2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate)

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

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

Justification for type of information:

1. SOFTWARE
EPISuite (v4.11)
2. MODEL (incl. version number)
BCFBAF v3.01
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES : CCCCCC(CCCCCCCC)C(=O)OCC(COC(=O)C(CCCCCCCC)CCCCCC)(COC(=O)C(CCCCCCCC)CCCCCC)COC(=O)C(CCCCCCCC)CCCCCC
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
A reliable QSAR model was used to calculate the bioaccumulation potential of 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate). BCF values were calculated using the BCFBAF v3.01 module embedded within the EPISuite v4.11 computer model.
EPISuite and its modules (including BCFBAF) have been utilized by the scientific community for prediction of phys/chem properties and environmental fate and effect properties since the 1990’s. The program underwent a comprehensive review by a panel of the US EPA’s independent Science Advisory Board (SAB) in 2007. The SAB summarized that the EPA used sound science to develop and refine EPISuite. The SAB also stated that the property estimation routines (PERs) satisfy the Organization for Economic Cooperation and Development (OECD) principles established for quantitative structure-activity relationship ((Q)SAR) validation. The EPISuite modules (including BCFBAF) have been incorporated into the OECD Toolbox. Inclusion in the OECD toolbox requires specific documentation, validation and acceptability criteria and subjects EPISuite to international use, review, providing a means for receiving additional and on-going input for improvements. BCFBAF is listed as one of the QSARs for use in predicting bioaccumulation values in the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance. In summary, the EPISuite modules (including BCFBAF) have had their scientific validity established repeatedly. https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface
- Defined endpoint and unambiguous algorithm:
BCFBAF v3.01 comprises the three following models:
(1) Regression-based BCF model (based on Meylan et al., 1997; Meylan et al., 1999)
The original estimation methodology used by the original BCFWIN program is described in a document prepared for the U.S. Environmental Protection Agency (Meylan et al., 1997). The estimation methodology was then published in journal article (Meylan et al, 1999). The BCFBAF Program updated the BCF estimation methodology of the BCFWIN program by using an updated and better evaluated BCF database for selecting training and validation datasets. The exact same regression methodology used to derive the original BCFWIN method was used to derive the BCFBAF method for estimating BCF.
The BCFBAF method classifies a compound as either ionic or non-ionic. Non-Ionic compounds are separated into three divisions by Log Kow value (Log Kow < 1.0, Log Kow 1.0-7.0, Log Kow > 7.0). For each division, a "best-fit" straight line was derived by common statistical regression methodology.
For Log Kow 1.0 to 7.0 the derived QSAR estimation equation is:
Log BCF = 0.6598 Log Kow - 0.333 + Σ correction factors
(n = 396, r2 = 0.792, Q2 = 0.78, std dev = 0.511, avg dev = 0.395)
For Log Kow > 7.0 the derived QSAR estimation equation is:
Log BCF = -0.49 Log Kow + 7.554 + Σ correction factors
(n = 35, r2 = 0.634, Q2 = 0.57, std dev = 0.538, avg dev = 0.396)
For Log Kow < 1.0 the derived QSAR estimation equation is: All compounds with a log Kow of less than 1.0 are assigned an estimated log BCF of 0.50.
(2) Biotransformation rate model (Arnot et al., 2008b)
The final multiple-linear regression-derived equation (which is used by the BCFBAF program to estimate the kM Biotransformation Half-Life) is:
Log kM/Half-Life (in days) = 0.30734215*LogKow - 0.0025643319*MolWt - 1.53706847 + Σ(Fi*ni)
where LogKow is the log octanol-water partition coefficient, MolWt is the Molecular Weight, and Σ(Fi*ni) is the summation of the individual Fragment coefficient values (Fi) times the number of times the individual fragment occurs in the structure ( ni). The -1.53706847 is the equation constant.

(3) Arnot-Gobas BAF-BAF
The Arnot and Gobas (2003) food web bioaccumulation model is a simple, single mass-balance equation. The model requires few input parameters (i.e. only Kow and metabolic transformation rate, if available – the default is zero), and derives the BAF as the ratio of the substance concentration in an upper trophic level organism and the total substance concentration in unfiltered water (it also estimates an overall biomagnification factor for the food web). It accounts for the rates of substance uptake and elimination (a number of simple relationships have been developed to estimate the rate constants for organic substances in fish from Gobas, 1993), and specifically includes bioavailability considerations. The BAF and BCF values for the 3 general trophic positions of fish (upper, middle, and lower) are derived using the BAF-QSAR model calibration methods (Arnot and Gobas, 2003).

