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Bioaccumulation: aquatic / sediment

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Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
February 2014
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Qualifier:
according to guideline
Guideline:
other: QSAR prediction using BCF model (Meylan) (version 1.0.0) (VEGA).
Deviations:
no
Principles of method if other than guideline:
The model is based on the method proposed by Meylan et al (Meylan W.M., Howard P.H., Boethling R.S. et al. Improved Method for Estimating Bioconcentration / Bioaccumulation Factor from Octanol/Water Partition Coefficient. 1999, Environ. Toxicol. Chem. 18(4): 664-672) et implemented in the EPI Suite BCFBAF module (http://www.epa.gov/oppt/exposure/pubs/episuite.htm). The model provides a BCF prediction based on different regression equations or fixed values, selected on the basis of an initial classification between ionic and non-ionic compounds, and on the value of the predicted logP value.
For the purpose of the model, ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds). All other compounds are classified as non-ionic. The logP prediction is provided by the VEGA logP model.
The original dataset from EPI Suite has been taken, then processed and cleared from duplicates andcompounds provided with structure that had problems. The final dataset has 662 compounds.
GLP compliance:
no
Specific details on test material used for the study:
Not applicable - QSAR
Radiolabelling:
no
Details on sampling:
Not applicable - QSAR
Vehicle:
no
Details on preparation of test solutions, spiked fish food or sediment:
Not applicable - QSAR
Test organisms (species):
other: Not applicable - QSAR
Details on test organisms:
Not applicable - QSAR
Route of exposure:
other: Not applicable - QSAR
Test type:
other: Not applicable - QSAR
Water / sediment media type:
not specified
Hardness:
Not applicable - QSAR
Test temperature:
Not applicable - QSAR
pH:
Not applicable - QSAR
Dissolved oxygen:
Not applicable - QSAR
TOC:
Not applicable - QSAR
Salinity:
Not applicable - QSAR
Details on test conditions:
Not applicable - QSAR
Nominal and measured concentrations:
Not applicable - QSAR
Details on estimation of bioconcentration:
Please refer to QPRF attachment below.
Key result
Type:
BCF
Value:
166.4 L/kg
Basis:
other: QSAR
Calculation basis:
other: QSAR
Remarks on result:
other: Geometric mean calculation
Remarks:
Conc.in environment / dose:Not applicable.
Details on kinetic parameters:
Not applicable - QSAR
Metabolites:
Not applicable - QSAR
Results with reference substance (positive control):
Not applicable - QSAR
Details on results:
Model assessment: Prediction is logBCF = 1.86 to 2.58 but the result may be not reliable for the following reasons:
- no similar compounds with known experimental value in the training set have been found
- similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value
- reliability of logP value used by the model is not optimal
Validity criteria fulfilled:
yes
Conclusions:
Model assessment: Prediction is logBCF = 1.86 to 2.58 with a BCF value of 166.4 L/kg (geometric mean) but the result may be not reliable for the following reasons:

- no similar compounds with known experimental value in the training set have been found
- similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value
- reliability of logP value used by the model is not optimal

Executive summary:

It is understood that Annex  XI, section  1.3  allows  adaptation of the standard testing requirement by making use of (Q)SAR only if the following conditions are met:

(i) results are derived from a (Q)SAR  model  whose scientific validity has  been  established,

(ii) the substance falls within the applicability domain of the (Q)SAR model,

(iii) results are adequate for the purpose of classification and labelling and/or risk assessment, and

(iv) adequate and  reliable documentation of  the  applied method is  provided.

