Nonanoic acid, mixed diesters, with oxybis[propanol] and dodecanoic acid

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:

Not applicable

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:

The value is not an experimental result, however the QSAR model is recommended by the ECHA guidance document on information requirements, is well documented with regard to validation parameters according to OECD principles. The estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow. All fragments of test substance are represented in the model training set and the molecular weights are within definition of the model. However, as predicted log Kow values for C27- and C30-compounds are greater than 9, the BCF predictions are considered reliable with restrictions and are considered rather as qualitative than quantitative.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

2. MODEL (incl. version number)
BCFBAF v3.01

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C24-compounds: Predicted log Kow at 7.84
- CCCCCCCCC(=O)OC(C)COCC(C)OC(=O)CCCCCCCC
- CCCCCCCCC(=O)OCC(C)OC(C)COC(=O)CCCCCCCC
- CCCCCCCCC(=O)OC(C)COC(C)COC(=O)CCCCCCCC
C27-compounds: Predicted log Kow at 9.31
- CCCCCCCCC(=O)OC(C)COCC(C)OC(=O)CCCCCCCCCCC
- CCCCCCCCC(=O)OCC(C)OC(C)COC(=O)CCCCCCCCCCC
- CCCCCCCCC(=O)OC(C)COC(C)COC(=O)CCCCCCCCCCC
C30-compounds: Predicted log Kow at 10.79
- CCCCCCCCCCCC(=O)OC(C)COCC(C)OC(=O)CCCCCCCCCCC
- CCCCCCCCCCCC(=O)OCC(C)OC(C)COC(=O)CCCCCCCCCCC
- CCCCCCCCCCCC(=O)OC(C)COC(C)COC(=O)CCCCCCCCCCC

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF
- Defined endpoint: Bioconcentration Factor (BCF) and Bioaccumulation Factor (BAF).
- Unambiguous algorithm: BCFBAF v3.01 contains two methods for estimating BCFs: the BCF model using regression-based estimate method and Arnot-Gobas BCF/BAF model. In this endpoint study record, the second method is presented. Indeed, the regression based estimate method, proposed by the QSAR model, was not assessed as it does not take into account rapid metabolism of the substance and therefore is not relevant.
The Arnot-Gobas method has been expanded to calculate both BCF as well as BAF for three general trophic levels of fish. This method is based on the multiple-linear regression-derived equation which is used by the BCFBAF program to estimate the kM Biotransformation Half-Life.
- Defined domain of applicability: The estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow. With a molecular weight comprised between 414.63 and 498.79 g/mol, the substance is in the range of the training set (from 68.08 to 959.17 g/mol). However, with log Kow comprised between 7.84 and 10.79, the substance is outside the range of the training set (from 0.31 to 8.7) for C27- and C30-compounds. The bioconcentration factor estimates are less accurate for compounds outside the molecular weight and log Kow ranges of the training set compounds.
- Appropriate measures of goodness-of-fit and robustness and predictivity: Arnot-Gobas BCF and BAF statistics for the kM biotransformation half-life of the training dataset are; Number = 421 / r² = 0.821 / std deviation = 0.494 / avg deviation = 0.383. For the kM validation dataset; Number = 211 / r² = 0.734 / std deviation = 0.602 / avg deviation = 0.446.
- Mechanistic interpretation: no data

5. APPLICABILITY DOMAIN
See attached QPRF

6. ADEQUACY OF THE RESULT
See attached QPRF

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May 2008

Deviations:

no

Principles of method if other than guideline:

BCF calculated using Arnot-Gobas method.
See attached QMRF and QPRF (the QMRF is only available for the former version of the QSAR model).

