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Administrative data

Description of key information

There are valid study data available to assess the sensitising potential of ethoxylated trimethylolpropane triacrylate (TMPeoTA) - see below description.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
Data from a Buehler test available performed in accordance to OECD testing guideline 406 and GLP
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Age at study initiation: about 6 weeks
- Weight at study initiation: 355-433 g
- Housing: 5 animals/cage in stainless steel wire cages with plastic-coated grating, minimum floor area: 2000 cm2
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 15 days before the first test substance application


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
undiluted test substance was used for all three inductions, test substance 75% in doubly distilled water was used for the 1st challenge, test substance
50% in doubly distilled water was used for the 2nd challenge.
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
undiluted test substance was used for all three inductions, test substance 75% in doubly distilled water was used for the 1st challenge, test substance
50% in doubly distilled water was used for the 2nd challenge.
No. of animals per dose:
20 animals in the test group and 10 animals in the control group
Details on study design:
RANGE FINDING TESTS:
In accordance with the guideline a slightly irritating concentration should be used in the main test for induction whereas the maximum non-irritant
concentration should be applied for challenge.
Amount applied :
2 x 2 cm gauze patches (6 layers surgical gauze Ph . Eur. from Lohmann GmbH & Co. KG) containing 0.5 ml of the test substance / test substance
formulation were applied to the skin of the flanks under an occlusive dressing. The dressing consisted of rubberized linen patches (4 x 4 cm from
Russka), patches of Idealbinde (5 x 5 cm from Pfälzische Verbandstoff-Fabrik) and Fixomull Stretch (adhesive fleece) from Beiersdorf AG.
Duration of exposure:
- 6 hours
Site of application:
- right and left flank
Application frequency:
- one application
Number of test animals:
- 3 per test concentration
Readings:
- 1, 24 and 48 h after removal of the patches

Results:
24 hours after removal of the patch: discrete or patchy erythema was noted in two animals treated with the undiluted test substance. In one of these
animals erythema persisted until 48 hours. The animals treated with a 75% test substance preparation did not show any skin reactions 24 and 48 hours after removal of the patch. Therefore undiluted test substance was chosen for the inductions.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: three inductions were conducted
- Exposure period: 6 hours
- Test groups: treated with 0.5 ml of the undiluted test material
- Control group: The control group was not treated, since the test substance was applied undiluted and thus no vehicle was used
- Site: intact flank, always on the same application area
- Frequency of applications: one application per week; days 0, 7 and 14
- Duration: the animals were exposed to the test substance for 6 hours
- Concentrations: undiluted


B. CHALLENGE EXPOSURE
- No. of exposures: two
- Day(s) of challenge: the 1st challenge was carried out 14 days after the third induction. A 2nd challenge was performed one week after the 1st
challenge
- Exposure period: 6 hours
- Test groups: treated with 0.5 ml of the test substance solutions (75% 1st challenge, 50% 2nd challenge)
- Control group: treated with 0.5 ml of the test substance solutions (75% 1st challenge, 50% 2nd challenge)
- Site: intact flank
- Concentrations: 1st challenge with 0.5 ml of a 75% solution of the test material, 2nd challenge with 0.5 ml of a 50% solution of the test material
- Evaluation (hr after challenge): 24 and 48 hours after removal of the patch
Challenge controls:
A positive control (reliability check) with a known sensitizer is not included in this study. However, a separate study is performed twice a year in the
laboratory . The positive controls with Alpha-Hexylcinnamaldehyde, techn. 85% showed that the test system was able to detect sensitizing compounds under the laboratory conditions chosen.
Positive control substance(s):
yes
Remarks:
Alpha-Hexylcinnamaldehyde, techn. 85%
Positive control results:
A positive comtrol group was not included in this specific study. The positive control study is perfomed twice a year in th used laboratory and used as a reliability check. The positive controls with Aplha-Hexylcinnamaldehyde (85%) induced the expected positve response, proving the validity of the test system.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
75% test substance
No. with + reactions:
8
Total no. in group:
20
Remarks on result:
other:
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 75% test substance. No with. + reactions: 8.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
75% test substance
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other:
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 75% test substance. No with. + reactions: 2.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
75% test substance
No. with + reactions:
6
Total no. in group:
20
Remarks on result:
other:
Remarks:
Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 75% test substance. No with. + reactions: 6.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
75% test substance
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other:
Remarks:
Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 75% test substance. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
50% test substance
No. with + reactions:
9
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 50% test substance. No with. + reactions: 9.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
50% test substance
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 50% test substance. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50% test substance
No. with + reactions:
3
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 50% test substance. No with. + reactions: 3.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
50% test substance
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 50% test substance. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
24
Group:
positive control
Dose level:
5%
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
The first until third induction caused discrete or patchy to intense erythema 
and swelling in the test group animals.

