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EC number: 203-652-6 | CAS number: 109-16-0
- 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)
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- Determination of in vitro hydrolysis rates of methacrylate esters; determination of half-lifes in rat liver microsomes and whole rat blood.
- GLP compliance:
- yes
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): triethylene glycol dimethacrylate
- Radiolabelling:
- no
- Species:
- other: rat liver microsomes and rat blood
- Vehicle:
- DMSO
- Duration and frequency of treatment / exposure:
- 120 min (samples collected at 0, 2, 5, 15, 30, 60 and 120 minutes)
- Dose / conc.:
- 0.25 other: mM
- No. of animals per sex per dose / concentration:
- not applicable; in vitro test
- Control animals:
- other: not applicable; in vitro test
- Positive control reference chemical:
- Methyl methacrylate
- Details on dosing and sampling:
- METABOLITE CHARACTERISATION STUDIES
- Method type(s) for identification: liquid chromatography separation with accurate mass quadrupole/time-of-flight mass spectrometry detection (LC/QTOF-MS) to quantitate methacrylic acid concentrations
- Limits of detection and quantification: LLQ = 0.0117 mM methacrylic acid - Type:
- metabolism
- Results:
- the ester was rapidly converted to Methacrylic acid (MAA) in whole rat blood and rat liver microsomes: half life 3.01 min (liver microsomes) / 5.68 min (blood)
- Conclusions:
- The metabolism data show that TREGDMA is rapidly hydrolysed in vitro.
- Executive summary:
This in vitro metabolism study was conducted to investigate in vitro hydrolysis rates of TREGDMA. Half-lifes were determined in rat liver microsomes and whole rat blood.
TREGDMA was rapidly converted to MAA in whole rat blood and rat liver microsomes with hydrolysis half lives of 3.01 min (liver microsomes) and 5.68 min (blood).
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Read across from the alcohol metabolite.
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1ff
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1
3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters
4. DATA MATRIX
see attached category document, table in chapter 1.2 and endpoint specific chapters - Reason / purpose for cross-reference:
- read-across source
- Objective of study:
- excretion
- Principles of method if other than guideline:
- Administration of C14-triethyleneglycol to the rat.
- GLP compliance:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): triethylene glycol
- Analytical purity: 99.9%
- Locations of the label (if radiolabelling): randomly labeled 14C-triethylene glycol
- Specific activity (if radiolabelling): 5.13 µc/mg - Radiolabelling:
- yes
- Species:
- rat
- Strain:
- other: albino
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Albimno Farms, Red Bank, New Jersey, USA
- Metabolism cages: yes
- Diet: ad libitum; during study no food was allowed
- Water: ad libitum - Route of administration:
- oral: gavage
- Vehicle:
- water
- Dose / conc.:
- 125 mg/kg bw/day
- Dose / conc.:
- 140 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- Dose / conc.:
- 600 mg/kg bw/day
- No. of animals per sex per dose / concentration:
- 2
- Control animals:
- yes
- Type:
- excretion
- Results:
- 66% of dose recovered in urine chloroform extracts (125 mg/kg bw group) after 24 h
- Type:
- excretion
- Results:
- 65% of dose recovered in urine chloroform extracts (140 mg/kg bw group) after 24 h
- Type:
- excretion
- Results:
- 38% of dose recovered in urine chloroform extracts (250 mg/kg bw group) after 24 h
- Type:
- excretion
- Results:
- 56% of dose recovered in urine chloroform extracts as hydroxyacid (250 mg/kg bw group) aftger 24 h
- Type:
- excretion
- Results:
- 27% of dose recovered in urine chloroform extracts (600 mg/kg bw group) after 24 h
- Type:
- excretion
- Results:
- 40% of dose recovered in urine chloroform extracts as hydroxyacid (600 mg/kg bw group) after 24 h
- Type:
- excretion
- Results:
- 91-98% of dose recovered (14C elimination) after 5 days
- Details on excretion:
- Following administration of 14C-triethyleneglycol to the rat, 86-94% of the radioactivity was recovered in the urine in the subsequent 5-day period. The total excretion by way of the urine and faeces amounted to 94-97%. The expired air over a 60-h period contained approximately 1% of the administered dose.
