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Diss Factsheets

Administrative data

Description of key information

LEE011-A4 did not cause any relevant changes in ear weight or LN weight up to a concentration of 25% in DAE433. LEE011-A4 did not exceed LN count threshold but showed statistical significance when compared to vehicle and showed a dose response. The substance is non-sensitizing.

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
Study period:
Feb 2014 - July 2014
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)
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
Balb/c
Sex:
female
Details on test animals and environmental conditions:
Mouse, Balb/c strain, inbred, SPF-Quality. 30 females (nulliparous and non-pregnant), six females per group.
Vehicle:
other: DAE433
Concentration:
Correction of the purity/composition of the test substance is not applicable, since the test method requires a logical concentration range rather than specific dose levels to be dosed.
The accuracy of preparation was considered acceptable if the mean measured concentrations were 85-115% of the target concentration for suspensions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%.
No. of animals per dose:
Pre-screen test
Four young adult animals were selected and two test item concentrations were tested, each on two animals. Concentrations of 10% and 25% were tested. Trial formulations showed that 25% was the highest concentration that could be prepared homogeneously to a visible acceptable level.

Main study
Three groups of six animals were treated with one test item concentration per group. The highest test item concentration was selected from the pre-screen test. One group of six animals was treated with vehicle and one group with the positive control item.
Details on study design:
A pre-screen test was conducted in order to select the highest test item concentration to be used in the main study.
Three groups of six animals were treated with one test item concentration per group. The highest test item concentration was selected from the pre-screen test. One group of six animals was treated with vehicle and one group with the positive control item.
Positive control substance(s):
other: 0.5% 1-Chloro-2,4-Dinitrobenzene (DNCB)
Statistics:
Calculations were performed in MS EXCEL and statistical analysis was performed with GraphPad Prism 4 (Kruskal-Wallis test, followed by the Mann Whitney test).
Positive control results:
The positive control item DNCB elicited a reaction pattern with increased LN hyperplasia, which was in congruence with the expected mode of action of a contact allergen.
Key result
Parameter:
other: Ear weight index
Value:
ca. 1.03
Test group / Remarks:
0.25% LEE011-A4
Key result
Parameter:
other: Ear weight index
Value:
ca. 1.03
Test group / Remarks:
2.5% LEE011-A4
Key result
Parameter:
other: Ear weight index
Value:
ca. 1.04
Test group / Remarks:
25% LEE011-A4
Key result
Parameter:
other: local lymph node weight index
Value:
ca. 0.88
Test group / Remarks:
0.25% LEE011-A4
Key result
Parameter:
other: local lymph node weight index
Value:
ca. 1
Test group / Remarks:
2.5% LEE011-A4
Key result
Parameter:
other: local lymph node weight index
Value:
ca. 0.91
Test group / Remarks:
25% LEE011-A4
Key result
Parameter:
other: Cell count index
Value:
ca. 1.03
Test group / Remarks:
0.25% LEE011-A4
Key result
Parameter:
other: Cell count index
Value:
ca. 1.17
Test group / Remarks:
2.5% LEE011-A4
Key result
Parameter:
other: Cell count index
Value:
ca. 1.29
Test group / Remarks:
25% LEE011-A4
Key result
Parameter:
SI
Test group / Remarks:
0.25% LEE011-A4
Remarks on result:
not measured/tested
Key result
Parameter:
SI
Test group / Remarks:
2.5% LEE011-A4
Remarks on result:
not measured/tested
Key result
Parameter:
SI
Test group / Remarks:
25% LEE011-A4
Remarks on result:
not measured/tested

No irritation of the ears was noted after visual examination in the majority of animals. Yellow staining of test substance remnants on the dorsal surface of the ears of the animals treated at 25% did not hamper scoring for erythema.Visual examination of the nodes revealed that all nodes of the experimental animals were considered normal in size when compared to the vehicle control group. No macroscopic abnormalities of the surrounding areas were noted in any of the animals.

Body weights and body weight gain of experimental animals remained in the same range as controls over the study period. There were no clinical observations attributable to treatment with LEE011-A4.

The positive control item DNCB elicited a reaction pattern with increased LN hyperplasia, which was in congruence with the expected mode of action of a contact allergen.

LEE011-A4 did not cause any relevant changes in ear weight or LN weight up to a concentration of 25% in DAE433. LEE011-A4 did not exceed LN count threshold but showed statistical significance when compared to vehicle and showed a dose response.

Interpretation of results:
other: no sensitizing or irritating potential was ascribed to LEE011-A4
Conclusions:
In conclusion, no sensitizing or irritating potential was ascribed to LEE011-A4 in the murine LLNA TIER I.
Based on these results LEE011-A4 would not be regarded as a skin sensitizer according to the recommendations made in the test guidelines. It does not have to be classified and has no obligatory labelling requirement for sensitization by skin contact according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007) (including all amendments).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

In the 4-week toxicity study (dogs): Inflammatory changes in the lungs of dogs were considered secondary to aspiration of test-article and are indicative of the irritant potential of the formulated test-article in the respiratory tract.)

Justification for classification or non-classification

LEE011-A4 did not cause any relevant changes in ear weight or LN weight up to a concentration of 25% in DAE433. LEE011-A4 did not exceed LN count threshold but showed statistical significance when compared to vehicle and showed a dose response. The substance is non-sensitizing.