that MAA is not extensively distributed to the various tissues and organs. […] … The most likely explanation for this […] very low tissue distribution of MAA is connected to its physical characteristics, and specifically its ionisation state in vivo. MAA has a pKa of 4.66 and at a pH of 7.4 would exist predominantly in its ionised form. […] Membranes because of their lipid nature are much less permeable to compounds in the ionised state; therefore MAA is likely to permeate these barriers less readily at physiological pH. Furthermore, MAA in its ionised form is likely to have decreased lipid solubility than in its non-ionised form. These characteristics combined appear to result in MAA possessing lower apparent tissue-blood partition coefficients than initially predicted. Since the tissue distribution of MAA is so limited, systemic build up of this chemical in any tissues is very unlikely to occur.”

 

Conclusions

MAA is expected to be readily absorbed by all routes. It will be rapidly cleared from blood and, after reaction with CoA, enters the standard physiological pathway of Valine catabolism, 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, more likely in rodents than in humans.

 

References not in the MAA IUCLID dataset

Boehringer (1992). Biochemical Pathways, Mannheim

Crout DHG, Lloyd EJ, Singh J (1982). Metabolism of methyl methacrylate: evidence for metabolism by the valine pathway of catabolism in rat and man. Xenobiotica 12, 821-829.

ICI (1977a). The biological fate of methylmethacrylate in rats; Rep. CTL/R/396 by Hathaway DE and Bratt H; Zeneca, Alderly Park, Macclesfield, Cheshire.

McCarthy TJ, Witz G (1991). Structure-activity relationships of acrylate esters: reactivity towards glutathione and hydrolysis by carboxylesterase in vitro. Adv. Exp. Med. Biol. 283, 333-335.

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.