1-methyltrimethylene dimethacrylate

Endpoint summary

Description of key information

Acute oral toxicity

LD50 (rat): > 2000 mg/kg bw OECD Guideline 420; GLP study, Klimisch score = 1 (HMRTF, 2021)

Acute inhalation toxicity: no relevant route of exposure
Acute dermal toxicity: no relevant route of exposure

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:

Experimental start date: 14 January 2021 - Experimental completion date: 02 February 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

OECD 420, GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Version / remarks:

adopted 17 December 2001

Deviations:

yes

Remarks:

The relative humidity in the animal room was between approximately 19-65% instead of 45-65% for several hours on several days due to a defective air humidifier. This deviation to the study plan, however, does not affect the validity of the study.

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Version / remarks:

Commission Regulation No. 440/2008, Part B, Method B.1 bis. Acute Oral Toxicity: Fixed Dose Procedure. 30 May 2008

Deviations:

yes

Remarks:

The relative humidity in the animal room was between approximately 19-65% instead of 45-65% for several hours on several days due to a defective air humidifier. This deviation to the study plan, however, does not affect the validity of the study.

Principles of method if other than guideline:

Following a sighting test at a dose level of 2000 mg/kg b.w. in one female rat per dose group, a further group of four fasted females was given a single oral dose of Visiomer® 1,3-BDDMA, as a solution in corn oil, at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored in all animals during the study. All animals were subjected to gross necropsy.

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Specific details on test material used for the study:

Test sustance: Visiomer® 1,3-BDDMA; 1,3-Butanediol dimethacrylate

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Test animals:
Strain: Wistar Han TM
Source: Janvier Labs, CS4105 Le Genest Saint Isle, 53941 Saint Berthevin Cedex / France
Sex: Female
Other: Females were nulliparous and non-pregnant
Number of animals for the pre-test: 1 female
Number of animals for the main study: 4 females at the maximum tolerated dose
Age (beginning of treatment): 8 - 12 weeks
Identification: The animals were distributed into the test groups at random. If possible, all animals belonging to the same experimental group were kept in one cage. The animals were individually marked by fur clippings. A colour-coded card was prepared for each project, giving details of the test type, project number, treatment start, dose level, sex and number of animals.
Acclimatization: At least 5 days prior to the start of dosing under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

Husbandry
Housing: groups of one to five rats (of the same sex and dose group)
Cage Type: Makrolon Type IV, with wire mesh top
Bedding: granulated soft wood bedding
Feed: 2018C Teklad Global 18% protein rodent diet (certified), ad libitum (except for overnight fasting prior to dosing; diet was returned immediately after dosing was complete)
Water: tap water, ad libitum
Environment: temperature 22 +/- 2°C relative humidity approx. 45-65% (except for deviations) (with the aim of 50 – 60%) artificial light 6.00 a.m. - 6.00 p.m. ventilation: at least eight air changes per hour
Environmental enrichment: provided throughout the study period (e.g., wooden chew blocks, fun tunnels or suitable nesting material)

Formulation
The test item was formulated at a concentration of 220 mg/mL in the vehicle and administered at a constant dose volume of 10 mL/kg body weight. Vortexing was used to formulate the test item.
Test substance formulations were freshly prepared on the day of dosing, issued at room temperature and administered as soon as possible (within 4 hours of preparation). The formulations were assumed to be stable for this period unless specified otherwise by the Sponsor.
Samples of test substance formulations were not taken for analysis and consequently the homogeneity, concentration and stability of the test item were not determined.

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

2000 mg/kg

No. of animals per sex per dose:

4

Control animals:

no

Details on study design:

Serial Observations
Morbidity/Mortality Inspection and Clinical Observations
Clinical observations and inspections for morbidity / mortality were performed at least three times within the first six hours after application (i.e., 30 minutes and 1 hour, 2 hours and 4 hours after dosing), thereafter at least once daily for 14 days. All animals were observed for 14 days after dosing.
The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation for all individual animals. If applicable, the time of death/humane kill was recorded as precisely as possible. Observations included changes in the skin and fur, eyes and mucous membranes, and respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behavior pattern. Particular attention was directed to the observation of tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma.

Fate of the Animals
Animals were sacrificed by carbon dioxide asphyxiation followed by cervical dislocation.

Determination of Body Weight
Body weights were recorded on Day 0 (prior to dosing), Day 7, and 14, or (if applicable) at death (unscheduled).

Terminal Investigations
Necropsy
A gross necropsy was performed on all animals that died or were humanely killed during the study (if applicable) and at the end of the in-life part. Any macroscopic abnormalities were recorded. Routinely no organs or tissues were retained.

Data evaluation
Evaluation of data includes the identification of the number of animals that died during the study (or that were killed for humane reasons), and determination of the nature, severity, onset and duration of the toxic effects. If possible, the signs of toxic effects of evident toxicity are described. Evident toxicity refers to the toxic effects of sufficient severity that administration of the next higher dose level could result in development of severe signs of toxicity and probable mortality. Effects on body weights and abnormalities noted at necropsy were identified.
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was made.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: LD50: 220 mg/mL (adjusted to purity with a correction factor of 1.10.)

Mortality:

There were no deaths during the study.

