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Short-term toxicity to fish

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Reference
Endpoint:
short-term toxicity to fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
Detailed justification for the QSAR prediction is provided in the attached QMRF and QPRF reports. A summary is provided below:

1. SOFTWARE: ECOSAR version 1.11

2. MODEL: Fish 96h LC50 Neutral Organic SAR

3. SMILES USED AS INPUT FOR THE MODEL: N#CC=C(CCC=C(CC)C)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The ECOSAR Class Program and underlying methodology has been developed over a period of more than 25 years by EPA/OPPT. The current ECOSAR version (v1.11, May 2012) is programmed to identify 111 chemical classes and allows access to 704 QSARs for numerous endpoints and organisms. The neutral organic 96-hour fish LC50 QSAR is one of these QSARs. The model is valid according to the following five OECD principles.
1. Defined Endpoint: Acute toxicity to fish
2. Unambiguous algorithm: Log LC50 (mmol/L) = -0.8981 log Kow + 1.7108
- to convert the LC50 from mmol/L to mg/L, multiply by the molecular weight of the substance
- In ECOSAR version 1.11, all QSARs have been derived using predicted log Kow values for the training set chemicals. The log Kow values were predicted using the KOWWIN program.
3. Applicability domain: The Neutral Organic SAR is applicable to nonionizable and nonreactive chemicals with a Log Kow of < 5 and a molecular weight of < 1000.
4. Statistical characteristics: a) internal performance; n = 296, r2 = 0.878, Q2 = 0.78, b) External validation; A number of supporting validation exercises have been performed in conjunction with EPA and other stakeholders on the ECOSAR models and are listed in the "Methodology Document for the Ecological Structure-Activity Relationship Model (ECOSAR) Class Program v1.11"
5. Mechanistic interpretation: The mechanistic basis for the model is nonpolar narcosis, which has been shown to be positively correlated with lipophilicity (as modelled by log Kow) up to a log Kow limit of 5 (for acute effects on fish and daphnia) and 6.4 (for green algae).

5. APPLICABILITY DOMAIN
- Lemonile is a non-ionised chemical with an estimated logKow of 3.957 and molecular weight of 163. As such it falls within the applicability domain described above.
- Lemonile is a mixture of stereoisomers. The stereochemical features will not affect the reliability of the prediction, which is based on 2D chemical structure and the predicted logarithm of the n-octanol / water partition coefficient. Moreover, an experimental determination of the log Kow of Lemonile shows that all the stereoisomers of Lemonile have approximately the same log Kow (3.1 to 3.2).
- Based on the chemical structure, the ECOSAR programme attributes Lemonile to the chemical class of vinyl/allyl nitriles and estimates toxicity to aquatic organisms using both the Neutral Organic SAR and Vinyl/Allyl Nitrile Class SAR. The validity of the latter SAR is questionable given that it is based on a very small training set of 3 chemicals. As such any predictions using the Vinyl/Allyl Nitrile Class SAR should be treated with caution. Furthermore, although Lemonile is an alpha,beta-unsaturated nitrile, it contains two alkyl substituents at the beta position. Such encumbered nitriles are not expected to exhibit “excess aquatic toxicity” through Michael-type acception mechanisms. Moreover, predicted versus measured values for daphnid and green algae indicate that Lemonile does not exhibit “excess aquatic toxicity” but acts via simple non-polar narcosis (see table 1 in IUCLID section "Any other information on results incl. tables"). Therefore, it is considered that the Neutral Organic SAR is the most appropriate ECOSAR model for Lemonile.

6. ADEQUACY OF THE RESULT
- The prediction value can be considered reliable taking into account that predicted and experimental data for closest neighbours in the log Kow descriptor space (log Kow of between 3.9 and 4.1) are in close agreement (see QPRF for details). Moreover, the experimental and predicted values for these analogues fall within the same acute aquatic hazard classification criterion range: E(L)C50 > 1mg/L and <= 10mg/L. Thus the fish 96-hr LC50 prediction value of 2.4 mg/L for Lemonile is consider suitable for regulatory purposes. The prediction, in fact, may be slightly conservative taking into account that a) the measured log Kow for Lemonile of 3.1 to 3.2 is lower than the predicted value of 3.957 which was used in the LC50 estimation, and b) the predicted E(L)C50 values for Daphnid and Green Algae using similar ECOSAR Neutral Organic SAR regressions are slightly lower (i.e. more conservative) than the measured values.
Principles of method if other than guideline:
ECOSAR v1.11 neutral organic 96-hour fish LC50 QSAR
Specific details on test material used for the study:
The following were used as input for the ECOSAR v1.11 model.
- SMILES: N#CC=C(CCC=C(CC)C)C
- Predicted log Kow of 3.957 (automatically estimated within the ECOSAR programme)
- Molecular weight of 163.26 (automatically calculated within the ECOSAR programme)
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
2.4 mg/L
Remarks on result:
other: estimated by QSAR

Table 1: Comparison of Lemonile measured and predicted L(E)C50 values for Daphnid & Green Algae

 

 

Daphnid

48-hr L(E)C50 (mg/L)

Green Algae

96-hr EC50

(mg/L)

Measured Values:

Presented within the REACH registration dossier

2.7

3.6

ECOSAR v1.11 Predicted Values:

 Neutral Organic SAR

 

 

1.595

 

 

2.508

 Vinyl/Allyl Nitriles

0.358

0.193

Conclusions:
The substance Lemonile was predicted to have a fish 96-hr LC50 of 2.4 mg/L. The prediction value can be considered reliable taking into account that the ECOSAR Neutral Organic SAR is an appropriate QSAR for Lemonile. This is supported by a comparison of experimental and predicted values for the daphnia and green algal endpoints.

Description of key information

The predicted fish 96-hr LC50 is 2.4 mg/L. 

Key value for chemical safety assessment

LC50 for freshwater fish:
2.4 mg/L

Additional information

The acute toxicity to fish of Lemonile has been assessed using a QSAR approach. The QSAR approach works within the spirit of REACH and the stated aim of the legislation to reduce animal testing where possible. Lemonile was predicted to have a fish 96-hr LC50 of 2.345 mg/L using the ECOSAR v1.11 Neutral Organic SAR. This QSAR model is scientifically valid and Lemonile falls within its applicability domain.