- Metabolites identified:
- yes
- Details on metabolites:
- The chromatograms of chloroform extracts of urine showed no evidence of ethylene glycol or diethyleneglycol.
One oxidation product is suggested to be a monocarboxylic acid which arises by metabolic oxidation of a single terminal hydroxyl group of the parent glycol. - Conclusions:
- Interpretation of results no bioaccumulation potential based on study results
High degree of elimination of triethyleneglycol and its metabolites via the urine and additionally via faeces - Executive summary:
Exctretion of triethylene glycol was investigated in male albino rats. Following administration of 14C-triethyleneglycol to the rat, 86-94% of the radioactivity was recovered in the urine in the subsequent 5-day period. The total excretion by way of the urine and faeces amounted to 94-97%. The expired air over a 60-h period contained approximately 1% of the administered dose. Therefore Triethylene glycol is expected to pass the organism without further metabolism.
- Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Justification for type of information:
- Read across from the methacrylic metabolite donor substance.
REPORTING FORMAT FOR THE ANALOGUE APPROACH
see attached category document
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
see attached category document, chapter 1.1ff
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document, chapter 1
3. ANALOGUE APPROACH JUSTIFICATION
see attached category document, chapter 5 (Toxikokinetics) and endpoint specific chapters
4. DATA MATRIX
see attached category document, table in chapter 1.2 and endpoint specific chapters - Reason / purpose for cross-reference:
- read-across source
- Objective of study:
- absorption
- metabolism
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans.
- GLP compliance:
- not specified
- Species:
- other: rat and human
- Strain:
- other: Wistar/Fischer F344/ not applicable
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Epidermal membrane absorption studies
Skin was used from male rats of the Wistar-derived strain (supplied by Charles River UK Ltd, Margate, Kent, UK.) aged 28 days ± 2 days
Whole skin absorption studies
Skin was taken from male Fischer F344 (supplied by Harlan Olac) rats weighing between 200 and 250 g.
Human epidermal membrane absorption studies
Extraneous tissue was removed from human abdominal whole skin samples obtained post mortem in accordance with local ethical guidelines. - Route of administration:
- intravenous
- 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. The studies confirmed that alkyl-methacrylate esters are rapidly hydrolyzed by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. In vivo measurements of rat liver indicated this organ has the greatest esterase activity. Similar measurements for skin microsomes indicated approximately 20-fold lower activity than for liver. However, this activity was substantial and capable of almost complete first-pass metabolism of the alkyl-methacrylates. For example, no parent ester penetrated whole rat skin in vitro for n-butyl methacrylate, octyl methacrylate or lauryl methacrylate tested experimentally with only methacrylic acid identified in the receiving fluid. In addition, model predictions indicate that esters of ethyl methacrylate or larger would be completely hydrolyzed before entering the circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters such that the rate is within the metabolic capacity of the skin. Parent ester also was hydrolyzed by S9 fractions from nasal epithelium and was predicted to be effectively hydrolyzed following inhalation exposure.
- Type:
- metabolism
- Results:
- Half-life of MMA after i.V. injection: 4.4 min (PBPK estimate)
- Metabolites identified:
- yes
- Details on metabolites:
- Methacrylic acid
- Conclusions:
- 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).
- Endpoint:
- dermal absorption
- Type of information:
- calculation (if not (Q)SAR)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- accepted calculation method
- Principles of method if other than guideline:
- The physico chemical parameters of MW, Log P and saturated aqueous solubility have been used in the evaluation of 56 methacrylate compounds. An output of predicted steady-state flux was calculated using the principles defined in the Potts and Guy prediction model. (Potts RO and Guy RH (1992). Predicting Skin Permeability. Pharm. Res. 9(5): 663- 669)
- GLP compliance:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Triethyleneglycol dimethacrylate
- Details on test animals or test system and environmental conditions:
- not applicable; in silico modelling
- Type of coverage:
- other: not applicable; in silico modelling
- No. of animals per group:
- not applicable; in silico modelling
- Absorption in different matrices:
- predicted flux 4.989 μg/cm²/h; the relative dermal absorption is low
- Conclusions:
- The dermal absorption of TREGDMA is predicted to be low; the predicted flux is 4.989 μg/cm²/h.
- Executive summary:
The dermal absorption (steady-state flux) of TREGDMA has been estimated by calculation using the principles defined in the Potts and Guy prediction model.