After the 1st challenge discrete or patchy to moderate and confluent erythema 
and swelling could be observed in the test group animals. Due to discrete or 
patchy erythema observed in two control group animals the test substance 
concentration was reduced for the 2nd challenge.
The 2nd challenge caused discrete or patchy to moderate and confluent erythema in 
test group animals only.


The number of animals with skin findings after the 1st challenge and 2nd 
challenge is summarized in the following:

	        1st challenge	        2nd challenge
	        Test substance          Test substance
                75% in doubly           50% in doubly
                distilled water	        distilled water
	        24 h	48 h	Total	24 h	48 h	Total
Control group	2/10	0/10	2/10	0/10	0/10	0/10
Test group	8/20	6/20	9/20	9/20	3/20	9/20

x/y: number of positive reactions/number of animals tested 
(reading at 24  h and/or 48 h after the removal of the patch)
Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
Based on the results of this study and applying the evaluation criteria (at least 15% of the test animals exhibit skin reactions) it was concluded that the test substance has a sensitizing effect on the skin of the guinea pig in the BUEHLER Test under the test conditions chosen. Therefore, in accordance to classification criteria when ≥ 15 % responding at > 20 % topical induction dose, then a subcategorisation of Skin Sens1B is considered appropriate for the test substance.
Executive summary:

The test substance was tested for its sensitizing effect on the skin of the guinea pig in the BUEHLER Test based on the method of BUEHLER, E .V. (1965).

The test substance concentrations for the main test were selected based on the results of the pretest. All inductions were performed with the undiluted test substance, for the 1st challenge a 75% and for the 2 nd challenge a 50% test substance preparation in double distilled water was chosen. The study was performed using 1 control group and 1 test group. The inductions were performed on days 0, 7 and 14 . Two challenges were carried out 14 and 21 days after the last induction.

The first until third induction caused discrete or patchy to intense erythema and swelling in the test group animals. After the 1st challenge discrete or patchy to moderate and confluent erythema and swelling could be observed in the test group animals. Due to discrete or patchy erythema observed in two control group animals the test substance concentration was reduced for the 2nd challenge. The 2nd challenge caused discrete or patchy to moderate and confluent erythema in test group animals only. The number of animals with skin findings after the 1st challenge and 2nd challenge is summarized in the following table :

1 st challenge 2nd challenge

Control group: 2/10 0/10

Test group: 9/20 9/20

Based on the results of this study it was concluded that the test substance has a sensitizing effect on the skin of the guinea pig in the BUEHLER Test under the test conditions chosen.

Therefore, in accordance to classification criteria when≥ 15 % responding at > 20 % topical induction dose, then a subcategorisation of Skin Sens1B is considered appropriate for the test substance.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

There are valid study data available to assess the sensitising potential of ethoxylated trimethylolpropane triacrylate (TMPeoTA).


 


Guideline conform studies:


TMPeoTA was tested for its sensitizing effect on the skin of the guinea pig in the BUEHLER Test based on the method of BUEHLER, E .V. (1965) according to OECD 406 (BASF, 2004). The test substance concentrations for the main test were selected based on the results of the pretest. All inductions were performed with the undiluted test substance, for the 1st challenge a 75% and for the 2nd challenge a 50% test substance preparation in doubly distilled water was chosen. The study was performed using 1 control group and 1 test group. The inductions were performed on days 0, 7 and 14 . Two challenges were carried out 14 and 21 days after the last induction. The first until third induction caused discrete or patchy to intense erythema and swelling in the test group animals . After the 1st challenge discrete or patchy to moderate and confluent erythema and swelling could be observed in the test group animals. Due to discrete or patchy erythema observed in two control group animals the test substance concentration was reduced for the 2nd challenge. The 2nd challenge caused discrete or patchy to moderate and confluent erythema in test group animals only. The number of animals with skin findings after the 1st challenge and 2nd challenge is summarized: Control group: 1st challenge 2/10; Test group: 1st challenge 9/20, Control group: 2nd challenge 0/10; Test group: 2 nd challenge 9/20. Based on the results of this study it was concluded that TMPeoTA has a sensitizing effect on the skin of the guinea pig in the BUEHLER Test under the test conditions chosen.


