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Short-term toxicity to aquatic invertebrates

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Endpoint:
short-term toxicity to aquatic invertebrates
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
November 2017
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: Ecosar v2.0

2. MODEL (incl. version number): Aldehyde (Mono), Daphnia 48-hr LC50

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: O=CC1=CC=C(C(C)C)C=C1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The ECOSAR Class Program and underlying methodology have been developed over a period of more than 25 years by EPA/OPPT. The current ECOSAR version (v2.0, October 2017) is programmed to identify over 120 chemical classes and allows access to more than 600 QSARs. The aldehyde (Mono) 48-hr Daphnid LC50 QSAR is one of these QSARs. The model is valid according to the following five OECD principles.
- Defined endpoint: Daphnia 48 hr LC50
- Unambiguous algorithm: Log 48-h LC50 (mmol/L) = -0.5193 (log Kow) – 0.2171
- Defined domain of applicability: Mono aldehyde, maximum log Kow 5, maximum MW 1000
- Appropriate measures of goodness-of-fit and robustness and predictivity: n = 14 (training set) + 3 (validation set), r2 = 0.7311
- Mechanistic interpretation: The hypothesis is that chemicals that share the same mode of action for aquatic toxicity (i.e. same chemical class) can be grouped together for the prediction of short-term toxicity to daphnia and that there is a positive correlation between the LC50 and log Kow up to a maximum log Kow of 5.0.

5. APPLICABILITY DOMAIN
- Descriptor domain: 4-Isopropylbenzaldehyde has a log Kow of 2.8 (measured) and 3.166 (estimated), which falls within the applicability domain of the ECOSAR Aldehydes (Mono) SAR (maximum log Kow is 5.0).
- Structural and mechanistic domains: 4-Isopropylbenzaldehyde has a molecular weight of 148.21 which falls within the applicability domain of the ECOSAR Aldehydes (Mono) SAR (maximum MW is 1000). Based on the chemical structure, ECOSAR v2.0 attributed the 4-Isopropylbenzaldehyde to the chemical class of Aldehydes, Mono.
- Similarity with analogues in the training set: The closest neighbours in the log Kow descriptor space are Salicylaldehyde, Cyclohexaneacetaldehyde and 2,4,6-trimethylbenzaldehyde (see next section)

6. ADEQUACY OF THE RESULT
- The ECOSAR training set contains measured fish data for 4-isopropylbenzaldehyde (96-hr LC50 = 6.6mg/L, Reference = DUL). A comparison of this measured value with ECOSAR v2.0 estimates (Table 1), confirms that the aldehyde SAR provides a reliable prediction of aquatic toxicity of 4-isopropylbenzaldehyde since the predicted values of 2.5 and 3.75 mg/L are conservative (i.e. slightly less than the measured value of 6.6 mg/L) and both predicted and measured values are within the same environmental classification band of >1 and < 10 mg/L.
- The predicted and experimental daphnia 48-hr E(L)C50 values for close analogues in the training set are provided in table 2. The results indicate that the “Aldehyde, Mono” SAR provides a reliable estimate of the aquatic toxicity for all three substances. All predicted and measured value are within the same acute aquatic hazard classification band of > 1 and <=10 mg/L.

Thus the predicted Daphnia 48-h LC50 values of 2.04 mg/L (based on estimated log Kow of 3.166) and 3.16 mg/L (based on measured log Kow of 2.8) are considered adequate for classification and labelling purposes and/or risk assessment. The predicted value of 2.04 mg/L is considered conservative and worst case given that it is based on an estimated Log Kow (3.166) which is significantly higher than the measured log Kow (2.8) and given that the measured data for fish more closely match the predicted values based on measured log Kow (Table 1).
Guideline:
other:
Version / remarks:
REACH Guidance: Chapter R.6: QSARs and grouping of chemicals, May 2008.
Principles of method if other than guideline:
ECOSAR v2.0; Aldehydes (Mono), 48-hr Daphnid LC50 regression model.
Specific details on test material used for the study:
SMILES USED AS INPUT FOR THE MODEL: O=CC1=CC=C(C(C)C)C=C1

The registration substance is a monoconstituent substance with a concentration range of >= 90% to 100%. The QSAR prediction reported is for the structure of the single constituent.

Cuminic aldehyde may contain the isomeric impurities:
2-isopropylbenzaldehyde (0-5%), SMILES : O=CC1=CC=CC=C1C(C)C
3-isopropylbenzaldehyde (0-5%), SMILES O=CC1=CC=CC(C(C)C)=C1
The presence of the above impurities will not affect the reliability of the prediction. A separate prediction was performed for the mono-constituent (attached study report) and both isomeric impurities (attached background). All gave the same results. This is explained by the fact that all structures are assigned to the same ECOSAR class, have the same predicted log Kow of 3.166 (Kowwin v 1.68) and same molecular weight.