Based on a molecular weight of 286.32 g/mol and a log Kow of 2.3, the predicted flux of TREGDMA is 4.989 μg/cm²/h; the relative dermal absorption is low.
Referenceopen allclose all
Negative controls in the rat liver microsome experiments included incubations with heat-inactivated microsomes, no microsomes and no NADPH. Removal of NADPH made little or no difference in hydrolysis rates. Heat inactivation significantly reduced hydrolysis rates, and absence of microsomes resulted in no hydrolysis.
TREGDMA was rapidly converted to MAA in whole rat blood and rat liver microsomes with hydrolysis half-lives of 3.01 min (liver microsomes) and 5.68 min (blood).
These studies showed that any systemically absorbed parent ester will be effectively removed during the first pass through the liver (CL as % LBF,
see table). In addition, removal of methacrylic acid from the blood also
occurs rapidly (T50%; see table).
Table 1:
Rate constants for ester hydrolysis by rat-liver microsomes and predicted
systemic fate kinetics for methacrylates following i.v. administration:
Ester Vmax Km CL T50% Cmax Tmax
----------------------------------------------------------
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
----------------------------------------------------------
Vmax (nM/min/mg) and Km (µM) from rat-liver microsome (100 µg/ml)
determinations;
CL = clearance as % removed from liver blood flow, T50% = Body elimination time
(min) for 50% parent ester, Cmax = maximum concentration (mg/L) of MAA in
blood, Tmax = time (min) to peak MAA concentration in blood from model
predictions.
---
Table 2:
Rate constants for ester hydrolysis by human-liver microsome samples:
Ester Vmax (nM/min*mg) Km (mM) CL (µL/min*mg)
-----------------------------------------------
MMA 1721 4103 419
EMA 936 1601 584
i-BMA 80 441 181
n-BMA 211 158 1332
HMA 229 66 3465
2EHMA 53 48 1109
OMA 243 38 6403
----------------------------------------------------------
CL is calculated from the mean Vmax and Km
Based on a molecular weight of 286.32 g/mol and a log Kow of 2.3, the predicted flux of TREGDMA is 4.989 μg/cm²/h; the relative dermal absorption is low.
Description of key information
TREGDMA is likely to be readily absorbed by all routes. Due to the low vapour pressure, the dermal route is the primary route of exposure, since inhalation is unlikely. The dermal absorption rate however is calculated to be low.
The ester is rapidly hydrolysed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol triethylene glycol (TREG). MAA is metabolized to succinic acid which will be degraded through the tricarboxylic acid cycle and primarily excreted as CO2. Orally administered TREG is excreted either unchanged or oxidized to the di-carbolic acid of TREG, predominantly via urine.
Based on physico chemical properties, no potential for bioaccumulation is to be expected.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
- Absorption rate - oral (%):
- 50
- Absorption rate - dermal (%):
- 50
- Absorption rate - inhalation (%):
- 100
Additional information
Absorption
Oral absorption
The physico chemical properties of TREGDMA (log Pow = 2.3), the relatively high water solubility of 3.6 g/L and the molecular weight of 286.32 g/mol are in a range suggestive of absorption from the gastrointestinal tract subsequent to oral ingestion. For chemical safety assessment an oral absorption rate of 50% is assumed as a worst case default value in the absence of other data (ECHA R.8 guidance, 2012).
Dermal absorption
Based on a QSAR Prediction of Dermal Absorption (extract from Heylings JR, 2013) TREGDMA is predicted on the basis of their molecular weight and lipophilicity to have a relatively low ability to be absorbed through the skin. The predicted flux was 4.989 μg/cm²/h. However, for chemical safety assessment, a dermal absorption rate of 50% is assumed as a worst case default value (ECHA R.8 guidance, 2012).
Inhalative absorption
No vapour pressure is available for TREGDMA itself but for the structurally related substance ET3EGMA which boiling point is lower than TREGDMA. The vapour pressure of ET3EGMA (0.077 Pa@20 °C) was used to characterize TREGDMA. Due to the low vapour pressure exposure to TREGDMA via inhalation is unlikely. For chemical safety assessment an inhalative absorption rate of 100% is assumed as a worst case default value (R8 guidance, 2012).
