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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Objective of study:
metabolism
Principles of method if other than guideline:
Determination of half-life in blood after i.v. application
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
Fischer 344
Sex:
male
Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
Single i.v. injections of 10 or 20 mg/kg at a dosing volume of 2 ml/kg in physiological saline
No. of animals per sex per dose:
2 at 10 mg/kg
3 at 20 mg/kg
Control animals:
no
Details on study design:
A series of in vitro and in vivo studies with a series of methacrylates were used to develop PBPK models that accurately predict the metabolism and fate of these monomers. This study segment was performed in order to validate the model.
Details on dosing and sampling:
Blood samples were taken at defined intervals post-dosing. Not more than 10 % of the total average blood volume were taken.
Toxicokinetic parameters:
half-life 1st: 1.7 min
Toxicokinetic parameters:
other: Vmax = 19.8 mg/ hr * SRW
Remarks:
SRW = standard rat weight (250 g)
Toxicokinetic parameters:
other: km = 20.3 mg/L

Non-compartmental analysis of the blood concentration data for MAA at the two doses, gives volumes of distribution of 23 ml (10 mg kg-1) and 35 ml (20 mg kg-1). The clearance of MAA was calculated to be 0.324 L hr-1 SRW-1 at the 10 mg kg-1 dose and 0.25 L hr-1 SRW-1 at the 20 mg kg-1 dose. The change in clearance from the lower dose to the higher dose indicates non-linear saturable metabolism in the rat.

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/hrxSRW; 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:
In conclusion, from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination the half-life of MAA in blood was calculated to 1.7 min.
Executive summary:

The PBPK model data were validated by i.v. administration of MAA in rats and subsequent analysis of blood from the tail vein.

In conclusion, from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination, the half-life of MAA in blood was calculated to 1.7 min.

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
other: adsorption and development of analytical method
Principles of method if other than guideline:
The test material was administered by gavage and analytically determined in blood
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Sex:
not specified
Details on test animals and environmental conditions:
The test animals weighed 3-400 g
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
2 ml of the test substance were administered as a 1 M aqueous solution.
Duration and frequency of treatment / exposure:
Animals were sacrificed at various(not specified) times after administration and blood was collected for determination of MAA.
Details on dosing and sampling:
Analysis by HPLC/UV-VIS; detection at 210/240 nM
LoQ: 0.5 µM
Conclusions:
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 HPLC. The maximum concentration was found after 10 min, whereas after 60 min no more methacrylic acid was detectable.
Executive summary:

The presence of methacrylic acid (quantity not determined) was reported in Wistar rat blood serum 10 min after oral gavage administration of 2 ml of a 1 M solution of sodium methacrylate. After 60 min MAA could not anymore be detected in the blood serum (detection limit 0.5 µmol/l).

Endpoint:
basic toxicokinetics, other
Remarks:
(Q)SAR
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
1. SOFTWARE OECD toolbox
2. SMILES USED AS INPUT FOR THE MODEL CC(=C)C(=O)OCCOC(=O)C(=C)C
Principles of method if other than guideline:
Protein/GSH reactivity modelling with OECD Toolbox
GLP compliance:
no

The algorithm of the OECD toolbox has been used to predict GSH/protein reactiviry.

Test Chemical / Compound Identity

Acronym

SMILES

Molecular Weight

Protein Binding Potency

2-ethylhexyl methacrylate

EHMA

O=C(OCC(CCCC)CC)\C(=C)C

198.3

Slightly reactive (GSH) >> Methacrylates (MA)

ethyl methacrylate

EMA

CCOC(=O)C(=C)C

114.14

Slightly reactive (GSH) >> Methacrylates (MA)

isobutyl methacrylate

iBMA

CC(C)COC(=O)C(=C)C

142.2

Slightly reactive (GSH) >> Methacrylates (MA)

