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Environmental fate & pathways

Bioaccumulation: aquatic / sediment

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Reference
Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2019
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
Additional expert judgement statements are provided by the model author; the prediction is relevant and reliable and demonstrates absence of bioaccumulation concern when considering metabolism. The generated prediction is additionally, considered conservative and protective/worst case for the substance (and chemical class: aldehydes).
Justification for type of information:
1. SOFTWARE
BCF base-line model v.03.10 ; within OASIS CATALOGIC v.5.13.1.156
Contact LMC University:
Prof. As. Zlatarov,
LMC University,
Laboratory of Mathematical Chemistry,
Bourgas,
Bulgaria
URL: www.oasis-lmc.org
More information available at:
http://oasis-lmc.org/products/models/environmental-fate-and-ecotoxicity/

2. MODEL (incl. version number)
BCF base-line model v.0.3.10
May 2014 (QMRF publication); July 2018 (QMRF updated)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See QPRF attached: ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of (4E)-5-cyclohexyl-2,4-dimethylpent-4-enal’ version 1.0; 08 May 2019.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Full details of the method are provided in the attached QMRF named ‘QMRF Title: BCF base-line model for predicting log BCF of chemicals.’ - model: BCF base-line model v.0.3.10 - software package: OASIS CATALOGIC v.5.13.1.156, version 1.0; date: 01 May 2014; updated 01 July 2018.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See QPRF attached: ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of (4E)-5-cyclohexyl-2,4-dimethylpent-4-enal’ version 1.0; 08 May 2019.
- Descriptor domain: All constituents are in domain.

- Structural and mechanistic domains: All constituents are 71.43% correctly predicted ACF (structural domain) (and 85.71% if ignoring inert substitutions). However, additional expert judgement statements are provided by the model author (attached) which indicate that: although the test item is treated as being outside of the models applicability domain. Unknown ACFs do not belong to the training set chemicals. Incorrect ACFs are associated with the chemicals from the training set for which the model predictions exceed the 95% variation of the experimental data of 0.75 lu. An analysis is provided by the model author indicating where the incorrect ACFs originate in the model structural domain, whilst indicating that the despite not being entirely within the structural domain, that there is no apparent bioaccumulation concern and that any prediction should be both protective/worst-case. Full details are provided in attachment. All constituents are within the mechanistic domain.
- Similarity with analogues in the training set: . An analysis is provided by the model author indicating where the incorrect ACFs originate in the model structural domain. See attachments for further information.
- Other considerations (as appropriate): The result should be considered in relation to corresponding information presented and in accordance with the tonnage driven information requirements of REACH Regulation (EC) 1907/2006. For classification purposes, Regulation (EC) No 1272/2008 allows the use of non-standard approaches as mentioned in 4.1.1.2.2. REACH Regulation (EC) 1907/2006: Annex XI, 1.3 allows the use of a (Q)SAR instead of testing when certain conditions are met (use of valid (Q)SAR, adequate and reliable information is provided etc). During PBT/vPvB assessment for Regulation (EC) No 1907/2006, for screening purposes, experimentally determined octanol/water partitioning coefficient may be used and/or (Section 3.1.2 (a)), in accordance with the revised Annex XIII Section 3.1.2 (b), the use of other information provided its suitability and reliability can be reasonably demonstrated. In line with Annex XIII Section 3.2.2 for the assessment of B and vB either; (a) Results from a bioconcentration or bioaccumulation study in aquatic species or (b) Other information on the bioaccumulation potential provided that its suitability and reliability can be reasonably demonstrated. Such as information on toxicokinetics. The model and the supporting model author analysis provides information within this approach.