Distribution
As a small, water soluble molecule with a logP > 0, a wide distribution can be expected (ECHA guidance 7c, 2017). No information on potential target organs is available. However, due to the low log Pow bioaccumulation in particular tissues is not predicted.
Metabolism
Metabolism of Methacrylic esters
Di- and monoester hydrolysis
Ester hydrolysis has been established as the primary step in the metabolism of methacrylate esters. In the case of diol di-methacrylate esters the first step would be hydrolysis of one of the ester bonds to produce the corresponding mono-ester followed by subsequent hydrolysis of the second ester bond to produce methacrylic acid (MAA) and the corresponding alcohol triethylene glycol. The metabolic pathway is described in the category document.
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. For multifunctional methacrylates mostly the same would be the case except that because of the lower vapour pressure and hence lower likelihood of inhalation exposure the involvement of the nasal epithelium is less likely.
Kinetics data have been reported for the hydrolysis of two multifunctional methacrylates (EGDMA and TREGDMA) by porcine liver carboxylesterase in vitro. For comparison reasons, the results from two lower alkyl methacrylates (EMA and BMA), are also presented in the table below (McCarthy and Witz, 1997). The four studied substances showed comparable hydrolysis rates in vitro.
Hydrolysis of Acrylate Esters by Porcine Liver Carboxylesterase in vitro (extract from McCarthy and Witz., 1997):
Ester |
Km (mM) |
Vmax (nmol/min) |
Ethyl methacrylate (EMA) |
159±90 |
5.2±2.5* |
Butyl methacrylate (BMA) |
72±28* |
1.8±0.6* |
Ethyleneglycol dimethacrylate (EGDMA) |
64±24* |
6.9±2.4 |
Tetraethyleneglycol dimethacrylate (TTEGDMA) |
39±15* |
2.9±1.0* |
* Significantly different (p < 0.05) from ethyl acrylate
A recent study, designed to extend an ealier work on lower alkyl methacrylates (Jones 2002), see below) to higher and more complex methacrylate esters, studies the in vitro metabolism of higher and more complex methacrylate esters in rat blood and liver microsomes. This study included three esters of the multifunctional methacrylate category (TREGDMA, EGDMA and 1,4 -BDDMA) (DOW, 2013). The results of those studies are summarized in the table below.
Elimination Rates, Intrinsic Clearance and Half-life in Rat Liver Microsomes and Whole Rat Blood for Five Methacrylate Esters at 0.25 mM Substrate Concentration:
|
Liver Microsomes |
Whole Blood |
||||
Molecule |
Clint |
ke |
Half‐Life (min) |
Clint (μl/min) |
ke |
Half‐Life (min) |
MMA |
1192 |
2.38 |
0.29 |
19 |
0.01 |
63.00 |
HEMA |
74 |
0.15 |
4.62 |
12 |
0.01 |
99.00 |
EGDMA |
142 |
0.28 |
2.45 |
796 |
0.44 |
1.56 |
1,4-BDDMA |
78 |
0.16 |
4.46 |
304 |
0.17 |
4.10 |
TREGDMA |
116 |
0.23 |
3.01 |
219 |
0.12 |
5.68 |
ke: elimination rate
Clint: intrinsic clearance (ke x volume of incubation / mg/mL microsomal
protein)
All studied methacrylate esters were rapidly converted to MAA in whole rat blood and rat liver microsomes. Hydrolysis half-lives ranged from 1.56 to 99 minutes, and from 0.06 to 4.95 minutes for blood and liver microsomes, respectively.
The incubations in whole rat blood and rat liver microsomes were performed on three separate days with MMA included as a positive control on each day. The table above shows elimination rates (ke), intrinsic clearance (Clint) and half-life values for each molecule in whole rat blood and rat liver microsomes at 0.25 mM starting concentrations.
Rat liver microsome hydrolysis rates for the positive control (MMA) were somewhat variable between days. This was likely due to the rapidity of hydrolysis of MMA. Often, measurable levels of MAA were present even in the zero minute samples and the substrate was completely hydrolysed by 2 minutes. This made it difficult to accurately calculate hydrolysis rates for MMA in these experiments. However, generally the calculated rates were similar to rates for hydrolysis for MMA reported previously (Jones, 2002; Mainwaring et al., 2001) and confirmed that the in vitro test systems were enzymatically active for each day of incubation experiments. The other studies exhibited rat liver microsome hydrolysis rates approximately 10 fold lower than MMA. For its vers rapid degradation to MAA, MMA can be understood as suitable donor for MAA as common primary metabolite of all catergory members.
