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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:
not applicable; in vitro test
Control animals:
other: not applicable; in vitro test
Positive control:
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)

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).

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:
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 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:
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:
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 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

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

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 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

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.

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.

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
(μl/min/mg)

ke

HalfLife (min)

Clint (μl/min)

ke

HalfLife (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.
Kapp[L/mol/min]

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
(0.406±0.059

Tetraethyleneglycol dimethacrylate (TTEGDMA)

1.45±1.0
(0.725±0087)*

         

 *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

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