2-methoxyethyl methacrylate

Endpoint summary

Description of key information

Acute oral toxicity:
Oral LD50 (rat, male/female) > 2000 mg/kg bw; OECD Guideline 401; GLP compliant, RL1
Acute dermal toxicity:
Dermal LD50 (rat, male/female) > 2000 mg/kg bw; OECD Guideline 402; GLP compliant, RL1; read-across from ETMA

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1997-03-17 to 1997-04-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted 24 February 1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Sprague-Dawley CD (Crl:CD BR)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-12 weeks
- Weight at study initiation: main study, 226-239 g (males), 200-219 g (females)
- Fasting period before study: yes, overnight + 3-5 h after dosing
- Housing: in groups of up to 5 in solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 44-53
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2.04 mL/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: bodyweights were recorded on days 0, 7, 14; clinical signs: 1/2, 1, 2, 4 h after dosing, once daily thereafter
- Necropsy of survivors performed: yes

Dose selection based on the results of a range finding study:
2000 mg/kg bw of the test substance was administered to 1 male and 1 female rat
Animals were observed for clinical signs 1/2, 1, 2, 4 h after dosing, once daily thereafter for 5 days

Preliminary study:

There were no deaths in the range-findng study (dose level 2000 mg/kg bw). Clinical signs of toxicity noted in both animals 0.5 hour to one day after dosing were hunched posture, lethargy, pilo-erection, ataxia and decreased respiratory rate with additional signs of red/brown staining around the mouth and an isolated incident of increased salivation in the male. Animals recovered two days after dosing.
Based on this information, a dose level of 2000 mg/kg bodyweight was selected for the main study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: mortality: 0/10

Mortality:

There were no deaths

Clinical signs:

other: 3/5 males and 3/5 females showed no clinical signs at all. Common signs of systemic toxicity noted in 2/5 males and 2/5 females were hunched posture, lethargy and piloerection with additional signs of decreased respiratory rate 4 h to 2 d after dosing. An

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of MTMA in rat is >2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study according to OECD guideline 401 (adopted 24 February 1987), groups of fasted, 8 to 12 weeks old Sprague-Dawley CD (Crl:CD BR) rats, 5/sex were given a single oral dose of MTMA (no information on purity) 2000 mg/kg bw and observed for 14 days.

No animal died during the study. 3/5 males and 3/5 females showed no clinical signs. Common signs of systemic toxicity noted in 2/5 males and 2/5 females were hunched posture, lethargy and piloerection with additional signs of decreased respiratory rate 4 h to 2 d after dosing. Animals had recovered 2 to 3 days after dosing. 

All animals showed the expected body weight gain during the study, except for one female which showed a loss in bodyweight during the second week. No abnormalities were noted at necropsy.

Oral LD50 in males/females (rat) > 2000 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP compliant and of high quality (Klimisch score = 1).

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 and target substances have similar toxicological properties because
• they are manufactured from similar or identical precursors under similar conditions
• they share structural similarities with common functional groups: methacrylate esters
• the metabolism pathway leads to comparable products (methacrylic acid and short chain alcohol).

Therefore, read-across from the existing (eco)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 cross reference “Justification for read-across”

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

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

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Species:

rat

Sex:

male/female

Type of coverage:

semiocclusive

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: 20% mortality at this dose level

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 in rats is >2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is GLP compliant and of high quality (Klimisch score = 1).

Additional information

No experimental data on MTMA are available for the assessment of acute dermal toxicity. However, a study is available for the source substance ETMA. ETMA is of similar low toxicity by the oral route so comparable dermal toxicity would be expected. A detailed justification for read-across is attached to IUCLID section 13.

 

Hypothesis for the analogue approach

 

The read-across hypothesis relies on the close structural similarity between the source substance ETMA and the target substance MTMA, differing only by one CH₂-group. This read-across hypothesiscorresponds to scenario 2 -different compounds have qualitatively similar properties- of the read-across assessment framework i.e.properties of the target substance are predicted to be quantitatively equal to those of the source substance. Namely, the structurally similar source substance ETMApredicts the toxicological properties of the target substance MTMA.

 

Based on the available data, including physicochemical data (water solubility and log Kow) and acute oral toxicity, the read-across strategy is supported by close structural analogy and similar toxicological profile of the substances.

 

Toxicological data are summarised in the data matrix; robust study summaries are included in the Technical Dossier in the respective sections.

 

Therefore, read-across from the existing toxicity studies conducted with the source substance is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

A detailed justification for the proposed read-across approach is attached to Iuclid section 13.

 

Common assessment elements for analogue approaches:

AE A.1 Characterisation of source and target substances

 

There is close structural similarity between the source and the target substances and the identity and characterisation of these substances is unambiguous thereby giving a high level of confidence in the validity of the read across.

The target and source substances are highly pure mono-constituent substances. They do not contain impurities, which would be of toxicological concern.

 

The target substance MTMA is an ester of Methacrylic acid and 2-Methoxyethanol. It is produced by esterification of Methacrylic acid and 2-Methoxyethanol.

 

The source substance ETMA is an ester of Methacrylic acid and 2-Ethoxyethanol. It is produced by esterification of Methacrylic acid and 2-Ethoxyethanol. ETMA is different to MTMA in only one CH2-group.

