2-ethoxyethyl methacrylate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Repr. 1 B

NOAEL (fertility effects) = 163 mg/kg bw/d (read-across from 2-ethoxyethanol)

Link to relevant study records

Reference

Endpoint:

fertility, other

Remarks:

subchronic toxicity study with additional assessment of reproduction toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source substances are both metabolites of the target substance and fast metabolism occurs.
Therefore, read-across from the existing toxicity studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached “Justification for read-across”

3. ANALOGUE APPROACH JUSTIFICATION
see attached “Justification for read-across”

4. DATA MATRIX
see attached “Justification for read-across”

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Dose descriptor:

NOAEL

Effect level:

163 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

not measured/tested

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive effects observed:

yes

Lowest effective dose / conc.:

323 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to other toxic effects:

reproductive effects in the absence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

yes

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

163 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No experimental data on ETMA are available for the assessment of fertility effects. However, studies are available for the source substances 2-ethoxyethanol and methacrylic acid. A detailed justification for read-across is attached to IUCLID section 13.

 

Hypothesis for the analogue approach

The read across hypothesis relies on the observation that alkyl esters are rapidly hydrolysed by carboxylesterase enzymes within the body to release methacrylic acid (MAA) and free alcohol. Local effects, including genotoxicity and sensitisation, if they occur are likely to be due to electrophilic reactivity of the parent ester 2-Ethoxyethyl methacrylate (ETMA). Due to the short half-life of the parent ester within the body systemic exposure to parent ester is extremely unlikely so the observed systemic toxicity profile is determined by the systemic toxicity profile of the primary metabolites Methacrylic acid (MAA) and 2-Ethoxyethanol.

 

This read-across hypothesis corresponds to scenario 1 – biotransformation to common compounds – of the read-across assessment framework) i.e.Property of the target substance is predicted to be quantitatively equal to those of the source substance. Namely, the metabolites Methacrylic acid and 2-Ethoxyethanol predict the toxicological properties of the parent compound ETMA.

 

Based on the available experimental data, including data from acute toxicity and genotoxicity studies, the read-across hypothesis is supported by close structural analogy and similar toxicological profile of the substances.

Toxicokinetics

AE 1.1 Formation of common (identical) compound(s)

The focus of this AE is on the scientific explanation and documentation on how the (bio)transformation from source and target substances to the common compound(s) occur. It will be shown that biotransformation from parent ester to primary metabolite occurs rapidly within the body and that the ensuing metabolism of these primary metabolites is well understood thereby providing a high confidence in the assertion that the metabolites alone influence systemic toxicity alone.

 

After oral or inhalation administration, methacrylate esters are expected to be rapidly absorbed via all routes and distributed. Dermal absorption of esters is extensive only with occlusion of the site. Heylings (2013) used a QSPeR model for whole human skin based on that described by Potts and Guy (1992) to predict the dermal penetration rate of a large number of methacrylate esters, including ETMA (Heylings, 2013). For ETMA a low rate of dermal penetration is predicted (8.261 µg/cm²/h).

Toxicokinetics seem to be similar in man and experimental animals. MMA and other short chain alkyl-methacrylate esters are initially hydrolyzed by non-specific carboxylesterases to methacrylic acid and the structurally corresponding alcohol in several tissues, including but not limited to liver, olfactory epithelium, stratum corneum and blood. This has been shown for linear alkyl esters, several ether methacrylates, diesters as well as cycloalkyl and -aryl esters (Jones 2002, DOW 2013, McCarthy and Witz, 1997). Because of the structural similarity of ETMA to the other esters rapid hydrolysis is expected in the order of minutes.

Methacrylic acid (MAA) is subsequently cleared predominantly via the liver (valine pathway and the TCA (Tricarboxylic Acid) cycle).

The carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin. 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.

 

2-ethoxyethanol is mainly metabolized toethoxyacetic acid and ethylene glycol. Exhalation of unmetabolized glycol ether is a minor route of elimination (Medinsky MA et al., 1990).

 

Alternative(minor) pathway: GSH Conjugation

Methacrylate esters can conjugate with glutathione (GSH) in vitro, although they show a low reactivity, since the addition of a nucleophile at the double bond is hindered by the alpha-methyl side-group (Cronin, 2012, Freidig et al. 1999). Hence, ester hydrolysis is considered to be the major metabolic pathway for alkyl-methacrylate esters, with GSH conjugation only playing a minor role in their metabolism, and then possibly only when very high tissue concentrations are achieved.

