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Description of key information

Acute skin sensitisation properties of asymmetrical epoxy amine adduct Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA were assessed using a read across approach from data on symmetrical epoxy amine adducts Reaction products of IPDA with bisphenol A diglycidylether (BADGE) and Reaction products of MXDA with bisphenol A diglycidylether (BADGE), as these substances were considered to show similar toxicological properties. In Local Lymph Node Assay performed with Reaction products of IPDA with bisphenol A diglycidylether (BADGE) or Reaction products of MXDA with bisphenol A diglycidylether (BADGE) skin sensitising properties were confirmed for both substances. Based on the results obtained, Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA was considered to be a skin sensitizer. There was no evidence for respiratory sensitisation from occupational use.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
from 2008-05-07 to 2008-06-20
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)
Version / remarks:
April 2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
2004/73/EC
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Hungarian Supplier: WOBE Kereskedelmi Kft. H-1164, Budapest, Garmada u. 10.
- Age at study initiation: Young adult, 9 - 10 weeks old, age-matched within one week
- Weight at study initiation: The weight variation in animals involved in the study did not exceed ± 20 % of the mean weight.
- Housing: Individual caging Type II. polypropylene/ polycarbonate
- Diet: Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany ad libitum
- Water: Tap water from municipal supply, as for human consumption from 500 mL bottle ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes: 8 - 12 air exchange/hour by central air-condition system
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Vehicle:
propylene glycol
Concentration:
25, 10 , 5, 2.5 % (w/v)
No. of animals per dose:
4 animals/treatment group
Details on study design:
In the main assay, twenty female CBA/Ca mice were allocated to five groups of four animals each:
- Four groups received the appropriate formulation of Reaction products of IPDA with bisphenol A diglycidylether (BADGE) at concentrations of 25, 10, 5 and 2.5 % (w/v)
- the negative control group received the solvent propylene glycol (PG)
Each substance was applied on the external surface of each ear (25 µL/ear) for three consecutive days (Day 0, 1 and 2) at the appropriate concentrations. On Day 5, the cell proliferation in the local lymph nodes was measured by in corporation of tritiated methyl-thymidine (3HTdR) and the values obtained were used to calculate the stimulation indices (SI)
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
The positive control substance alpha-Hexylcinnamaldehyde (HCA) was examined at a concentration of 25 % in the relevant vehicle. A significant lymphoproliferative response (SI >= 3) was noted for HCA with stimulation index value of 7.5, in accordance with our previous data.
Key result
Parameter:
SI
Value:
5.9
Test group / Remarks:
25 % solution
Key result
Parameter:
SI
Value:
6.1
Test group / Remarks:
10 % solution
Key result
Parameter:
SI
Value:
5.7
Test group / Remarks:
5 % solution
Key result
Parameter:
SI
Value:
4.6
Test group / Remarks:
2.5 % solution
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Under the conditions of the present assay Reaction products of IPDA with bisphenol A diglycidylether (BADGE), dissolved in an appropriate solvent up to the maximum feasible concentration (25 %), was shown to have sensitisation potential (sensitiser) in the Local Lymph Node Assay. The EC3 value was below the lowest tested concentration of 2.5 %.
Executive summary:

A Local Lymph Node Assay according to OECD 429 and Commission Directive 2004/73/EC, B.42 was performed with CBA/Ca Ola Hsd mice. The maximum concentration of Reaction products of IPDA with bisphenol A diglycidylether (BADGE) in an acceptable solvent was established according to the principles of the relevant guidelines. The maximum attainable concentration based on solubility was 50 % in Propylene glycol (PG) after heating to approximately 80 °C, but because of a very high viscosity, application of this formulation on the ears of animals would not be possible. The next concentration recommended by the relevant guideline is 25 % and this formulation was considered to be physically acceptable for topical application on the ears. A preliminary irritation/toxicity test indicated that the maximum concentration of test item of 25 % in PG was acceptable.

