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Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Basic absorption, distribution,metabolism and excretion (ADME), toxicokinetics

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 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.

Trends/Results

Taken from the EU Risk Assessment on MMA; “after oral or inhalation administration, methyl methacrylate is rapidly absorbed and distributed. In vitroskin absorption studies in human skin indicate that methyl methacrylate can be absorbed through human skin, absorption being enhanced under occluded conditions. However, only a very small amount of the applied dose (0.56%) penetrated the skin under unoccluded conditions (presumably due to evaporation of the ester from the skin surface (Syngenta/CEFIC, 1993)). After inhalation exposure to rats 10 to 20% of the substance is deposited in the upper respiratory tract where it is metabolized (by non-specific esterases to the acid, MAA (Morris, 1992)). 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 tissue concentrations (McCarthy and Witz, 1991; Elovaara et al., 1983) ”.

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

Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively). 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.

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, McCarthy et al., 1994, Tanii and Hashimoto, 1982). 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.

Studies completed after the MMA RA have confirmed that all short chain alkyl-methacrylate esters are rapidly hydrolysed by ubiquitous carboxylesterases (see table below, adapted from Jones; 2002). 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 (%LBF; see table below) resulting in their relatively rapid elimination from the body (T50%; see table below).

 

Table: Rate Constants for ester hydrolysis by rat-liver microsomes and predicted systemic fate kinetics following i.v. administration

Ester

Rat liver microsomes (100µg ml-1)

Vmax               Km    (nM min-1mg-1)

 M)

CL

(%LBF)

T50%(min)

Cmax(MAA)

(mg L-1)

Tmax(MAA)

(min)

MAA

-

-

51.6%

-

-

-

MMA

445.8

164.3

98.8%

4.4

14.7

1.7

EMA

699.2

106.2

99.5%

4.5

12.0

1.8

i-BMA

832.9

127.4

99.5%

11.6

7.4

1.6

n-BMA

875.7

77.3

99.7%

7.8

7.9

1.8

HMA

376.4

34.4

99.7%

18.5

5.9

1.2

2EHMA

393.0

17.7

99.9%

23.8

5.0

1.2

OMA

224.8

11.0

99.9%

27.2

5.0

1.2

 

HMA – hexyl methacrylate; OMA – octyl methacrylate. Fate kinetics determined using the “well-stirred” model; CL%LBF – Clearance as percentage removed from liver blood flow i.e. first pass clearance; T50%- time taken for 50% of parent ester to have been eliminated from the body; Cmax– maximum concentration of MAA in circulating blood; Tmax– time in minutes to peak MAA concentration in blood “Jones, 2002”.

 

Table: Summary of the results for the peak rates of absorption of MAA & alkylmethacrylate 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

 

In terms of MAA, the common metabolite for these esters, the following can be taken from the EU ESR: “Methacrylic acid is rapidly absorbed in rats after oral and inhalative administration. A high dose orally administered methyl methacrylate is rapidly hydrolyzed by esterases and the methacrylic acid concentration in the blood serum reached a very low level after one hour. In an inhalation study deposition efficiency of 95% was measured in the surgically isolated upper respiratory tract of anaesthetized rats (Morris and Frederick, 1995). However, the degree of penetration to underlying cells could not be derived from this experiment. There are no studies which specifically address the metabolism of exogenously applied methacrylic acid. ”

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).

Trends

Short chain esters and MAA are absorbed by all routes. The rate of absorption decreases with increasing ester chain length. All esters are rapidly hydrolysed in local tissues as well as in blood by non-specific esterases. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length (table 11). The primary metabolite, MAA, is cleared rapidly from blood in all cases.

Conclusions

MMA and the other methacrylate esters are readily absorbed by all routes and rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Clearance of the parent ester from the body is in the order of minutes. The primary metabolite, MAA, is subsequently cleared rapidly 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 resulting from the hydrolysis of the ester to MAA are only observed following inhalation exposure and this has been shown to be due to the localised concentration of non-specific esterases in nasal olfactory tissues. In summarising the available PBPK data on MMA SCOEL concluded that “ExtensivePBPK modeling work has predicted that on kinetic grounds for a given level of exposure to MMA human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA” (SCOEL, 2005).

