Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: LD50 (rat, combined) = 10066 mg/kg bw; OECD Guideline 401; pre-GLP study
Acute inhalation toxicity: no relevant route of exposure due to the low vapour pressure (see IUCLID section 7.1)
Acute dermal toxicity: Study in progress

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:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study performed before implementation of GLP
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Appraisal of the safety of chemicals in foods, drugs and cosmetics, by the Staft of the Division of Pharmacology, US FDA (1959)
Principles of method if other than guideline:
Study performed before implementation of the corresponding guideline, but performance complies to a large extent to the later implemented international guideline.
GLP compliance:
no
Remarks:
Study performed before implementation of GLP
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 1,4-Butandioldimethacrylat
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: no data
- Weight at study initiation: 160 – 240 g
- Fasting period before study: 16 h before study initiation
- Housing:individually
- Diet (e.g. ad libitum): laboratory rodents standard diet, ad libitum
- Water (e.g. ad libitum): 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): 12/12

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 12.60 mL/kg bw
Doses:
7.94, 8.97, 10.00, 11.30, 12.60 mL/kg bw corresponding to 8131, 9185, 10240, 11571 and 12902 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: weighing day 0, day 14; clinical signs 20 min, 1 h, 3 h, 24 h, 7 d 14 d post application
- Necropsy of survivors performed: yes
Statistics:
LD50-calculation by probit analysis
Sex:
male/female
Dose descriptor:
LD50
Effect level:
10.066 mg/kg bw
Based on:
test mat.
95% CL:
9 400 - 10 035
Sex:
male/female
Dose descriptor:
LD50
Effect level:
9.83 mL/kg bw
Based on:
test mat.
95% CL:
9.18 - 10.47
Mortality:
- 7.94 mL/kg bw dose group: 1/5 males, 2/5 females died
- 8.97 mL/kg bw dose group: 2/5 males, 2/5 females died
- 10.00 mL/kg bw dose group: 3/5 males, 2/5 females died
- 11.30 mL/kg bw dose group: 3/5 males, 3/5 females died
- 12.60 mL/kg bw dose group: 4/5 males, 4/5 females died
animals died within 3 days p.a.
Clinical signs:
- reduced activity, piloerection and ataxia starting 1 to 3 hours after application, lasting for 24 hours; in the highest dose group lasting for 7 days
Body weight:
- body weight gain of surviving animals was similar in all dose groups
Gross pathology:
- redness of stomach and intestinal mucosa in died and surviving animals
Other findings:
n/a
Interpretation of results:
GHS criteria not met
Conclusions:
On the basis of the results obtained after a single oral administration, the oral LD50 was determined to be 9.83 mL/kg bw corresponding to 10.06 g/kg bw referring to 100 % active substance (based on a density of 1.024 g/cm³).
Executive summary:

In an acute oral toxicity study similar to OECD guideline 401, groups of fasted Wistar rats (5 males + 5 females) were given a single oral dose of undiluted 1,4-BDDMA (according to supplier's information: purity ca. 90%, reactive ester content of 98 %) at doses of 7.94, 8.97, 10.00, 11.30 and 12.60 mL/kg (corresponding to 8131, 9185, 10240, 11571 and 12902 mg/kg bw based on a density of 1.024 g/cm³) and observed for 14 days.

  

The following mortality was observed: 1 male and 2 females in the 7.94 mL/kg dose group, 2 males and 2 females at 8.97 mL/kg, 3 males and 2 females at 10.00 mL/kg, 3 males and 3 females at 11.30 mL/kg, 4 males and 4 females at 12.60 mL/kg. The surviving animals showed reduced activity, piloerection and ataxia starting 1 to 3 hours after application and lasting for 24 hours; in the highest dose group the symptoms lasted up to 7 days. No changes in body weight gain were observed in the surviving animals throughout all dose groups. At necropsy redness of stomach and intestinal mucosa in died and surviving animals was observed.