The log Kow of Cuminic aldehyde was determined by the Reverse Phase High Performance Liquid Chromatographic Method according to OECD Guidelines for Testing of Chemicals, Method No. 117 (see IUCLID section 4.7). The chromatogram shows one peak corresponding to a partition coefficient (log value) of 2.8. The presence of one peak indicates that the three isomers have the same log Kow
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
2.04 mg/L
Remarks on result:
other: ECOSAR prediction using estimated log Kow of 3.17
Key result
Duration:
48 h
Dose descriptor:
LC50
Effect conc.:
3.16 mg/L
Remarks on result:
other: ECOSAR prediction using measured log Kow of 2.8
Details on results:
- The ECOSAR v2.0 result files are attached under "full study report".
- The predicted daphnid 48-h LC50 values of 2.04 and 3.16 mg/L are considered reliable estimates because the model is scientifically valid and 4-isopropyl benzaldehyde falls within its applicability domain.
- The ECOSAR aldehyde (mono) training set contains measured fish data for 4-isopropylbenzaldehyde (96-hr LC50 = 6.6mg/L, Reference = DUL). A comparison of this measured value with ECOSAR v2.0 estimates (Table 1), confirms that the aldehyde SAR provides a reliable prediction of aquatic toxicity of 4-isopropylbenzaldehyde.
- The predicted daphnia 48-h LC50 value of 2.04 mg/L is considered conservative and worst case given that it is based on an estimated Log Kow (3.166) which is significantly higher than the measured log Kow (2.8) and given that the measured data for fish more closely match the predicted values based on measured log Kow (Table 1). Thus the more realistic value of 3.16 mg/L has been chosen as the key value.
- The reliability of the daphnia LC50 prediction is further supported by three analogues from the training set which are nearest neighbours in the log Kow descriptor space (see table 2 below and QPRF report for details). The predicted values are in close agreement with the experimental values and within the same acute aquatic hazard classification and labeling criteria range of E(L)C50 > 1mg/L and <= 10 mg/L.


Table 1: Comparison of measured and predicted L(E)C50 values for Fish

 

Fish

96-hr LC50 (mg/L)

Measured Values:

Available from ECOSAR Training Set.

6.6

Predicted Values, ECOSAR v1.11:

Aldehydes, Mono SAR

- estimated log Kow of 3.17

- measured log Kow of 2.8

 

 

2.50

3.75

Table 2: Predicted and experimental daphnia 48h LC50 values for aldehyde in ECOSAR training set (nearest neighbours to 4-isopropylbenzaldehyde in the log Kow descriptor space)

CAS

Chemical name

Log Kow (EPI)

Predicted, 48-h LC50 (mg/L)

Measured

48-h LC50 (mg/L)

Aldehyde

Phenol

90-02-8

Salicylaldehyde

2

6.72

7.15

5.4-5.8

(3 values)

2109-22-0

Cyclohexane-

acetaldehyde

3

2.32

-

1.2

487-68-3

2,4,6-trimethylbenzaldehyde

3.4

1.63

 

4.5

 

Validity criteria fulfilled:
yes
Remarks:
See attached QPRF document for full discussion.
Conclusions:
The registration substance, 4-isopropyl benzaldehyde, was predicted to have a daphnid 48-h LC50 value of 2.04 mg/L (based on estimated log Kow of 3.166) and 3.16 mg/L (based on measured log Kow of 2.8) using the ECOSAR v2.0 aldehyde (mono) SAR. The prediction result is considered reliable according to OECD principles; the QSAR model is scientifically valid and 4-isopropyl benzaldehyde falls within its applicability domain. The reliability of the prediction is supported by three analogues in the model training set, where predicted values are in close agreement to the experimental values and all within the same acute aquatic classification band of > 1 and <= 10 mg/L. The predicted value of 2.04 mg/L is considered conservative and worst case given that it is based on an estimated Log Kow (3.166) which is significantly higher than the measured log Kow (2.8) and given that the measured data for fish more closely match the predicted values based on measured log Kow. Thus the more realistic value of 3.16 mg/L has been chosen as the key value and is being used in a weight-of-evidence approach, along with one other reliable QSAR prediction, to fill the short-term toxicity to aquatic invertebrates endpoint.
Endpoint:
short-term toxicity to aquatic invertebrates
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
Nov 2017
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: CC(C)c1ccc(C=O)cc1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: daphnia magna, 48h, EC50
- Unambiguous algorithm: EC50 = +0.896 + 1.33 * log Kow, log(1/mol/L)
- Defined domain of applicability: Aquatic toxicity classification by ECOSAR = aldehydes (mono); Protein binding by OASIS v1.4 = No alert; Protein binding by OECD = no alert; Acute aquatic toxicity MOA by OASIS = aldehydes; Acute aquatic toxicity classification by Verhaar = Class 3 (unspecific reactivity, chemical elements = Group 14 - Carbon and Group 16 - Oxygen; log Kow estimated within QSAR Toolbox of >= 1.79 and <=3.77
- Appropriate measures of goodness-of-fit and robustness and predictivity: N=4, R2=0.989, Q2=0.925
- Mechanistic interpretation: The hypothesis is that chemicals that share the same mode of action for aquatic toxicity can be grouped together for the prediction of the daphnia short-term toxicity. This assumption is supported by the robust trend found between EC50 and log Kow for all analogues.

