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Environmental fate & pathways

Bioaccumulation: aquatic / sediment

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Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2018
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
BCF base-line model v.02.09 ; within OASIS CATALOGIC v.5.12.1
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.02.09
May 2014 (QMRF publication); July 2017 (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 (10E)-oxacycloheptadec-10-en-2-one’ version 1.0; 06 April 2018.

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.02.09 - software package: OASIS CATALOGIC v.5.12.1, version 1.0; date: 01 May 2014; updated 01 July 2017.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See QPRF attached: ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of (10E)-oxacycloheptadec-10-en-2-one’ version 1.0; 06 April 2018.
- Descriptor domain: All constituents are in domain.
- Structural and mechanistic domains: All constituents are 100% correctly predicted ACF (in domain). All constituents are within the mechanistic domain.
- Similarity with analogues in the training set: The applicant is aware of ‘similar substances’ (macrocyclic esters and ketones) data being present within the various LMC OASIS models training sets. The results are consistent with established chemical/environmental fate literature.
- 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.

6. ADEQUACY OF THE RESULT
1) QSAR model is scientifically valid. 2) The substance falls within the general properties, structural and mechanistic applicability domains of the QSAR model. Expert judgement considers the results reliable and relevant and the results are consistent with established literature. 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 = 46 ± 117 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 v5.21.1 - BCF base-line model v.02.09 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.02.09 - software package: OASIS CATALOGIC v.5.12.1, version 1.0; date: 01 May 2014; updated 01 July 2017.
- 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.02.09 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 705 chemicals with 1535 correct fragments, 171 fuzzy fragements (treated as correct fragments) and 186 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.
- 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. 46 L/kg
Basis:
not specified
Remarks on result:
other: ±117 (± 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.02.09 Bioconcentration factor (BCF), July 2017

Platform version: CATALOGIC 5.12.1

 

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

BCF (Bioconcentration Factor):

Constituent 1:  Estimated Log BCF = 1.66 ± 2.07 ; BCF = 47 ± 117 L/kg wet-wt

 

Full details of the constituents are provided in the attached ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of (10E)-oxacycloheptadec-10-en-2-one’ version 1.0; 06 April 2018.

 

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 (10E)-oxacycloheptadec-10-en-2-one’ version 1.0; 06 April 2018 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.02.09 - software package: OASIS CATALOGIC v.5.12.1, version 1.0; date: 01 May 2014; updated 01 July 2017. 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 5.87 (measured OECD TG 121 Log Kow input); Mw: 252, WS (mg/L) 0.31

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

All constituents are 100% correctly predicted ACF (in domain). All constituents are within the mechanistic domain. The high percentage of correctly predicted atom centred fragments (>80%) allows that the conclusion that the predictions are relevant. This is supported by the fact that the ranges of predicted BCF considering the variation are still much below the cut off value of 500 (for chronic effects).

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.02.09 - software package: OASIS CATALOGIC v.5.12.1, version 1.0; date: 01 May 2014; updated 01 July 2017. The high percentage of correctly predicted atom centred fragments (> 80%) allows to conclude that the predictions are relevant. This is supported by the fact that the ranges of predicted BCF considering the variation are still much below the cut off value of 500 (for chronic effects). The substance can therefore be considered within the interpolation structural space of the model. Relevant analogues are considered to be present in the model training set. No further comments on the uncertainty of the prediction are provided by the author.

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

OASIS Catalogic v5.12.1 - BCF base-line model v.02.09, Bioconcentration factor (BCF), July 2017

Estimated Log BCF = 1.66 ± 2.07

BCF = 47 ± 117 L/kg wet-wt

 

Adequacy of assessment of the (Q)SAR results:

1) QSAR model is scientifically valid. 2) The substance falls within the general properties, structural and mechanistic applicability domains of the QSAR model. Expert judgement considers the results reliable and relevant and the results are consistent with established literature. 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.