GLP compliance:

no

Specific details on test material used for the study:

As the log Kow value of the substance could not be determined experimentally and as log Kow values for each compounds (C24, C27 and C30) cannot be extrapolated individually, the predicted log kow values determined by the model (Kowwin) were considered:
C24: predicted log Kow at 7.84
C27: predicted log Kow at 9.31
C30: predicted log Kow at 10.79

Radiolabelling:

no

Details on sampling:

Not applicable

Details on preparation of test solutions, spiked fish food or sediment:

Not applicable

Details on test organisms:

Not applicable

Test type:

other: QSAR

Water / sediment media type:

not specified

Hardness:

Not applicable

Test temperature:

Not applicable

pH:

Not applicable

Dissolved oxygen:

Not applicable

TOC:

Not applicable

Salinity:

Not applicable

Details on test conditions:

Not applicable

Nominal and measured concentrations:

Not applicable

Reference substance (positive control):

no

Details on estimation of bioconcentration:

Not applicable

Key result

Type:

BCF

Value:

>= 6.49 - <= 9.42 L/kg

Basis:

whole body w.w.

Remarks:

C24-compounds

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates. Depending on the trophic level (upper to lower trophic).

Key result

Type:

BCF

Value:

>= 1.42 - <= 1.73 L/kg

Basis:

whole body w.w.

Remarks:

C27-compounds

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates. Depending on the trophic level (upper to lower trophic).

Key result

Type:

BCF

Value:

>= 0.94 - <= 1.01 L/kg

Basis:

whole body w.w.

Remarks:

C30-compounds

Remarks on result:

other: Arnot-Gobas Method, including a biotransformation rate estimates. Depending on the trophic level (upper to lower trophic).

Details on kinetic parameters:

Not applicable

Metabolites:

Not applicable

Results with reference substance (positive control):

Not applicable

Details on results:

Arnot-Gobas Method: It's more relevant to consider the result including biotransformation rate estimates instead of the result assuming a biotransformation rate of zero.

Reported statistics:

Not applicable

C24-compounds:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag L Kow MolWt Const	2 2 1 4 16 2 * * *	Linear C4 terminal chain [CCO-CH3] Ester [-C(=O)-O-C] Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH- [linear] Log Kow = 7.84 (KowWin estimate) Molecular Weight Parameter Equation Constant	0.0341 -0.7605 -0.0232 0.2451 0.0242 -0.1912 0.3073	0.0682 -1.5211 -0.0232 0.9804 0.3870 -0.3825 2.4099 -1.0633 -1.5371
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		-0.6816 0.2082

- Biotransformation rate constant: kM (rate constant) = 3.329 / day (10 gram fish).

- Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 0.812 (BCF = 6.487 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = 0.935 (BCF = 8.619 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 0.974 (BCF = 9.416 L/Kg wet-wt).

- Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 3.626 (BCF = 4229 L/Kg wet-wt).

C27-compounds:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag L Kow MolWt Const	2 2 1 4 19 2 * * *	Linear C4 terminal chain [CCO-CH3] Ester [-C(=O)-O-C] Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH- [linear] Log Kow = 9.31 (KowWin estimate) Molecular Weight Parameter Equation Constant	0.0341 -0.7605 -0.0232 0.2451 0.0242 -0.1912 0.3073	0.0682 -1.5211 -0.0232 0.9804 0.4596 -0.3825 2.8627 -1.1712 -1.5371
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		-0.2641 0.5444

- Biotransformation rate constant:kM (rate constant) = 1.273 / day (10 gram fish).

- Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 0.151 (BCF = 1.417 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = 0.218 (BCF = 1.651 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 0.239 (BCF = 1.734 L/Kg wet-wt).

- Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 2.579 (BCF = 379 L/Kg wet-wt).

C30-compounds:

TYPE	NUM	LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION	COEFF	VALUE
Frag Frag Frag Frag Frag Frag L Kow MolWt Const	2 2 1 4 22 2 * * *	Linear C4 terminal chain [CCO-CH3] Ester [-C(=O)-O-C] Aliphatic ether [C-O-C] Methyl [-CH3] -CH2- [linear] -CH- [linear] Log Kow = 9.31 (KowWin estimate) Molecular Weight Parameter Equation Constant	0.0341 -0.7605 -0.0232 0.2451 0.0242 -0.1912 0.3073	0.0682 -1.5211 -0.0232 0.9804 0.5321 -0.3825 3.3155 -1.2791 -1.5371
RESULT RESULT NOTE		Log Bio Half-life (days) Bio Half-life (days) Bio Half-life Normalized to 10 g fish at 15°C		0.1534 1.424

- Biotransformation rate constant:kM (rate constant) = 0.4869 / day (10 gram fish).

