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Endpoint:
dermal absorption
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Remarks:
QSAR model based on several hundred chemicals tested in the same human skin model at the Central Toxicology laboratory and dermal Technology Laboratory .
Principles of method if other than guideline:
In silico prediction of skin permeation (human skin)
Absorption in different matrices:
The absorption rate of Butyldiglycol methacrylate through human skin was predicted to be 24.992 µg/cm²/h (moderate absorption)

In silico prediction of dermal absorption of higher methacrylates

In a QSAR model based on the physico-chemical properties (MW, logPow and satutared aqueous solubility) of chemicals the permeability of dermal absorption of a group of higher methacrylates was calculated. QSARs, when applied to estimating dermal permeability coefficients are also known as quantitative structure-permeability relationships (QSPeRs or QSPRs). The prediction model used in this investigation for a set of 54 methacrylate chemicals was based on an established model [Potts and Guy, (1992). Predicting Skin Permeability, Pharm. Res. 9(5): 663-669], using data derived with human epidermal membranes. The QSPeR approach can be used to identify compounds that are more likely to cross the stratum corneum barrier. Well dermal absorbed compounds include a low molecular weight, a general tendency towards being lipophilic in order to partition into the lipid rich stratum corneum/epidermis, but having sufficient aqueous solubility to cross the more polar regions of the dermis, prior to resorption into the blood circulation.

 

The dermal absorption was expressed using the permeability coefficient Kp which characterises the steady-state permeation rate of a chemical from a specific vehicle through a given membrane.

 

Terms used for categorising absorption of chemicals through human skin

Kp

(cm/h)

Absorption Rate

(µg/cm²/h)

Relative Absorption Rate Category

Predicted Absorption fromExposure

1 x 10-2– 10-1

> 500

Fast

very high

1 x 10-3– 10-2

100-500

rapid –fast

high

1 x 10-4– 10-3

10-50

50-100

slow – moderate

moderate – rapid

moderate

1 x 10-5– 10-4

0.1-10

very slow – slow

low

1 x 10-6– 10-5

0.001-0.1

extremely – very slow

minimal

 < 1 x 10-6

< 0.001

extremely slow

negligible

 

The absorption rate of Butyldiglycol methacrylate was predicted to be 24.992 µg/cm²/h. Therefore the dermal absorption is predicted to be moderate.

Conclusions:
In a QSAR model based on the physico-chemical properties (MW, logPow and satutared aqueous solubility) of chemicals the permeability of dermal absorption of a group of higher methacrylates was calculated. The absorption rate of Butyldiglycol methacrylate through human skin was predicted to be 24.992 µg/cm²/h. Therefore the dermal absorption is predicted to be moderate.
Executive summary:

In a QSAR model based on the physico-chemical properties (MW, logPow and satutared aqueous solubility) of chemicals the permeability of dermal absorption of a group of higher methacrylates was calculated.

The dermal absorption was expressed using the permeability coefficient Kp which characterises the steady-state permeation rate of a chemical from a specific vehicle through a given membrane.

The absorption rate of Butyldiglycol methacrylate was predicted to be 24.992 µg/cm²/h. Therefore the dermal absorption is predicted to be moderate.

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2021
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
Qualifier:
no guideline available
Principles of method if other than guideline:
Metabolic stability of the test item was analysed using pooled liver S9 fractions from male Sprague Dawley (SD) rats. Based on the knowledge gained during method development, in the present metabolic stability study of BDGMA the following test conditions were used: 20 μM of BDGMA were incubated in glass vials with 0.5 mg/ml S9 fractions and after 0, 2, 5,10,15 and 30 minutes samples were collected for analytical detection via LC-MS.

Two types of negative control (NC; n=3) i.e. heat-inactivated S9 fraction and pure assay buffer w/o S9 mix, respectively, were run in parallel to the experimental incubations to verify that any apparent loss of test article in the assay incubation was due to metabolism.