 

AE A.2 Link of structural similarities and structural differences with the proposed prediction

The target substance MTMA differs from the source substance ETMA by one CH₂-group. The physicochemical properties (water solubility and log Kow) are, however, very similar. Thus, a comparable bioavailability by oral and dermal route can be expected. Additionally, acute oral toxicity data are available for MTMA and ETMA demonstrating low systemic acute toxicity, which further support the read-across.

 

	Target substance: MTMA	Source substance: ETMA
Substance type	Mono-constituent	Mono-constituent
IUPAC name	2-Propenoic acid, 2-methyl-, 2-methoxyethyl ester	2-Propenoic acid, 2-methyl-, 2-ethoxyethyl ester
EC name	2-methoxyethyl methacrylate	2-ethoxyethyl methacrylate
EC number	230-241-9	219-135-3
CAS number	6976-93-8	2370-63-0
Molecular weight	144.2 g/mol	158.2 g/mol
Log Kow	1.3 at 23.3°C   (OECD Guideline 117/EU Method A.8; HPLC method)	1.8 at 23.3°C   (OECD Guideline 117/EU Method A.8; HPLC method)
Water solubility	31.33 g/L (pH 7.6) at 20°C   (OECD Guideline 105/EU Method A.6; flask method)	17.05 g/L (pH 5.3) at 20°C   (OECD Guideline 105/EU Method A.6; flask method)

 

AE A.3 Impact of impurities on the prediction

Both, the target substance and the source substance, are highly pure mono-constituent substances.

They do not contain impurities, which would be of toxicological concern.

 

AE A.4 Consistency of properties in the data matrix

The results of the acute oral toxicity studies demonstrate a low acute toxicity for both the target and the source substance.

 

AE A.5 Reliability and adequacy of the source data

All available studies have been conducted according to OECD guidelines and have been assigned a reliability of 1 or 2 as documented in the data matrix (see detailed justification for read-across attached to Iuclid section 13).

 

Overall, the study design of the respective source studies is adequate and reliable for the purpose of this read-across.The results of the selected key studies are adequate for classification and labelling and for risk assessment purposes.

 

Data availability

Acute oral toxicity

A fully reliable study is available for acute oral toxicity of MTMA, so read across is not employed.

 

In an acute oral toxicity study according to OECD guideline 401 the oral LD50 for MTMA in rats was > 2000 mg/kg bw.

 

Consistency of data on read-across chemicals:

The source substances were of similarly low toxicity after single administration.

In an acute oral toxicity study according to OECD guideline 401 the LD50 of ETMA (rat, male/female) was > 2000 mg/kg bw.

Additionally, data from the metabolites 2-methoxyethanol and methacrylic acid are included into the dossier to justify the read-across for repeated dose toxicity and toxicity to reproduction.

Diluted Methacrylic acid had an LD50 of >2000 mg a.i./kg bw (25% dilution in water or 10% dilution in corn oil). The LD50 of 2-methoxyethanol was 2460 mg/kg bw in rat. The comparable outcome of the acute toxicity studies conducted with the target substance and the source substances supports the read-across hypothesis.

 

Acute inhalation toxicity

A study on acute inhalation toxicity is unjustified in accordance to REACH regulation Annex VIII, column 2 due to exposure considerations as well as in accordance to REACH regulation Annex XI due to scientific considerations. The use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. Furthermore, systemic toxicity relevant to humans did not appear in acute by oral or dermal exposure. Considering the exposure probability and the available information on the intrinsic toxic activity of the substance, an inhalative systemic toxicity risk to humans is unlikely and therefore, the conduct of an inhalative toxicity study is not scientifically necessary. Thus, also animal welfare is respected according to REACH intentions.

 

Acute dermal toxicity

In an acute dermal toxicity study according to OECD guideline 402, adopted 24 February 1987, 5 male and 5 female app. 8 weeks old Sprague-Dawley ICO: OFASD rats were dermally exposed to ETMA (99.94% a.i.) for 24 hours under a semiocclusive dressing to approx. 10% of body surface area at a single dose of 2000 mg/kg bw. Animals then were observed for 14 days.

2/5 females were found dead 24 h after treatment without any preclinical signs.

No clinical signs and cutaneous reactions were observed during the study.

Between days 1 and 5, a decrease in body weight was noted for 1/5 males, the bodyweight gain was slightly reduced for 1/5 males and 2/5 females. The body weight of these animals showed an improvement during the remainder of the observation period. This finding was probably due to the stress caused by the experimental conditions and was not attributed to treatment with the test substance. The body weight gain of the surviving animals was normal.

Macroscopic examination of the main organs of the animals found dead during the study or sacrificed at the end of the study revealed no apparent abnormalities.

Dermal LD50 of ETMA (rat, male/female) > 2000 mg/kg bw.

 

There are no data gaps in acute toxicity. Even though there is no information on acute toxicity in humans, there is no reason to believe that the low acute toxicity observed in experimental animals would not be relevant for human health. 

Justification for classification or non-classification

Based on the available data, MTMA does not need to be classified for acute toxicity according to regulation (EC) 1272/2008. Thus, no labelling is required.