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Administrative data

Description of key information

Acute oral toxicity: LD50 (rat) = 10837 mg/kg bw; LD50 (mouse) = 10750 mg/kg bw; no information on test procedure; no GLP
Acute inhalation toxicity: no relevant route of exposure
Acute dermal toxicity: LD50 (mouse) > 2000 mg/kg bw; 14 d-dose ranged finding study, GLP

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Article in Russian. Only abstract in English.
Qualifier:
no guideline available
Principles of method if other than guideline:
no data on guideline available
GLP compliance:
no
Test type:
other: no data on testing procedure
Specific details on test material used for the study:
- Name of test material (as cited in study report): ТРИЭТИЛЕНГЛИКОЛЬДИМЕТАКРИЛАТ (Trietilenglikoldimetacrilat), TGM-3
- Physical state: liquid
- Analytical purity: no data
- Impurities (identity and concentrations): technical TGM-3: 3,5% Toluene, 0,071% Hydroquinone; treated TGM-3: 0,0043% Hydroquinone
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
not specified
Doses:
no data
No. of animals per sex per dose:
no data
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
10 837 mg/kg bw
Based on:
not specified
Remarks on result:
other: rat
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 of TREGDMA is reported to be 10837 mg/kg bw in rats.
Executive summary:

The acute oral LD50 of TREGDMA is reported to be 10837 mg/kg bw in rats.

Endpoint:
acute toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
Pre-guideline study.
Justification for type of information:
Read across from an analogous substance within the category.
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
Qualifier:
according to
Guideline:
other: "Appraisal of the safety of chemicals in foods, drugs and cosmetics, FDA"
Principles of method if other than guideline:
Method: in accordance with Appraisal of the safety of chemicals in food, drugs and cosmetics, FDA (1959)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF Wistar rats, Zucht Winkelmann, Paderborn, Germany
- Age at study initiation: no data
- Weight at study initiation: 145 - 225 g
- Fasting period before study: 16 hours
- Housing: 5 m, 5 w animals per group
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 45 - 55 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
7.94, 8.89, 10.00, 11.20, 12.60 ml/kg
No. of animals per sex per dose:
5f/5m per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighting: 20 min, 1h, 3h, 24h, 48h, 7d, 14d
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: reflexes, emotions, consciousness, central
symptoms, autonomous functions, tone
Sex:
male/female
Dose descriptor:
LD50
Effect level:
8 300 mL/kg bw
Based on:
test mat.
95% CL:
7.69 - 8.96
Remarks on result:
other: 14 days LD50; equals LD50: 8700 mg/kg with a density of 1.055
Mortality:
In all the dose groups mortalities occurred within 5 days. In the first group 4/10 and second dose group 7/10 animals died, in the third dose group 8/10 and in the fourth and fifths dose group 10/10 animals died after 14 days.
Clinical signs:
Dose-dependent effects e.g. decreased activity, distributed coordination, piloerection; in high dose groups: anomalous attitude, tremor; symptoms occurred 20 min after administration of TS and lasted for 24 h, after that all animals showed normal behaviour.

Table (I) Mortality (mortalities occurred within 5 days p.a.)

 group   dose  24 hours (p.a.)  14 days (p.a.)
 (I)  7.94 ml/kg  0/10  4/10
 (II)  8.89 ml/kg   3/10  7/10
 (III)  10.0 ml/kg  6/10  8/10
 (IV)  11.20 ml/kg  6/10  10/10
 (V)  12.60 ml/kg  8/10  10/10

Table(II) Weight development

group/ number of animals   mean weight (ante application; a.a.)   mean weight (post application; p.a.) after 14days
 (I) / 5f, 5m  166.0 g  190.8 g
 (II) / 5f, 5m   194.0 g  221.7 g
 (III) / 5f, 5m   177.0 g  170.0 g
 (IV) / 5f, 5m  178.5 g    - 
 (V) / 5f, 5m  168.5 g    - 

Remark: Except the animals I-9 and III-8 (very haggard animals) all the other test animals showed at the  end of the post exposure period of 14 days normal body weight gain.