As positive control 1 μM verapamil was incubated in parallel to the test item (n=3), and the depletion of the compound was monitored to demonstrate the enzymatic activity of the S9 fractions. Positive control samples were taken after 0 and 30 minutes.
GLP compliance:
no
Specific details on test material used for the study:
TEST MATERIAL:
- Name of test material: BDGMA
Radiolabelling:
no
Species:
other: Rat liver S9 fractions
Strain:
Sprague-Dawley
Sex:
male
Vehicle:
DMSO
Duration and frequency of treatment / exposure:
sampling after 0, 2, 5,10,15 and 30 minutes
Dose / conc.:
20 other: µM
Remarks:
The final test concentration was determined during experimental development.
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:
As positive control 1 μM verapamil was incubated in parallel to the test item (n=3), and the depletion of the compound was monitored to demonstrate the enzymatic activity of the S9 fractions. Positive control samples were taken after 0 and 30 minutes.
Details on study design:
- Dose selection rationale: based on experimantal method development (analytical detection)
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Time and frequency of sampling: after 0, 2, 5, 10, 15 and 30 minutes


METABOLITE CHARACTERISATION STUDIES
- Method type(s) for identification: Liquid chromatography – mass spectrometry (LC-MS)
- Limits of detection and quantification:
- Other: after incubation time samples were samples were processed for ACN precipitation and quantitative bioanalysis (addition of two volumes (i.e. 400 μl) stop solution (ACN containing the ISTD).
Statistics:
Descriptive statistics were used, i.e., mean ± standard deviation. All calculations in the database were conducted using Microsoft Excel.
Type:
metabolism
Results:
The ester was rapidly converted into MAA and the respective alcohol. (approx. 1.3 min)
Metabolites identified:
yes
Details on metabolites:
Methacrylic acid (MAA) and Butyl diglycol

The metabolic stability of the test item butyldiglycol methacrylate (BDGMA) was analysed using rat liver S9 fractions fortified with Phase I metabolism cofactor NADPH. The time-dependent decrease of the initial test concentration of 20 µM BDGMA was investigated after incubation with liver S9 mix (0.5 mg microsomal protein/ml) for several incubation time points (i.e. 0, 2, 5, 10, 15 and 30 minutes). Moreover, the formation of the primary metabolites, i.e. methacrylic acid and butyldiglycol was detected as an additional proof of the enzymatic metabolism.

Negative controls served as a monitoring system for non-enzymatic degradation or non-specific binding effects of the test item. One negative control (NC) with heat-inactivated S9 fractions and another one with buffer only (i.e. negative control without S9 mix and NADPH) were integrated in the assay.

Remaining BDGMA concentrations and percentages of test item remaining after 30 minutes of incubation with rat liver S9 fractions as well as the formation of the two metabolites methacrylic acid and butyldiglycol are shown in Table 1 - Table 3 . Depletion of parent compound and formation of the two metabolites were in good accordance reflecting well the rapid and complete hydrolysis of BDGMA. However, found BDGMA concentrations were only 35% of the initial test concentration (i.e. 7038.8 nM, see Table 1), indicating a very fast degradation immediately after the reaction start.

In the negative control group with heat-inactivated S9 mix, 97.9% remaining BDGMA was measured after 30 min of incubation. In the negative control group using only buffer without S9 mix, BNMA was also stable. 108% of the test item could be detected after 30 minutes of incubation. These findings confirm that non-CYP mediated metabolic degradation processes as well as unspecific binding of the test item to the assay system can be excluded.

Table 2: Remaining BDGMA (nominal initial concentration: 20 µM): measured concentration and calculated percentage of remaining test item after incubation with rat liver S9 fractions for different time points, (n=3)

 

Remaining BDGMA concentration

% remaining BNMA of initial concentration

Time [min]
(±0.25 min)

Mean (nM)

SD (nM)

%CV[1]

Time [min]
(±0.25 min)

Mean (%)

0

7038.8

1032.5

14.7

0

100.0

2

2603.2

222.5

8.5

2

37.0

5

484.4

25.4

5.2

5

6.9

10

483.7

110.9

22.9

10

6.9

15

178.8

16.8

9.4

15

2.5

30

0.0

0.0

n.a.