 


In another test the skin sensitizing potential of TMPeoTA was assessed using the non-radioactive variant of the Murine Local Lymph Node Assay (BASF, 2006). Groups of 6 female CBA/Ca mice each were treated with 3%, 10% and 30% w/w preparations of the test substance in acetone or with the vehicle alone . The study used 3 test groups and 2 control groups. Each test animal was applied with 25 µL per ear of the respective test-substance preparation to the dorsum of both ears for three consecutive days. One control group was treated with 25 µL per ear of the vehicle alone, the other control group remained untreated to serve as a control for the immunological status of the animals. Three days after the last application the mice were sacrificed and the auricular lymph nodes were removed. Lymph node response was evaluated by measuring the cellular content (indicator of cell proliferation) and weight of each animal's pooled lymph nodes. Moreover, a defined area with a diameter of 0.8 cm was punched out of the apical part of each ear and for each animal the weight of the pooled punches was determined in order to obtain an indication of possible skin irritation. No signs of systemic toxicity were noticed. The test substance induced a statistically significant and biologically relevant response of the auricular lymph nodes when applied as 3%, 10% and 30% preparations in acetone. The statistically significant increased ear weights and additional clinical signs of skin irritation (eczematoid skin changes in 4 animals applied with the 10% preparation and in all animals of the 30% test group) indicate the induction of slight to moderate ear skin irritation by these concentrations. Taking into account the strong lymph node response, however, even in the low concentration with only weak ear skin irritation, the test substance is considered to be a skin sensitizer. In conclusion, the test substance has a skin sensitizing effect in the Murine Local Lymph Node Assay. The threshold concentration for sensitization induction was < 3% under the test conditions chosen.


 


A further murine local lymph node assay with another batch of TMPeoTA was performed equivalent to OECD 429 (BASF, 2002(a)). This sensitisation test was performed in two steps. In the first step concentrations of 3, 10 and 30% of the test substance in acetone were used. As lymph node reactions were produced by all concentrations, in the second step concentrations of 1, 0.3 and 0.1% were examined in order to determine a concentration not inducing lymph node reactions. Groups of 6 female CBA/Ca mice each were treated with several concentrations of preparations of the test substance in acetone or with the vehicle alone. Each step of the study used 3 test groups and 2 control groups. Each test animal was applied with 25 µL per ear of the respective test substance preparation to the dorsum of both ears for three consecutive days. No signs of systemic toxicity were noticed. A statistically significant increase in lymph node cellularity and in lymph node weights was induced by test substance concentrations of 3% and above. Based on the results of the study it is concluded, that under the test conditions chosen the test substance does have a sensitizing effect in the murine Local Lymph Node Assay. The maximum concentration which did not produce lymph node responses and thus is considered to represent the no effect concentration for sensitization induction in this test model is 1%.


 


Another test was performed to assess the sensitising potential of TMPeoTA (BASF, 2002(b)). Therefore groups of 6 female CBA/Ca mice each were treated with 3, 10 and 30% of the test substance diluted in acetone or with the vehicle alone. The study used 3 test groups and 2 control groups and was conducted equivalent to OECD guideline. Each test animal was applied with 25 µL per ear of the respective test substance preparation to the dorsum of both ears for three consecutive days. No signs of systemic toxicity were noticed. A statistically significant increase in lymph node cellularity and in lymph node weights was observed in animals treated with test substance concentrations of 3, 10 and 30%. The increased ear weights and clinical signs of skin irritation (eczematoid skin changes in 4 animals, applied with the 10% preparation and in all animals of the 30% test group) indicated a significant irritant property of the test substance when applied in these concentrations. Taking into account the strong lymph node response, however, even in the lowest concentration with only moderate ear skin irritation, the test substance is considered to be a skin sensitizer. From the results of the study no threshold concentration for sensitization induction can be derived.