- Arnot-Gobas BCFBAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = -0.027 (BCF = 0.9391 L/Kg wet-wt).

Estimated Log BCF (mid trophic) = -0.002 (BCF = 0.9948 L/Kg wet-wt).

Estimated Log BCF (lower trophic) = 0.004 (BCF = 1.01 L/Kg wet-wt).

- Arnot-Gobas BCFBAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 1.168 (BCF = 14.73 L/Kg wet-wt).

Validity criteria fulfilled:

not applicable

Conclusions:

The BCF for the substance using the Arnot-Gobas method is comprised between 0.94 and 9.42 L/Kg wet-wt, using the predicted log Kow values and including biotransformation rate estimates. Based on restrictions on the applicability domain, these predictions are considered rather as qualitative than quantitative.

Executive summary:

The bioconcentration factor (BCF) of the substance was evaluated with BCFBAF model v3.01 from EPI Suite v4.1, which fulfilled all OECD principles. The BCFBAF model v3.01 contains two methods for estimating BCFs: the BCF model using regression-based estimate method and Arnot-Gobas BCF/BAF model. Only the second method is presented in the Endpoint Study Record. The regression-based estimate method, proposed by the QSAR model, was not assessed as it does not take into account rapid metabolism of the substance and therefore is not relevant.

The estimated BCF values using Arnot-Gobas methodology and including biotransformation rate estimates were all comprised between 0.94 and 9.42 L/kg.

The substance is not completely falling into the applicability domain. Indeed, the estimation domain for BCF is based on the number of instances given for each correction factor in any of the training set compounds, and the minimum and maximum values for molecular weight and log Kow. All fragments of test substance are represented in the model training set and the molecular weights are within definition of the model. However, as predicted log Kow values for C27- and C30-compounds are greater than 9, the BCF predictions are considered reliable with restrictions and are considered rather as qualitative than quantitative.

Description of key information

No bioaccumulation expected.

Additional information

According to ECHA Guidance Chapter R.11 Version 3.0 (June 2017), the Bioaccumulation criterion is unlikely to be triggered for substances with a log Kow higher than 10.

Indeed, for highly hydrophobic substances, like the registered substance with a log Kow > 6, experimentally derived BCF values tend to decrease with increasing log Kow. Several explanations of this breakdown of linerarity can be given. Conceptual explanations of this non-linearity mainly refer to either biotransformation, reduced membrane permeation kinetics or reduced biotic lipid solubility for large molecules. A low bioavailability and uptake of these substances in the organism will thus occur. Other factors comprise experimental artefacts, such as equilibrium not being reached, reduced bioavailability due to sorption to organic matter in the aqueous phase, and analytical errors. In addition, as the registered substance is readily biodegradable, it is quite likely that, in an experimental study (via food or water), a low bioavailability, a metabolic hydrolysis and a reduced membrane uptake rate will thus occur. The uptake by oral route is more critical (dietary fedding study). In this case, the substance is likely to be broken in the gut and any bioaccumulation would be due to oral consumption of the narcotic by-products and the weak acid.

 

To confirm that no bioaccumulation is expected for the registered substance considering the high hydrophobic properties and rapid metabolisation (ester hydrolysis) of the substance, QSAR predictions using Arnot-Gobas methodology was performed, including biotransformation rate estimates. The estimated BCF values were all comprised between 0.94 and 9.42 L/kg. The registered substance is not bioaccumulable according to CLP (BCF < 500) and PBT criteria (BCF < 2000). However, based on restrictions on the applicability domain, these predictions are considered rather as qualitative than quantitative.

 

Also, the registered substance presents no toxicity for mammals. The "No Observed Adverse Effect Level", NOAEL, was determined at the highest tested dose in the sub-acute toxicity study and sub-chronic oral toxicity studies. This observation confirm the limit absorption and therefore the limited bioaccumulation of the registered substance.