30

0.0

 

Table 3: Measured concentration and calculated percentage of formed metabolite benzyl alcohol after incubation of BDGMA (nominal initial concentration: 20 µM) with rat liver S9 fractions for different time points, (n=3)

Formed butyldiglycol concentration

% formed butyldiglycol of initial concentration in BDGMA

Time [min]
(±0.25 min)

Mean (nM)

SD (nM)

%CV

Time [min]
(±0.25 min)

Mean (%)

0

16032.1

3793.5

23.7

0

80.2

2

18597.8

642.6

3.5

2

93.0

5

21735.7

885.1

4.1

5

108.7

10

17063.4

5768.2

33.8

10

85.3

15

18961.3

2316.1

12.2

15

94.8

30

20902.4

1419.3

6.8

30

104.5

 

Table 3: Measured concentration and calculated percentage of formed metabolite methacrylic acid after incubation of BDGMA (nominal initial concentration: 20 µM) with rat liver S9 fractions for different time points, (n=3)

Formed methacrylic acid concentration

% formed methacrylic acid of initial concentration in BDGMA

Time [min]
(±0.25 min)

Mean (nM)

SD (nM)

%CV

Time [min]
(±0.25 min)

Mean (%)

0

15998.0

1286.3

8.0

0

80.0

2

18639.3

485.5

2.6

2

93.2

5

19576.3

1584.3

8.1

5

97.9

10

15923.2

5189.9

32.6

10

79.6

15

18533.2

360.7

1.9

15

92.7

30

22321.8

1424.4

6.4

30

111.6

 

 

 

Conclusions:
The aims of the present study were to characterise the test item butyldiglycol methacrylate (BDGMA) with respect to its metabolic stability in rat liver S9 fractions and the quantitative determination of its two primary metabolites methacrylic acid and butyldiglycol.
Metabolic stability of the test item was analysed using pooled liver S9 fractions from male Sprague Dawley (SD) rats. In the present metabolic stability study of BDGMA the following test conditions were used: 20 µM of BDGMA were incubated in glass vials with 0.5 mg/ml S9 fractions and after 0, 2, 5, 10, 15 and 30 minutes samples were collected for analytical detection via LC-MS. Test item BDGMA was rapidly metabolised resulting in a half-life of 1.3 minutes and a Clint value of 1074.5 µl/min/mg protein.
In the negative control groups using only buffer without S9 mix or heat-inactivated S9 mix, BDGMA was stable over the investigated incubation period: 108.0% and 97.9% remaining compound could be detected after 30 minutes of incubation, respectively.
Additionally, quantitative determination of the two BDGMA metabolites methacrylic acid and butyldiglycol was performed reflecting well the rapid hydrolysis of the test item.
Executive summary:

The aims of the present study were to characterise the test item butyldiglycol methacrylate (BDGMA) with respect to its metabolic stability in rat liver S9 fractions and the quantitative determination of its two primary metabolites methacrylic acid and butyldiglycol.

Metabolic stability of the test item was analysed using pooled liver S9 fractions from male Sprague Dawley (SD) rats. In the present metabolic stability study of BDGMA the following test conditions were used: 20 µM of BDGMA were incubated in glass vials with 0.5 mg/ml S9 fractions and after 0, 2, 5, 10, 15 and 30 minutes samples were collected for analytical detection via LC-MS. Test item BDGMA was rapidly metabolised resulting in a half-life of 1.3 minutes and a Clint value of 1074.5 µl/min/mg protein.  

In the negative control groups using only buffer without S9 mix or heat-inactivated S9 mix, BDGMA was stable over the investigated incubation period: 108.0% and 97.9% remaining compound could be detected after 30 minutes of incubation, respectively.

Additionally, quantitative determination of the two BDGMA metabolites methacrylic acid and butyldiglycol was performed reflecting well the rapid hydrolysis of the test item.

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.

