Reaction mass of (((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-methylacrylate) and (1,3-phenylenebis(oxy))bis(propane-3,1-diyl) bis(2-methylacrylate) and 3-(3-(2-(2-(methacryloyloxy)ethoxy)ethoxy)phenoxy)propyl methacrylaterate

Bioaccumulation: aquatic / sediment

Administrative data

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

28 Jul 2021

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
: CATALOGIC 5.14.1.5

2. MODEL (incl. version number)
: BCF base-line model v.04.11

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
DiBrOER2M A: CC(=C)C(=O)OCCCOc1cc(OCCOCCOC(=O)C(C)=C)c(Br)cc1Br
DiBrORMA: CC(=C)C(=O)OCCCOc1cc(OCCCOC(=O)C(C)=C)c(Br)cc1Br
DiBrER4MA: CC(=C)C(=O)OCCOCCOc1cc(OCCOCCOC(=O)C(C)=C)c(Br)cc1Br

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: The BCF base-line model consists of two major components: a model for predicting the maximum potential for bioaccumulation based solely on chemicals’ lipophilicity (based on multi-compartment diffusion), and a set of mitigating factors that account for the reduction of the bioaccumulation potential of chemicals based on chemical (e.g., molecular size, ionization, etc.) and organism-dependent factors (e.g., metabolism). In the BCF base-line model the tissue metabolism simulator is used to account for the effect of metabolism.
- Unambiguous algorithm:
- Defined domain of applicability: The applicability domain of the BCF base-line model contains four layers:
General properties requirements
Structural domain
Mechanistic domain (discriminates between modes of bioaccumulation - passive (partitioning in lipid phase) or active (based on protein binding). Only chemicals with expected passive diffusion driven bioaccumulation are considered to be in the mechanistic domain of the model)
Metabolic domain (describes how well the metabolism is simulated based on the available observed metabolism in the database of the model)
- Appropriate measures of goodness-of-fit and robustness and predictivity:
Residual Sum of Squares = 198
Coefficient of Correlation, R = 0.92
Root mean square error, 0.50
Distribution of residual error: ca. 90% of residuals of the fitted data are ≤0.75 log units

- Mechanistic interpretation: The BCF base-line model reflects the current understanding of the process by which lipophilic organic chemicals are bioaccumulated in fish through the respiratory organs only. Chemicals, bioaccumulating by other mechanisms (e.g., binding to proteins) are considered out of the mechanistic domain of the model. The BCFmax model is a theoretical model based on the assumption that the only driving force of bioconcentration is lipophilicity and the effect of any other factors are insignificant. Its mathematical formalism is derived considering multi-compartment diffusion. The bioconcentration predicted by BCFmax model could be limited by variety of mitigating factors that account for the reduction of the bioaccumulation potential of chemicals based on chemical and organism-dependent factors. The effect of mitigating factors mathematically is quantified by probabilities: to penetrate through the cell membrane, to be ionized, to be metabolised, etc. In the BCF base-line model the tissue metabolism simulator is used to account for the effect of metabolism. It consists of a sequence of spontaneous abiotic and enzyme controlled steps. Probabilities of these molecular transformations are assessed by fitting the training set data.

5. APPLICABILITY DOMAIN
- Descriptor domain: General properties requirements (log Kow, MW, WS) are in domain.
- Structural domain:
Correct fragments = 87-89%
Incorrect fragments = 0%
Unknown fragments = 11-13%. "Unknown" structural features are atom centered fragments which do not have a prediction. The "unknown" features in this substance relate to the methacrylate unit and the dibromoresorcinol core. Acrylates and methacrylates are represented in the training set and have a specific transformation in the metabolic model. The assignment as unknown is therefore considered an artifact of atom-centered fragment generation. While resorcinol is not represented in the training set, the training set contains brominated or chlorinated benzenes, phenols, and cresols. The unknown fragments are not considered to exclude this substance from the applicability domain of the model.
- Mechanistic domain: Active bioaccumulation not expected.
- Similarity with analogues in the training set: Three analogs found, see Any other information on results including tables.