Supporting information on Alkyl methacrylates
The above mentioned EMA and n-BMA were also studied in an elaborate series of in vitro studies on carboxylesterase activity with 7 alkyl methacrylates ranging from methyl methacrylate to octyl methacrylate (with increasing ester size; Jones, 2002). This was used to establish a PB-PK model of in vivo clearance for several tissues (blood, liver, skin and nasal epithelium) from rats and humans, which showed that methacrylate mono-esters are rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. The validity of the model was verified with targeted in vivo experiments. Whilst there was a trend of increasing half-life of alkyl methacrylates with increasing chain length (up to octyl), clearance of the parent ester from the body was always in the order of minutes.
Although the absolute rate measurements obtained by Jones differ slightly to those determined by McCarthy and Witz, presumably due to differences in experimental conditions such as protein content etc., the rates obtained for the two lower alkyl methacrylates (EMA and BMA) can be used to draw parallels between the work of the two researchers indicating that the kinetics for the hydrolysis of EGDMA and TREGDMA fall within the range observed by Jones for lower alkyl methacrylates. On this basis the parent ester would be expected to have a short systemic half–life within the body being effectively cleared from the blood within the first or second pass through the liver. Hydrolysis of the di- and monoester would yield the common metabolite methacrylic acid and the respective alcohol.
Subsequent metabolism:
Methacrylic acid (MAA, CAS 79-41-4)
From the available extensive toxicokinetic data on lower alkyl methacrylates it has been established that the common primary metabolite methacrylic acid is subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively; ECB, 2002; OECD SIAR, 2009). Methyl methacrylate (MMA) is rapidly degraded in the body to MAA and can thus be understood as metabolite donor for MAA. The metabolic pathway is shown in the category document.
Triethylene glycol(TREG, CAS 112-27-6)
In an earlier study, oral doses of radio-labelled TREG were excreted by rats and rabbits in both unchanged and oxidized form. The data suggest that one of the oxidation products is a monocarboxylic acid which arises by metabolic oxidation of a single terminal hydroxyl group of the parent glycol. The rat eliminated only trace quantities of14C activity as respiratory carbon dioxide. A small but measurable amount of radioactivity was found in the feces. The major part of the radioactivity appeared in the urine. The data from fractionation of the urine indicated that only negligible quantities (if any) of14C were present as oxalic acid (the completely fragmented acid). The major metabolic products had properties which suggested that triethylene glycol is degraded by the route: TREG → mono-carboxylic acid of TREG → di-carboxylic acid of TREG. The authors concluded that the high degree of elimination of triethylene glycol and its metabolites by way of the urine, is consistent with many findings pointing to the low or limited toxicity of triethylene glycol. The total elimination of radioactivity (in urine, feces, and expired air) during the 5-day period following a single oral dose (22.5 mg) was 91–98% (McKennis et al., 1962).
Alcohol dehydrogenase and aldehyde dehydrogenase were found to be involved in the metabolism of polyethylene glycols including TREG in humans and animals. Enzymatic key parameters of alcohol dehydrogenase were 810±50 mM kmand 19±2 nmol/min Vmaxfor TREG (Herold et al., 1989).
Glutathione reactivity:
A QSAR model for TREGDMA predicted only slight reactivity with glutathione for the category members and no reactivity for the primary metabolite, methacrylic acid. (Cronin, 2012)
QSAR prediction of GSH reactivity (Protein Binding Potency), Cronin, 2012
Abbreviation |
SMILES |
Molecular Weight |
Log P |
Sat. Water Sol. (µg/mL) |
Protein Binding Potency |
TREGDMA |
O=C(OCCOCCOCCOC(=O)\C(=C)C)\C(=C)C |
286.32 |
2.3 |
3600 mg/l |
Slightly reactive |
Studies with methacrylates in vitro confirm low reactivity with GSH, in particular compared to the corresponding acrylates, and have proposed that this is due to steric hindrance of the addition of a nucleophile at the double bond by the alpha-methyl side-group (McCarthy & Witz, 1991, McCarthy et al., 1994, Tanii and Hashimoto, 1982). This is also confirmed by the publication of Nocca et al. (2011) who found a low levels of GSH adducts of TREGDMA when erythrocytes and gingival fibroblasts were exposed to 2 mM (573 mg/L) TREGDMA in vitro.