6. ADEQUACY OF THE RESULT
1) QSAR model is scientifically valid. 2) The substance falls acceptably within the applicability domains of the QSAR model when incorporating the model authors expert judgement analysis. Additional expert judgement statements are provided by the model author; the prediction is relevant and reliable and demonstrates absence of bioaccumulation concern when considering metabolism. The generated prediction is additionally, considered conservative and protective/worst case for the substance (and chemical class: aldehydes). 3) The prediction is adequate as contributing data for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The outcome of the model for the constituents are considered suitable for the assessment of the bioaccumulation potential of each constituent of the substance, and the outcome facilitates the conclusion that none of the constituents have the potential to bioaccumulate in organisms. The predicted values are in the range: BCF = 4.5 ± 2 L/kg wet wt, which are values much lower than the cut off values for chronic classification (500 L/kg wet wt) and PBT assessment (2000 L/kg wet wt) purposes). The assessment indicates that the OASIS Catalogic v5.13.1 - BCF base-line model v.03.10 model prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements.
Guideline:
other: REACH Guidance on QSARs R.6, May/July 2008
Qualifier:
according to
Guideline:
OECD Guideline 305 E (Bioaccumulation: Flow-through Fish Test)
Version / remarks:
Used for training set
Principles of method if other than guideline:
Full details of the method are provided in the attached QMRF named ‘QMRF Title: BCF base-line model for predicting log BCF of chemicals.’ - model: BCF base-line model v.03.10 - software package: OASIS CATALOGIC v.5.13.1, version 1.0; date: 01 May 2014; updated 01 July 2018.
- The model applies the following methodology to generate predictions:
Model prediction is based solely on the chemical structure and the implemented in the simulator of metabolism documented and expert knowledge for the possible rat liver molecular transformations. Although the simulator was developed on the basis of documented mammalian metabolism, its fish specificity was accounted by the probabilities of occurrence of metabolic transformations estimated by fitting fish BCF values. These probabilities are used to determine the effect of metabolism on the bioconcentration.
Predictions include: BCF base-line model v.03.10 Bioconcentration factor (BCF) - in Fish expressed as L/kg and on the decimal logarithmic scale: Log (BCF) (L/kg). Concomitant model predictions are additionally calculated.
The model accounts for a number of mitigating factors, such as molecular size, metabolism of parent chemical, water solubility and ionization.
More information on the explicit algorithms utilised is provided in the following publication: (i) S. Dimitrov, et al., Simulation of chemical metabolism for fate and hazard assessment. I. Approach for simulating metabolism, SAR and QSAR in Environ. Res. (2011) 22(7-8): 699-718. and (ii) S. Dimitrov, et al., Simulation of chemical metabolism for fate and hazard assessment. III. New developments of the bioconcentration factor base-line model. SAR and QSAR in Environ. Res. (2012) 23(1-2): 17-36. Domain applicability is described within: (ii) S. Dimitrov et al., A stepwise approach for defining the applicability domain of SAR and QSAR models. J Chem Inf. Model, 45 (4), (2005) 839-849.
- The model and the training sets are collated and published by Prof. As. Zlatarov, LMC University, (Bulgaria).
The training set of the model currently consists of 826 chemicals with 1849 correct fragments, 210 fuzzy fragments (treated as correct fragments) and 158 incorrect fragments. Further details on the training set are provided in the attached QMRF.
The experimental BCF values in the training set and validation set were measured using one or more methods equivalent or similar to the following guidelines:
- Bioaccumulation in Fish: Aqueous and Dietary Exposure (OECD TG 305) or equivalent where appropriate.
A full list of experimental reference citations is provided in the CATALOGIC software with additional reference citations in the QMRF attached.
Further expert statements are provided by the model author to support the domain assessment. In attachment.
- Justification of QSAR prediction: The result should be considered in relation to corresponding information presented and in accordance with the tonnage driven information requirements of REACH Regulation (EC) 1907/2006. The prediction is adequate as contributing data for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The outcome of the model for the constituents are considered suitable for the assessment of the bioaccumulation potential of each constituent of the substance, and the outcome facilitates the conclusion that none of the constituents have the potential to bioaccumulate in organisms.
Specific details on test material used for the study:
Detailed information on the 'test material identity' is provided in the attached QSAR Prediction Reporting Format (QPRF) document including information on individual constituents.
Type:
BCF
Value:
ca. 4.5 L/kg
Basis:
not specified
Remarks on result:
other: ±2 (± BCF Corrected)

1. Defined Endpoint:

QMRF 3. Ecotoxic effects

QMRF 2.4a. Bioconcentration BCF fish

 

Reference to type of model used and description of results:

BCF base-line model v.03.10 Bioconcentration factor (BCF), July 2018

Platform version: CATALOGIC 5.13.1

 

2. Description of results and assessment of reliability of the prediction:

BCF (Bioconcentration Factor):

Constituent 1:  Estimated Log BCF = 0.66 ± 0.07 ; BCF = 4.5 ± 2 L/kg wet-wt

Full details of the constituents are provided in the attached ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of(4E)-5-cyclohexyl-2,4-dimethylpent-4-enal’ version 1.0; 08 May 2019.

Assessment of the substance within the applicability domain as documented within the corresponding See QPRF attached: ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of(4E)-5-cyclohexyl-2,4-dimethylpent-4-enal’ version 1.0; 08 May 2019 within section 5, by comparison to the QMRF named ‘QMRF Title: BCF base-line model for predicting log BCF of chemicals.’ - model: BCF base-line model v.03.10 - software package: OASIS CATALOGIC v.5.13.1, version 1.0; date: 01 May 2014; updated 01 July 2018. This indicates:

a. Descriptors domain:

(i) Falls within the Log Kow domain of: Min -4.05 to Max 16.07 (general domain for the model); (ii) Molecular weight: Min 16.04 to Max 1130 Daltons and; (iii) Water Solubility: Min 0 to Max 1000000 mg/L.