 

Within the model used, the conditions(i), (iii) and (iv) are considered to be met for the BCF model (Meylan) (version 1.0.0)

 

Within these models, condition (ii) was not fulfilled for the following reasons:

- no similar compounds with known experimental value in the training set have been found

- similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value

- reliability of logP value used by the model is not optimal

 

This study was therefore assigned as Klimisch level 3 study. A geometric mean BCF was calculated for the purposes of hazard assessment. The BCF value is estimated to be 166.4 L/kg therefore the substance is not considered to be bioaccumulative on the basis of the QSAR data developed.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
February 2014
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
Qualifier:
according to guideline
Guideline:
other: QSAR prediction using BCF Read-Across (version 1.0.0) (VEGA).
Deviations:
no
Principles of method if other than guideline:
The model performs a read-across and provides a quantitative prediction of bioconcentration factor (BCF) in fish, given in log(L/kg). It is implemented inside the VEGA online platform, accessible at: http://www.vega-qsar.eu/

The model performs a read-across on a dataset of 860 chemicals. This dataset has been made by Istituto di Ricerche Farmacologiche Mario Negri, merging experimental data from several reliable sources, including the original dataset of the CAESAR BCF model (note that experimental values may differ from the ones in the CAESAR BCF dataset, as this new dataset has been built including more sources).
The read-across is based on the similarity index developed inside the VEGA platform; the index takes into account several structural aspects of the compounds, such as their fingerprint, the number of atoms, of cycles, of heteroatoms, of halogen atoms, and of particular fragments (such as nitro groups).
The index value ranges from 1 (maximum similarity) to 0. On the basis of this structural similarity index, the three compounds from the dataset resulting most similar to the chemical to be predicted are taken into account: the estimated BCF value is calculated as the weighted average value of the experimental values of the three selected compounds, using their similarity values as weight.
GLP compliance:
no
Specific details on test material used for the study:
Not applicable - QSAR
Radiolabelling:
no
Details on sampling:
Not applicable - QSAR
Vehicle:
no
Details on preparation of test solutions, spiked fish food or sediment:
Not applicable - QSAR
Test organisms (species):
other: Not applicable - QSAR
Details on test organisms:
Not applicable - QSAR
Route of exposure:
other: Not applicable - QSAR
Test type:
other: Not applicable - QSAR
Water / sediment media type:
not specified
Hardness:
Not applicable - QSAR
Test temperature:
Not applicable - QSAR
pH:
Not applicable - QSAR
Dissolved oxygen:
Not applicable - QSAR
TOC:
Not applicable - QSAR
Salinity:
Not applicable - QSAR
Details on test conditions:
Not applicable - QSAR
Nominal and measured concentrations:
Not applicable - QSAR
Details on estimation of bioconcentration:
Please refer to QPRF attachment below.
Key result
Type:
BCF
Value:
130 L/kg
Basis:
other: QSAR
Calculation basis:
other: QSAR
Remarks on result:
other: Same value for all 5 structures evaluated.
Remarks:
Conc.in environment / dose:Not applicable.
Details on kinetic parameters:
Not applicable - QSAR
Metabolites:
Not applicable - QSAR
Results with reference substance (positive control):
Not applicable - QSAR
Details on results:
Model assessment: Read-Across prediction is logBCF = 2.11 to 2.12, the result appears reliable. See attached report for details.
Validity criteria fulfilled:
yes
Conclusions:
The model is considered to be appropriate for assessment. The assessed structures were within the applicability domain of the model. The model is considered suitable for use in the context of a weight of evidence approach. As the substance is a UVCB, the four most abundant structures (> 10% w/w) present in the substance were assigned.
The substance is not considered to be bioaccumulative on the basis of the QSAR data developed.
Executive summary:

It is understood that Annex  XI, section  1.3  allows  adaptation of the standard testing requirements by making use of (Q)SAR only if the following conditions are met:

(i) results are derived from a (Q)SAR  model  whose scientific validity has  been  established,

(ii) the substance falls within the applicability domain of the (Q)SAR model,

(iii) results are adequate for the purpose of classification and labelling and/or risk assessment, and

(iv) adequate and  reliable documentation of  the  applied method is  provided.