 

 

Description of key information

Based on the physico-chemical data, BDGMA is mainly absorbed after oral application. Inhalation of the substance can be excluded since the vapour pressure (0.032 Pa) is below the cut off value of 0.5 kPa and spray application are excluded. In a well-established QSAR prediction, the dermal absorption rate was classified as moderate only. This is supported by in vivo data on skin/ eye irritation and skin sensitisation showing no toxic effects.


The ester is hydrolysed within 1.3 minutes by carboxylesterases to methacrylic acid (MAA) and BDGE (Pharmacelsus, 2021). The primary metabolite, MAA, is subsequently cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2, while the other primary metabolite is primarily oxidised to 2-(2-butoxyethoyx) acetate and excreted via urine. Based on physicochemical properties, NO potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

Absorption



  1. a) Oral


Based on the some physico-chemical properties of BDGMA (e.g. molecular weight, physical state, water solubility, lipophilicity), the conditions for absorption from the gastrointestinal tract are very good.


For chemical safety assessment an oral absorption rate of 100% is assumed as a worst-case default value according to R8 guidance (ECHA, 2012).


 


b) Inhalation


The vapour pressure of BDGMA was determined to be 0.0022 hPa (0.00022 kPa) at 20°C. This is clearly below the general cut-off value of 0.5 kPa indicating a low volatility and hence poor availability for inhalation as vapour (ECHA, 2017).


Nevertheless, for chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst-case default value according to R8 guidance (ECHA, 2012).


 


c) Dermal


Based on the physico-chemical properties of BDGMA (e.g. the water solubility and the partition coefficient), the dermal availability of the substance is good. The water solubility of the substance can be classified as high and favours the partitioning from the stratum corneum into the epidermis. Besides, the logPow of 1.0 also favours the penetration into the stratum corneum and hence the absorption across the skin. In a well conducted QSAR model, the predicted steady-state flux of BDGMA is 24.992 µg/cm²/h μg/cm²/h (Heylings, 2013) and is classified by the author as moderate in comparison to other methacrylates.


In accordance with the final decision on CCh, ECHA concluded that the dermal route is not the most appropriate way of administration, because the absorption rate of BDGMA through human skin was predicted to be moderate only. Furthermore, no toxicity was observed in skin/ eye irritation and skin sensitisation in vivo studies.


 


Nevertheless, for chemical safety assessment a dermal absorption rate of 100% is assumed as a worst-case default value according to R8 guidance (ECHA, 2012).


Distribution


Since BDGMA undergoes enzymatic hydrolysis (see chapter 4.1.1.3.) especially in the gastrointestinal tract, the breakdown products (MAA and BDGE) are likely to be widely distributed due to their small size and solubility in aqueous media. Due to the logPow of 1.0, the parent compound could migrate across lipid membranes which is very unlikely based on the data of the in vitro metabolism study with BDGMA (Pharmacelsus, 2021). The degradation products of BDGMA do not contain any lipophilic groups, a migration across membranes is unlikely. Available data does not show accumulation in any organ or tissue, either. No target organs have been identified for BDGMA.


Metabolism


For the understanding of the toxicokinetic of BDGMA it is important to understand the general metabolism of methacrylate esters in mammals. The ester hydrolysis described in the following chapter is well accepted by authorities (see CLH dossier of 1,4-BDDMA written by Finnish MSCA). 


Ester hydrolysis induced by carboxylesterases has been established as the primary step in the metabolism of methacrylate esters. For MMA and other short-chain alkyl-methacrylate mono esters extensive toxicokinetic data are available, for example in the EU Risk Assessment for MMA (2002) as well as the OECD SIAR for short-chain alkyl-methacrylate esters (2009). On BDGMA, toxicokinetic data generated in an in vitro study in also available.


Hence, the first step in metabolism of aromatic methacrylate esters, e.g. BDGMA is the cleavage of the ester bond to produce thus the carboxylic acid (i.e. methacrylic acid) and the corresponding alcohol, i.e. BDGE .


These primary metabolites are further metabolised in vivo which highlights the hydrolysis as key event in the detoxification process of methacrylates. Consequently, the hydrolysis rate provides information about the toxicity potential and indicates whether the hazard assessment can be based on the metabolites MAA and the respective alcohol.