Methacrylic acid

MAA

CC(=C)C(=O)O

100.12

No alert found

Methyl methacrylate

MMA

CC(=C)C(=O)OC

100.12

Slightly reactive (GSH) >> Methacrylates (MA)

n-butyl methacrylate

nBMA

CCCCOC(=O)C(=C)C

142.2

Slightly reactive (GSH) >> Methacrylates (MA)

n-Hexyl methacrylate

n-HMA

CCCCCCOC(=O)C(=C)C

170.25

Slightly reactive (GSH) >> Methacrylates (MA)

ter-Butyl Methacrylate

tBMA

CC(=C)C(=O)OC(C)(C)C

142.2

Slightly reactive (GSH) >> Methacrylates (MA)

Diethylaminoethyl methacrylate

DEAEMA

O=C(OCCN(CC)CC)C(=C)C

185.263

Slightly reactive (GSH) >> Methacrylates (MA)

2-tert-Butylaminoethyl methacrylate

TBAEMA

O=C(OCCNC(C)(C)C)C(=C)C

185.26

Slightly reactive (GSH) >> Methacrylates (MA)

2-Dimethylaminoethyl methacrylate

MADAME

CC(=C)C(=O)OCCN(C)C

157.22

Slightly reactive (GSH) >> Methacrylates (MA)

2-(2-Butoxyethoxy) ethyl methacrylate, Butyldiglycol methacrylate

BDGMA

CCCCOCCOCCOC(=O)C(=C)C

230.3

Slightly reactive (GSH) >> Methacrylates (MA)

2-(2-(2-Ethoxy ethoxy)-thoxyethyl methacrylate

ET3EGMA

O=C(OCCOCCOCCOCC)C(=C)C

246.3

Slightly reactive (GSH) >> Methacrylates (MA)

2-Methoxyethyl methacrylate

MTMA

CC(=C)C(=O)OCCOC

144.08

Slightly reactive (GSH) >> Methacrylates (MA)

2-Ethoxyethyl methacrylate

ETMA

CCOCCOC(=O)C(=C)C

158.09

Slightly reactive (GSH) >> Methacrylates (MA)

Phenoxyethyl Methacrylate

PTMA

CC(=C)C(=O)OCCOC1=CC=CC=C1

206.24

Slightly reactive (GSH) >> Methacrylates (MA)

Allyl methacrylate

AMA

CC(=C)C(=O)OCC=C

126.15

Slightly reactive (GSH) >> Methacrylates (MA)

Benzyl methacrylate

BNMA

CC(=C)C(=O)OCC1=CC=CC=C1

176.21

Slightly reactive (GSH) >> Methacrylates (MA)

Cyclohexyl methacrylate

c-HMA

O=C(OC(CCCC1)C1)C(=C)C

168.23

Slightly reactive (GSH) >> Methacrylates (MA)

Isobornyl methacrylate

IBOMA

CC(=C)C(=O)OC1CC2CCC1(C2(C)C)C

222.32

Slightly reactive (GSH) >> Methacrylates (MA)

Phenyethyl methacrylate

Phenylethyl MA

 CC(=C)C(=O)OCCC1=CC=CC=C1

190.24

Slightly reactive (GSH) >> Methacrylates (MA)

Phenyl methacrylate

PHMA

CC(=C)C(=O)OC1=CC=CC=C1

162.19

Slightly reactive (GSH) >> Methacrylates (MA)

3,3,5-Trimethylcyclohexyl methacrylate

TMCHMA

CC1CC(CC(C1)(C)C)OC(=O)C(=C)C

210.31

Slightly reactive (GSH) >> Methacrylates (MA)

Tridecyl methacrylate

TDMA C13MA

CCCCCCCCCCCCCOC(=O)C(=C)C

268.43

Slightly reactive (GSH) >> Methacrylates (MA)

Isodecyl methacrylate

IDMA

CC(C)CCCCCCCOC(=O)C(=C)C

226.36

Slightly reactive (GSH) >> Methacrylates (MA)