 

Within the model used, the conditions (i) through (iv) are considered to be met for the BCF Read-Across (version 1.0.0) - VEGA Tool

 

The structures assessed with this model were deemed to fall within the applicability domain of the model, and this is demonstrated within the relevant QPRF. Due to the fact that QSAR is utilised, this was assigned as a Klimisch level 2 study.

 

The substance is not considered to be bioaccumulative on the basis of the QSAR data developed.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
February 2014
Reliability:
3 (not reliable)
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
Qualifier:
according to guideline
Guideline:
other: QSAR prediction using VEGA CAESAR BCF Model version 2.1.11
Deviations:
no
Principles of method if other than guideline:
Two models, Model A and Model B, have been used to build hybrid model, Model C. In the proposed approach, the outputs of the individual models (Model A and B) were used as inputs of the hybrid model. Model A was developed by Radial Basis Function Neural Networks (RBFNN) using an heuristic method to select the optimal descriptors; Model B was developed by RBFNN using genetic algorithm for the descriptors selection. RBFNN was used with a Matlab function for building the models. An in-house software made as a PC-Windows Excel macro was used to combine Models A and B within the Model C. Model A used an heuristic method to select the optimal descriptors and Model B used genetic algorithm for the descriptors selection. Full reference and details of the used formulas can be found in:
Zhao, C., Boriani, E., Chana, A., Roncaglioni,A., Benfenati, E. A new hybrid system of QSAR models for predicting bioconcentration factors (BCF). Chemosphere (2008), 73, 1701-1707. Lombardo A, Roncaglioni A, Boriani E, Milan C, Benfenati E. Assessment and validation of the CAESAR predictive model for bioconcentration factor (BCF) in fish. Chemistry Central Journal (2010), 4 (Suppl 1).
The descriptors used are the following:
- Moriguchi octanol-water partition coefficient (MlogP).
- Moran autocorrelation of lag 5, weighted by atomic van der Waals volumes (MATS5V): molecular descriptor calculated from the molecular graph by summing the products of atom weights of the terminal atoms of all paths of the considered path length (the lag).
- Number of chlorine atoms (Cl-089), Cl attached to carbon (sp2).
- Second highest eigenvalue of Burden matrix, weighted by atomic polarizabilities (BEHp2).
- Geary autocorrelation of lag 5, weighted by atomic van der Waals volumes (GATS5V): molecular descriptor calculated from the molecular graph by summing the products of atom weights of the terminal atoms of all paths of the considered path length (the lag).
- Solvation connectivity index chi-0 (XOSolv): molecular descriptor designed for modeling solvation entropy and describing dispersion interactions in solution
- Sum of all -Cl groups E-state values in molecule (SsCl).
- Absolute eigenvalues sum from electronegativity weighted distance matrix (Aeige).
The descriptors were calculated, in the original CAESAR version, by means of dragonX software and are now entirely calculated by an in-house software module in which they are implemented as described in: R. Todeschini and V. Consonni, Molecular Descriptors for Chemoinformatics, Wiley-VCH, 2009.
GLP compliance:
no
Specific details on test material used for the study:
Not applicable - QSAR
Radiolabelling:
no
Details on sampling:
Not applicable - QSAR
Vehicle:
no
Details on preparation of test solutions, spiked fish food or sediment:
Not applicable - QSAR
Test organisms (species):
other: Not applicable - QSAR
Details on test organisms:
Not applicable - QSAR
Route of exposure:
other: Not applicable - QSAR
Test type:
other: Not applicable - QSAR
Water / sediment media type:
not specified
Hardness:
Not applicable - QSAR
Test temperature:
Not applicable - QSAR
pH:
Not applicable - QSAR
Dissolved oxygen:
Not applicable - QSAR
TOC:
Not applicable - QSAR
Salinity:
Not applicable - QSAR
Details on test conditions:
Not applicable - QSAR
Nominal and measured concentrations:
Not applicable - QSAR
Details on estimation of bioconcentration:
Please refer to QPRF attachment below.
Key result
Type:
BCF
Value:
6.6 L/kg
Basis:
other: QSAR
Calculation basis:
other: QSAR
Remarks on result:
other: Geometric mean measurement.
Remarks:
Conc.in environment / dose:Not applicable.
Details on kinetic parameters:
Not applicable - QSAR
Metabolites:
Not applicable - QSAR
Results with reference substance (positive control):
Not applicable - QSAR
Details on results:
Model assessment: Prediction is logBCF = 0.71 to 0.9, but the result may be not reliable for the following reasons:
- no similar compounds with known experimental value in the training set have been found
- accuracy of prediction for similar molecules found in the training set is not optimal
- similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value
- the maximum error in prediction of similar molecules found in the training set has a moderate value, considering the experimental variability
The following relevant fragments have been found: Carbonyl residue (SR 02); >C=O group (PG 09)