5. APPLICABILITY DOMAIN
- Descriptor domain: The logKow of the target as estimated by the QSAR Toolbox v3.4.0.17 is 3.17 , which falls within the applicability domain of >= 1.79 and <=3.77
- Structural and mechanistic domains: The target substance falls within the mechanistic domain as defined by the five aquatic toxicity profilers and chemical element profiler in the QSAR Toolbox (see "Defined domain of applicability" above and attached QSAR Toolbox report for full details).
- Similarity with analogues in the training set: The target 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 the category members (see attached QSAR Toolbox report), it can be seen that the five primary profiles for all members are identical and as such it is concluded that all are expected to act via the same mode of action. From a structural perspective all analogues and the target are alkyl / alkoxy /phenoxy substituted benzaldehydes. Therefore the group is considered robust enough to obtain a reliable prediction. The high R2 and Q2 values for the regression equation support the reliability of the prediction.

6. ADEQUACY OF THE RESULT
- 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) the target falls within the applicability domain of the model.
- Thus the predicted daphnia 48-hr EC50 value of 1.17 mg/L is considered adequate for regulatory purposes.

For further details see the attached QSAR Toolbox report.
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 FOR THE MODEL: CC(C)c1ccc(C=O)cc1

The registration substance is a monoconstituent substance with a purity of => 90% up to 100%. The QSAR prediction has been performed on the structure of the single consitutent. Isomeric impurities that may be present (3-isopropyl benzaldehyde and 2-isopropyl benzaldehyde) would be predicted to have the same aquatic toxicity because they have the same estimated log Kow.
Key result
Duration:
48 h
Dose descriptor:
EC50
Effect conc.:
1.17 mg/L
Remarks on result:
other: Predicted value using trend analysis
Details on results:
Category definition:
The target substance was profiled using the five primary profilers relevant to acute aquatic toxicity endpoints (see section 4.5). Since the chemical is inert (i.e. contains no structural alerts for protein binding using the mechanistic profilers), the “aquatic toxicity classification by ECOSAR” profiler was used for developing the initial category since it is the most detailed aquatic endpoint profiler in terms of the number of alerts.
The target is classified as a mono aldehyde by the ECOSAR profiler. Thus an initial category was formed from chemicals in the publicly available aquatic toxicity databases available in the Toolbox that are classified as mono aldehydes. A trend analysis was performed for the endpoint tree "daphnia magna, 48h, EC50". This gave an initial category of 56 chemicals. Sub-categorised was performed using the five aquatic toxicity profiles to ensure the category only contained analogues that would exert their effect by the same mode of action (i.e. by removal of analogues with different profiles to the target) and by removing analogues with different chemical elements to the target. The final category contained 4 analogues.

Prediction Approach:
Trend analysis from category members; linear approximation.
EC50 = 0.896 + 1.33 Log Kow, log(1/mol/L), N=4, r2=0.989, Q2 = 0.925

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).

Other datagap filling methods were explored. Read-across taking the average based on the nearest 4 and 2 neighbours gave EC50 predictions or 1.99 and 1.31 mg/L respectively. Thus only the more conservative value from the trend analysis has been included.
Validity criteria fulfilled:
yes
Remarks:
The model approach is scientifically valid and the target falls within its applicability domain (see attached QSAR Toolbox prediction report for details).
Conclusions:
The registration substance, 4-isopropylbenzaldehyde, was predicted to have a daphnid 48-hr Ec50 of 1.17 mg/L. The prediction result is considered reliable according to OECD principles; the prediction model approach is scientifically valid and 4-isopropylbenzaldehyde falls within its applicability domain. The predicted value is being used in a weight-of-evidence approach, along with one other reliable QSAR prediction, to fill the short-term toxicity to aquatic invertebrates endpoint.

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 well-established software tools have been used, OECD QSAR Toolbox v3.4.0.17 and ECOSAR v2.0. The predicted 48 hour daphnid EC50/LC50 values were 1.17 and 3.16 mg/L respectively. The prediction results are considered reliable according to OECD principles. The prediction models are scientifically valid and 4 -isopropyl benzaldehyde falls within their applicability domain.

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. Furthermore, 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.

Key value for chemical safety assessment

Additional information