Table: Apparent Second-Order Rate Constants for the Reaction of Glutathione with Methacrylate Esters (extract from McCarthy et al.,1994)
Ester |
App. 2ndorder rate const. |
Methyl methacrylate (MMA) |
0.325±0.059 |
Ethyl methacrylate (EMA) |
0.139±0.022 |
Butyl methacrylate (BMA) |
No appreciable reaction rate |
Ethyleneglycol dimethacrylate (EGDMA) |
0.83±0.12 |
Tetraethyleneglycol dimethacrylate (TTEGDMA) |
1.45±1.0 |
*Bifunctional esters calculated as two independent esters.
In vivo data on category members are absent. However, in an inhalation study with MMA at an overtly cytotoxic exposure level off 566 ppm and absolute deposition rates of 35-42μg/min under unidirectional flow, a 20% lowering of nasal non-protein sulfhydryl (NPSH) content was observed, indicative of direct protein reactivity, whereas methacrylic acid exposures had no effect, even at higher delivered dose rates. Around the local (nasal) LOAEL, at an exposure concentration of 109 ppm, MMA had no effect on nasal NPSH levels (Morris and Frederick, 1995).
Hence, ester hydrolysis is considered to be the major metabolic pathway for alkyl and multifunctional methacrylate esters, with GSH conjugation only playing a minor role in their metabolism.
Excretion
As the ester will not survive first pass metabolism in the liver, excretion of the parent compound is of no relevance. The primary metabolite, MAA, is cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.
In summary, the metabolism data and modelling results show that TREGDMA would be rapidly hydrolysed in the rat.
Dermal absorption
Table: QSAR prediction of dermal absorption (extract from Heylings, 2013)
Substance |
Molecular Weight |
Log P |
Predicted Flux (μg/cm2/h) |
(Relative Dermal Absorption |
TREGDMA |
286.32 |
2.3 |
4.989 |
Low |
DEGDMA |
242.27 |
2.2 |
5.997 |
Low |
EGDMA |
198.22 |
2.4 |
6.109 |
Low |
GDMA |
228.24 |
2.05 |
24.986 |
Moderate |
1,3-BDDMA |
226.27 |
3.1 |
2.895 |
Low |
1,4-BDDMA |
226.27 |
3.1 |
2.895 |
Low |
1,6-HDDMA |
254.32 |
4.08 |
0.917 |
Low |
TMPTMA |
338.4 |
4.193 |
0.296 |
Low |
All members of the MfMA category, but GDMA, are predicted on the basis of their molecular weight and lipophilicity to have a relatively low ability to be absorbed through the skin (Heylings, 2013)
Trends
MfMA esters are typically predicted to have a relatively low potential for skin absorption. There is a suggestion of trend for predicted absorption decreasing with increasing ester
chain length and increasing lipophilicity. The larger members of the category, like TMPTMA, are extremely unlikely to be absorbed through the skin to any significant extent.
Human information
There are no relevant toxicokinetic data for MfMA in humans.
For lower alkyl methacrylates there is information indicating that skin absorption rates are lower in human skin compared to rat skin, while for MMA it has been demonstrated that
human fate kinetics is similar to those in rats (Jones, 2002).
Summary and discussion on toxicokinetics
Methacrylate esters are absorbed by all routes while the dermal absorption is limited with the larger members of the category. Due to the low vapour pressure of the multifunctional methacrylates, the dermal route is the primary route of exposure, since inhalation is unlikely. The rate of dermal absorption decreases with increasing ester chain length. All esters are rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. In the case of di- and triesters the apparent rate of hydrolysis is highest for the parent ester, but this likely reflects the higher number of hydrolysable target sites instead as opposed to any greater specific activity. Ester hydrolysis can occur in local tissues at the site of contact as well as in blood and other organs by non-specific carboxylesterases. By far the highest enzyme activity has been shown in liver microsomes indicating that the parent ester will be fully metabolized in the liver. Clearance of the parent ester from the body is in the order of minutes. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length, however, none of the esters will survive first pass metabolism in the liver to any significant extent. The primary methacrylic metabolite, MAA, is subsequently cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2. The respective alcohol moieties will undergo further metabolism in the liver.