 

The fast hydrolysis observed for other Methacrylic acid esters is predicted to occur also for ETMA. Thus, following systemic exposure to ETMA the organisms will be mainly exposed to the metabolites Methacrylic acid and 2-Ethoxyethanol.

 

On this basis the systemicbiological targets for the common compound(s)(AE 1.2) and the exposure of these systemic biological target(s) to the common compound(s) (AE 1.3) will be the same for ETMA as they are for the primary metabolites.

 

Furthermore, since carboxylesterases are widely distributed throughout the body and the half-life of the parent ester is very short the impact of parent compound (AE 1.4) is unlikely to be significant other than at the site of initial contact. Indeed, local hydrolysis at the site of contact is likely to be very rapid thereby minimising exposure to parent ester even at local targets. Since the source and target compounds are monoconstituents of high purity there are no impurities worthy of consideration. Finally, since the hydrolysis of the parent ester to Methacrylicacid and 2-Ethoxyethanol is equimolar and does not involve the formation ofnon-common compounds (AE 1.5) (including possible intermediates) their possible impact on the property under consideration does not have been considered.

Data availability

Rats and dogs were administered different concentrations of the test substance 2-ethoxyethanol (orally, subcutaneously, intravenously) in order to evaluate reproductive toxicity. At a dose of 200 µL/kg bw/day serious testes damage was observed in male rats and dogs (interstitium loosened oedematously). Therefore, the corresponding NOAEL for reproductive toxicity is 100 µL/kg bw/day, corresponding to 93 mg/kg bw/day.

 

In a 90 d inhalation study with methacrylic acid histopathology of the sexual organs and additional fertility parameters were investigated. Up to 350 ppm (1232 mg/m³) no effects were seen on gross pathology including organ weights, histopathology, sperm motility or sperm morphology.

The metabolite mainly determining reproductive toxicity is 2-ethoxyethanol. Thus, the overall NOAEL for the endpoint toxicity to reproduction (fertility effects) is based on the NOAEL of 93 mg/kg bw/d obtained in a subchronic toxicity study focussing on the reproductive organs in rat. The NOAEL of ETMA for effects to fertility is 163 mg/kg bw/d (extrapolated based on molecular weight).

 

There are no data gaps for the endpoint fertility. There is no reason to believe that the results would not be relevant to humans. 

Effects on developmental toxicity

Description of key information

Repr. 1 B

NOAEL (embryotoxicity) = 40 mg/kg bw/d (read-across from 2-ethoxyethanol)

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source substances are both metabolites of the target substance and fast metabolism occurs.
Therefore, read-across from the existing toxicity studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached “Justification for read-across”

3. ANALOGUE APPROACH JUSTIFICATION
see attached “Justification for read-across”

4. DATA MATRIX
see attached “Justification for read-across”

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Species:

rat

Dose descriptor:

NOAEL

Effect level:

644 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: no effects observed

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

skeletal malformations

Abnormalities:

effects observed, treatment-related

Localisation:

other: skeletal

Developmental effects observed:

yes

Lowest effective dose / conc.:

163 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

yes

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No experimental data on ETMA are available for the assessment of developmental toxicity. However, studies are available for the source substances 2-ethoxyethanol and methacrylic acid. A detailed justification for read-across is attached to IUCLID section 13.

Hypothesis for the analogue approach

The read across hypothesis relies on the observation that alkyl esters are rapidly hydrolysed by carboxylesterase enzymes within the body to release methacrylic acid (MAA) and free alcohol. Local effects, including genotoxicity and sensitisation, if they occur are likely to be due to electrophilic reactivity of the parent ester 2-Ethoxyethyl methacrylate (ETMA). Due to the short half-life of the parent ester within the body systemic exposure to parent ester is extremely unlikely so the observed systemic toxicity profile is determined by the systemic toxicity profile of the primary metabolites Methacrylic acid (MAA) and 2-Ethoxyethanol.

 

This read-across hypothesis corresponds to scenario 1 – biotransformation to common compounds – of the read-across assessment framework) i.e.Property of the target substance is predicted to be quantitatively equal to those of the source substance. Namely, the metabolites Methacrylic acid and 2-Ethoxyethanol predict the toxicological properties of the parent compound ETMA.

 

Based on the available experimental data, including data from acute toxicity and genotoxicity studies, the read-across hypothesis is supported by close structural analogy and similar toxicological profile of the substances.

Toxicokinetics

AE 1.1 Formation of common (identical) compound(s)

The focus of this AE is on the scientific explanation and documentation on how the (bio)transformation from source and target substances to the common compound(s) occur. It will be shown that biotransformation from parent ester to primary metabolite occurs rapidly within the body and that the ensuing metabolism of these primary metabolites is well understood thereby providing a high confidence in the assertion that the metabolites alone influence systemic toxicity alone.

