2-methylpentyl 2-hydroxybenzoate

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2021

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 analysis are provided by the model author; the prediction is relevant and reliable and demonstrates absence of bioaccumulation concern when considering metabolism. The prediction is demonstrated as being consistent with published experimental data on structural analogues within the chemical class: salicylates.

Justification for type of information:

1. SOFTWARE
BCF base-line model v.05.12 ; within OASIS CATALOGIC v.5.15.2
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.0.5.12
May 2014 (QMRF publication); October 2021 (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 2-methylpentyl 2-hydroxybe’ version 1.0; 09 December 2021.

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.0.5.12 - software package: OASIS CATALOGIC v.5.15.2, version 1.0; date: 01 May 2014; updated 01 October 2021.

5. APPLICABILITY DOMAIN
See ‘any other information on results incl. tables’.
See QPRF attached: ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of 2-methylpentyl 2-hydroxybe’ version 1.0; 09 December 2021.
- Descriptor domain: The substance is in domain.

- Structural and mechanistic domains: The substance is 90.91% correctly predicted ACF (structural domain) and fragments in non-correctly predicted training chemicals : 0.00%, fragments not present in the training chemicals : 9.09%. 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. However, it is seen that the known fragments extracted from correctly predicted training set chemicals contain carboxylic group and benzene ring as a first neighbour or hydroxyl group and benzene ring as a first neighbour. The only unknown fragment from the target contains benzene ring as a centre and carboxylic group and hydroxyl group on o – position as first neighbours. The reason this fragment to appear as unknown is that salicylates (chemical class) are not presented among the training set chemicals. The details for unknown and known fragments in 2-methylpentyl 2-hydroxybenzoate can be found in Supplemental material I (provided in attachment). The two main simulated metabolic transformations are ester hydrolysis where the carboxylic group takes place independently of the substitute on o – position and glucuronide conjugation to hydroxyl group and this happens again no matter of presence or absence of substitute to the aromatic ring next to the hydroxyl group. Both transformations are correctly simulated by the model, with experimental and theoretical supports. The details for experimental support can be found in Appendix 5 of the attached QPRF, with theoretical support in Supplemental material II and III (provided in attachment). All constituents are within the mechanistic domain. An analysis is provided by the model author indicating where the unknown fragment ACFs originate in the model structural domain, with further consideration on structural analogues with experimental BCF data. Thereby indicating that for the target substance: being predominantly (> 90% ACF) but not being entirely within the OASIS BCF base-line model structural domain, that the unknown fragments have no effect on the prediction and/or that there is no apparent bioaccumulation concern. Full details are provided in attachment.
- Similarity with analogues in the training set: An analysis is provided by the model author indicating where the unknown ACFs originate in the model structural domain. See attachments for further information. To support adequacy of simulated metabolism for the target (2-methylpentyl 2-hydroxybenzoate), structural analogues of the target chemical are searched in the database of the model with documented metabolism, and which have same or similar metabolism as the simulated one for the target chemical. The search is also expanded in the external literature sources. Structural analogues experimental data in the public domain is cited therein.
- 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 author analysis provides further 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 with supporting evidence are provided by the model author; the prediction is relevant and reliable and demonstrates absence of bioaccumulation concern when considering metabolism. The prediction is demonstrated as being consistent with published experimental data on structural analogues within the chemical class: salicylates. 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 substance are considered suitable for the assessment of the bioaccumulation potential of the substance, and the outcome facilitates the conclusion that the substance does not have the potential to bioaccumulate in organisms. The predicted values are in the range: BCF = 85.11 ± 2.51 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 v5.15.2 - BCF base-line model v.05.12 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

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.05.12 - software package: OASIS CATALOGIC v.5.15.2, version 1.0; date: 01 May 2014; updated 01 October 2021.
- 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.05.12 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 842 chemicals with 1905 correct fragments, 181 fuzzy fragments (treated as correct fragments) and 163 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 and/or an analysis 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 substance are considered suitable for the assessment of the bioaccumulation potential of the substance, and the outcome facilitates the conclusion that the substance does not 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.