Triethylene glycol dimethacrylate will rapidly be hydrolyzed by unspecific carboxyl esterases in the liver into methacrylic acid and triethylene glycol.
Excretion of triethylene glycol was investigated in male albino rats. Following administration of 14C-triethyleneglycol to the rat, 86-94% of the radioactivity was recovered in the urine in the subsequent 5-day period. The total excretion by way of the urine and faeces amounted to 94-97%. Only negligible quantities (if any) of14C were present as oxalic acid (the completely fragmented acid). The expired air over a 60-h period contained approximately 1% of the administered dose. Therefore triethylene glycol is expected to pass the organism without further metabolism. No bioaccumulation of triethyleneglycol is expected.
Compliance to REACh requirements
The information requirement is covered with reliable in vitro studies on the primary metabolism, reliable in vitro/ in vivo studies on the metabolism of the methacrylic metabolite MAA as well as reliable publication data on the passway the alcohol metabolite TREG . All mentioned sources are reliable (Reliability 1 or 2) so that the category/read across approach can be done with a high level of confidence.
Abbreviations, CAS-Nos and physico chemical properties of the above mentioned substances:
Abbreviation |
Name |
CAS |
MW* g/mol |
BP** °C |
logPow |
Ws*** |
MAA |
Methacrylic acid |
79-41-4 |
86 |
162 |
0.93 |
98 g/l |
MMA |
Methyl methacrylate |
80-62-6 |
100 |
100.3 |
1.38 |
15.3 g/l |
EMA |
Ethyl methacrylate |
97-63-2 |
114 |
118 |
1.87 |
4.69 g/l |
n-BMA |
n-Butyl methacrylate |
97-88-1 |
142 |
163 |
3.03 |
0.36 g/l |
HEMA |
Hydroxyethyl methacrylate |
868-77-9 |
130 |
213 |
0,42 |
miscible |
HPMA |
Hydroxypropyl methacrylate |
27813-02-1 |
144 |
209 |
0.97 |
107.9 g/l |
EGDMA |
Ethyleneglycol dimethacrylate |
97-90-5 |
198 |
275 |
2.04 |
1.09 g/l |
TTEGDMA |
Tetraethyleneglycol dimethacrylate |
109-17-1 |
330 |
352a) |
1.39a) |
532 mg/la) |
TREGDMA |
Triethyleneglycol dimethacrylate |
109-16-0 |
286 |
> 310 |
2.3 |
3.6 g/l |
ET3EGMA |
Ethyltriglycol methacrylate |
39670-09-2 |
246 |
292 |
2.08 |
61 g/l |
ETMA |
2-Ethoxyethyl methacrylate |
2370-63-0 |
158 |
184 |
1.49 |
3,71 g/l |
MTMA |
2-Methoxyethyl methacrylate |
6976-93-8 |
144 |
163a) |
1.00a) |
11.2 g/la) |
BGDMA |
Butyldiglycol methacrylate |
7328-22-5 |
230 |
271 |
3.1 |
2.56 g/l |
1,3-BDDMA |
1,3-Butandiol dimethacrylate |
1189-08-8 |
226 |
> 200 |
3.1 |
243 mg/l |
1,4-BDDMA |
1,4-Butandiol dimethacrylate |
2082-81-7 |
226 |
> 200 |
3.1 |
243 mg/l |
1,6-HDDMA |
1,6-Hexanediol dimethacrylate |
6606-59-3 |
254 |
> 190 |
4.08 |
23 mg/l |
TMPTMA |
Trimethylpropane trimethacrylate |
3290-92-4 |
338 |
> 270 |
4.19 |
20.1 mg/l |
DEGDMA |
Diethyleneglycol dimethacrylate |
2358-84-1 |
242 |
> 200 |
2.2 |
2745 mg/l |
GDMA |
Glycerol dimethacrylate |
1830-78-0 |
228 |
> 110 |
2.05 |
12 g/l |
*MW = molecular weight
**BP = boiling point
*** WS = water solubility
a)calculated
References
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