The cutaneous effect observed in the 25 % dose group was considered not to be a classical irritation response and there were no cutaneous effects in lower doses, where a clear lymph node proliferation effect was observed. Hence, in the absence of confounding effects of significant local or systemic toxicity at the applied concentrations, the proliferation values obtained are considered to reflect the real potential of the test item to cause lymphoproliferation in the Local Lymph Node Assay.

A significant lymphoproliferative response (SI >= 3) was noted for Reaction products of IPDA with bisphenol A diglycidylether (BADGE) at all of the applied concentrations. The proliferation values obtained corresponded to the conventional biological dose-response. With proliferation values above 3 obtained at all of the applied concentration and the clear dose-response observed Reaction products of IPDA with bisphenol A diglycidylether (BADGE) was considered a skin sensitiser. 

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For read-across justification please refer to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Key result
Parameter:
SI
Value:
5.9
Test group / Remarks:
25 % solution
Key result
Parameter:
SI
Value:
6.1
Test group / Remarks:
10 % solution
Key result
Parameter:
SI
Value:
5.7
Test group / Remarks:
5 % solution
Key result
Parameter:
SI
Value:
6.6
Test group / Remarks:
2.5 % solution
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
from 2008-05-13 to 2008-06-20
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)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
2004/73/EC
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Hungarian Supplier: WOBE Kereskedelmi Kft. H-1164, Budapest, Garmada u. 10.
- Age at study initiation: Young adult, 9 - 10 weeks old, age-matched within one week
- Weight at study initiation: The weight variation in animals involved in the study did not exceed ± 20 % of the mean weight.
- Housing: Individual caging Type II. polypropylene/ polycarbonate
- Diet: Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany ad libitum
- Water (e.g. ad libitum): Tap water from municipal supply, as for human consumption from 500 mL bottle ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes: 8 - 12 air exchange/hour by central air-condition system.
- Photoperiod: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Vehicle:
propylene glycol
Concentration:
25, 10, 5, 2.5 % (w/v)
No. of animals per dose:
4 female/treatment group
Details on study design:
In the main assay, twenty female CBA/Ca mice were allocated to five groups of four animals each:
- Four groups received the appropriate formulation of Reaction products of MXDA with bisphenol A diglycidylether (BADGE) at concentrations of 25, 10, 5 and 2.5 % (w/v)
- the negative control group received the solvent propylene glycol (PG)
Each substance was applied on the external surface of each ear (25 µL/ear) for three consecutive days (Day 0, 1 and 2) at the appropriate concentrations. On Day 5, the cell proliferation in the local lymph nodes was measured by in corporation of tritiated methyl-thymidine (3HTdR) and the values obtained were used to calculate the stimulation indices (SI)
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
The positive control substance alpha-Hexylcinnamaldehyde (HCA) was examined at a concentration of 25 % in the relevant vehicle. A significant lymphoproliferative response (SI >= 3) was noted for HCA with stimulation index value of 7.5, in accordance with previous data.
Key result
Parameter:
SI
Value:
26
Test group / Remarks:
25 % test group
Key result
Parameter:
SI
Value:
13
Test group / Remarks:
10 % test group
Key result
Parameter:
SI
Value:
12.3
Test group / Remarks:
5 % test group
Key result
Parameter:
SI
Value:
7.5
Test group / Remarks:
2.5 % test group
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Reaction products of MXDA with bisphenol A diglycidylether (BADGE), dissolved in an appropriate solvent up to the maximum feasible concentration (25 %), was shown to have sensitisation potential in the Local Lymph Node Assay. The EC3 value was below the lowest tested concentration of 2.5 %.
Executive summary:

A Local Lymph Node Assay according to OECD 429 and Commission Directive 2004/73/EC, B.42 was performed with CBA/Ca Ola Hsd mice. The aim of this study was to determine the skin sensitisation potential of Reaction products of MXDA with bisphenol A diglycidylether (BADGE) following dermal exposure in the Local Lymph Node Assay. The maximum concentration of test item in an acceptable solvent was established according to the principles of the relevant guidelines. The maximum attainable concentration based on solubility and applicability on the ears was 25 % in Propylene glycol (PG). A preliminary irritation/toxicity test was performed showing that the maximum concentration of test item of 25 % in PG was acceptable.

