5-methyl-5-phenylhexan-3-one

Toxicity to aquatic algae and cyanobacteria

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

toxicity to aquatic algae and cyanobacteria

Remarks:

EC10/NOEC

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

Remarks:

Rel 2 is assigned because of the method being a QSAR

Qualifier:

according to guideline

Guideline:

other: REACH guidance R.6

Version / remarks:

In the QMR attached the model specifications are presented. In this QMR is referenced to the Methodology document for the ecological Structure-Activity Relationship model (ECOSAR) Class Programm MS Windows v1.1'. United States Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington DC (2011).

Key result

Duration:

96 h

Dose descriptor:

EC10

Effect conc.:

2.75 mg/L

Nominal / measured:

not specified

Conc. based on:

test mat.

Basis for effect:

growth rate

Validity criteria fulfilled:

yes

Remarks:

The substance is in the applicability domain of the model.

Conclusions:

The EC10 is 2.75 mg/l

Executive summary:

The chronic algae EC10 for the neutral organic substanceDamascolis predicted to be2.75mg/L based on the ECOSAR SAR for neutral organics using a partition coefficient (Log Kow) of 3.33,a molecular weight (MW) of 190.29 and the equation:Log ChV(mmol/L) = -0.6029 Log Kow + 0.1648.

Damascolis in the applicability domain of the ECOSAR prediction because: a)Damascolis aketonepresenting the toxicity solely by its bioavailability (i.e. without fragments that activate thisneutral organic); b) its predicted Log Kow is 3.33 (measured 3.5) (=< 8.0); c) its MW is 190.29 (< 1000); and d) the toxicity predicted is below its water solubility of 95 mg/l.

The fit in the applicability domain and the availability of an analogue in the training set results in limited uncertainty of theDamascolprediction. This shows that the prediction is reliable and a Klimisch 2 can be assigned. In accordance with REACH Annex XI, the validity of the (Q)SAR is documented in a QMR for chronic algae toxicity on neutral organics (see attached report). The adequate and reliable documentation, presented in the study record, further supports this prediction.

Reference 2

Endpoint:

toxicity to aquatic algae and cyanobacteria

Remarks:

ErC50 at 96h

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

Remarks:

QSAR

Justification for type of information:

QSAR Prediction Report Template: Neutral organics and Acute Algae Toxicity for Damascol (CAS# 4927-36-0) Using ECOSAR™ v1.11
This report was created on 01-02-2017 and based on QPRF, version 1.1, May 2008.
1 Substance Damascol
1.1 CAS number: 4927-36-0
1.2 EC number: 225-561-0
1.3 Chemical name: 5-Methyl-5-phenyl-3-hexanone
1.4 Structural formula: C13H18O and Molecular weight: 190.29
1.5 Structure codes:
a. SMILES: CCC(=O)CC(C)(C)c1ccccc1
b. InChI:InChI=1/C13H18O/c1-4-12(14)10-13(2,3)11-8-6-5-7-9-11/h5-9H,4,10H2,1-3H3
c. Chemical structure

d. Other structural representation: Not relevant
e. Stereochemical features: Not relevant