The full report is appended below.
Validity criteria fulfilled:
yes
Conclusions:
The accuracy of prediction for similar molecules found in the training set is not optimal. No similar compounds with known experimental value in the training set have been found and similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value. The maximum error in prediction of similar molecules found in the training set has a moderate value, considering the experimental variability This QSAR assessment was therefore categorised as unreliable (Klimisch 3). The BCF value is estimated to be 6.6 L/kg therefore the substance is not considered to be bioaccumulative on the basis of the QSAR data developed.
Executive summary:

It is understood that Annex  XI, section  1.3  allows  adaptation of the standard testing requirement by making ise of (Q)SAR only if the following conditions are met:

(i) results are derived from a (Q)SAR  model  whose scientific validity has  been  established,

(ii) the substance falls within the applicability domain of the (Q)SAR model,

(iii) results are adequate for the purpose of classification and labelling and/or risk assessment, and

(iv) adequate and  reliable documentation of  the  applied method is  provided.

 

Within the model used, the conditions (i), (iii) and (iv) are considered to be met for the BCF model (CAESAR) (version 2.1.11)

 

Within these models, condition (ii) was not fulfilled for a number of reasons. These included:

- no similar compounds with known experimental value in the training set have been found

- accuracy of prediction for similar molecules found in the training set is not optimal

- similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value

- the maximum error in prediction of similar molecules found in the training set has a moderate value, considering the experimental variability

This study was therefore assigned as Klimisch level 3 study. A geometric mean BCF was calculated for the purposes of hazard assessment. The BCF value is estimated to be 6.6 L/kg therefore the substance is not considered to be bioaccumulative on the basis of the QSAR data developed.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
February 2014
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
Qualifier:
according to guideline
Guideline:
other: QSAR prediction using US EPA On-Line EPI Suite™ v4.11 model BCFBAF.
Deviations:
no
Principles of method if other than guideline:
The BCFBAF method classifies a compound as either ionic or non-ionic. Ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds). All other compounds are classified as non-ionic.
GLP compliance:
no
Specific details on test material used for the study:
Not applicable - QSAR
Radiolabelling:
no
Details on sampling:
Not applicable - QSAR
Vehicle:
no
Details on preparation of test solutions, spiked fish food or sediment:
Not applicable - QSAR
Test organisms (species):
other: Not applicable - QSAR
Details on test organisms:
Not applicable - QSAR
Route of exposure:
other: Not applicable - QSAR
Test type:
other: Not applicable - QSAR
Water / sediment media type:
not specified
Hardness:
Not applicable - QSAR
Test temperature:
Not applicable - QSAR
pH:
Not applicable - QSAR
Dissolved oxygen:
Not applicable - QSAR
TOC:
Not applicable - QSAR
Salinity:
Not applicable - QSAR
Details on test conditions:
Not applicable - QSAR
Nominal and measured concentrations:
Not applicable - QSAR
Details on estimation of bioconcentration:
Please refer to QPRF attachment below
Key result
Type:
BCF
Value:
55.54 L/kg
Basis:
other: QSAR
Calculation basis:
other: QSAR
Remarks on result:
other: A geometric mean result is applied
Remarks:
Conc.in environment / dose:Not applicable.
Details on kinetic parameters:
Not applicable - QSAR
Metabolites:
Not applicable - QSAR
Results with reference substance (positive control):
Not applicable - QSAR
Details on results:
Model assessment: Similar molecules found in the training set have experimental values that agree with the target compound predicted value.