 


Another sensitisation test equivalent to OECD 429 was performed in two steps (BASF, 2004(d)). 0.1% 0.3%, 1%, 3%, 10% and 30% test substance in acetone were used to determine a concentration not inducing lymph node reactions. Groups of 6 female CBA/Ca mice each were treated with several concentrations of preparations of the test substance in acetone or with the vehicle alone. No signs of systemic toxicity were noticed. The test substance induced a statistically significant and biologically relevant proliferation of the auricular lymph nodes and cell counts when applied as 1%, 3% or 10% test substance preparation in acetone. A statistically significant increase in lymph node cellularity but not in Lymph node weight was observed for 0.3% test substance concentration. The threshold concentration for sensitization induction was > 0.3% < 1% under the test conditions chosen. This study was less documented and is there only used as underlining information and not taken into account for assessment.


 


Tests according to other guidelines:


A Local Lymph Node Assay was conducted to assess the sensitising potential of TMPeoTA (BASF, 2004(c)). Therefore 6 mice per dose group received 25µL 3% test substance in acetone (or pure acetone; control group) during the induction phase and 14 days later 1% during the challenge phase dermally applied to the ear. The Test substance induced a statistically significant increase of lymph node cellularity and lymph node weights in both the induction and the challenge phase compare to the control. Based on the results of the study it was concluded, that under the test conditions chosen the test substance has a sensitizing effect in the murine Local Lymph Node Assay. This study was only less documented and is there only used as underlining information and not taken into account for assessment.


 


Assessment sensitisation:


All available information is taken into account to assess the sensitising potential ethoxylated trimethylolpropane triacrylate (TMPeoTA). Due to the less documentation (short detailed summary) of four BASF studies ( (BASF, 2004(a-d) these studies are rated lower for assessment. Nevertheless, the results obtained from these four studies confirmed the result of the more reliable documented studies from BASF (BASF, 2004 and BASF, 2006). All available studies showed sensitising effects for TMPeoTA and one study derives a threshold of 1 % (NOEC), whereas most other conducted studies were performed with much higher concentration. Overall, TMPeoTA is a skin sensitizer, with a possible threshold below 3% (based on the result of non-radioactive LLNA with good documentation).


 


Key study assignment:


Due to the less documentation of four BASF studies (BASF, 2004m (a-d) these studies are rated as less reliable than the other available studies. All remaining available studies are equal in quality. Both studies are conducted according to OECD guideline (BASF, 2004 and BASF, 2006)) and showed both sensitizing effects, but the LLNA test was done non-radioactive which is a method under debate. Therefore the Buehler test is chosen as key study (BASF, 2004) as it represents the most reliable and relevant study. Nevertheless, all other studies were entered as supporting studies.


 


Short description of key information:


Buehler test, guineapig, OECD 406: sensitising, 9/20 positive (@50%) (BASF, 2004)


LLNA, mice, non-radioactive, OECD 429: sensitising; threshold < 3% (BASF, 2006)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Skin sensitisation:

According to GHS, substances shall be classified as skin sensitizer if there are positive results from appropriate animal test. A Buehler test revealed positive findings for 9/20 tested animals (well more than 15%) showing the sensitising potential of the test substance. All inductions were performed with the undiluted test substance, for the 1st challenge a 75% and for the 2nd challenge a 50% test substance preparation in doubly distilled water was chosen. Therefore, in accordance with classification criteria when ≥ 15 % responding at > 20 % topical induction dose, then a subcategorization of Skin Sens 1B is considered appropriate for TMPeoTA.

This is also underlined by different positive mouse local lymph node assays.

Hence TMPeoTA needs to be classified according to GHS (Regulation (EU) 1272/2008) as sensitising to skin (Skin Sens 1B).

 

Labelling for skin sensitisation:

GHS: sensitising to skin (Skin Sens 1B)

 

Respiratory sensitisation:

No labelling can be derived due to lack of information