Registration Dossier

Administrative data

Description of key information

1. BASF AG, 2005. N-Ethyl-2-pyrrolidon - Murine Local Lymph Node Assay (LLNA). Report No.45H0033/042269. Data waiving from a related substance.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Rationale for reliability incl. deficiencies:
other:
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer also to Read-Across Statement attached in Section 13

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across strategy aims to close data gaps for 2-Pyrrolidone (2-P, CAS 616-45-5) utilizing data of N-Ethyl-2-pyrrolidone (NEP, CAS 2687-91-4), in accordance with Regulation No 1907/2006 (REACH), Annex XI. The basis for this read-across approach is the “Read-Across Assessment Framework” (RAAF) (ECHA 2017).
The target substance is a 2-P ring system consisting of a 5-membered lactam. The source substance NEP share this structure with the target substance 2-P, but additionally contain an alky group as substituent at the N-position and thus is a tertiary amine. The alky group, an ethyl group, has only minor influence on physical-chemical parameters. Regarding read across of environmental fate or (eco)toxicological effects, the decisive properties like small molecular size < 200 g/mol, high water solubility > 10 g/L and low partition coefficient (LogKow) values < 0 are shared by both substances. Therefore, the read-across hypothesis for the analogue approach is that 2-P and NEP exhibit a similar (eco) toxicological profile and environmental fate as a result of structural similarity. According to the RAAF this approach is covered by scenario 2: “Different compounds have the same type of effect(s)”.
“This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds with qualitatively similar properties. For the REACH information requirement under consideration, the property investigated in a study conducted with one source substance is used to predict properties that would be observed in a study with the target substance if it were to be conducted. Qualitatively similar properties or absence of effect are predicted. The predicted property may be similar or based on a worst-case approach” (ECHA 2017).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical:
Chemical name: N-Ethyl-2-pyrrolidone (NEP)
Molecular formula: C6H11NO
SMILES: CCN1CCCC1=O
CAS: 2687-91-4
EC: 220-250-6
Purity: pure substance

Target chemical:
Chemical name: 2-pyrrolidone (2-P)
Molecular formula: C4H7NO
SMILES: O=C1CCCN1
CAS: 616-45-5
EC: 210-483-1
Purity: pure substance

3. ANALOGUE APPROACH JUSTIFICATION
This read across is justified based on structural and physical-chemical similarities of all three substances as well as on similar profiling results and similar toxicokinetic behaviour.
In summary, based on available information for 2-P and NEP the following assumptions can be made:
- Experimental data reveal that 2-P and NEP are not acutely toxic after single dermal administration and not irritating to skin according to OECD 404.
- both substances share an irritation potential to eyes according to QSAR profiling, which is confirmed by experimental data.
- Based on physical-chemical properties both substances are expected to be absorbed via oral and dermal route.
- Experimental results show that the source substance NEP, as well as the target substance is negative in gene mutation and cytogenicity tests
On this basis, it is justifiable to use the available study for NEP to fill data gaps for 2-P for toxicological endpoint skin sensitisation.

