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Description of key information

Short description of key information on bioaccumulation potential result: 
Using a reliable experimental method, the in vivo and in vitro investigations as well as the PBPK models developed from the data showed that alkyl-methacrylate esters are rapidly absorbed and are hydrolyzed at exceptionally high rates to methacrylic acid by high capacity, ubiquitous carboxylesterases. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For n-BMA the half-life was 7.8 minutes and 99.7 % was removed by first-pass metabolism in the liver.
Methacrylate esters, including n-butyl methacrylate, 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.
Short description of key information on absorption rate:
The absorption of nBMA was evaluated through rat and human epidermis and through whole (viable) rat skin in an in vitro system. Glass diffusion cells are employed to measure the amount of n-BMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of nBMA to the epidermal surface. The mean rate of absorption was 1540, 76.7 and 40.9 (appearance of MAA) µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 18 (over 24 hours), 2 (over 24 hours) and 0.4% (over 10 hours), respectively. nBMA appears readily absorbed through rat and human epidermis, but human epideremis is 20 times less permeable to nBMA than rat epidermis.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
2

Additional information

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

 

For t-BMA is no data available for metabolism in vitro and in vivo. As a member of a category of lower methacrylate esters there is sufficient data available to confirm applicability of this data across all members of the category.

Data availability:

 

There is some basic information available for the structural analogue n-BMA for metabolism in vitro and in vivo, as well as dermal absorption through rat and human skin. Furthermore, n-BMA is a member of a category of lower methacrylate esters, of which 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

The OECD SIAR on short chain methacrylate esters concluded that: “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). In many regards, therefore, n-BMA behaves similarly to its close structural analogue MMA.

Taken from the EU Risk Assessment on MMA; “after oral or inhalation administration, methyl methacrylate is rapidly absorbed and distributed. In vitro skin 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) ”.

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). Data with n-BMA indicate that GSH conjugation is negligible (McCarthy et al. 1994). Hence, ester hydrolysis is considered to be the only significant metabolic pathway for n-BMA.  Therefore, 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 (including n-BMA), 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)

 (µM)

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, another study using intravenous injection of MAA in rats demonstrated very rapid clearance from the blood (half-life < 5min), suggestive of rapid subsequent metabolism (Jones, 2002).

 

Discussion on absorption rate:

The absorption of n-butyl methacrylate was evaluated through rat and human epidermis and through whole (viable) rat skin in anin vitrosystem (Jones, 2002). Glass diffusion cells are employed to measure the amount of n-BMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of nBMA to the epidermal surface. The mean rate of absorption was 1540, 76.7 and 40.9 (appearance of MAA) µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 18 (over 24 hours), 2 (over 24 hours) and 0.4% (over 10 hours), respectively.

Conclusion

 

n-BMA and as analogous substance t-BMA, like other short chain esters and MAA are absorbed by all routes. The rate of absorption decreases with increasing ester chain length so it will be absorbed less rapidly than MMA. All esters are rapidly hydrolysed in local tissues as well as in blood by non-specific esterases to methacrylic acid (MAA) and the respective alcohol. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length. The half life of n-BMA is still, however, in the order of minutes (7.8). 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.

Like with MMA, local effects resulting from the hydrolysis of the ester to MAA might be expected following inhalation exposure. In the case of MMA this has been shown to be due to the localised concentration of non-specific esterases in nasal olfactory tissues. In subacute inhalation studies with n-BMA the NOAEC for this lesion is 310 ppm compared with the NOAEC of 25 ppm for MMA, indicating lower reactivity in the nose. In the case of MMA SCOEL concluded that “Extensive PBPK modelling 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). This would suggest that humans are also less sensitive than rodents to the local inhalation effects of n-BMA.

 

References quoted from the EU ESR on MMA and other documents, but not copied into the IUCLID dataset:

 

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

CEFIC (1993). Methyl methacrylate: in vitro absorption through human epidermis: Ward RJ and Heylings JR, Zeneca Central Toxicology Lab., Unpublished study on behalf of CEFIC Methacrylates Toxicology Committee, Brussels

European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methacrylic Acid. European Union - Risk Assessment Report, Vol. 25, Doc. No. EUR 19837 EN

European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methyl methacrylate. European Union - Risk Assessment Report, Vol. 22. Doc. No. EUR 19832 EN

ECETOC (1995) Joint Assessment of Commodity Chemicals No 30 ; Methyl Methacrylate, CAS No. 80-62-6. European Centre for Ecotoxicology and Toxicology of Chemicals, Avenue Van Nieuwenhuyse 4, (Bte 6) B-1160,. ISSN-0773-6339-30

ECETOC (1996a) Joint Assessment of Commodity Chemicals No 35 ; Methacrylic acid, CAS No. 79-41-4. European Centre for Ecotoxicology and Toxicology of Chemicals, Avenue Van Nieuwenhuyse 4, (Bte 6) B-1160,. ISSN-0773-6339-35

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.Hext PM., Pinto PJ, Gaskell BA. (2001) Methyl methacrylate toxicity in rat nasal epithelium: investigation of the time course of lesion development and recovery from short term vapour inhalation. Toxicology 156: 119-128

FrederickCB (1998). Interim report on interspecies dosimetry comparisons with a hybrid computational fluid dynamics and physiologically-based pharmacokinetic inhalation model. Rohm and Haas Co.,.

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

Junge W, Krisch K (1975) The carboxylesterases/amidases of mammalian liver and their possible significance. Critical Reviews in Food Science and Nutrition, 371-434.Mainwaring G, Foster JR, Lund V, Green T (2001) Methyl methacrylate toxicity in rat nasal epithelium: Studies of the mechanism of action and comparisons between species. Toxicology 158, 109-118

Mainwaring G, Foster JR, Lund V, Green T (2001) Methyl methacrylate toxicity in rat nasal epithelium: Studies of the mechanism of action and comparisons between species. Toxicology 158, 109-118

Morris JB (1992). Uptake of Inspired Methyl Methacrylate and Methacrylic Acid Vapors in the Upper Respiratory Tract of the F344 Rat. Prepared by of, Univ. for US Methacrylate Producers Association (MPA).Washington, DC

OECD (2004) SIDS Initial Assessment Report for18: Short-Chain Alkyl Methacrylates; http://webnet.oecd.org/hpv/UI/handler.axd?id=1da0a7af-3b11-45b7-865f-acad8b19c6c3

 

Discussion on absorption rate:

The absorption of n-butyl methacrylate was evaluated through rat and human epidermis and through whole (viable) rat skin in an in vitro system (Jones, 2002). Glass diffusion cells are employed to measure the amount of n-BMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of nBMA to the epidermal surface. The mean rate of absorption was 1540, 76.7 and 40.9 (appearance of MAA) µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 18 (over 24 hours), 2 (over 24 hours) and 0.4% (over 10 hours), respectively.