Reaction mass of (E)-3,7-dimethylocta-2,6-dien-1-yl formate and 3,7-dimethyloct-6-en-1-yl formate

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

Sept - Oct 2016

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:

1. SOFTWARE
QSAR Toolbox version 3.4.0.17

2. MODEL (incl. version number)
Not applicable

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Constituent 1, (E)-3,7-dimethylocta-2,6-dien-1-ol, C/C(C)=C/CC/C(C)=C/COC([H])=O
Constituent 2, 3,7-dimethyloct-7-en-1-yl formate, CC(CCC=C(C)C)CCOC=O
Note: A separate prediction was done for each constituent

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: immobilisation, EC50, 48h, daphnia magna
- Unambiguous algorithm: Read-across from category members taking average value from 5 nearest neighbours based on log Kow
- Defined domain of applicability: Esters by ECOSAR Aquatic toxicity classification, log Kow estimated within QSAR Toolbox of >= 3.48 and <=4.3 (5 nearest neighbours for constituent 1), >= 3.51 and <=4.42 (5 nearest neighbours for constituent 2)
- Appropriate measures of goodness-of-fit and robustness and predictivity: Not applicable, calculation approach takes average from five nearest neighbours
- Mechanistic interpretation / Category Justification: The two constituents were profiled using the five primary profilers in the QSAR Toolbox that are relevant to acute aquatic toxicity endpoints (OECD 2013) and have identical profiles. Since both are inert (i.e. contain no structural alerts for protein binding), the "aquatic toxicity classification by ECOSAR" was used to develop the initial category since it is the most detailed aquatic endpoint profiler in terms of the number of alerts. The target is classified as an Ester by the ECOSAR profiler. Thus a category was formed from chemicals classified as Esters present in the Givaudan Aquatic Toxicity Database, which had been imported into Toolbox. The category consisted of 25 esters of which 20 had reliable experimental data for acute toxicity to daphnia magna. No sub-categorisation was performed.

5. APPLICABILITY DOMAIN
- Descriptor domain: Log Kow of Constituent 1 as estimated by the QSAR toolbox is 3.93, which falls within the applicability domain of >= 3.48 and <=4.3; Log Kow of Constituent 2 as estimated by the QSAR toolbox is 4.01, which falls within the applicability domain of >= 3.51 and <=4.42
- Structural and mechanistic domains:Consituent 1 and 2 belongs to the Ester ECOSAR class
- Similarity with analogues in the training set: The target (constituent 1 and constituent 2) and category members have been profiled using the five primary profilers relevant to acute aquatic toxicity endpoints (OECD 2013). By comparing the profiles for the target substance and five category members used in the read-across it is concluded that all are expected to act via the same mode of action (see attached QSAR Toolbox reports for details).


6. ADEQUACY OF THE RESULT
- Hydrophobicity (as modelled by Log Kow) is the major determinant of the toxicity in aquatic organisms for inert chemicals. The predicted EC50 values of 5.80 mg/L for constituent 1 and 4.80 mg/L for constituent 2 are considered reliable since they are based on high quality experimental data for the 5 nearest neighbours according to Log Kow (Log Kow range = 3.40-4.3 and 3.51-4.42 for respective 5 nearest neighbours of constituent 1 and 2).
- The predictions are considered reliable estimates of the daphnia 48 hour EC50 as i) the model is scientifically valid and meets the requirements of the OECD principles and ii) both consituents fall within the applicability domain of the model.
- Furthermore the predicted values of 5.80 mg/L (constituent 1) and 4.80 mg/L (constituent 2) and the experimental results for the 5 nearest neighbours (EC50 experimental value range = 1.2 - 33mg/L) are all above the regulatory environmental classification threshold value of 1mg/L.
- Based on the above, the prediction is considered adequate for a regulatory conclusion.

For further details see the attached QSAR Toolbox reports (separate report for each constituent).

Guideline:

other:

Version / remarks:

REACH Guidance: Chapter R.6: QSARs and grouping of chemicals, May 2008.

Principles of method if other than guideline:

Category formation using QSAR Toolbox and datagap filling using read-across from nearest neighbours.

Specific details on test material used for the study:

SMILES USED AS INPUT FOR THE MODEL
Constituent 1, (E)-3,7-dimethylocta-2,6-dien-1-ol, C/C(C)=C/CC/C(C)=C/COC([H])=O
Constituent 2, 3,7-dimethyloct-7-en-1-yl formate, CC(CCC=C(C)C)CCOC=O
Note: A separate prediction was done for each constituent

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

5.8 mg/L

Remarks on result:

other: Predicted value for Constituent 1

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

4.8 mg/L

Remarks on result:

other: Predicted value for Constituent 2

Details on results:

Category Definition:
The two constituents were profiled using the five primary profilers in the QSAR Toolbox that are relevant to acute aquatic toxicity endpoints (OECD 2013) and found to have identical profiles. Since both are inert (i.e. contain no structural alerts for protein binding), the "aquatic toxicity classification by ECOSAR" was used to develop the initial category since it is the most detailed aquatic endpoint profiler in terms of the number of alerts. The two constituents are classified as an Ester by the ECOSAR profiler. Thus a category was formed from chemicals classified as Esters present in the Givaudan Aquatic Toxicity Database, which had been imported into Toolbox. The category consisted of 25 esters of which 20 had reliable experimental data for acute toxicity to daphnia magna. No sub-categorisation was performed.