 

After oral or inhalation administration, methacrylate esters are expected to be rapidly absorbed via all routes and distributed. Dermal absorption of esters is extensive only with occlusion of the site. Heylings (2013) used a QSPeR model for whole human skin based on that described by Potts and Guy (1992) to predict the dermal penetration rate of a large number of methacrylate esters, including ETMA (Heylings, 2013). For ETMA a low rate of dermal penetration is predicted (8.261 µg/cm²/h).

Toxicokinetics seem to be similar in man and experimental animals. MMA and other short chain alkyl-methacrylate esters are initially hydrolyzed by non-specific carboxylesterases to methacrylic acid and the structurally corresponding alcohol in several tissues, including but not limited to liver, olfactory epithelium, stratum corneum and blood. This has been shown for linear alkyl esters, several ether methacrylates, diesters as well as cycloalkyl and -aryl esters (Jones 2002, DOW 2013, McCarthy and Witz, 1997). Because of the structural similarity of ETMA to the other esters rapid hydrolysis is expected in the order of minutes.

Methacrylic acid (MAA) is subsequently cleared predominantly via the liver (valine pathway and the TCA (Tricarboxylic Acid) cycle).

The carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin. 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.

 

2-ethoxyethanol is mainly metabolized to ethoxyacetic acid and ethylene glycol. Exhalation of unmetabolized glycol ether is a minor route of elimination (Medinsky MA et al., 1990).

 

Alternative(minor) pathway: GSH Conjugation

Methacrylate esters can conjugate with glutathione (GSH) in vitro, although they show a low reactivity, since the addition of a nucleophile at the double bond is hindered by the alpha-methyl side-group (Cronin, 2012, Freidig et al. 1999). Hence, ester hydrolysis is considered to be the major metabolic pathway for alkyl-methacrylate esters, with GSH conjugation only playing a minor role in their metabolism, and then possibly only when very high tissue concentrations are achieved.

 

The fast hydrolysis observed for other Methacrylic acid esters is predicted to occur also for ETMA. Thus, following systemic exposure to ETMA the organisms will be mainly exposed to the metabolites Methacrylic acid and 2-Ethoxyethanol.

 

On this basis the systemicbiological targets for the common compound(s) (AE 1.2) and the exposure of these systemic biological target(s) to the common compound(s) (AE 1.3) will be the same for ETMA as they are for the primary metabolites.

 

Furthermore, since carboxylesterases are widely distributed throughout the body and the half-life of the parent ester is very short the impact of parent compound (AE 1.4) is unlikely to be significant other than at the site of initial contact. Indeed, local hydrolysis at the site of contact is likely to be very rapid thereby minimising exposure to parent ester even at local targets. Since the source and target compounds are monoconstituents of high purity there are no impurities worthy of consideration. Finally, since the hydrolysis of the parent ester to Methacrylic acid and 2-Ethoxyethanol is equimolar and does not involve the formation of non-common compounds (AE 1.5) (including possible intermediates) their possible impact on the property under consideration does not have been considered.

Data availability

Two teratogenicity studies conducted with 2-ethoxyethanol in rats and rabbits indicate that levels of 175 to 250 ppm may be around the threshold level for teratogenicity; 175 to 250 ppm has been shown to be fetotoxic in both rats and rabbits, and 50 ppm is mildly fetotoxic in rats, although there were no effects in rabbits. These studies overall indicate a marginal fetotoxic effect level of 50 ppm and a clear no-effect level of 10 ppm in both species.

 

In a developmental toxicity study mice, rats and rabbits were administered the test substance 2-ethoxyethanol at different concentrations subcutaneousely or orally. The lowest NOAEL according to embryotoxicity in rats and rabbits was 25 µL/kg/day.

 

No significant increase in embryo/fetal lethality or fetal malformations were observed after exposure to methacrylic acid. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.

The metabolite mainly determining developmental toxicity is 2-ethoxyethanol. Thus, the overall NOAEL for the endpoint developmental toxicity is based on the NOAEL of 23 mg/kg bw/d obtained in a prenatal developmental toxicity study in rat. After molecular weight correction, the overall NOAEL used as a starting point to derive the DNEL is 40 mg/kg bw/d for the target substance ETMA.

 

There are no data gaps for the endpoint developmental toxicity. There is no reason to believe that the results would not be relevant to humans. 

Justification for classification or non-classification

Based on the available data, ETMA is classified as Repr. 1B (H360FD) according to the criteria given in regulation (EC) 1272/2008