Validity criteria fulfilled:
yes
Conclusions:
The model is considered to be appropriate for assessment. Similar compounds with known experimental values in the training set were found. The accuracy of prediction for similar molecules found in the training set is good. The model is considered suitable for use in the context of a weight of evidence approach. As the substance is a UVCB, the five most abundant structures (> 10% w/w) present in the substance were assessed. A geometric mean BCF is therefore applied for the purposes of hazard assessment. The substance is not considered to be bioaccumulative on the basis of the QSAR data developed.
Executive summary:

It is understood that Annex  XI, section  1.3  allows  adaptation of the standard testing requirements by making use of (Q)SAR only if the following conditions are met:

(i) results are derived from a (Q)SAR  model  whose scientific validity has  been  established,

(ii) the substance falls within the applicability domain of the (Q)SAR model,

(iii) results are adequate for the purpose of classification and labelling and/or risk assessment, and

(iv) adequate and  reliable documentation of  the  applied method is  provided.

 

Within the model used, the conditions (i) through (iv) are considered to be met for the US EPA On-Line EPI Suite™v4.0 model BCFBAF

 

The structures assessed with this model were deemed to mainly fall within the applicability domain of the model, and this is demonstrated within the relevant QPRF. The model is recognized, and referenced within ECHA’s own guidance. Due to the fact that QSAR was utilised, this was assigned a Klimisch level 2.

In order to derive a BCF for the purposes of dossier preparation, it is considered appropriate to utilise a geometric mean across the data set. The document “Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment”states under section“R.10.2.2 Evaluation and interpretation of data” that:

 

Where there is more than one set of data on the same species, (strain if known), endpoint, duration, life stage and testing condition the greatest weight is attached to the most reliable and relevant one. When there is more than one set of data with the same reliability rating, it might be necessary tolook into more detail at the study reports to see whether a specific reason could explain the difference. If no explanation can be found and the results are for the same species and endpoints and are not more than one order of magnitude apart, they can be harmonised by a geometric mean.

 

A geometric mean BCF is therefore applied for the purposes of hazard assessment. The substance is not considered to be bioaccumulative on the basis of the QSAR data developed.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
March 2014
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
Qualifier:
according to guideline
Guideline:
other: QSAR prediction using US EPA T.E.S.T. (version 4.1) (Toxicity Estimation Software Tool).
Deviations:
no
Principles of method if other than guideline:
Consensus method: The predicted BCF is estimated by taking an average of the predicted toxicities from the following QSAR methods (provided the predictions are within the respective applicability domains): Hierarchical method, FDA method, Single model method, Group contribution method, Nearest neighbor method.
GLP compliance:
no
Specific details on test material used for the study:
Not applicable - QSAR
Radiolabelling:
no
Details on sampling:
Not applicable - QSAR
Vehicle:
no
Details on preparation of test solutions, spiked fish food or sediment:
Not applicable - QSAR
Test organisms (species):
other: Not applicable - QSAR
Details on test organisms:
Not applicable - QSAR
Route of exposure:
other: Not applicable - QSAR
Test type:
other: Not applicable - QSAR
Water / sediment media type:
not specified
Hardness:
Not applicable - QSAR
Test temperature:
Not applicable - QSAR
pH:
Not applicable - QSAR
Dissolved oxygen:
Not applicable - QSAR
TOC:
Not applicable - QSAR
Salinity:
Not applicable - QSAR
Details on test conditions:
Not applicable - QSAR
Nominal and measured concentrations:
Not applicable - QSAR
Details on estimation of bioconcentration:
Please refer to QPRF attachment below
Key result
Type:
BCF
Value:
5.88 L/kg
Basis:
other: QSAR
Calculation basis:
other: QSAR
Remarks on result:
other: A geometric mean result is applied
Remarks:
Conc.in environment / dose:Not applicable.
Details on kinetic parameters:
Not applicable - QSAR
Metabolites:
Not applicable - QSAR
Results with reference substance (positive control):
Not applicable - QSAR
Details on results:
See documents attached below. Similar chemicals exist in the training set for the model.
Geometric mean of BCFs for 5 structures = 5.88 L/kg.

