5-methyl-5-phenylhexan-3-one

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Endpoint:

short-term toxicity to aquatic invertebrates

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

Justification for type of information:

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: October 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 daphnia (48h-LC50 in mg/L)
b. Dependent variable: Log LC50 (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 for using ECOSAR™ v1.11: Neutral organics and the acute (48h-EC50) daphnid toxicity presented as LC50 (in OECD terminology this is EC50)”, Word document attached to IUCLID
d) Predicted value (model result): LC50 = 6.5 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 6.5 mg/l.
e) Predicted value (comments): The prediction is based on the ECOSAR-neutral organics equation for acute daphnia toxicity.
The equation is: Log 48h LC50 (mmol/L) = -0.858 Log Kow + 1.3848
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 4.451 mg/L while the measured value is 7.8 mg/L.
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 daphnia toxicity may vary a factor of three too. The acute daphnia toxicity data from the analogues confirm the fact that variability is less than the factor of three.
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 daphnia: 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 daphnia 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 daphnia regression equation REACH needs/requirements for Annex VIII
Endpoint Acute daphnia toxicity Acute daphnia toxicity Acute daphnia toxicity
Algorithm/ methodology Prediction for Damascol
48h-LC50 (mg/L) = 190.29 (MW) x
10^(-0.858 *
3.33 (Log Kow) + 1.3848) = 6.5 Regression equation:
Log 48h-LC50 (mmol/L) = -0.858 Log Kow + 1.3848 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=98 and r2=0.77 It is assumed that (Q)SAR should have a similar uncertainty as OECD TG 202
Mechanistic domain Damascol is a neutral organic and its acute daphnia toxicity can be predicted with a model based on neutral organics The acute daphnia 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 202
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 daphnia toxicity of ECOSAR, based on structural features, Log Kow and molecular weight (see Table 1 above for a summary).
- The Damascol prediction for acute daphnia toxicity results in a 48h-LC50 of 6.5 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):

Daphnia sp.

Water media type:

freshwater

Total exposure duration:

48 h

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

6.5 mg/L

Nominal / measured:

estimated

Conc. based on:

test mat.

Basis for effect:

mobility

Remarks on result:

other: ECOSAR class: Neutral organics

Validity criteria fulfilled:

yes

Remarks:

The substance is in the applicability domain of the model.

Conclusions:

The Daphnia 48-h EC50 is 6.5 mg/L

Executive summary:

The 48h acute daphnia EC50 for the neutral organic substanceDamascolis predicted to be6.5mg/L based on the ECOSAR SAR for neutral organics using a predicted Log Kow of 3.33,a molecular weight (MW) of 190.29 and the equation:

48h LC50(mg/L) = MW x 10^ (-0.858 Log Kow + 1.3848)

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. The difference in log Kow between measured and predicted is small (3.5 versus 3.33) and is not considered in the prediction. 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 daphnia toxicity on neutral organics (see attached report). The adequate and reliable documentation, presented in the study record, further supports this prediction.

Description of key information

The 48h acute daphnia LC50 for the neutral organic substance Damascol is predicted to be 6.5 mg/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:48h LC50(mg/L) = MW x 10^ (-0.858 Log Kow + 1.3848).

Damascol is in the applicability domain of the ECOSAR prediction because: a) Damascol is a ketone presenting the toxicity solely by its bioavailability (i.e. without fragments that activate this neutral 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 the Damascol prediction. 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 daphnia toxicity on neutral organics (see attached report). The adequate and reliable documentation in the study record further supports this prediction.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

6.5 mg/L