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

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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: growth rate, EC50, 72h, Pseudokirchnerella subcapitata
- Unambiguous algorithm: Read-across from category members taking average value from 3 nearest neighbours based on log Kow
- Defined domain of applicability: Esters by ECOSAR Aquatic toxicity classification, log Kow estimated within QSAR Toolbox of >= 3.93 and <=4.3 (3 nearest neighbours for constituent 1 and constituent 2)
- Appropriate measures of goodness-of-fit and robustness and predictivity: Not applicable, calculation approach takes average from three 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 16 had reliable experimental data for toxicity to Pseudokirchnerella subcapitata.

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 >= 3.93 and <=4.3
- 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 three 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 ErC50 values of 2.48 mg/L for constituent 1 and 2.51 mg/L for constituent 2 are considered reliable since they are based on high quality experimental data for the 3 nearest neighbours according to Log Kow (Log Kow range = 3.93 - 4.01).
- The predictions are considered reliable estimates of the algae 72 hour ErC50 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 2.48 mg/L (constituent 1) and 2.51 mg/L (constituent 2) and the experimental results for the 3 nearest neighbours (EC50 experimental value range = 1.8-6.0 mg/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 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

A separate prediction was done for each constituent

Key result

Duration:

72

Dose descriptor:

EC50

Effect conc.:

2.48 mg/L

Basis for effect:

growth rate

Remarks on result:

other: Predicted value for constituent 1

Key result

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

2.51 mg/L

Basis for effect:

growth rate

Remarks on result:

other: Predicted value for constituent 2

Details on results:

Category Definition:
Consituent 1 and 2 were profiled using the five primary profilers in the QSAR Toolbox that are relevant to acute aquatic toxicity endpoints (OECD 2013). Since the chemicals are inert (i.e. contains 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 16 had reliable experimental data for the endpoint: growth rate, EC50, 72h, Pseudokirchnerella subcapitata.

Prediction Approach:
Read-across from category members taking average value from the 3 nearest neighbours.

Predicted value (comments):
- Hydrophobicity (as modelled by Log Kow) is the major determinant of the toxicity in aquatic organisms for inert chemicals. The predicted ErC50 values of 2.48 and 2.51 mg/L for the two constituents are considered reliable since they are based on high quality experimental data for the 3 nearest neighbours according to Log Kow (Log Kow range = 3.93-4.30). The three nearest neighbours were used instead of the default setting of five to give a narrow log Kow domain.
- The predicted values of 2.48 and 2.51 mg/L and the experimental results for the 3 nearest neighbours (1.8 - 6mg/L) are within the same environmental classification band of > 1mg/L and <=10 mg/L. Thus, the prediction is considered adequate for a regulatory conclusion.
- Although not reported, the predicted values using the alternative data gap filling approach in the QSAR Toolbox of "trend analysis" also gave a result within the 1-10mg/L classfication band (ErC50 = 6.1 and 6.8 mg/L for constituents 1 and 2 respectively, n=9, R2=0.802 after sub-categorisation ro remove phenols, aldehydes, benzodioxoles, vinyl/allyl esters).

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

Validity criteria fulfilled:

yes

Remarks:

The model approach is scientifically valid and the two target chemicals fall within the applicability domain.

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 an algae 72h ErC50 of 2.48 mg/L and 2.51 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:

toxicity to aquatic algae and cyanobacteria

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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, 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: growth rate, EC50, 72h, Pseudokirchnerella subcapitata
- Unambiguous algorithm: EC50 = +2.35 +0.590 * log Kow, log(1/mol/L)
- Defined domain of applicability: Esters by ECOSAR Aquatic toxicity classification, log Kow estimated within QSAR Toolbox of >= 0.395 and <=5.28
- Appropriate measures of goodness-of-fit and robustness and predictivity: N=26, R2 = 0.697
- 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 databases publicly available in the OECD QSAR Toolbox (Aquatic ECETOC, Aquatic Japan MoE, Aquatic Oasis, ECHA Chem, ECOTOX). The category consisted of 1478 esters of which 101 had experimental data for the endpoint tree: growth rate, EC50, 72h, Pseudokirchnerella subcapitata. Sub-categorisation was performed by eliminating analogues that had a log Kow > 6 (i.e. no effects above water solubility expected) and analogues that might act via different mechanisms (i.e. those with additional ECOSAR classes and different profiles for protein binding by OASIS, protein binding by OECD, MoA by OASIS or Verhaar class). The final category contained 26 analogues with experimental data from the ECHA CHEM database.

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 >= 0.395 and <=5.28
- Structural and mechanistic domains:Consituent 1 and 2 belong 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 category members 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 predictions are considered reliable estimates of the algae 72 hour ErC50 as i) the model is scientifically valid and meets the requirements of the OECD principles and ii) both constituents falls within the applicability domain of the model.
- Thus the predicted values of 3.87 mg/L (constituent 1) and 3.51 mg/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 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

A separate prediction was done for each constituent

Key result

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

3.87 mg/L

Basis for effect:

growth rate

Remarks on result:

other: Predicted value for constituent 1

Key result

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

3.51 mg/L

Basis for effect:

growth rate

Remarks on result:

other: Predicted value for constituent 2

Details on results:

Category Definition:
Consituent 1 and 2 were profiled using the five primary profilers in the QSAR Toolbox that are relevant to acute aquatic toxicity endpoints (OECD 2013). Since the chemicals are inert (i.e. contains 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 101 had experimental data for the endpoint tree: growth rate, EC50, 72h, Pseudokirchnerella subcapitata. Sub-categorisation was performed by eliminating analogues that had a log Kow > 6 (i.e. no effects above water solubility expected) and analogues that might act via different mechanisms (i.e. those with additional ECOSAR classes and different profiles for protein binding by OASIS, protein binding by OECD, MoA by OASIS or Verhaar class). The final category contained 26 analogues with experimental data from the ECHA CHEM database.

Prediction Approach:
Trend analysis from category members; linear approximation.
EC50 = +2.35 +0.590 Log Kow, log(1/mol/L), N=26, r2=0.697

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

Validity criteria fulfilled:

yes

Remarks:

The model is scientifically valid and the two target chemicals fall within the applicability domain.

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 an algae 72h ErC50 of 3.87 mg/L and 3.51 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 toxicity to aquatic algae. 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 algae ErC50 values ranged from 2.48 to 3.87 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 2.48 mg/L has been selected as the key value for chemical safety assessment.

Key value for chemical safety assessment

EC50 for freshwater algae:

2.48 mg/L