Validity criteria fulfilled:
yes
Conclusions:
The model is considered to be appropriate for assessment. Similar compounds with known experimental values in the training set were found. The model is considered suitable for use in the context of a weight of evidence approach. As the substance is a UVCB, the five most abundant structures (> 10% w/w) present in the substance were assessed. A geometric mean BCF is therefore applied for the purposes of hazard assessment. The substance is not considered to be bioaccumulative on the basis of the QSAR data developed.
Executive summary:

It is understood that Annex  XI, section  1.3  allows  adaptation of the standard testing requirement by making use of (Q)SAR only if the following conditions are met:

(i) results are derived from a (Q)SAR  model  whose scientific validity has been established,

(ii) the substance falls within the applicability domain of the (Q)SAR model,

(iii) results are adequate for the purpose of classification and labelling and/or risk assessment, and

(iv) adequate and  reliable documentation of  the  applied method is  provided.

 

Within the model used, the conditions (i) through (iv) are considered to be met for the US EPA T.E.S.T. (version 4.1) (Toxicity Estimation Software Tool) model.

 

The structures assessed with this model were deemed to mainly fall within the applicability domain of the model, and this is demonstrated within the relevant QPRF. Due to the fact that QSAR is utilised, this was assigned a Klimisch level 2 study.

 

In order to derive a BCF for the purposes of dossier preparation, it is considered appropriate to utilise a geometric mean across the data set. The document “Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment”states under section“R.10.2.2 Evaluation and interpretation of data” that:

 

Where there is more than one set of data on the same species, (strain if known), endpoint, duration, life stage and testing condition the greatest weight is attached to the most reliable and relevant one. When there is more than one set of data with the same reliability rating, it might be necessary tolook into more detail at the study reports to see whether a specific reason could explain the difference. If no explanation can be found and the results are for the same species and endpoints and are not more than one order of magnitude apart, they can be harmonised by a geometric mean.

 

A geometric mean BCF is therefore applied for the purposes of hazard assessment. The substance is not considered to be bioaccumulative on the basis of the QSAR data developed.

Description of key information

Based on QSAR modelling, the BCF value for the test substance is estimated to be 34.88 L/kg ww (geometric mean).

Key value for chemical safety assessment

BCF (aquatic species):
34.88 L/kg ww

Additional information

The test substance was assessed for bioaccumulation potential using recognised QSAR derivation software as follows:

 

BCF model (CAESAR) (version 2.1.11)

BCF model (Meylan) (version 1.0.0)

BCF Read-Across (version 1.0.0)

US EPA On-Line EPI Suite™v4.11 model BCFBAF

US EPA T.E.S.T. (version 4.1) (Toxicity Estimation Software Tool)

As the substance is a UVCB, the QSAR modelling was conducted using the SMILES codes for the most abundant structures present in the substance (> 10% w/w).

 

It is understood that Annex XI, section 1.3 allows adaptation of the standard testing requirements by making use of (Q)SAR only if the following conditions are met:

 

(i) results are derived from a (Q)SAR model whose scientific validity has been established,

(ii) the substance falls within the applicability domain of the (Q)SAR model,

(iii) results are adequate for the purpose of classification and labelling and/or risk assessment, and

(iv) adequate and reliable documentation of the applied method is provided.