Interpretation of results:
GHS criteria not met
Conclusions:
According to the test result: LD50(14days) 8700 mg/kg bw the test substance Ethylene glycol dimethacrylate has to be classified as nontoxic in respect of its acute oral toxicity.
Executive summary:

In an pre-guideline acute oral toxicity study, groups of fasted male and female SPF Wistar rats were given a single oral dose of Ethylene glycol dimethacrylate > 98.5 % at doses of 7.94, 8.89, 10.00, 11.20 and 12.60 ml/kg bw and observed for 14 days.

 

Oral LD50Combined = 8.30 ml/kg bw equals ca. 8700  mg/kg  bw

GHS Category 5 ranges from 2000 -5000 mg/kg bw and represents the lowest hazard category for classifying the acute oral toxicity of a chemical substance. ("Criteria for hazard Category 5 are intended to enable the identification of the test substances which are of relatively low acute toxicity hazard but which, under certain circumstances may present a danger to vulnerable populations". (OECD guideline 425 annex 4)).

    

Ethylene glycol dimethacrylate is of very low oral toxicity based on this LD50 test in males and females.

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:
10 387 mg/kg bw

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:
experimental study
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
Qualifier:
no guideline followed
Principles of method if other than guideline:
subacute study according to EPA Dermal Bioassay Workshops (April 28-29, 1987 and May 18-19, 1988), 14 d dose range finder

GLP compliance:
yes
Test type:
other: 14 d dose-range finding study
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): triethylene glycol dimethacrylate
Species:
mouse
Strain:
other: C3H/HeNHsd
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley (Indianapolis, IN)
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2-3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-77
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
open
Vehicle:
acetone
Details on dermal exposure:
TEST SITE
applied to the clipped interscapular region of the back
- Type of wrap if used: no wrap
- Time intervals for shavings or clipplings: during the week prior to the first dose and as needed during the dosing period, the fur was clipped from the dorsal area of the trunk

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 µL
- Concentration (if solution): 25, 50, 100%

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Duration of exposure:
14 d
Doses:
50 µl of 25, 50, 100% corresponding to approximately 500, 1000 and 2000 mg/kg bw/d

(density = 1.092 g/cm³; body weight assumed 25 g; purity 91%; resulting in 500 mg/kg bw/d for 25% dose group,1000 mg/kg bw/d for 50% dose group and 2000 mg/kg bw/d for 100% dose group)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: dose was applied daily for 14 days
Mortality:
no mortality occurred in all dose groups
Clinical signs:
no significant clinical observations
Gross pathology:
No necropsy findings on internal organs
Interpretation of results:
not classified
Conclusions:
The dermal LD50 of TREGDMA is greater than 2000 mg/kg bw even when this dose is not applied once, but daily for 14 days.
Executive summary:

In a dose-range-finding study for a repeated-dose dermal toxicity study, TREGDMA (95% a.i.) was applied to the shaved skin of 5 male C3H/HeNHsd mice/dose at dose levels of 0, 25, 50 and 100% (applied in 50 µL) corresponding to approx. 500, 1000 and 2000 mg/kg bw/d for 14 days.

No mortality, no significant clinical signs, and no necropsy findings on internal organs were observed in all dose groups.

Desquamation and exfoliationwas the only skin finding noted during the study and at necropsy in the 50 and 100% TREGDMA treated groups. Microscopic changes in the treated skin primarily consisted of dermatitis, intracorneal pustule formation, acanthosis, and hyperkeratosis. Epidermal necrosis or ulceration was not evident in the treated mice. 