Dodecyl methacrylate

LMA

CCCCCCCCCCCCOC(=O)C(=C)C

254.41

Slightly reactive (GSH) >> Methacrylates (MA)

n-Octyl methacrylate

n-OMA

CCCCCCCCOC(=O)C(=C)C

198.3

Slightly reactive (GSH) >> Methacrylates (MA)

2-Hydroxyethyl methacrylate

HEMA

CC(=C)C(=O)OCCO

130.1

Slightly reactive (GSH) >> Methacrylates (MA)

Hydroxypropyl methacrylate

(propyleneglycol monoester)
= isomer mixture of
< 80 % 2-Hydroxypropyl methacrylate
> 20% 2-Hydroxy-1-methylethyl methacrylate

HPMA

CC(COC(=O)C(=C)C)O



CC(CO)OC(=O)C(=C)C

144.17

Slightly reactive (GSH) >> Methacrylates (MA)

Hydroxypropyl methacrylate

(propyleneglycol monoester)
= isomer mixture of
< 80 % 2-Hydroxypropyl methacrylate
> 20% 2-Hydroxy-1-methylethyl methacrylate

HPMA

CC(CO)OC(=O)C(=C)C

144.17

Slightly reactive (GSH) >> Methacrylates (MA)

N-butoxymethyl methacrylamide

N-BMMA

CCCCOCNC(=O)C(=C)C

157.21

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

N-Methylol methacrylamide

N-MMAA

CC(=C)C(=O)NCO

115.13

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

N,N'-methylenbis(methacrylamide)

 

O=C(NCNC(=O)\C(=C)C)\C(=C)C

154.19

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

N-Dimethylaminopropyl methacrylamide

DMAPMA

CC(=C)C(=O)NCCCN(C)C

170.25

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

Methacrylamide

MAA

CC(=C)C(=O)N

85.1

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

1,12-Dodecanediol dimethacrylate

1,12 DDDMA

O=C(OCCCCCCCCCCCCOC(=O)\C(=C)C)\C(=C)C

338.48

Slightly reactive (GSH) >> Methacrylates (MA)

1,3-Butandiol dimethacrylate

1,3-BDDMA

CC(CCOC(=O)C(=C)C)OC(=O)C(=C)C

226.27

Slightly reactive (GSH) >> Methacrylates (MA)

1,4-Butandiol dimethacrylate

1,4-BDDMA

CC(=C)C(=O)OCCCCOC(=O)C(=C)C

226.27

Slightly reactive (GSH) >> Methacrylates (MA)

1,6-Hexanediol dimethacrylate

1,6 HDDMA

O=C(OCCCCCCOC(=O)\C(=C)C)\C(=C)C

254.32

Slightly reactive (GSH) >> Methacrylates (MA)

Ethylene glycol dimethacrylate

EGDMA

CC(=C)C(=O)OCCOC(=O)C(=C)C

198.22

Slightly reactive (GSH) >> Methacrylates (MA)

Trimethylpropane trimethacrylate

TMPTMA

CCC(COC(=O)C(=C)C)(COC(=O)C(=C)C)COC(=O)C(=C)C

338.4

Slightly reactive (GSH) >> Methacrylates (MA)

Ethoxylated bisphenol A dimethacrylate

2EBADMA

CC(C)(C1=CC=C(C=C1)O)C2=CC=C(C=C2)O.C=CC(=O)O.C(CO)O

ID of reference isomer:
CC(=C)C(=O)OC1=CC=C(C=C1)C(C)(C)C1=CC=C(OC(=O)C(C)=C)C=C1

452.5394

Slightly reactive (GSH) >> Methacrylates (MA)