Individual Clinical Observations and Mortality Data – 2000 mg/kg
------------------------------------------------------------------------------------------------------------------------------------------
Dose Level Animal Number Effects Noted After Dosing Effects Noted During Period After Dosing (Days)
mg/kg and sex (hours) (days)
-------------------------------------------------------------------------------------------------------------------------------------------
1/2 1 2 4 1 2 3 4 5 6 7 8 9 10 11 12 13 14
-------------------------------------------------------------------------------------------------------------------------------------------

2000 Female 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Female 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Female 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Female 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Female 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
-------------------------------------------------------------------------------------------------------------------------------------------
0 = No signs of systemic toxicity

Clinical signs:

other: There were no clinical signs of reaction to treatment throughout the study. There were no signs of systemic toxicity noted in the animals.

Other findings:

No relevant abnormalities were noted in any animal at the macroscopic examination at study termination on Day 14. The Peyer’s patches were enlarged in three out of five animals, however this was considered to be unspecific.

Interpretation of results:

GHS criteria not met

Remarks:

Classification based on the criteria of 286/2011/EU Criteria used for interpretation of results: EU

Conclusions:

The acute median lethal oral dose (LD50) to rats of Visiomer® 1,3-BDDMA was demonstrated to be greater than 2000 mg/kg body weight. No signs of relevant toxicity were observed.
The results of this study allow/warrant to classify Visiomer® 1,3-BDDMA with “Category 5/Unclassified”, according to the Globally Harmonised System (UN-GHS),

Executive summary:

In an acute oral toxicity study according to OECD 420 (Fixed dose method) with GLP, one group of female Wistar rats were given a single oral dose of 1,3 -Butanediol dimethacrylate (1,3 -BDDMA) at a dose level of  2000 mg/kg suspension in corn oil. The animals were observed for 14days.

 

Oral LD₅₀ female= > 2000 mg/kg bw

   

1,3 -Butanediol dimethacrylate is oral practically non toxic in Wistar rats (EU GHS no category) based on this LD₅₀test in female rats.

UN GHS: Category 5

Conclusion

The acute median lethal oral dose (LD50) to rats of Visiomer® 1,3-BDDMA was demonstrated to be greater than 2000 mg/kg body weight. No signs of relevant toxicity were observed.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Quality of whole database:

One relevant, reliable (Klimisch score = 2) and adequate publication (peer-reviewed handbook data, pre-guideline study) is available.

Additional information

Reliable (RL1), relevant and adequate data are available for the acute oral toxicity of 1,3 -BDDMA:

 

Acute oral toxicity

In an acute oral toxicity study according to OECD 420 (Fixed dose method) with GLP, one group of female Wistar rats were given a single oral dose of 1,3 -Butanediol dimethacrylate (1,3 -BDDMA) at a dose level of  2000 mg/kg suspension in corn oil. The animals were observed for 14days. Klimisch score = 1 (HMRTF, 2021)

 

Oral LD₅₀female= > 2000 mg/kg bw

   

1,3 -Butanediol dimethacrylate is oral practically non toxic in Wistar rats (EU GHS no category) based on this LD₅₀test in female rats.

UN GHS: Category 5

Conclusion

The acute median lethal oral dose (LD50) to rats of Visiomer® 1,3-BDDMA was demonstrated to be greater than 2000 mg/kg body weight. No signs of relevant toxicity were observed.

This study result with the substance 1,3 -BDDMA (HMRTF, 2021) confirms to the result of an older study in rats done with 1,3 -BDDMA itself (Lawrence 1974). Due to the limited available data, the reliability is rated with Klimisch 4. In this study, the acute oral LD50 was found to be 5762 mg/kg bw in rats.

 

Acute inhalative 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 substance has a low vapour pressure. 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

The acute dermal LD50 of 1,3-BDDMA is reported to be >3000 mg/kg bw in rabbit in a screening study, whose reliability is rated with Klimisch 2 (peer-reviewed handbook data).

Based on the low systemic toxicity after acute oral administration and the calculated low dermal absorption potential (Heylings 2013, see chapter Toxicokinetics), no classification according UN-GHS is warranted.

 

Based on the available information, the acute toxicity of 1,3-BDDMA is low for oral and dermal routes of administration in rat and rabbits. There are no data gaps in acute toxicity. Even though there is no information on acute inhalative toxicity, there is no reason to believe that the acute toxicity is higher for this route of exposure. 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 selection of acute toxicity – oral endpoint
pre-guideline study similar to OECD guideline, pre-GLP; read across from the analogous substance 1,4 -BDDMA (read across justified in the category document)

Justification for selection of acute toxicity – inhalation endpoint
Inhalation is no relevant route of exposure and testing by inhalation is not appropriate. Exposure of humans via inhalation is unlikely taking into account the low vapour pressure and the low possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for selection of acute toxicity – dermal endpoint
pre-guideline study, pre-GLP, peer-reviewed handbook data

Compliance to REACH requirements

The acute oral requirement is covered with a reliable (reliability: 1) oral, rat study according to OECD 420 with the substance 1,3-BDDMA (HMRTF, 2021) and a low reliability oral rat study, performed with the substance itself. The acute dermal requirement is covered with and an reliable acute dermal study in rabbits, performed with the substance itself. An acute inhalation study is waived for exposure reasons (low vapour pressure).

Justification for classification or non-classification

Based on the available data, 1,3-BDDMA does not need to be classified for acute toxicity according to regulation (EC) 1272/2008 or UN-GHS. Thus, no labelling is required.