In the main assay twenty female CBA/Ca mice were allocated to five groups of four animals each:

- four groups received the appropriate formulation of Reaction Reaction products of MXDA with bisphenol A diglycidylether (BADGE) at concentrations of 25 %, 10 %, 5 % or 2.5%,

- the negative control group received the solvent (PG).

Each substance was applied on the external surface of each ear (25 µL/ear) for three consecutive days (Day 1, 2 and 3) at the appropriate concentrations. On Day 6, the cell proliferation in the local lymph nodes was measured by incorporation of tritiated methyl-thymidine (3HTdR) and the values obtained were used to calculate stimulation indices (SI).

No mortality or systemic clinical signs were observed during the study. No treatment related effect on the body weights was observed. No sign of a classical irritation was observed in any of the treated groups.

Significant loss of hair was observed in the 25% dose group (4/4 animals) from Day 2 after the second treatment: the affected area enlarged after the subsequent treatment and the skin was dry and exfoliating on the hairless area (3/4 animals) from Day 4 or 5 to the study termination. No redness or damage of the skin integrity was observed. No cutaneous effect was observed in the other dose groups.

A lymphoproliferative response (SI >= 3) was noted for Reaction products of MXDA with bisphenol A diglycidylether (BADGE) at all of the applied concentrations. The stimulation index values (SI) were 26.0, 13.0, 12.3 and 7.5 at concentrations of 25 %, 10 %, 5 % and 2.5 %, respectively. The stimulation index values corresponded to the conventional biological dose-response. The EC3 value (potency) was below the lowest tested concentration of 2.5%.

The result of the latest reliability check (performed within an interval of no longer than six months) was used to demonstrate the appropriate performance of the assay in accordance with the OECD guideline 429 (Ref. 1). The positive control substance alpha-Hexylcinnamaldehyde (HCA) was examined at a concentration of 25 % in the relevant vehicle. A significant lymphoproliferative response (SI >= 3) was noted for HCA with stimulation index value of 7.5 in accordance with the historical control data. The result confirms the validity of the LLNA in this laboratory.

Under the conditions of the present assay Reaction products of MXDA with bisphenol A diglycidylether (BADGE), dissolved in an appropriate solvent up to the maximum feasible concentration (25 %), was shown to have sensitisation potential (sensitiser) in the Local Lymph Node Assay.

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
For read-across justification please refer to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Key result
Parameter:
SI
Value:
26
Test group / Remarks:
25 % test group
Key result
Parameter:
SI
Value:
13
Test group / Remarks:
10 % test group
Key result
Parameter:
SI
Value:
12.3
Test group / Remarks:
5 % test group
Key result
Parameter:
SI
Value:
7.5
Test group / Remarks:
2.5 % test group
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Acute skin sensitisation properties of asymmetrical epoxy amine adduct Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA was assessed using a read across approach from data on symmetrical epoxy amine adducts Reaction products of IPDA with bisphenol A diglycidylether (BADGE) and Reaction products of MXDA with bisphenol A diglycidylether (BADGE), as these substances were considered to show similar toxicological properties.

IPDA

A Local Lymph Node Assay according to OECD 429 and Commission Directive 2004/73/EC, B.42 was performed with CBA/Ca Ola Hsd mice. The maximum concentration of Reaction products of IPDA with bisphenol A diglycidylether (BADGE) in an acceptable solvent was established according to the principles of the relevant guidelines. The maximum attainable concentration based on solubility was 50 % in Propylene glycol (PG) after heating to approximately 80 °C, but because of a very high viscosity, application of this formulation on the ears of animals would not be possible. The next concentration recommended by the relevant guideline is 25 % and this formulation was considered to be physically acceptable for topical application on the ears. A preliminary irritation/toxicity test indicated that the maximum concentration of test item of 25 % in PG was acceptable.

The cutaneous effect observed in the 25 % dose group was considered not to be a classical irritation response and there were no cutaneous effects in lower doses, where a clear lymph node proliferation effect was observed. Hence, in the absence of confounding effects of significant local or systemic toxicity at the applied concentrations, the proliferation values obtained are considered to reflect the real potential of the test item to cause lymphoproliferation in the Local Lymph Node Assay.

