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Bioaccumulation: aquatic / sediment

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Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Study period:
2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
1. SOFTWARE
OASIS Catalogic v5.11.19

2. MODEL (incl. version number)
BCF base-line model v02.09 - July 2016

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See section 'Test Material'.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF.

5. APPLICABILITY DOMAIN
See attached QPRF.

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QMRF).
- The model estimates the Bioconcentration factor (BCF) as required information point according to Regulation (EC) No 1907/2006 [REACH], Annex IX, 9.3.2 Bioaccumulation in aquatic species (preferably fish);
further related predictions: Apparent effect of mitigating factors / Maximum bioconcentration factor (BCFmax) / Maximum diameter of energetically stable conformers / Whole body primary biotransformation half-life / Metabolic biotransformation rate constant Km / Metabolites and their quantitative distribution
- See attached QPRF for reliability assessment.
Principles of method if other than guideline:
Calculation using Catalogic v.5.11.19, BCF base-line model v.02.09
GLP compliance:
no
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: OASIS Catalogic v5.11.19 [BCF base line model - v.02.09]
Key result
Type:
BCF
Value:
7.4 L/kg
Remarks on result:
other: considering all mitigating factors; the substance is not within the applicability domain of the model.
Type:
BCF
Value:
10.2 L/kg
Remarks on result:
other: without considering any mitigating factors; the substance is not within the applicability domain of the model.
Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Principles of method if other than guideline:
Estimation of BCF, BAF and biotransformation rate using BCFBAF v3.01
GLP compliance:
no
Test organisms (species):
other: fish
Details on estimation of bioconcentration:
BASIS INFORMATION
- Calculated logPow: 13.25

BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.01
- Result based on measured log Pow of: 4.7
Type:
BCF
Value:
3.16 L/kg
Basis:
not specified
Remarks on result:
other: The substance is within the molecular weight but outside of the logKow range of the applicability domain of the BCFBAF submodel: Bioconcentration factor (BCF; Meylan et al., 1997/1999). One of the fragments for the correction factors was exceeded.
Type:
BCF
Value:
0.904 L/kg
Basis:
not specified
Calculation basis:
steady state
Remarks on result:
other: Upper trophic, incl. biotransformation estimates; The result may be less accurate as the logKow is not within the range of the training set compounds.
Type:
BCF
Value:
0.941 L/kg
Calculation basis:
steady state
Remarks on result:
other: Upper trophic, incl. biotransformation estimates of zero; The result may be less accurate as the the logKow is not within the range of the training set compounds.
Type:
BAF
Value:
32.4 L/kg
Basis:
not specified
Remarks on result:
other: Upper trophic, incl. biotransformation estimates; The result may be less accurate as the logKow is not within the range of the training set compounds.
Type:
BAF
Value:
243 L/kg
Basis:
not specified
Remarks on result:
other: Upper trophic, incl. biotransformation rate of zero; The result may be less accurate as the logKow is not within the range of the training set compounds.
Details on kinetic parameters:
Biotransformation half-life (days): 134.1
Biotransformation rate (kM, normalised to 10 g fish at 15 °C): 0.005168/day
The substance is not within the applicability domain of the BCFBAF submodel: Biotransformation rate in fish (kM; Arnot et al., 2008a/b).
Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
(Q)SAR
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Principles of method if other than guideline:
T.E.S.T. is a toxicity estimation software tool. The program requires only the molecular structure of the test item, all other molecular descriptors which are required to estimate the toxicity are calculated within the tool itself. The molecular descriptors describe physical characteristics of the molecule (e.g. E-state values and E-state counts, constitutional descriptors, topological descriptors, walk and path counts, connectivity, information content, 2d autocorrelation, Burden eigenvalue, molecular property (such as the octanol-water partition coefficient), Kappa, hydrogen bond acceptor/donor counts, molecular distance edge, and molecular fragment counts). Each of the available methods uses a different set of these descriptors to estimate the toxicity.
The bioaccumulation factor (BCF) was estimated using several available methods: hierarchical clustering method; FDA method, single model method; group contribution method; nearest neighbor method; consensus method. The methods were validated using statistical external validation using separate training and test data sets.
The experimental data set was obtained from several different databases (Dimitrov et al., 2005; Arnot and Gobas, 2006; EURAS; Zhao, 2008). From the available data set salts, mixtures and ambiguous compounds were removed. The final data set contained 676 chemicals.

References:
- Dimitrov, S., N. Dimitrova, T. Parkerton, M. Combers, M. Bonnell, and O. Mekenyan. 2005. Base-line model for identifying the bioaccumulation potential of chemicals. SAR and QSAR in Environmental Research 16:531-554.
- Arnot, J.A., and F.A.P.C. Gobas. 2006. A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms. Environ. Rev. 14:257-297.
- EURAS. Establishing a bioconcentration factor (BCF) Gold Standard Database. EURAS [cited 5/20/09]. Available from http://www.euras.be/eng/project.asp?ProjectId=92.
- Zhao, C.; Boriani, E.; Chana, A.; Roncaglioni, A.; Benfenati, E. 2008. A new hybrid system of QSAR models for predicting bioconcentration factors (BCF). Chemosphere 73:1701-1707.
GLP compliance:
no
Test organisms (species):
other: fish
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: US EPA T.E.S.T. v4.2.1

Applied estimation methods:
- Hierarchical clustering
- FDA
- Single model
- Group contribution
- Nearest neighbor
- Consensus
Key result
Type:
BCF
Value:
17.88 dimensionless
Remarks on result:
other: method: consensus (average of reasonable results from all models); log BCF = 1.25; Based on the mean absolute error, the confidence in the predicted BCF values is low.