The dermal LD50 in this study was greater than 2000 mg/kg bw even when this dose is not applied once, but daily for 14 days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

According to REACH regulation Annex XI, 1 the testing of acute oral toxicity of TREGDMA is scientifically unjustified. The available data are sufficient for classification, labelling and hazard assessment.

 

Although there is only a Russian study of low reliability (RL=4) available for TREGDMA showing low toxicity (LD50 = 10837 mg/kg bw in rats; LD50 = 10750 mg/kg bw in mice), this is nevertheless consistent with data for higher (8-9 EO) and lower (1 EO) ethoxylated glycol dimethacrylates (PEG400DMA, EGDMA) partially from the multifunctional Methacrylate category. All members of this category show a consistently very low toxicity by the oral route. Based on interpolation it can be assumed that TREGDMA is also of low toxicity by the oral route.

 

Moreover, for TREGDMA a combined repeated dose toxicity study with the Reproduction/Developmental Toxicity Screening Test (OECD guideline 422) is available in which no adverse effects have been observed up to the highest tested dose of 1000 mg/kg bw/d when administered for 33 to 40 consecutive days. This also suggests low acute oral toxicity.

 

According to Seidle et al. (2010) a “historical data review has demonstrated that 28-day repeated dose toxicity studies can be used to identify compounds that are not acutely toxic (LD50 > 2000 mg/kg), which suggests that in vivo testing could be avoided for these substances, thereby substantially reducing animal use in acute toxicity testing“.

 

Creton et al. (2010) have reviewed an approach to use a repeated dose NOAEL for the prediction of the LD50: “Using an empirical approach, a repeat-dose NOAEL of ≥ 200 mg/kg was selected as a threshold, with the expectation that compounds with a NOAEL ≥200 mg/kg would be considered as non-toxic (LD50 >2000 mg/kg) after acute oral exposure. This threshold enabled a correct identification of 63% of non-acutely toxic chemicals (those with an LD50 >2000 mg/kg), while less than 1% of chemicals in the database were misclassified as non-toxic when they actually had an LD50 ≤2000 mg/kg”.

 

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 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

No acute dermal toxicity study is available for TREGDMA. However, a reliable (RL=2), relevant and adequate 14 day-dose range finding study conducted with the test substance is available:

In a dose-range-finding study for a repeated-dose dermal toxicity study, TREGDMA (95% a.i.) was applied to the shaved skin of 5 male C3H/HeNHsd mice/dose at dose levels of 0, 25, 50 and 100% (applied in 50 µL), corresponding to approximately 0, 500, 1000 and 2000 mg/kg bw/d for 14 days. In deviation to the common guidelines for acute dermal toxicity testing, this dose was not applied once, but daily for 14 days.

No mortality, no significant clinical signs, and no necropsy findings on internal organs were observed in all dose groups. Desquamation and exfoliation was the only skin finding noted during the study and at necropsy in the 50 and 100% TREGDMA treated groups. Microscopic changes in the treated skin primarily consisted of dermatitis, intracorneal pustule formation, acanthosis, and hyperkeratosis. Epidermal necrosis or ulceration was not evident in the treated mice.   

The dermal LD50 in this study was greater than 2000 mg/kg bw even when this dose is not applied once, but daily for 14 days.

 

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.

 

Compliance to REACh requirements

The requirements are covered with a low reliability oral rat study and a short-term dermal study, both performed with the substance itself. An acute inhalation study is waived for exposure reasons (low vapour pressure).

References

Seidle T. et al.: Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing, TOXICOLOGICAL SCIENCES 116(2), 382–396 (2010).

Creton S. et al.: Acute toxicity testing of chemicals—Opportunities to avoid redundant testing and use alternative approaches. Critical Reviews in Toxicology, 2010; 40(1): 50–83

Justification for classification or non-classification

Based on the available data, TREGDMA does not need to be classified for acute toxicity according to regulation (EC) 1272/2008.

Based on the available data, TREGDMA does not need to be classified for acute toxicity according to UN-GHS.