Discussion on bioaccumulation potential result:

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 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.

Trends/Results

Taken from the EU Risk Assessment on MMA; “after oral or inhalation administration, methyl methacrylate is rapidly absorbed and distributed.In vitroskin absorption studies in human skin indicate that methyl methacrylate can be absorbed through human skin, absorption being enhanced under occluded conditions. However, only a very small amount of the applied dose (0.56%) penetrated the skin under unoccluded conditions (, presumably due to evaporation of the ester from the skin surface (CEFIC, 1993)). After inhalation exposure to rats 10 to 20% of the substance is deposited in the upper respiratory tract where it is metabolized (by non-specific esterases to the acid, MAA (Morris, 1992)). 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 tissue concentrations (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).

 

Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively). The carboxylesterasesare 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.

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, McCarthy et al., 1994, Tanii and Hashimoto, 1982). 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.

Studies completed after the MMA RA have confirmed that all short chain alkyl-methacrylate esters are rapidly hydrolysed by ubiquitous carboxylesterases (see table below, adapted from Jones; 2002). 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 (%LBF; see table below) resulting in their relatively rapid elimination from the body (T50%; see table below).

 

Table: Rate Constants for ester hydrolysis by rat-liver microsomes and predicted systemic fate kinetics following i.v. administration

Ester

Rat liver microsomes (100mg ml-1)

Vmax          Km(nM min-1mg-1)

      (mM)

CL

(%LBF)

T50%(min)

Cmax(MAA)

(mg L-1)

Tmax(MAA)

(min)

MAA

-

-

51.6%

-

-

-

MMA

445.8

164.3

98.8%

4.4

14.7

1.7

EMA

699.2

106.2

99.5%

4.5

12.0

1.8

i-BMA

832.9

127.4

99.5%

11.6

7.4

1.6

n-BMA

875.7

77.3

99.7%

7.8

7.9

1.8

HMA

376.4

34.4

99.7%

18.5

5.9

1.2

2EHMA

393.0

17.7

99.9%

23.8

5.0

1.2

OMA

224.8

11.0

99.9%

27.2

5.0

1.2

HMA – hexyl methacrylate; OMA – octyl methacrylate. Fate kinetics determined using the “well-stirred” model; CL%LBF – Clearance as percentage removed from liver blood flow i.e. first pass clearance; T50%- time taken for 50% of parent ester to have been eliminated from the body; Cmax– maximum concentration of MAA in circulating blood; Tmax– time in minutes to peak MAA concentration in blood “Jones, 2002”.

 

In terms of MAA, the common metabolite for these esters, the following can be taken from the EU ESR: “Methacrylic acid is rapidly absorbed in rats after oral and inhalative administration (Bereznowski et al., 1994).A high dose orally administered methyl methacrylate is rapidly hydrolyzed by esterases and the methacrylic acid concentration in the blood serum reached a very low level after one hour. In an inhalation study deposition efficiency of 95% was measured in the surgically isolated upper respiratory tract of anaesthetized rats (Morris and Frederick, 1995). However, the degree of penetration to underlying cells could not be derived from this experiment.There are no studies which specifically address the metabolism of exogenously applied methacrylic acid.

Studies completed after the RA 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).

Trends

Short chain esters and MAA are absorbed by all routes. The rate of absorption decreases with increasing ester chain length. All esters are rapidly hydrolysed in local tissues as well as in blood by non-specific esterases. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length (table 11). The primary metabolite, MAA, is cleared rapidly from blood in all cases.

Conclusions

MMA and the other methacrylate esters are readily absorbed by all routes and rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Clearance of the parent ester from the body is in the order of minutes. The primary metabolite, MAA, is subsequently cleared rapidly 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 resulting from the hydrolysis of the ester to MAA are only observed following inhalation exposure and this has been shown to be due to the localised concentration of non-specific esterases in nasal olfactory tissues. In summarising the available PBPK data on MMA SCOEL concluded that “ExtensivePBPK modeling work has predicted that on kinetic grounds for a given level of exposure to MMA human nasal olfactory epithelium will be at least 3 times less sensitive than that of rats to the toxicity of MMA” (SCOEL, 2005).