Input descriptors:

Constituent 1: Log Kow 4.38 (measured OECD TG 117 Log Kow input); Mw: 194.318, WS (mg/L) 8.5

b. Structural domain (Atom Centred Fragments, ACFs):

All constituents are 71.43% correctly predicted ACF (structural domain) and fragments in non-correctly predicted training chemicals : 14.29%, fragments not present in the training chemicals : 14.29% . The correctly predicted ACF was considered to rise to 85.71% ACF if ignoring inert substituents. Additional expert judgement statements are provided by the model author (attached) which indicate that: although the test item is treated as being outside of the models applicability domain: Unknown ACFs do not belong to the training set chemicals. Incorrect ACFs are associated with the chemicals from the training set for which the model predictions exceed the 95% variation of the experimental data of 0.75 lu. An analysis is provided by the model author indicating where the incorrect ACFs originate in the model structural domain, whilst indicating that the despite not being entirely within the structural domain, that there is no apparent bioaccumulation concern and that any prediction should be both protective/worst-case. Full details are provided in attachment.

c. Mechanistic Domain:

The expected uptake mechanism of the target is passive diffusion across biological membranes via hydrophobicity driven uptake. The substance is within the mechanistic domain of the model.

 

3. Uncertainty of the prediction and mechanistic domain:

The BCF base-line model has been externally validated. For example: BCF base-line model – 794 experimental BCF values were used by NITE Japan (2006) to validate the model. A summary of this information is presented by the applicant in attachment with relevant citations. For more information see: ‘‘QMRF Title: BCF base-line model for predicting log BCF of chemicals.’ - model: BCF base-line model v.03.10 - software package: OASIS CATALOGIC v.5.13.1, version 1.0; date: 01 May 2014; updated 01 July 2018. The model author’s expert statement attached indicates: supporting metabolism information (with literature citations) relevant to the chemical class and that the substance, belongs to the parametric and mechanistic domain of the model. The substance is out of the structural sub-domain of the model, although a very high percentage of the chemical is within the model domain: The substance is 71.43% within the structural model domain. This increases to 85.71% (structural domain ACF) if ignoring inert substituents in the ACF. There is 14.29% atom centered fragments not presented among the correctly predicted training set chemicals accounting for the variation of the experimental error (± 0.75 lu). However, this categorization for aldehydes has been determined by incorrect BCF prediction for the single aldehyde chemical in the training set of the model. The model author highlights that the difference between predicted BCF value and experimentally found BCF for this aldehyde only slightly exceeds the variation of experimental data (1.08 lu vs. 0.75 lu). Further, it was considered to be incorrect as the model was overestimating bioaccumulation, meaning any used predictions would be protective.

Validity criteria fulfilled:
yes
Conclusions:
The results are adequate for the regulatory purpose.
Executive summary:

OASIS Catalogic v5.13.1 - BCF base-line model v.03.10, Bioconcentration factor (BCF), July 2018

Estimated Log BCF = 0.66 ± 0.07

BCF = 4.5 ± 2 L/kg wet-wt

 

Adequacy of assessment of the (Q)SAR results:

1) QSAR model is scientifically valid. 2) The substance falls acceptably within the applicability domains of the QSAR model when incorporating the model authors expert judgement analysis. Additional expert judgement statements are provided by the model author; the prediction is relevant and reliable and demonstrates absence of bioaccumulation concern when considering metabolism. The generated prediction is additionally, considered conservative and protective/worst case for the substance (and chemical class: aldehydes). 3) The prediction is adequate as contributing data for the Classification and Labelling or risk assessment of the substance as indicated in REACH Regulation (EC) 1907/2006: Annex XI Section 1.3. The outcome of the model for the constituents are considered suitable for the assessment of the bioaccumulation potential of each constituent of the substance, and the outcome facilitates the conclusion that none of the constituents have the potential to bioaccumulate in organisms. The predicted values are in the range: BCF = 4.5 ± 2 L/kg wet wt, which are values much lower than the cut off values for chronic classification (500 L/kg wet wt) and PBT assessment (2000 L/kg wet wt) purposes). The assessment indicates that the OASIS Catalogic v5.13.1 - BCF base-line model v.03.10 model prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements.

Description of key information

BCF QSAR Fish: 4.5 ± 2 L/kg wet-wt, BCF base-line model v.03.10; OASIS Catalogic v5.13.1, 2019

Key value for chemical safety assessment

BCF (aquatic species):
4.5 L/kg ww

Additional information

OASIS Catalogic v5.13.1 - BCF base-line model v.03.10, Bioconcentration factor (BCF), July 2018

Estimated Log BCF = 0.66 ± 0.07

BCF = 4.5 ± 2 L/kg wet-wt