Prediction Approach:
- Read-across from category members taking average value from the 5 nearest neighbours.
- Due to the slight difference in the predicted log Kow of the two constituents (3.93 and 4.01) the 5 nearest neighbours were not identical for the two constituents. Four nearest neighbours were common to both but the fifth was different category member (see each QSAR Toolbox Prediction report for details and the plots below in the "Illustration" Section)

Predicted value (comments):
- Hydrophobicity (as modelled by Log Kow) is the major determinant of the toxicity in aquatic organisms for inert chemicals. The predicted EC50 values of 5.80 mg/L for constituent 1 and 4.80 mg/L for constituent 2 are considered reliable since they are based on high quality experimental data for the 5 nearest neighbours according to Log Kow (Log Kow range = 3.40-4.3 and 3.51-4.42 for respective 5 nearest neighbours of constituent 1 and 2).
- The predicted values of 5.80 mg/L (constituent 1) and 4.80 mg/L (constituent 2) and the experimental results for the 5 nearest neighbours (EC50 experimental value range = 1.2 - 33mg/L) are all above the regulatory environmental classification threshold value of 1mg/L. Thus, the prediction is considered adequate for a regulatory conclusion.
- Although not reported, the predicted values using the alternative data gap filling approach of "trend analysis" gave a similar result of 3.89 mg/L for constituent 1 and 3.49 mg/L for constituent 2 (n=20, R2=0.728)

Validity criteria fulfilled:

yes

Remarks:

The model approach is scientifically valid and the constituents fall within its applicability domain (see attached QSAR Toolbox prediction report for details).

Conclusions:

The two constituents of the registration substance, reaction mass of (E)-3,7-dimethylocta-2,6-dien-1-yl formate and 3,7-dimethyloct-6-en-1-yl formate, were predicted to have a daphnid 48-hr EC50 of 5.8 mg/L and 4.8 mg/L respectively.

The prediction results are considered reliable according to OECD principles. The prediction model approach is scientifically valid and the two constituents fall within its applicability domain.

Reference 2

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

Sept - Oct 2016

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:

1. SOFTWARE
QSAR Toolbox version 3.4.0.17

2. MODEL (incl. version number)
Trend analysis from category members

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Constituent 1, (E)-3,7-dimethylocta-2,6-dien-1-ol, C/C(C)=C/CC/C(C)=C/COC([H])=O
Constituent 2, 3,7-dimethyloct-7-en-1-yl formate, CC(CCC=C(C)C)CCOC=O
Note: A separate prediction was done for each constituent

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: immobilisation, EC50, 48h, daphnia magna
- Unambiguous algorithm: EC50 = 2.28 + 0.655 Log Kow, log(1/mol/L)
- Defined domain of applicability: ECOSAR Aquatic toxicity classification = Ester only; Verhaar classification = Class 3; log Kow estimated within QSAR Toolbox of >= 0.355 and <=5.87
- Appropriate measures of goodness-of-fit and robustness and predictivity: N=9, r2=0.943
- Mechanistic interpretation / Category Justification: The two constituents were profiled using the five primary profilers in the QSAR Toolbox that are relevant to acute aquatic toxicity endpoints (OECD 2013) and have identical profiles. Since both are inert (i.e. contain no structural alerts for protein binding), the "aquatic toxicity classification by ECOSAR" was used to develop the initial category since it is the most detailed aquatic endpoint profiler in terms of the number of alerts. The target is classified as an Ester by the ECOSAR profiler. Thus a category was formed from chemicals classified as Esters present in the acute aquatic toxicity databases publicly available in the OECD QSAR Toolbox (Aquatic ECETOC, Aquatic Japan MoE, Aquatic Oasis, ECHA, ECOTOX). The category consisted of 1478 esters of which 31 had experimental data for acute toxicity to daphnia magna. Sub-categorisation was performed by eliminating analogues that are assigned additional ECOSAR classes and different Verhaar classes (i.e. might act via additional mechanisms). The final category contained 9 analogues with experimental data from the Aquatic ECETOC and Aquatic Japan MoE databases.

