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Diss Factsheets

Administrative data

Description of key information

LLNA: skin sensitiser , EC3 = 0 .5% (BASF SE, 2009)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA:J
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, 97633 Sulzfeld
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 -12 weeks
- Weight at study initiation: 19.3 g - 22.8 g
- Housing: single (Makrolon cage, type II
- Diet (e.g. ad libitum): Kliba-Labordiät (Maus / Ratte Haltung “GLP”), Provimi Kliba SA, Kaiseraugst, Basel, Switzerland, ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 28 days before the first test-substance application

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
methyl ethyl ketone
Concentration:
0.1, 0.3 and 1%
No. of animals per dose:
5
Details on study design:
The study comprised three treatment groups and a vehicle control group. Each group consisted of 5 mice. A check for dead or moribung animals was made twice each workday (beginning and end) and once on Saturdays, Sundays and on public holidays.
No detailed clinical examination of the individual animals was performed but any obvious signs of systemic toxicity and/or local inflammation at the application sites were noted in the raw data.
Body weight determination: Individual body weights on day 0 prior to the first application and on day 5 prior to the sacrifice of the animals.
Signs and symptoms: No detailed clinical examination of the individual animals was performed but any obvious signs of systemic toxicity and/or local inflammation at the application sites were noted in the raw data.
Form of application: Epicutaneous application is simulating dermal contact with the compound which is possible to occur under practical use conditions.
Application volume: 25 μL per ear
Site of application: Dorsal part of both ears
Frequency of application: 3 consecutive applications (day 0 – day 2) to the same application site
On study day five (about 66 to 72 hours after the last application of test substance to the ears) the mice were injected intravenously with 20 μCi of 3H-thymidine in 250 μl of sterile saline into a tail vein.
The animals were sacrificed on study day 5 about 5 hours after 3H-thymidine injection by cervical dislocation.
Determination of ear weight: Immediately after the death of each animal a circular piece of tissue (diameter 0.8 cm) was punched out of the apical part of each ear of all animals. The weight of the pooled punches was determined for each test group. These measurements serve for detecting a potential inflammatory ear swelling.
Removal and weight determination of the lymph nodes: Immediately after removal of the ear punches the left and right auricular lymph nodes were dissected. The weight of the pooled lymph nodes from both sides was determined for each animal.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Parameter:
EC3
Value:
0.5
Cellular proliferation data / Observations:
Cell count, 3H-thymidine incorporation and lymph node weight
The test substance induced a biologically relevant response (increase to 1.5 fold or above of control value = stimulation index (SI) ≥ 1.5) in the auricular lymph node cell counts when applied as 1% preparation in MEK. There was a relevant increase in lymph node weights, as well. Concomitantly, the increase of 3H-thymidine incorporation into the cells was biologically relevant (increase above the cut off stimulation index of 3) at this concentration (see figures below). No relevant lymph node reaction was caused by the 0.3% and 0.1% concentrations.
Ear weight
Some increase in ear weights was observed in mice treated with the 1% test-substance preparation indicating ear skin irritation. The mild degree of irritation, however, does not fully explain the considerable increases in cell counts and 3H-thymidine incorporation observed.
Body weights
The expected body weight gain was generally observed in the course of the study.

Test group Treatment Cell Count
Stimulation Index
³H -thymidine
incorporation Stimulation Index
Lymph Node Weight
Stimulation Index
Ear Weight
Stimulation Index
1 vehicle MEK 1. 00 1. 00 1.00 1.00
2 0.1% in MEK 1. 21 1. 07 1.08 0.95
3 0.3% in MEK 1. 22 1. 61 1.15 1.00
4 1% in MEK 2.39 7.87 1.90 1.14
Interpretation of results:
Category 1A (indication of significant skin sensitising potential) based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

The skin sensitizing potential of 1,4-Butandioldiacrylat was assessed using the radioactive Murine Local Lymph Node Assay. The assay simulates the induction phase for skin sensitization in mice. It determines the response of the auricular lymph nodes on repeated application of the test substance to the dorsal skin of the ears. Groups of 5 female CBA/J mice each were treated with 1%, 0.3% and 0.1% w/w preparations of the test substance in MEK (methyl ethyl ketone) or with the vehicle alone. The study used 3 test groups and 1 control group. 25 μL of the test substance solution each were applied to the dorsum of both ears for three consecutive days. The control group was treated with 25 μL per ear of the vehicle alone. Three days after the last application the mice were injected intravenously with 20 μCi of 3H-thymidine in 250 μL of sterile saline into a tail vein. About 5 hours after the 3H-thymidine injection, the mice were sacrificed and the auricular lymph nodes were removed. The weights of each animal’s pooled lymph nodes were determined. No signs of systemic toxicity were noticed. No relevant lymph node reaction was caused by the 0.3% and 0.1% concentrations. Some increase in ear weights was observed in mice treated with the 1% test-substance preparation indicating ear skin irritation. The mild degree of irritation, however, does not fully explain the considerable increases in cell counts and 3H-thymidine incorporation observed. Thus it is concluded that 1,4-Butandioldiacrylat shows a skin sensitizing effect in the Murine Local Lymph Node Assay under the test conditions chosen. The threshold concentration for sensitization induction was > 0.3% < 1%. The estimated concentration that leads to the SI of 1.5 for cell count (EC 1.5) and the estimated concentration that leads to the SI of 3.0 for 3H-thymidine incorporation (EC 3) was calculated by linear regression from the results of the 0.3% and 1% concentrations to be 0.5%, respectively.

This positive result is confirmed in the two publications by Bjoerkner et al. In the GPMT assays (intradermal induction 1%), 10 of 15 animals reacted to a challenge of 0.2% BDDA in petrolatum. The use of acetone during challenge reduced the number of positive reactions to 7 out of 15.

In the publication by VanDerWalle, no sensitizing potential was observed after an intradermal inducation with 11%. This negative result is thought to reflect an overdose effect and not a true indication of the lack of sensitziting potential.

Also, workers tested for an existing allergy to BDDA by Malten et al., 1979, did not show a positive response during patch testing. But due to the low number of people examined and lack of details in the study, no definite conclusion can be drawn from this publication.

In a broader review of patch test results in Sweden between 1985 and 1995, 22 of 484 patients with a history of exposure to methacrylates or acrylates (no further details known) reacted to BDDA (Kanverva, 1997). It is unclear, if all patients were tested against BDDA, nor, which of them had been previously exposed to the substance, but the results confirm the results from the animal experiments.

The results of a case report of a woman who reacted to the glue used in an insulin infusion pump also suggest a sensitizing property of BDDA. Patch testing with 0.1% BDDA yielded a positive result, though this was also the case for many other (meth)acrylates tested, and since the glue components are not known, the substance she was originally exposed to could not be deteremined.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the results of the skin sensitization testing, the test item is classified as skin sensitization cat. 1A (H317) according to Regulation (EC) No 1272/2008 (CLP).

Nevertheless, for the substance an entry in Table 3.1 of Annex VI of Regulation (EC) No 1272/2008 (CLP) exists. Thus, the substance is classified for skin sensitization cat. 1 (H317).