 

Within the five models used, the conditions (i) through (iv) are considered to be met for three of the models:

 

•      US EPA On-Line EPI Suite™v4.0 model BCFBAF

•      BCF Read-Across (version 1.0.0)

• US EPA T.E.S.T. (version 4.1) (Toxicity Estimation Software Tool) 

 

The structures assessed with these models were deemed to mainly fall within the applicability domain of the model, and this is demonstrated within the relevant QPRF's. Due to the fact that QSAR is utilised, these were assigned as Klimisch 2 level studies.

 

Within the five models used, the conditions (i), (iii) and (iv) are considered to be met for two of the models:

 

•      BCF model (CAESAR) (version 2.1.11)

•      BCF model (Meylan) (version 1.0.0)

 

Within these models, condition (ii) was not fulfilled for the following reasons:

- no similar compounds with known experimental value in the training set have been found

- accuracy of prediction for similar molecules found in the training set is not optimal

- similar molecules found in the training set have experimental values that strongly disagree with the target compound predicted value

- the maximum error in prediction of similar molecules found in the training set has a moderate value, considering the experimental variability

- reliability of logP value used by the model is not optimal

 

These studies were therefore assigned as Klimisch 3 level studies and the values obtained using these studies were not used to calculate the geometric mean.

 

Overall

On the basis of a weight of evidence approach, there is sufficient information available to state that the substance is not bioaccumulative. Whilst it is not possible to provide a definitive BCF value for the substance due to the variation in the results, none of the values determined via QSAR are above the threshold value quoted in the REACH Regulation of 2000 or 5000 which indicates the potential to bioaccumulate. In order to derive a BCF for the purposes of dossier preparation, it is considered appropriate to utilise a geometric mean across the Klimisch 2 studies. The document “Guidance on information requirements and chemical safety assessment Chapter R.10: Characterisation of dose [concentration]-response for environment” states under section“R.10.2.2 Evaluation and interpretation of data” that:

 

Where there is more than one set of data on the same species, (strain if known), endpoint, duration, life stage and testing condition the greatest weight is attached to the most reliable and relevant one. When there is more than one set of data with the same reliability rating, it might be necessary to look into more detail at the study reports to see whether a specific reason could explain the difference. If no explanation can be found and the results are for the same species and endpoints and are not more than one order of magnitude apart, they can be harmonised by a geometric mean.

 

A geometric mean BCF is therefore applied for the purposes of hazard assessment.

 

Endpoint study

BCF (L/kg ww) (geometric mean)

EPIWIN BCFBAF Results [L/kg]

55.54

BCF Read-Across (version 1.0.0) [L/kg]

130

T.E.S.T. (version 4.1) [L/kg]

5.88

Geometric Mean BCF overall

34.88

 

Whilst this mean result is presented as only a general indication, this supports the overall conclusion that the substance is not considered to be bioaccumulative. Furthermore, the substance is likely to be readily metabolised to fatty acids and trimethylolpropane via enzymatic hydrolysis therefore is expected to have a low potential to bioaccumulate. The substance is predicted to have a high Kow value (>9.66) and a value in excess of 4.5 is considered to be of concern as potential for bioaccumulation, according to screening criteria for bioaccummulation in ECHA guidance (Chapter R.11 PBT Assessment). The likely reliability of the log Kow is, however, considered to diminish above a value of 6, as noted in Appendix R.11-1 Annex 1 of ECHA guidance on PBT Assessment. Substances with log Kow between 4.5 and 6 are considered likely to be highly accumulating; however no substantial bioconcentration is assumed for compounds having log Kow values greater than 6. For compounds having log Kow greater than 6, a gradual decrease of the BCF is observed and it has been hypothesised within the published literature that a high log Kow is more an effect of solubility than a tendency of the substance to be lipophilic.