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 methacrylate esters, are the tissues at the primary site of contact, namely the skin, and systemically, the liver and blood. Oral and dermal route of exposure are also relevant for BDGMA. Due to the low vapour pressure, the exposure of the nasal epithelium toward vapour is very unlikely. Spray applications are excluded within the Exposure Scenarios. 


The metabolism of alkyl-methacrylates is well established (Corkill et al., 1976; McCarthy & Witz, 1991; McCarthy & Witz, 1997; Jones 2002). For lower methacrylates but also for higher and more complex methacrylates extensive information are available indicating the carboxylesterases-mediated rapid hydrolysis to methacrylic acid and the respective alcohol as primary metabolism step.


 


For BDGMA, the metabolic stability was determined in an in vitro study using rat liver S9 fractions. Furthermore, the primary metabolites, MAA and BDGE, were also measured in the experiment.


In the experiment, 20 µM of BDGMA were incubated in glass vials with 0,5 mg/ ml S9 fractions (from male SD rats) and after 0, 2, 5,10, 15 and 30 minutes samples were collected for analytical detection via LC-MS. Test item BDGMA was rapidly metabolised resulting in a half-life of 1.3 minutes and a Clint value of 1,074.5 μl/min/mg protein.


In the negative control (using only buffer without S9 fractions), BDGMA was stable, thus 108.0% of the ester could be detected after 30 minutes. Using heat-inactivated S9 fractions, the amount of remaining BDGMA was and 97.9%.


Additionally, quantitative determination of the two BDGMA metabolites MAA and BDGE was performed reflecting well the rapid hydrolysis of the test item. (Pharmacelsus, 2021).


 


The comparison of the BDGMA data with data on other methacrylates reveals that the enzymatic hydrolysis is very rapid (see table 4 below). Therefore, the read-across approach regarding scenario 1 is considered appropriate. The usage of data on MAA/ MMA and BDGE is justified.


 


Table 4: Comparison of pharmacokinetic parameters used in and obtained from a PBPK model developed by Jones, 2002


 



















































Substance



Clint [l*h-1*g-1]



T50% [min]



MAA



0.098



-



MMA



7.35



4.4



EMA



17.8



4.5



iBMA



17.7



11.6



nBMA



30.6



7.8



6HMA



29.5



18.5



2-EHMA



60.1



23.8



OMA



55.1



27.2



Excretion


The parent compound BDGMA is not likely to be excreted as such due to the rapid hydrolysis of the ester bond. The metabolites of the substance will be cleared from blood circulation by physiological pathways. The methacrylic moiety will mainly be exhaled as CO2. The alcohol moiety will mainly be excreted via urine. 


 


 Subsequent metabolism of the metabolites


Common methacrylic moiety: Methacrylic acid (MAA)


As taken from the OECD SIAR (2009): “Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively).”


Methyl methacrylate (MMA) is rapidly degraded in the body to MAA and can thus be understood as metabolite donor for MAA (ECETOC, 1995). 


1.1.2.2     Common alcohol moiety: BDGE


BDGE is rapidly metabolised and mainly excreted via urine, mostly within the first 24 h after administration. The excretion via faeces and exhalation are of minor importance. Due to the high excretion rate of DGBE, the concentration of DGBE in tissues is very low. In the urine, 5 different metabolites were determined. The main metabolite (approx. 50%) is 2-(2-Butoxyethoxy)acetic acid formed by oxidation of DGBE. A second metabolite is Diethylene glycol formed by hepatic microsomal O-dealkylation to remove the butyl substituent from DGBE. Furthermore, 2-(2-3- or 4-Hydroxybutoxy)ethoxy)ethanol was detected. This indicates that oxidation of the butyl substituent occurs without its subsequent removal (Diesinger and Guest, 1989).


After dermal application of BDGE, 2-(2-Butoxyethoxy)acetic acid was again the main urinary metabolite (60-80%). The glucoronidated form of BDGE was also found in the urine at amounts of 5-8 % (Boatman et al., 1993).