2,2-bis-[4-(3'-methacryloyloxy-2'-hydroxy)propoxyphenyl] propane

bis-GMA

O=C(OCC(O)COc1ccc(cc1)C(c2ccc(OCC(O)COC(=O)\C(=C)C)cc2)(C)C)\C(=C)C

512.61

Slightly reactive (GSH) >> Methacrylates (MA)

4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxy propane, reaction products with methacrylic acid

Bis-GMA NLP (DSM/Akzo/+others)

 

n.d

Slightly reactive (GSH) >> Methacrylates (MA)

Diethyleneglycol dimethacrylate

DEGDMA

CC(=C)C(=O)OCCOCCOC(=O)C(=C)C

242.27

Slightly reactive (GSH) >> Methacrylates (MA)

Glycerol dimethacrylate

GDMA

O=C(OCC(O)COC(=O)\C(=C)C)\C(=C)C

228.24

Slightly reactive (GSH) >> Methacrylates (MA)

7,7,9-(resp. 7,9,9-)trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diol-dimethacrylate

HEMATMDI

O=C(OCCOC(=O)NCCC(C)CC(C)(C)CNC(=O)OCCOC(=O)\C(=C)C)\C(=C)C

470,57

Slightly reactive (GSH) >> Methacrylates (MA)

Triethyleneglycol dimethacrylate

TREGDMA

O=C(OCCOCCOCCOC(=O)\C(=C)C)\C(=C)C

286.32

Slightly reactive (GSH) >> Methacrylates (MA)

Tetraethyleneglycol dimethacrylate

TTEGDMA/4EDMA

CC(=C)C(=O)OCCOCCOCCOCCOC(=O)C(=C)C

198.22

Slightly reactive (GSH) >> Methacrylates (MA)

2-hydroxyethyl methacrylate phosphate

HEMA phosphate

CC(=C)C(=O)OCCOP(=O)(O)O

228.14

Slightly reactive (GSH) >> Methacrylates (MA)

Methacrylic anhydride

MAAH

CC(=C)C(=O)OC(=O)C(=C)C

154.16

Slightly reactive (GSH) >> Methacrylates (MA)

Hydroxyethyl ethylene urea methacrylate

MEEUW

O=C1NCCN1CCOC(=O)\C(=C)C

129.16

Slightly reactive (GSH) >> Methacrylates (MA)

Tetrahydrofurfurylmethacrylat

THFMA

O=C(OCC1OCCC1)\C(=C)C

170.21

Slightly reactive (GSH) >> Methacrylates (MA)

2,2-dimethyl-1,3-dioxolan-4-ylmethyl methacrylate

 

CC(=C)C(=O)OCC1COC(O1)(C)C

200.23

Slightly reactive (GSH) >> Methacrylates (MA)

Polyethylengeglycol-200-dimethacrylate

PEG200DMA

for approximation see Tetraethyleneglycol dimathacrylate

no data

Slightly reactive (GSH) >> Methacrylates (MA)

2,2,2-Trifluoroethyl methacrylate

TFMEA 3FM

CC(=C)C(=O)OCC(F)(F)F

336

Slightly reactive (GSH) >> Methacrylates (MA)

N-Trimethylammoniumpropyl methacrylamide-chloride

MAPTAC

CC(=C)C(=O)NCCC[N+](C)(C)C.[Cl-]

220.74

Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)

2-Trimethylammoniummethyl methacrylate-chloride
2-(Methacryloyloxy)-N,N,N-trimethylethanaminium chloride

TMAEMC
DMCMA

CC(=C)C(=O)OCC[N+](C)(C)C.[Cl-]

207.7

Slightly reactive (GSH) >> Methacrylates (MA)

Conclusions:
No reactivity with GSH expected for MAA
A dataset with methacrylic acid derivatives has been assessed using the reactivity profiler in the OECD QSAR Toolbox. This profiler contains structural alerts derived from an analysis of experimental reactivity data as measured using glutathione (the Schultz assay). The profiler assigns chemicals to one of five potency classes (non-reactive, slightly reactive, moderately reactive, highly reactive and extremely reactive) based on the experimental results.

