Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 202-613-0 | CAS number: 97-86-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Short description of key information on bioaccumulation potential result:
Methacrylate esters, including isobutyl 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:
Isobutyl methacrylate appears readily absorbed through rat and human epidermis, but human epidermis is 20 times less permeable to i-BMA 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
Data availability:
There is some basic information available on i-BMA for metabolism in vitro and in vivo, as well as dermal absorption data through rat and human skin. Furthermore, i-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, i-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 i-BMA (Freidig et al. 1999) and the isomer n-BMA (McCarthy et al. 1994) indicate that GSH conjugation is negligible. Hence, ester hydrolysis is considered to be the only significant metabolic pathway for i-BMA.
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 <5mins), suggestive of rapid subsequent metabolism (Jones, 2002).
Conclusions
I-BMA, like other short chain esters and MAA is absorbed by all routes. The rate of absorption decreases with increasing ester chain length so, in consequence 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 (see table above). The half life of i-BMA is still, however, in the order of minutes (7.4 min). 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.
As 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, an isomer of i-BMA, the NOAEC for this lesion is 310ppm compared with the NOAEC of 25ppm 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 i-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 byof, 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
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.