Key result

Type:

BCF

Value:

ca. 85.11 L/kg

Basis:

not specified

Remarks on result:

other: ±2.51 (± BCF Corrected)

1. Defined Endpoint:

QMRF 2.4a. Bioconcentration BCF fish

 

Reference to type of model used and description of results:

BCF base-line model v.05.12 Bioconcentration factor (BCF), October 2021

Platform version: CATALOGIC 5.15.2

 

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

BCF (Bioconcentration Factor):
Estimated Log BCF = 1.93 ± 0.399
Estimated BCF = 85.11 ± 2.51 L/kg wet-wt
Full details of the substance constituents are provided in the attached ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of 2-methylpentyl 2-hydroxybenzoate’ version 1.0; 09 December 2021.
Note: The IUPAC name has been substituted into the QPRF title by the applicant in place of the (confidential) trivial name. Further details on the identity of the substance are indicated within the relevant QPRF and/or related attachments.
Assessment of the substance within the applicability domain as documented within the corresponding QPRF attached: ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of 2-methylpentyl 2-hydroxybenzoate’ version 1.0; 09 December 2021 within section 5, by comparison to the QMRF named ‘QMRF Title: BCF base-line model for predicting log BCF of chemicals.’ - model: BCF baseline
model v.05.12 - software package: OASIS CATALOGIC v.5.15.2, version 1.0; date: 01 May 2014;
updated 01 October 2018.

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.05.12 - software package: OASIS CATALOGIC v.5.15.2, version 1.0; date: 01 May 2014; updated 01 October 2021. 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 (> 90% ACF). To improve confidence and adequacy of the prediction, the model author’s additionally provides an analysis which indicated for the prediction : the unknown fragments have no effect on the prediction, with consideration to (i) training set, (ii) metabolic transformation/mechanistic domain and/or with reference to (iii) structural analogues with experimental BCF data and/or (iv) literature data referring to on the relevant structural fragments observed metabolism. Summarisation is given relevant to the prediction in the attached ‘QPRF Title: QSAR prediction for the Bioaccumulation potential of 2-methylpentyl 2-hydroxybenzoate’ version 1.0; 09 December 2021 and within the attached Supplementary material: I, II, III, IV, V and/or VI. The predictions should be considered both ‘relevant’ and ‘reliable’.

Validity criteria fulfilled:

yes

Conclusions:

The results are adequate for the regulatory purpose.

Executive summary:

OASIS Catalogic v5.15.2 - BCF base-line model v.05.12, Bioconcentration factor (BCF), October 2021

Estimated Log BCF = 1.93 ± 0.399

BCF = 85.11 ± 2.51 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 with supporting evidence are provided by the model author; the prediction is relevant and reliable and demonstrates absence of bioaccumulation concern when considering metabolism. The prediction is demonstrated as being consistent with published experimental data on structural analogues within the chemical class: salicylates. 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 substance are considered suitable for the assessment of the bioaccumulation potential of the substance, and the outcome facilitates the conclusion that the substance does not have the potential to bioaccumulate in organisms. The predicted values are in the range: BCF = 85.11 ± 2.51 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 v5.15.2 - BCF base-line model v.05.12 model prediction is suitable for the regulatory conclusion in accordance with the tonnage driven information requirements.

Description of key information

BCF QSAR Fish: 85.11 ± 2.51 L/kg wet-wt, BCF base-line model v.05.12; OASIS Catalogic v5.15.2, 2021

Key value for chemical safety assessment

BCF (aquatic species):

85 L/kg ww

Additional information

OASIS Catalogic v5.15.2 - BCF base-line model v.05.12, Bioconcentration factor (BCF), October 2021

Estimated Log BCF = 1.93 ± 0.399

BCF = 85.11 ± 2.51 L/kg wet-wt