4-isopropylbenzaldehyde

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:

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: Ecosar v2.0

2. MODEL (incl. version number): Aldehyde (Mono), Green Algae 96-hr EC50

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) Green Algae 96-hr EC50 QSAR is one of these QSARs. The model is valid according to the following five OECD principles.
- Defined endpoint: Green Algae 96-hr EC50
- Unambiguous algorithm:Log 96-h EC50 (mmol/L) = -0.4708 (log Kow) – 0.5444
- Defined domain of applicability: Mono aldehyde, maximum log Kow 6.4, maximum MW 1000
- Appropriate measures of goodness-of-fit and robustness and predictivity: n = 6 (training set) + 1 (Kow limit), r2 = 0.8115
- 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 toxicity to aqautic algae and that there is a positive correlation between the EC50 and log Kow up to a maximum log Kow of 6.4.

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 6.4).
- 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 2,4,6-trimethylbenzaldehyde (see next section). This substance is also a close structural analogue to 4-isopropyl benzaldehyde with both substances having the same basic benzaldehyde structure. The only difference is the nature and position of the alkyl substituents on the aromatic ring which is not expected to affect the aquatic toxicity profile given the similar lipophilicity.

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 Green Algae 96-hr EC50 value for the close analogue identified 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. All predicted and measured value are within the same acute aquatic hazard classification band of > 1 and <=10 mg/L.

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), Green Algae 96-hr EC50 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

Key result

Duration:

96 h

Dose descriptor:

EC50

Effect conc.:

2.03 mg/L

Remarks on result:

other: ECOSAR prediction using estimated log Kow of 3.17

Duration:

96 h

Dose descriptor:

EC50

Effect conc.:

1.37 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 green algae 96-h EC50 values of 1.37 and 2.03 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 green algae 96-h EC50 value of 1.37 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 2.03 mg/L has been chosen as the key value.
- The reliability of the green algae 96-h EC50 prediction is further supported by a close structural analogue from the ECOSAR training set; 2,4,6-trimethyl benzaldehyde (log kow 3.4). The predicted value of 1.12 mg/L for this analogue is in close agreement with the experimental value of 1.8 mg/L (table 2). This analogue has a higher log Kow compared to 4-isopropylbenzaldehyde and as such is expected to exhibit slightly higher aquatic toxicity. This further supports the use of the 2.03 mg/L predicted value as the key result in the assessment of the aqautic toxicity of 4-isopropyl benzaldehyde to green algae.
- All EC50 values (predicted for the target, predicted & measured for the analogue) are within the same acute aquatic hazard classification and labeling criteria range of E(L)C50 > 1mg/L and <= 10 mg/L. Thus the prediction results for 4-isopropyl benzaldehyde are considered adequate regulatory purposes.

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 green algae 96-h EC50 values for aldehyde in ECOSAR training set (nearest neighbour to 4-isopropylbenzaldehyde in the log Kow descriptor space)

CAS	Chemical name	Log Kow (EPI)	Predicted, 96-h LC50 (mg/L)	Measured 48-h LC50 (mg/L)
487-68-3	2,4,6-trimethylbenzaldehyde	3.4	1.12	1.8

Validity criteria fulfilled:

yes

Remarks:

See attached QPRF for full discussion

Conclusions:

The registration substance, 4-isopropyl benzaldehyde, was predicted to have a green algae 96-h EC50 value of 1.37 mg/L (based on estimated log Kow of 3.166) and 2.03 mg/L (based on measured log Kow of 2.8) using the ECOSAR v2.0 aldehyde (mono) SAR. The predicted value of 1.37 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. 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 the closest structural analogue in the model training set (2,4,6-trimethyl benzaldehyde, log Kow 3.4), where the predicted value of 1.12mg/L is in close agreement to the experimental value of 1.8 mg/L. This analogue has a higher log Kow compared to 4-isopropylbenzaldehyde and as such is expected to exhibit slightly higher aquatic toxicity. Thus the predicted value of 2.03 mg/L for 4-isopropyl benzaldehyde is considered the more realistic and has been chosen as the key value. It is being used in a weight-of-evidence approach, along with one other reliable QSAR prediction, to fill the toxicity to aquatic algae and cyanobacteria endpoint.

Reference 2

Endpoint:

toxicity to aquatic algae and cyanobacteria

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: growth rate, 72h, EC50, green algae
- Unambiguous algorithm: Not applicable - category formation, followed by datagap filling based on average of nearest neighbours in log Kow descriptor space
- Defined domain of applicability: Category defined by following aquatic toxicity profiles: 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). The group also contains only substances containing the chemical elements carbon and oxygen. Log Kow range of nearest neighbours => 2.80 and <=3.62
- Appropriate measures of goodness-of-fit and robustness and predictivity: The prediction is based on 2 values in the range 13.6 - 16.6 mg/L.
- 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 aquatic toxicity and that there is a positive correlation between the EC50 and log Kow up to a maximum log Kow limit. Chemicals with similar log kow are expected to exhibited a similar strength of aquatic toxicity which supports data-gap filling based on the average of the nearest neighbours in the log Kow descriptor space.

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 => 2.80 and <=3.62
- 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 substituted benzaldehydes. Therefore the group is considered robust enough to obtain a reliable prediction.

6. ADEQUACY OF THE RESULT
- The predictions are considered reliable estimates of the green algae 72h 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 green algae 72-hr EC50 value of 15.1 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 read-across from nearest neighbours.

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:

72 h

Dose descriptor:

EC50

Effect conc.:

15.1 mg/L

Remarks on result:

other: Predicted value using average of two nearest neighbours

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 "growth rate, 72h, EC50, green algae". This gave an initial category of 44 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 3 analogues.

Prediction Approach:
Trend analysis gave a predicted EC50 of 17mg/L while read-across for category members taking the average value from the 2 nearest neighbours in the log kow space gave a value of 15.1 mg/L. Since the latter is more conservative, the read-across approach was ultimately chosen.

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 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 green algae 72-hr Ec50 of 15.1 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 toxicity to aquatic algae 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 toxicity to aquatic algae. Two well-established software tools have been used, OECD QSAR Toolbox v3.4.0.17 and ECOSAR v2.0. The predicted algae EC50 values were 15.1 and 2.03 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 models are independent from each other (e.g. based on different training sets). Thus, the relatively close agreement among the predictions increases the confidence in the reliability of the predictions. The worst-case conservative value of 2.03mg/L is considered relevant for the regulatory purpose of classification and labelling.