For Methacrylic acid, no alert was found, while the majority of the methacrylate esters are slightly reactive. For methacrylate esters it is well known that the addition of an alkyl group on the alpha-carbon significantly reduces reactivity in the Michael addition reaction.

There are also a group of vinyl carboxamides (methacrylamide derivatives) that have been flagged as being moderately reactive. It should be noted, however, that in the underlying QSAR data in the TB there is no information regarding the effect of an alpha substituent for this class of chemical. In reality this means that no chemicals were tested with glutathione that contained an alpha alkyl substituent thus the prediction is being made based on the un-substituted parent (acrylamide; thus the over-cautious prediction). The investigator indicated that they are likely to be pretty unreactive in reality.
Executive summary:

A dataset with methacrylic acid derivatives has been assessed using the reactivity profiler in the OECD QSAR Toolbox. This profiler contains structural alerts derived from an analysis of experimental reactivity data as measured using glutathione (the Schultz assay). The profiler assigns chemicals to one of five potency classes (non-reactive, slightly reactive, moderately reactive, highly reactive and extremely reactive) based on the experimental results.

 

For Methacrylic acid, no alert was found, while the majority of the methacrylate esters are slightly reactive. For methacrylate esters it is well known that the addition of an alkyl group on the alpha-carbon significantly reduces reactivity in the Michael addition reaction.

 

There are also a group of vinyl carboxamides (methacrylamide derivatives) that have been flagged as being moderately reactive. It should be noted, however, that in the underlying QSAR data in the TB there is no information regarding the effect of an alpha substituent for this class of chemical. In reality this means that no chemicals were tested with glutathione that contained an alpha alkyl substituent thus the prediction is being made based on the un-substituted parent (acrylamide; thus the over-cautious prediction). The investigator indicated that they are likely to be pretty unreactive in reality.

Endpoint:
basic toxicokinetics
Type of information:
other: modelling
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
accepted calculation method
Objective of study:
toxicokinetics
Principles of method if other than guideline:
A hybrid 9 and physiologically based pharmacokinetic inhalation model was constructed based on modifications of a CFD-PBPK model for acrylic acid.
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Details on study design:
Chemical specific partitioning for a variety of tissues and physicochemical characteristics (molecular weight and pKa) were incorporated into the model. The rate of ionization was 100 ml/hr/µmol.

To model human physiology in the workplace, additional CFD simulations were conducted at a flow rate of 35 L/min which approximates the inspiratory flow rate associated with a work load of 50 W and minute volume of 20-25 L/min. An oral shunt of air flow into the nasopharynx was include din the model to accomodate the switch from nasal to oronasal breathing with increasing workload.

Liquid-air partitioning of acrylic acid vapor was evaluated for saline (buffered to pH 2.0) and rat blood, liver, kidney, inguinal fat and nasal tissue.
Details on absorption:
The 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.

Comparisons of predicted olfactory tissue concentrations of MAA following simulated exposure of rat, mouse, and human nasal cavities indictated that under identical exposure conditions (including resting physiology in all species), human olfacotry tissue woudl have a 2-3 fold lower concentration of MAA than comparable rodent tissue. Using human phsiology assocaited with light physical activity (workload of 50 W and a minute volume of 20.8 L/min) resulted in a range of values based onthe extent to which humanoral breathing is included in the evaluation (approximately 20% lower tissue concentration in humans with no oral breathing to a 4 fold lower tissue concentration with 80% oral breathing). 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. The lower tissue concentration predicted for human olfactory tissue relative to rodent tissue would suggest that no adverse histopathological effects would be observed in the human nasal cavity at this exposure level.
Details on distribution in tissues:
Shake-vial partitioning studies with tissue homogenates indicates that MAA partitions between air and liquid phases and between blood and tissues similarly to acrylic acid. The measured partition coefficients were blood:air (1900), liver:air (6000), kidney:air (3500), fat:air (430), combined nasal tissue:air (1500) and pH 2.0 buffer:air (1310).