4. DATA Matrix
Please refer to Read Across Statement, Chapter 4, table 2
Reason / purpose for cross-reference:
read-across source
Parameter:
SI
Test group / Remarks:
Test group which received 3 % preparations of the test substance
Remarks on result:
other: see Remark
Remarks:
In 3 %, 10 % and 50 % preparations of test substance Lymph Node Weight Index was 0.95, 0.92 and 1.20, respectively. Cell Count index: 0.99 (3 %), 10.1 (10 %) and 1.32 (50 %). Ear Weight Index is the same for all preparations: 1.05. All indices in control are 1.0.
Parameter:
SI
Test group / Remarks:
Test group which received 10 % preparations of the test substance
Remarks on result:
other: see Remark
Remarks:
In 3 %, 10 % and 50 % preparations of test substance Lymph Node Weight Index was 0.95, 0.92 and 1.20, respectively. Cell Count index: 0.99 (3 %), 10.1 (10 %) and 1.32 (50 %). Ear Weight Index is the same for all preparations: 1.05. All indices in control are 1.0.
Parameter:
SI
Test group / Remarks:
Test group which received 50 % preparations of the test substance
Remarks on result:
other: see Remark
Remarks:
In 3 %, 10 % and 50 % preparations of test substance Lymph Node Weight Index was 0.95, 0.92 and 1.20, respectively. Cell Count index: 0.99 (3 %), 10.1 (10 %) and 1.32 (50 %). Ear Weight Index is the same for all preparations: 1.05. All indices in control are 1.0.
Parameter:
other: Lymph Node Weight Index
Value:
0.95
Test group / Remarks:
Test group which received 3 % prepartions of the test substance
Parameter:
other: Lymph Node Weight Index
Value:
0.92
Test group / Remarks:
Test group which received 10 % prepartions of the test substance
Parameter:
other: Lymph Node Weight Index
Value:
1.2
Test group / Remarks:
Test group which received 50 % prepartions of the test substance
Parameter:
other: Cell Count Index
Value:
0.99
Test group / Remarks:
Test group which received 3 % preparations of the test substance
Parameter:
other: Cell Count Index
Value:
1.01
Test group / Remarks:
Test group which received 10 % preparations of the test substance
Parameter:
other: Cell Count Index
Value:
1.32
Test group / Remarks:
Test group which received 50 % preparations of the test substance
Parameter:
other: Ear Weight Index
Value:
1.05
Test group / Remarks:
Test group which received 3 % preparations of the test substance
Remarks on result:
other: The statistically increased ear weights, which were concentration independent, indicate irritation of the ear skin at all concentrations.
Parameter:
other: Ear Weight Index
Value:
1.05
Test group / Remarks:
Test group whcih received 10 % preparations of the test substance
Remarks on result:
other: The statistically increased ear weights, which were concentration independent, indicate irritation of the ear skin at all concentrations.
Parameter:
other: Ear Weight Index
Value:
1.05
Test group / Remarks:
Test group whcih received 50 % preparations of the test substance
Remarks on result:
other: The statistically increased ear weights, which were concentration independent, indicate irritation of the ear skin at all concentrations.

Table 1: Stimulation index

Test group

Treatment

Lymph node Weight Index

Cell Count Index

Ear Weight Index

1

Vehicle

1.00

1.00

1.00

2

3% in acetone

0.95

0.99

1.05

3

10% in acetone

0.92

1.01

1.05

4

50% in acetone

1.20

1.32

1.05

The statistical evaluations were preformed using the WILCOXON-test( # for p<= 0.05 ## for p<= 0.01).

The test substance did not induce a statistically significant or biologically relevant response of the auricular lymph nodes when applied as 3 % or 10 % preparations in acetone. The minimal but statistically significant increase in mice treated with the 50 % test substance preparation was too small to be considered biologically relevant. The statistically significant increases in ear weights, which were concentration independent, indicate irritation of the ear skin at all concentrations. The minimal increase in cell count and lymph node index in test group 4 is considered to be related to ear skin irritation produced by the combination of vehicle and test substance, which starts already at the 3 % concentration without relevant lymph node response.

Interpretation of results:
GHS criteria not met
Conclusions:
1-ethylpyrrolidin-2-one (NEP) - a structural analogue of 2-pyrrolidone is negative in the Local Lymph Node Assay.
Executive summary:

To determine the sensitizing potential of 1-ethylpyrrolidin-2-one (NEP) was applied in three different concentrations (3 %, 10 % and 50 % in acetone) to the dorsum of both ears of mice for three consecutive days. On day six the lymph nodes were removed, and number of proliferated lymphocytes were counted. Thereafter the stimulation indices were calculated. The cell count and the lymph node index were slightly increased only in the highest preparation group. This observation is considered not to be treatment related. The test material is not sensitizer in this assay.

It is expected that the registered substance 2 -pyrrolidone behaves as NEP and therefore 2 -pyrrolidone is also regarded as a non-sensitiser.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

N-ethylpyrrolidone, a related substance to 2 -pyrrolidone was applied in three different concentrations (3 %, 10 % and 50 % in acetone) to the dorsum of both ears of mice for three consecutive days (BASF, 2005). On day six the lymph nodes were removed, and number of proliferated lymphocytes were counted. Thereafter the stimulation indices were calculated. The cell count and the lymph node index were slightly increased only in the highest preparation group. This observation is considered not to be treatment related. The test material did not induce a positive response in LLNA. Thus, 1-ethylpyrrolidin-2-one is not sensitizer in this assay.

Additionally, 2-Pyrrolidone was reported as “not a potent skin sensitizer” following unspecified human patch tests (refer to section 7.10.4 of IUCLID file).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

There is no indication given for a classification according to this endpoint (no case reports known; non-sensitizing LLNA read across).


Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.