Description of key information

Significant accumulation in organisms is not to be expected.

Key value for chemical safety assessment

Additional information

In Article 13 of Regulation (EC) No 1907/2006, it is laid down that information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI (of the same Regulation) are met. Furthermore according to Article 25 of the same Regulation testing on vertebrate animals shall be undertaken only as a last resort.

According to Annex XI of Regulation (EC) No 1907/2006 (Q)SAR results can be used if (1) the scientific validity of the (Q)SAR model has been established, (2) the substance falls within the applicability domain of the (Q)SAR model, (3) the results are adequate for the purpose of classification and labeling and/or risk assessment and (4) adequate and reliable documentation of the applied method is provided.

For the assessment of EC 213-590-1 (Q)SAR results were used for aquatic bioaccumulation. The criteria listed in Annex XI of Regulation (EC) No 1907/2006 are considered to be adequately fulfilled and therefore the endpoint(s) sufficiently covered and suitable for risk assessment.

Therefore, and for reasons of animal welfare, further experimental studies on bioaccumulation are not provided.

 

The bioaccumulative potential of EC 213-590-1 was assessed in a weight of evidence approach including several QSAR estimations and data on the molecular size and log Kow.The single QSAR models and their results are summarized in the table below.

 

Model

BCF

Remarks

Catalogic v5.11.19; BCF base-line model v02.09

7.4

All mitigating factor applied; 76.67% in structural domain

EPISuite v4.11

Regression-based estimate

3.16

The substance is within the molecular weight range but outside the logKow range.

Arnot-Gobas upper trophic level; incl. biotransformation estimates

0.9044

The substance is within the molecular weight range but outside the logKow range.

Arnot-Gobas upper trophic level; incl. biotransformation rate of zero

0.9406

The substance is within the molecular weight range but outside the logKow range.

T.E.S.T. v4.2

17.88

Consensus method; in domain

VEGA v1.1.1; CAESAR v2.1.14

6

According to the model’s global AD index, the predicted substance is out of the Applicability Domain of the model.

VEGA v1.1.1; Meylan v1.03

5

According to the model’s global AD index, the predicted substance is out of the Applicability Domain of the model.

VEGA v1.1.1; Read-Across v1.1.0

1.78

According to the model’s global AD index, the predicted substance is out of the Applicability Domain of the model.

 

According to the results of the models the compound does not have a bioaccumulative potential. 

The BCF base-line model integrated in Catalogic is a sophisticated model which takes into account different mitigating factors, i.e. acids, metabolism, phenols, size and water solubility. The compound was inside the parametric and the mechanistic domains of the compound. 76.67% of the fragments of the target chemical are present in correctly predicted training chemicals and only 23.33% of the fragments were unknown to the tool. The result is regarded as reliable and suitable to be used in a weight of evidence approach. With all mitigating factors applied the BCF is determined as 7.4. The biggest influence on the bioaccumulative potential has the water solubility followed by the size of the compound both limiting the uptake. Furthermore, even without considering any mitigating factors the BCFmax is only at 10.2 L/kg which is clearly indicative of a low bioaccumulative potential.

US EPA’s EPISuite includes the regression-based estimation and the Arnot-Gobas model which takes biotransformation processes into account. The present chemical is within the molecular weight range but outside the log Kow range of both the regression-based estimation and the Arnot-Gobas model. The regression-based model predicted a BCF of 3.16 L/kg. Corrections for an aromatic sym-triazine ring and a tert-butyl ortho-phenol group were applied in the equation used for the estimation. The Arnot-Gobas model predicted BCF values of 0.9044 and 0.9406 L/kg for the upper trophic level including biotransformation rate estimates and biotransformation rates of zero. Although the substance is outside of the logKow range, the results concerning the BCF are regarded as suitable in a weight of evidence approach because calculated logKow values above 10 are usually indicative for chemicals with a lower bioaccumulative potential. The present substance has a calculated logKow of 13.25.

US EPA’s Toxicity Estimation Software Tool (T.E.S.T.) uses five submodels to estimate the BCF of the target chemical. These results are then averaged in the consensus approach to provide a higher reliability. With the exception of the Group Contribution Method, the target compound is inside of the applicability domain of the single submodels . However, the confidence in the estimated BCF values of the single submodels is not optimal. The consensus model predicts the BCF by calculating the average of the predicted BCF values from the other QSAR methodologies while taking the applicability domain of the models into account. This method typically provides the highest prediction accuracy since errant predictions are dampened by the predictions from the other methods. In addition, this method provides the highest prediction coverage because several methods with slightly different applicability domains are used to make a prediction. The averaged result of the consensus method was a BCF of 17.88.

The VEGA package includes three different estimations tools with each of them providing detailed information on the applicability domain. None of the models was considered in the weight of evidence approach because the domain scores delivered a non-optimal assessment resulting in the compound being out of the applicability domains. 

According to ECHA’s Guidance on Information Requirements and Chemical Safety Assessment chapter R.11 – PBT Assessment, compounds with an average maximum diameter of >1.7 nm together with molecular weight of greater than 1100 are unlikely to have a BCF of >2000. Although the compound has a molecular weight of only 588 the DiamMax-average is 2.1 nm and even the DiamMax-Min is 1.7 nm. Furthermore, the aquatic BCF of a substance is probably lower than 2000 if the calculated logKow is higher than 10. The present compound has a calculated logKow of 13.25.

In conclusion, using all available data in a weight of evidence approach, the compound does not have any bioaccumulative potential.