The model output reproduced the published total rat nose deposition data for MAA under unidirectional flow conditions. Comparisons of predicted olfactory tissue concentrations of MAA following simulated exposure of rat, mouse, and human nasal cavities 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.

Conclusions:
Using a valid modeling technique, it is predicted that exposure concentrations for human olfactory tissue relative to rodent tissue would be at least 50 % lower.
Executive summary:

Using a valid modeling technique, it is predicted that exposure concentrations for human olfactory tissue relative to rodent tissue would be at least 50 % lower.

Description of key information

MAAH is rapidly hydrolysed to Methacrylic acid (MAA) either by passive physical processes (see chapter "Hydrolysis") and biological processes with the help of ubiquiteous carboxylase enzymes. Based on studies of the toxicikinetic of methacrylic acid, which thus can be understood as the initial hydrolysis product and primary metabolite of methacrylic anhydride, methacrylic acid is readily absorbed by all routes and rapidly cleared from blood. As indicated by studies with methyl methacrylate(MMA), which functions as metabolite donor substance due to its rapid metablism to MAA, this metabolism is by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

It has been demonstrated in a physicochemical hydrolysis study that methacrylic anhydride has a half-life of a few minutes under the conditions of passive hydrolysis. In addition MAAH is stuturally related to an ester which makes it a substrate for carboxylesterase-catalysed hydrolysis in vivo. As methacrylic acid (MAA) thus can be understood as the initial hydrolysis product and primary metabolite of methacrylic anhydride, evaluation of toxicokinetics and fate is primarily based on methacrylic acid. While the properties of the original substance are relevant for local effects (absorption, irritation, sensitisation), systemic effects are most likely the result of the primary metabolite, methacrylic acid.

There are extensive data available for the methyl ester (MMA) which 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 450μg/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 HPLC. The maximum concentration was found after 10 min, whereas after 60 min no more methacrylic acid was detectable (Bereznowski et al., 1994).

As taken from the OECD SIAR: “Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively).”As methyl methacrylate (MMA) is rapidly degraded in the body to MAA, it can thus be understood as metabolite donor for MAA, with MAA as common metabolite of MAAH and MMA

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 GSH 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 MMA through rat & human epidermis

 

Rat epidermis

Human epidermis

Ester

Peak rate of absorption (μg/cm²/hr) ±SEM

Period of peak absorption rate (hours)

% age of applied dose absorbed over x hours

Peak rate of absorption (μg/cm²/hr) ±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

 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.

For methacrylic anhydride no in vivo absorption data exist. The rate of dermal absorption has been calculated with a human skin model (Heylings, 2012).

Chemical Class

Test Chemical / Compound Identity

Acronym

Molecular Weight

Log P

Predicted Flux (µg/cm2/h)

Relative Dermal Absorption

Alkyl basic MA tier 1

Methyl methacrylate

MMA

100.12

1.38

64.422

Moderate

Multi-func hydrophil spec / single

Methacrylic anhydride

MAAH

154.16

1.23

0.019

Minimal

In comparison, the predicted absorption rate for MAAH is substantially lower than that of the reference chemical methyl methacrylate in the same model. In relation, the predicted absorption rate for MMA is lower than the epidermal permeation rate shown above but is consistent with the only slightly lower absorption rate for human whole skin (33 µg/cm²/h) predicted from the experimental, epidermal data in the study by Jones(2002).

Conclusions

MAA is absorbed by all routes, while the actual absorption rates may be lower than for the reference chemicals methacrylic acid and methyl methacrylate. Due to the short half-life MAAH is rapidly converted to methacrylaic acid which, in turn, is 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 at the site of contact due to MAAH, but also because of the irritating/corrosive properties of MAA.