5. APPLICABILITY DOMAIN
- Descriptor domain: Log Kow of Constituent 1 and 2 as estimated by the QSAR toolbox is 3.93 and 4.01 respectively, which falls within the applicability domain of >= 0.355 and <=5.87
- Structural and mechanistic domains:Consituent 1 and 2 belongs to a) the Ester ECOSAR class and contains no other ECOSAR alerts; and b) Verhaar Class 3;
- Similarity with analogues in the training set: The target (constituent 1 and constituent 2) and category members have been profiled using the five primary profilers relevant to acute aquatic toxicity endpoints (OECD 2013). By comparing the profiles for the target substance and five category members used in the read-across it is concluded that all are expected to act via the same mode of action (see attached QSAR Toolbox reports for details).


6. ADEQUACY OF THE RESULT
- The prediction is considered a reliable estimate of the daphnia 48 hour EC50 as i) the model is scientifically valid and meets the requirements of the OECD principles and ii) both constituents fall within the applicability domain of the model.
- Thus the predicted daphnia 48-hr EC50 values of 2.55 (constituent 1) and 2.29mg/L (constituent 2) are considered adequate for regulatory purposes.

For further details see the attached QSAR Toolbox reports (separate report for each constituent).

Guideline:

other:

Version / remarks:

REACH Guidance: Chapter R.6: QSARs and grouping of chemicals, May 2008.

Principles of method if other than guideline:

Category formation using QSAR Toolbox and datagap filling using trend analysis

Specific details on test material used for the study:

SMILES USED AS INPUT FOR THE MODEL
Constituent 1, (E)-3,7-dimethylocta-2,6-dien-1-ol, C/C(C)=C/CC/C(C)=C/COC([H])=O
Constituent 2, 3,7-dimethyloct-7-en-1-yl formate, CC(CCC=C(C)C)CCOC=O

Note: A separate prediction was done for each constituent

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

2.55 mg/L

Remarks on result:

other: Predicted value for Constituent 1

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

2.29 mg/L

Remarks on result:

other: Predicted value for Constituent 2

Details on results:

Category Definition:
The two constituents were profiled using the five primary profilers in the QSAR Toolbox that are relevant to acute aquatic toxicity endpoints (OECD 2013) and found to have identical profiles. Since both are inert (i.e. contain no structural alerts for protein binding), the "aquatic toxicity classification by ECOSAR" was used to develop the initial category since it is the most detailed aquatic endpoint profiler in terms of the number of alerts. The two constituents are classified as an Ester by the ECOSAR profiler. Thus a category was formed from chemicals classified as Esters present in the acute aquatic toxicity databases publicly available in the OECD QSAR Toolbox (Aquatic ECETOC, Aquatic Japan MoE, Aquatic Oasis, ECHA, ECOTOX). The category consisted of 1478 esters of which 31 had experimental data for acute toxicity to daphnia magna. Sub-categorisation was performed by eliminating analogues that are assigned additional ECOSAR classes and different Verhaar classes (i.e. might act via additional mechanisms). The final category contained 9 analogues with experimental data from the Aquatic ECETOC and Aquatic Japan MoE databases.

Prediction Approach:
Trend analysis from category members; linear approximation.
EC50 = 2.28 + 0.655 Log Kow, log(1/mol/L), N=9, r2=0.943

See QSAR Toolbox Prediction report for full details including the list of category members. The category members shown with respect to the descriptor log Kow are shown graphically below (section Illustration).

Validity criteria fulfilled:

yes

Remarks:

The model approach is scientifically valid and the constituents fall within its applicability domain (see attached QSAR Toolbox prediction report for details).

Conclusions:

The two constituents of the registration substance, reaction mass of (E)-3,7-dimethylocta-2,6-dien-1-yl formate and 3,7-dimethyloct-6-en-1-yl formate, were predicted to have a daphnid 48-hr EC50 of 2.29 mg/L and 2.55 mg/L respectively.

The prediction results are considered reliable according to OECD principles. The prediction model approach is scientifically valid and the two constituents fall within its applicability domain.

Description of key information

In the absence of experimental data, the use of predicted values in a weight of evidence approach has been used to assess short-term toxicity to aquatic invertebrates. Two predictions were performed using the OECD QSAR Toolbox 3.4.0.17. One using a category formed from the aquatic toxicity databases available in the QSAR Toolbox (2016b) and one using a category formed from Givaudans' proprietary database (2016a). Separate predictions were performed for the two constituents present in the registered substance; Reaction mass of (E)-3,7-dimethylocta-2,6-dien-1-yl formate and 3,7-dimethyloct-6-en-1-yl formate.

The predicted 48 hour daphnid EC50 values ranged from 2.29 to 5.80 mg/L respectively. The prediction results are considered reliable according to OECD principles. The prediction models are scientifically valid and the two constituents fall within their applicability domain.

The models are independent from each other (e.g. based on different training sets). Thus, the agreement among the predictions increases the confidence in the reliability of the predictions. Furthermore, the predicted values are within the same acute aquatic toxicity classification band of >1 and <=10mg/L and as such are considered adequate for regulatory purposes. The lowest worst-case value of 2.29mg/L has been selected as the key value for chemical safety assessment.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

2.29 mg/L