Oral LD50 Combined = 9.83 mL/kg bw (95% c.i. 9.18 - 10.47 mL/kg bw) corresponding to 10.06 g/kg bw

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:
10 066 mg/kg bw
Quality of whole database:
One relevant, reliable (Klimisch score = 2) and adequate study is available.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
Although the acute dermal toxicity study was not requested by ECHA in a Compliance Check, the SIEF decided to conduct the study to find answers to the question whether 1,4-BDDMA has the potential to induce systemic toxicity after dermal application. The question has arisen since there were unclear, potential systemic effects observed in the LLNA (see Chapter 7.4.) with the registered substance that need to be clarified.
“On day 3, all test item treated animals showed unspecific clinical signs: reduced spontaneous activity, ruffled fur and hunched posture. After application, the animals tried to burrow themselves in the bedding. Furthermore, the animals treated with test item concentrations of 50 and 100% showed eye lid closure and abnormal walk on day 3. On day 4 all animals treated with test item concentrations of 50 and 100% showed ruffled fur and two animals treated with a test item concentration of 100% showed reduced spontaneous activity. Whether the clinical symptoms observed were signs of mild systemic toxicity or mere reactions to the irritant properties of the test item cannot be stated.
No cases of mortality were observed.
Burrowing in the bedding and ruffled fur are often observed in LLNA-studies since the mice do not like to have oily or wet substance on their fur. The mentioned signs can be interpreted as signs of discomfort linked with the dermal application. The increase of the body weight observed in all animals is a clear sign that the animals are healthy. Due to the potential oral intake of the test material by preening themselves or by preening the fur of another mouse, a systemic effect after oral administration cannot not be excluded completely.” (cited from the study report of LLNA)
The study will be conducted at ICCR Roßdorf, In den Leppsteinswiesen 19, 64380 Roßdorf, Germany. Regarding the study plan, we expect the draft report on 31st July 2021.
The REACH dossier will be updated without undue delay once the study finalised.

Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Reliable (RL2), relevant and adequate data are available for the acute oral toxicity of 1,4-BDDMA and the dermal toxicity of the closely related read-across substance 1,3-BDDMA.


 


Acute oral toxicity


In an acute oral toxicity study similar to OECD guideline 401, groups of fasted Wistar rats (5 males + 5 females) were given a single oral dose of undiluted 1,4-BDDMA according to supplier's information: purity ca. 90%, reactive ester content of 98 %) at doses of 7.94, 8.97, 10.00, 11.30 and 12.60 mL/kg (corresponding to 8131, 9185, 10240, 11571 and 12902 mg/kg bw based on a density of 1.024 g/cm³) and observed for 14 days.


The following mortality was observed: 1 male and 2 females in the 7.94 mL/kg dose group, 2 males and 2 females at 8.97 mL/kg, 3 males and 2 females at 10.00 mL/kg, 3 males and 3 females at 11.30 mL/kg, 4 males and 4 females at 12.60 mL/kg. The surviving animals showed reduced activity, piloerection and ataxia starting 1 to 3 hours after application and lasting for 24 hours; in the highest dose group the symptoms lasted up to 7 days. No changes in body weight gain were observed in the surviving animals throughout all dose groups. At necropsy redness of stomach and intestinal mucosa in died and surviving animals was observed.


Oral LD50 (rat) Combined = 9.83 mL/kg bw (95% c.i. 9.18 - 10.47 mL/kg bw) corresponding to 10.06 g/kg bw.


 


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


An acute dermal toxicity is in progress and the dossier will be updated without undue delay as soon as the lead registrant will have received the final report. 


 


Based on the available information, the acute toxicity of 1,4-BDDMA is low for the oral route of administration in rat and rabbits. There are no data gaps in acute toxicity. Even though there is no information on acute inhalative toxicity and there is only read across information available on acute dermal toxicity, there is no reason to believe that the acute toxicity is higher for these routes 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

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 possibility of exposure to aerosols, particles or droplets of an inhalable size.

Justification for selection of acute toxicity – dermal endpoint
An acute dermal toxicity study is in progress. 


 


Compliance to REACh requirements


The requirements are covered with an oral rat study. An acute inhalation study is waived for exposure reasons (low vapour pressure). An acute dermal study is waived due to low oral toxicity (LD50> 2000 mg/kg bw).

Justification for classification or non-classification

Based on the available data, 1,4-BDDMA does not need to be classified for acute toxicity according to regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.