6. ADEQUACY OF THE RESULT
The modeled result fulfills the need for a valid assessment of bioconcentration potential of the substance. Due to extensive metabolism, n-octanol:water partition coefficient substantially overpredicts bioconcentration. The results are used in risk assessment and PBT analysis.

Data source

Reference

Reference Type:

other: QSAR modeling report

Title:

CATALOGIC 5.14.1.5

Year:

2019

Bibliographic source:

BCF base-line model v.04.11

Report date:

2021

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

- Software tool(s) used including version: CATALOGIC 5.14.1.5
- Model(s) used: BCF base-line model v.04.11
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: 'Attached justification'

GLP compliance:

no

Remarks:

QSAR model

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of (((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-methylacrylate) and (1,3-phenylenebis(oxy))bis(propane-3,1-diyl) bis(2-methylacrylate) and 3-(3-(2-(2-(methacryloyloxy)ethoxy)ethoxy)phenoxy)propyl methacrylaterate

EC Number:

944-271-1

Cas Number:

2305048-54-6

Molecular formula:

not applicable for multi-constituent.

IUPAC Name:

Reaction mass of (((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-methylacrylate) and (1,3-phenylenebis(oxy))bis(propane-3,1-diyl) bis(2-methylacrylate) and 3-(3-(2-(2-(methacryloyloxy)ethoxy)ethoxy)phenoxy)propyl methacrylaterate

Specific details on test material used for the study:

SMILES
DiBrOER2M A: CC(=C)C(=O)OCCCOc1cc(OCCOCCOC(=O)C(C)=C)c(Br)cc1Br
DiBrORMA: CC(=C)C(=O)OCCCOc1cc(OCCCOC(=O)C(C)=C)c(Br)cc1Br
DiBrER4MA: CC(=C)C(=O)OCCOCCOc1cc(OCCOCCOC(=O)C(C)=C)c(Br)cc1Br

Note that the substance name DiBrÖRMA is distinct from the constituent DiBrORMA in the German character set.

Results and discussion

Bioaccumulation factor

Key result

Type:

BCF

Value:

ca. 5.5 - ca. 6 L/kg

Remarks on result:

other: QSAR model results for the three isomers

Any other information on results incl. tables

Table 1, specific results of BCF model

Isomer	log BCF	BCF
DiBrOER2MA	0.76±0.0941	5.8
DiBrORMA	0.78±0.0959	6.0
DiBrER4MA	0.74±0.0909	5.5

 

Table 2, predicted v. observed BCF values for validation set substances

Substance	predicted log BCF	predicted BCF	observed log BCF	observed BCF
2-ethylhexyl methacrylate	0.98	9.5	1.57	37
methyl (E)-3-methoxy-2-{2-[6- (trifluoromethyl) pyridin-2-yloxymethyl] phenyl}acrylate	1.88	76	2.46	288
pentabromobenzyl acrylate	1.37	23	0.690	4.9

Applicant's summary and conclusion

Validity criteria fulfilled:

not applicable

Conclusions:

Estimated BCF values for the main constituents of DiBrÖRMA range from 5.5-6.0

Executive summary:

QSAR modeling in the BCF base-line model v.04.11 of CATALOGIC 5.14.1 was done to address bioconcentration to support Classification and Labelling. This model is a validated QSAR with extensive parameterization to take molecular size, metabolism, and other parameters into account. The three main constituents are within the applicability domain of the model with regard to physical/chemical properties, structural features, mechanism of bioaccumulation (passive v. active accumulation) and metabolism. The resulting BCF values span a range of 5.5 - 6.0. This result agrees with the extensive in vivo metabolism that has been observed for methacrylate esters. The result is therefore considered reliable with restrictions and is suitable for Classification and Labelling.