A significant lymphoproliferative response (SI >= 3) was noted for Reaction products of IPDA with bisphenol A diglycidylether (BADGE) at all of the applied concentrations. The proliferation values obtained corresponded to the conventional biological dose-response. With proliferation values above 3 obtained at all of the applied concentration and the clear dose-response observed Reaction products of IPDA with bisphenol A diglycidylether (BADGE) was considered a sensitiser. 

Under the conditions of the present assay Reaction products of IPDA with bisphenol A diglycidylether (BADGE), dissolved in an appropriate solvent up to the maximum feasible concentration (25 %), was shown to have sensitisation potential (sensitiser) in the Local Lymph Node Assay. The EC3 value was below the lowest tested concentration of 2.5 %.

MXDA

A Local Lymph Node Assay according to OECD 429 and Commission Directive 2004/73/EC, B.42 was performed with CBA/Ca Ola Hsd mice. The aim of this study was to determine the skin sensitisation potential of Reaction products of MXDA with bisphenol A diglycidylether (BADGE) following dermal exposure in the Local Lymph Node Assay. The maximum concentration of test item in an acceptable solvent was established according to the principles of the relevant guidelines. The maximum attainable concentration based on solubility and applicability on the ears was 25 % in Propylene glycol (PG). A preliminary irritation/toxicity test was performed showing that the maximum concentration of test item of 25 % in PG was acceptable.

In the main assay twenty female CBA/Ca mice were allocated to five groups of four animals each:

-four groups received the appropriate formulation of Reaction products of MXDA with bisphenol A diglycidylether (BADGE) at concentrations of 25 %, 10 %, 5 % or 2.5%,

-the negative control group received the solvent (PG).

Each substance was applied on the external surface of each ear (25 µL/ear) for three consecutive days (Day 1, 2 and 3) at the appropriate concentrations. On Day 6, the cell proliferation in the local lymph nodes was measured by incorporation of tritiated methyl-thymidine (3HTdR) and the values obtained were used to calculate stimulation indices (SI).

No mortality or systemic clinical signs were observed during the study. No treatment related effect on the body weights was observed. No sign of a classical irritation was observed in any of the treated groups.

Significant loss of hair was observed in the 25 % dose group (4/4 animals) from Day 2 after the second treatment: the affected area enlarged after the subsequent treatment and the skin was dry and exfoliating on the hairless area (3/4 animals) from Day 4 or 5 to the study termination. No redness or damage of the skin integrity was observed. No cutaneous effect was observed in the other dose groups.

A lymphoproliferative response (SI >= 3) was noted for Reaction products of MXDA with bisphenol A diglycidylether (BADGE) at all of the applied concentrations. The stimulation index values (SI) were 26.0, 13.0, 12.3 and 7.5 at concentrations of 25 %, 10 %, 5 % and 2.5 %, respectively. The stimulation index values corresponded to the conventional biological dose-response. The EC3 value (potency) was below the lowest tested concentration of 2.5 %.

The result of the latest reliability check (performed within an interval of no longer than six months) was used to demonstrate the appropriate performance of the assay in accordance with the OECD guideline 429 (Ref. 1). The positive control substance alpha-Hexylcinnamaldehyde (HCA) was examined at a concentration of 25 % in the relevant vehicle. A significant lymphoproliferative response (SI >= 3) was noted for HCA with stimulation index value of 7.5 in accordance with the historical control data. The result confirms the validity of the LLNA in this laboratory. Under the conditions of the present assay Reaction products of MXDA with bisphenol A diglycidylether (BADGE), dissolved in an appropriate solvent up to the maximum feasible concentration (25 %), was shown to have sensitisation potential (sensitiser) in the Local Lymph Node Assay.

General conclusion

Based on the results obtained for the read across substances, Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA was considered to be a skin sensitiser.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is considered to be classified as skin sens. Cat. 1 for skin sensitisation under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EC) No 2017/776.