N-(n-octyl)-2-pyrrolidinone

Bioaccumulation: aquatic / sediment

Description of key information

Significant accumulation in organisms is not expected.

Additional information

QSAR-disclaimer:

In Article 13 of Regulation (EC) No 1907/2006, it is laid down that information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI (of the same Regulation) are met.

Furthermore, according to Article 25 of the same Regulation testing on vertebrate animals shall be undertaken only as a last resort.

According to Annex XI of Regulation (EC) No 1907/2006 (Q)SAR results can be used if (1) the scientific validity of the (Q)SAR model has been established, (2) the substance falls within the applicability domain of the (Q)SAR model, (3) the results are adequate for the purpose of classification and labeling and/or risk assessment and (4) adequate and reliable documentation of the applied method is provided.

For the assessment of NOP (CAS 2687 -94 -7), (Q)SAR results were used for aquatic bioaccumulation. The criteria listed in Annex XI of Regulation (EC) No 1907/2006 are considered to be adequately fulfilled and therefore the endpoint(s) sufficiently covered and suitable for risk assessment.

Therefore, and for reasons of animal welfare, further experimental studies on aquatic bioaccumulation are not provided.

 

Assessment:

NOP has a log Kow of 4.15 at pH 7; therefore, accumulation in organisms is possible.

QSAR calculations indicate that significant accumulation is not expected especially when mitigating factors like metabolism and water solubility are taken into consideration. The table below lists the applied models together with information on the applicability domain and calculation options. The Arnot-Gobas model shows the effect of biotransformation on the BCF. Without biotransformation the BCF is significantly higher than with biotransformation (1440 L/kg vs. 94.7 L/kg). NOP is not completely in the applicability domain of the BCF baseline model v03.10 (QASIS Catalogic v5.13.1). The substance is within the parametric and the mechanistic domain, but not completely within the structural domain. 71% of the fragments were correctly predicted in the training chemicals, but 29% of the fragments of the substance were not within the training set of the model. However, the results can still be considered sufficiently reliable to support the other QSAR data with regard to the influence of mitigating factors like metabolism, molecular size and water solubility. The BCF is reduced from 1250 L/kg to 5.4 L/kg mainly due to the effect of metabolism and molecular size.

The BCF baseline v03.10 model predicted 6 metabolites on the first level of metabolism. The log Kow of the metabolites is significantly lower than that of the parent substance (NOP: log Kow = 4.15, measured; metabolites: log Kow = -0.32 to 2.81). The BCF was also predicted for the metabolites taking mitigating factors (e.g. metabolism, water solubility, molecular size) into consideration. The BCF values of the predicted metabolites are in a range from 3.0 to 11.7 L/kg (log BCF = 0.48 to 1.07). It can be concluded that, NOP as well as its metabolites are not expected to exhibit a significant bioaccumulation potential.

Studies for toxicological endpoints conducted on rats support the QSAR findings. The data on several studies with substance application for 28 d, 90 d and 120 d reveal a slight increase of liver weight. The observed effect did not exacerbate with application time and occured at comparable doses in all studies. Thus no hints for a bioaccumulation of the substance in rats were observed.

It can be concluded that based on the results of the QSAR models and the toxicological data, significant accumulation in organisms is not expected. Therefore, and for reasons of animal welfare, no study on bioaccumulation in fish is proposed.

Applied QSAR models: BCF and applicability domain

Model	BCF [L/kg]	In AD
BCF baseline model v3.10 (OASIS Catalogic v5.13.1): including mitigating factors	5.4	No (The substance is in the parametric and the mechanistic domain, but not completely in the structural domain (correct: 71.4%).
BCFBAF v3.01 (EPI Suite v4.11): Meylan et al (1997/1999)	10.7	Yes
US EPA T.E.S.T.v4.2.1: Bioaccumulation: Consensus method	32.9	Yes
BCFBAF v3.01 (EPI Suite v4.11): Arnot-Gobas, upper trophic level, incl. biotransformation	94.7	Yes
BCFBAF v3.01 (EPI Suite v4.11): Arnot-Gobas, upper trophic level, without biotransformation	1440	Yes
BCF baseline model v3.10 (OASIS Catalogic v5.13.1): without mitigating factors	1250	No (The substance is in the parametric and the mechanistic domain, but not completely in the structural domain (correct: 71.4%).

 

Predicted metabolites (Catalogic BCF baseline v3.10 model): log Kow and corrected log BCF

Metab No	Level	Trans	Phase I reaction	Quantity (mol/mol parent)	Log Kow	Smiles	log BCF corrected
1 (parent)	0	0	-	0.002	4.15	CCCCCCCCN1CCCC1=O	0.73
2	1	310	Aliphatic C-oxidation	0.459	1.79	CCCCCCCCN1C(O)CCC1=O	0.57
3	1	310	Aliphatic C-oxidation	0.459	1.79	CCCCCCCC(O)N1CCCC1=O	0.55
4	1	415	N-dealkylation	4.8E-08	-0.32	O=C1CCCN1	0.48
5	1	415	N-dealkylation	4.8E-08	2.81	CCCCCCCCO	1.07
6	1	415	N-dealkylation	4.8E-08	2.26	CCCCCCCCNC(=O)CCCO	0.74
7	1	506	Omega oxidation	0.081	1.87	OCCCCCCCCN1CCCC1=O	0.57