Endpoint:
bioaccumulation in aquatic species: fish
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) No. 1907/2006 Annex XI, section 1.2 justification for not performing a bioaccumulation study includes expert assessment: 1. The components of the substance are not bioaccumulative despite having Log Kow > 4.0 since ring opened macrocycle lactones and their aliphatic mono-carboxylic acid formed by lactone hydrolysis are present in mammals via a food and are known to be metabolised. This is demonstrated by the following considerations on esters/carboxylic acids: (i) (via the oral route) the alkyl esters are hydrolysed by lipases to free fatty acids and absorbed; (ii) the esters are hydrolysed into alcohol and acid and then metabolised into two carbon fragments for subsequent inclusion in cellular respiration processes via oxidization to carbon dioxide and water and subsequent elimination. 2. Aliphatic esters and carboxylic acids are metabolized by the same metabolic processes to that of dietary fats and are extensively metabolized by carboxylesterase enzymes that are ubiquitous across vertebrate and invertebrate species (Leinweber, FJ. 1987. Possible physiological roles of carboxylic ester hydrolases. Drug Metab. Rev. 18: 379-439), including in fish species (Melancon, MJ, Lech, JJ. 1979. Xenobiotica 9: 317). Carboxylesterases are enzymes with relatively broad specificity, capable of hydrolyzing esters of a wide variety of carboxylic acids (Lehninger, AL. 1975. Biochemistry, Johns Hopkins University, Worth Publishers.). Ester/carboxylate chain lengths from the simple C1 (methyl) to greater than C8 (octyl, ethylhexyl, etc.) are equally metabolizable. For macrocyclic lactones (esters) this was documented in Belsito et al. Food and Chemical Toxicology, 49 (2011), citing Joint FAO/WHO Expert Committee on Food Additives (JECFA) review (1998 and 2002). Ester hydrolysis is a “phase I” reaction, i.e., a first-pass activation reaction that prepares molecules for eventual conjugation and elimination. This specific enzymatic activity for linear esters and macrocyclic esters (lactones) explains the discrepancy between model predictions and actual bioconcentration potential is the rapid metabolism of this class of chemistry by fish. Models that do not account for metabolism over predict bioaccumulation potential in fish. The applicant adapts the information requirement through (i) (Q)SAR assessment and (ii) providing evidence of substance metabolism and elimination within the literature, for a weight-of-evidence approach to the endpoint which indicates no reasonable foreseen bioaccumulation potential.

Description of key information

BCF QSAR Fish:47 ± 117 L/kg wet-wt, BCF base-line model v.02.09; OASIS Catalogic v5.12.1, 2018

Key value for chemical safety assessment

BCF (aquatic species):
47 L/kg ww

Additional information

In accordance with REACH Regulation (EC) No. 1907/2006 Annex XI, section 1.2 justification for not performing a bioaccumulation study includes expert assessment: The components of the substance are not bioaccumulative despite having Log Kow > 4.0 since the ring opened macrocycle lactones are known to be metabolised. Specifically, the ring opened aliphatic mono-carboxylic acid formed by lactone hydrolysis, which are metabolized by the same metabolic processes to that of dietary fats. Corresponding aliphatic esters are extensively metabolized by carboxylesterase enzymes that are ubiquitous across vertebrate and invertebrate species. Along with their successive beta-oxidation and citric acid cycle and eventual respiration/excretion. This was documented in Belsito et al. Food and Chemical Toxicology, 49 (2011), citing Joint FAO/WHO Expert Committee on Food Additives (JECFA) review (1998 and 2002). BCF models that do not account for metabolism over predict bioaccumulation potential in fish. The applicant adapts the information requirement through (i) (Q)SAR assessment and (ii) providing evidence of substance metabolism and elimination within the literature, for a weight-of-evidence approach to the endpoint which indicates no reasonable foreseen bioaccumulation potential.

 

OASIS Catalogic v5.12.1 - BCF base-line model v.02.09, Bioconcentration factor (BCF), July 2017

Estimated Log BCF = 1.66 ± 2.07

BCF = 47 ± 117 L/kg wet-wt