2. General information
2.1 Date of QPR: August 2016
2.2 QPR author and contact details: Ms. Dr. E. Hulzebos, International Flavours and Fragrances, P.O. Box 307, 1200 AH Hilversum, The Netherlands
3 Prediction
3.1 Endpoint (OECD Principle 1)
a. Endpoint: Acute toxicity to green aquatic algae (96h-ErC50 in mg/L)
b. Dependent variable: Log ErC50 (mmol/L)
3.2 Algorithm (OECD Principle 2)
a) Model or sub-model name: ECOSAR™
b) Model version: Version 1.11(2012)
c) Reference to QMR: Hulzebos, 2015, “QSAR Model Reporting Format for using ECOSAR™ v1.11: Neutral Organics E(L)C50 for Algae”, Word document attached to IUCLID
d) Predicted value (model result): ErC50 = 8.0 mg/L using a Log Kow of 3.33 and a molecular weight of 190.29. The final value used for the risk assesment will be 8.0 mg/l.
e) Predicted value (comments): The prediction is based on the ECOSAR-neutral organics equation for acute algae toxicity. The equation is: Log 96h ErC50 (mmol/L) = -0.6922 Log Kow + 0.9253
f) Input for prediction: SMILES
g) Descriptor values: Log Kow = 3.33 (predicted value)
3.3 Applicability domain (OECD principle 3)
a. Domains:
i. Descriptors: The predicted Log Kow of Damascol is 3.33 (measured 3.5) and the substance has a molecular weight of 190.29. The applicability domain of the model for Log Kow is =<6.4 and for molecular weight is <=1000. Damascol is within these applicability domains.
ii. Structural fragment domain: Damascol is a ketone and has no fragments indicating ‘excess toxicity’ and therefore it is within the structural domain.
iii. Mechanism domain: Damascol will present its toxicity solely due to its bioavailability, which is confirmed within ECOSAR by assigning this substance to Neutral Organics. Therefore this substance is within the mechanistic domain.
b. Structural analogues:
The closest analogue in the training set is trans-Anethole (CAS# 4180-23-8), which has a Log Kow of 3.388, a molecular weight of 148.21 and is also a neutral organic. The predicted value is 5.633 mg/L while the measured value is 4.24 mg/L.
c. Considerations on structural analogues:
The analogue presented shows sufficient similarity in chemical structure, Log Kow and molecular weight with Damascol to be considered a structural analogue.
3.4 The uncertainty of the prediction (OECD principle 4)
Damascol is categorised as a neutral organic and is expected to have a similar uncertainty as the data in the training set. The data used for deriving the regression equation deviate around a factor of three from the regression line. Therefore the variability of the Damascol prediction for acute algae toxicity may vary a factor of three too. The acute algae toxicity data from the analogues confirm the fact that variability is less than the factor of three. The difference between the measured log Kow of 3.5 versus the used predicted log Kow of 3.33 is considered minor (< 0.5) and not affecting the results.
3.5 The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5).
Damascol exhibits a neutral organic mode of action towards algae: the toxicity is solely based on the bioavailability using Log Kow as a parameter. This is also the mechanism of the neutral organics in the model, presenting that acute algae toxicity is inversely correlated with the hydrophobicity (Log Kow) of a substance.
4. Adequacy
The adequacy of the prediction is considered to be the overall result from the reliability of the prediction, the validity of the method and the REACH need/requirement when using such prediction. In the table below, a general adequacy assessment is outlined according to Hulzebos et al. 2010. From this outline the specific requirement of REACH Annex XI can be retrieved.

Table 1. Damascol and the adequacy of the prediction based on Hulzebos et al., 2010
OECD principles for assessing QSAR Reliability of the prediction of Damascol Validity of the ECOSAR acute algae regression equation REACH needs/requirements for Annex VIII
Endpoint Acute algae toxicity Acute algae toxicity Acute algae toxicity
Algorithm/ methodology Prediction for Damascol
ErC50 (mg/L) = 190.29 (MW) x
10^(-0.6922 *
3.33 (log Kow) + 0.9253) = 8.0 Regression equation:
Log 96h-ErC50 (mmol/L) = -0.6922 log Kow + 0.9253 According to Annex XI 1.3 (Q)SAR can be used.
Applicability domain Damascol is a neutral organic, Log Kow 3.33 and MW 190.29 The model is based on neutral organics with Log Kow =<6.4 and MW <=1000 Damascol has to be registered for REACH
Uncertainty of the prediction Damascol prediction has a similar uncertainty as presented by the training set of the model. Training set substances vary a factor of 3 from the regression line.
N=41 and r2=0.68 It is assumed that (Q)SAR should have a similar uncertainty as OECD TG 201
Mechanistic domain Damascol is a neutral organic and its acute algae toxicity can be predicted with a model based on neutral organics The acute algae toxicity of neutral organics is inversely related to its Log Kow being the parameter for bioavailability. The method should include the mechanisms which can be tested with the OECD TG 201
Klimisch type of scoring Rel 2 Val 2 Need 2
Klimisch type of scoring for adequacy Adequacy 2
Hulzebos, E., Gunnarsdottir, S., Rila, J.P., Dang, Z., Rorije, E., 2010, An Integrated Assessment Scheme for assessing the adequacy of (eco)toxicological information under REACH, Toxicol., Letters, 198, 255-263.

4.1 REACH purpose
The Damascol prediction meets the criteria of REACH Annex XI on (Q)SARs because the following criteria are met:
- The scientific validity of the model is met as presented in the QMR, which is summarized in Table 1 above.
- Damascol falls within the applicability domain of the neutral organic model for acute algae toxicity of ECOSAR, based on structural features, Log Kow and molecular weight (see Table 1 above for a summary).
- The Damascol prediction for acute algae toxicity results in a 96h-ErC50 of 8.0 mg/L, which is adequate for the purpose of classification and labelling and risk assessment.
- Adequate and reliable documentation is provided: A QMR for neutral organics of ECOSAR and a QPR for Damascol are provided and therefore the documentation requirements are fulfilled.

Qualifier:

according to guideline

Guideline:

other: REACH Guidance R.6: QSARs and grouping of chemicals. Version May 2008.

Version / remarks:

In the QMR attached the model specifications are presented. In this QMR is referenced to the Methodology document for the ecological Structure-Activity Relationship model (ECOSAR) Class Programm MS Windows v1.1'. United States Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington DC (2011).

Test organisms (species):

other: green algae

Water media type:

freshwater

Total exposure duration:

96 h

Key result

Duration:

96 h

Dose descriptor:

EC50

Effect conc.:

8 mg/L

Nominal / measured:

estimated

Conc. based on:

test mat.

Basis for effect:

growth rate

Remarks on result:

other: ECOSAR class: Neutral organics

Details on results:

The ErC50 is 8.0 mg/L

Validity criteria fulfilled:

yes

Remarks:

The substance is in the applicability domain of the model.

Conclusions:

The 96h-ErC50 is 8.0 mg/L.

Executive summary:

The acute algae ErC50 for the neutral organic substanceDamascolis predicted to be8.0mg/L based on the ECOSAR SAR for neutral organics using a partition coefficient (log Kow) of 3.33,a molecular weight (MW) of 190.29 and the equation:ErC50(mg/L) = MW x 10^ (-0.6922 log Kow + 0.9253).

Damascolis in the applicability domain of the ECOSAR prediction because: a)Damascolis aketonepresenting the toxicity solely by its bioavailability (i.e. without fragments that activate thisneutral organic); b) its predicted log Kow is 3.33 (measured 3.5) (=< 6.4); c) its MW is 190.29 (< 1000); and d) the toxicity predicted is below its water solubility of 95 mg/l.

The fit in the applicability domain and the availability of an analogue in the training set results in limited uncertainty of theDamascolprediction. This shows that the prediction is reliable and a Klimisch 2 can be assigned. In accordance with REACH Annex XI, the validity of the (Q)SAR is documented in a QMR for acute algae toxicity on neutral organics (see attached report). The adequate and reliable documentation, presented below, further supports this prediction.

Description of key information

Acute algae (ECOSAR-Neutral organics): 8 mg/l

EC10 algae (ECOSAR-Neutral organics): 2.75 mg/l

 

Key value for chemical safety assessment

EC50 for freshwater algae:

8 mg/L

EC10 or NOEC for freshwater algae:

2.75 mg/L

Additional information

The derived ErC50 and EC10 for algae are summarised below:

ErC50 for algae

The acute algae ErC50 for the neutral organic substanceDamascolis predicted to be8.0mg/L based on the ECOSAR SAR for neutral organics using a partition coefficient (log Kow) of 3.33,a molecular weight (MW) of 190.29 and the equation:ErC50(mg/L) = MW x 10^ (-0.6922 log Kow + 0.9253).

Damascolis in the applicability domain of the ECOSAR prediction because: a)Damascolis aketonepresenting the toxicity solely by its bioavailability (i.e. without fragments that activate thisneutral organic); b) its predicted log Kow is 3.33 (measured 3.5) (=< 6.4); c) its MW is 190.29 (< 1000); and d) the toxicity predicted is below its water solubility of 95 mg/l.

The fit in the applicability domain and the availability of an analogue in the training set results in limited uncertainty of theDamascolprediction. This shows that the prediction is reliable and a Klimisch 2 can be assigned. In accordance with REACH Annex XI, the validity of the (Q)SAR is documented in a QMR for acute algae toxicity on neutral organics (see attached report). The adequate and reliable documentation, presented in the study record further supports this prediction.

The EC10 for algae

The chronic algae EC10 for the neutral organic substanceDamascolis predicted to be2.75mg/L based on the ECOSAR SAR for neutral organics using a partition coefficient (Log Kow) of 3.33,a molecular weight (MW) of 190.29 and the equation:Log ChV(mmol/L) = -0.6029 Log Kow + 0.1648.

Damascolis in the applicability domain of the ECOSAR prediction because: a)Damascolis aketonepresenting the toxicity solely by its bioavailability (i.e. without fragments that activate thisneutral organic); b) its predicted Log Kow is 3.33 (measured 3.5) (=< 8.0); c) its MW is 190.29 (< 1000); and d) the toxicity predicted is below its water solubility of 95 mg/l.

The fit in the applicability domain and the availability of an analogue in the training set results in limited uncertainty of theDamascolprediction. This shows that the prediction is reliable and a Klimisch 2 can be assigned. In accordance with REACH Annex XI, the validity of the (Q)SAR is documented in a QMR for chronic algae toxicity on neutral organics (see attached report). The adequate and reliable documentation, presented in the study record, further supports this prediction.