- Defined domain of applicability:
Currently there is no universally accepted definition of model domain, for model (1) Regression-based BCF model (based on Meylan et al., 1997; Meylan et al., 1999) and (2) Biotransformation rate model (Arnot et al., 2008b). However, the documentation does provide information for reliability of the calculations. Estimates will possibly be less accurate for compounds outside the MW and logKow ranges of the training set compounds, and/or that have more instances of a given fragment than the maximum for all training set compounds. It is also possible that a compound may have a functional group(s) or other structural features not represented in the training set, and for which no fragment coefficient was developed; and that a compound has none of the fragments in the model’s fragment library.
The following MW and logKow ranges are covered by the individual models:
(1) Molecular Weight range (non-ionic): 68.08 - 959.17
Log Kow range (non-ionic): (-1.37) - 11.26
(2) Molecular Weight range: 68.08 - 959.17
Log Kow range: 0.31 – 8.70
For the (3) Arnot-Gobas BAF-BAF model predictions may be highly uncertain for chemicals that have estimated log KOW values > 9. The model is not recommended for chemicals that appreciably ionize, for pigments and dyes, or for perfluorinated substances.

- Appropriate measures of goodness-of-fit and robustness and predictivity:
(1)The Regression-based BCF model had the following statistics:
Training Set Accuracy: n=527 (466 Non-Ionic Compounds and 61 Ionic), r²=0.833
Validation Set Accuracy: n=158, r²=0.82
(2) The biotransformation rate model has the following statistics:
Training Set Accuracy: n=421, r2=0.821
Validation Set accuracy: n=211, r2=0.734
(3) The Arnot-Gobas BAF-BAF model may not adequately capture biotransformation at the first trophic level for chemicals that are readily biotransformed in invertebrates and plankton. The BAF calculations were derived from the parameterization and calibration of the model to a large database of measured BAF values from the Great Lakes (Lake Ontario, Lake Erie and Lake St. Clair). The measured BAFs are for chemicals that are poorly metabolized. Therefore, in the absence of metabolic biotransformation the BAF model predictions are in general agreement with measured BAFs in fish of these general trophic positions from the Great Lakes for chemicals that are poorly metabolized.

5. APPLICABILITY DOMAIN
As described above, according to the BCFBAF documentation, there is currently no universally accepted definition of model domain for any of the three models. In general, the intended application domain for all models embedded in EPISuite is organic chemical. Specific compound classes, besides organic chemicals, require additional correction factors. Indicators for the general applicability of the BCFBAF model are the logKow value of the target substance, the molecular weight of the target substance and the identified number of individual fragments in comparison to the training set.
(1) The molecular weight of 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) is 1075.79 and therefore exceeding the range of the training set for the regression-based model. But with a measured logKow of 11.03 the molecule is inside the training set logKow range and in addition, a correction factor is applied for the identified fragment.
Equation Used to Make BCF estimate:
Log BCF = -0.49 log Kow + 7.554 + Correction

Correction(s): Value
Alkyl chains (8+ -CH2- groups) -0.596

Estimated Log BCF = 1.553 (BCF = 35.71 L/kg wet-wt)

Though 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) is outside the given MW range, the calculated BCF can be considered indicative of low or no bioaccumulation potential. Especially considering that the BCF decreases for compounds with logKow values > 10 (see model documentation and ECHA Guidance Document Chapter R.11: PBT/vPvB assessment Version 3.0 – June 2017 Appendix R.11—1 Annex 1).

(2) The molecular weight of 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate)is 1075.79 and therefore outside the range of the training set of model (2), and also the calculated logKow (11.03) is outside of the training set range. But the biotransformation rate estimates given below show that all fragments of the substance were identified, although the number of individual fragments exceeds the maximum number of the fragments listed below:
Linear C4 terminal chain [CCC-CH3] (max. 3 fragments in any individual training set compound)
Ester [-C(=O)-O-C] (max. 2 fragments in any individual training set compound)
-CH2- [linear] (max. 28 fragments in any individual training set compound)
-CH- [linear] (max. 2 fragments in any individual training set compound)

Whole Body Primary Biotransformation Rate Estimate for Fish:
===========================================================
------+-----+--------------------------------------------+---------+---------
TYPE | NUM | LOG BIOTRANSFORMATION FRAGMENT DESCRIPTION | COEFF | VALUE
------+-----+--------------------------------------------+---------+---------
Frag | 8 | Linear C4 terminal chain [CCC-CH3] | 0.0341 | 0.2730
Frag | 4 | Ester [-C(=O)-O-C] | -0.7605 | -3.0421
Frag | 1 | Carbon with 4 single bonds & no hydrogens | -0.2984 | -0.2984
Frag | 8 | Methyl [-CH3] | 0.2451 | 1.9608
Frag | 51 | -CH2- [linear] | 0.0242 | 1.2335
Frag | 4 | -CH- [linear] | -0.1912 | -0.7649
L Kow| * | Log Kow = 11.03 (user-entered ) | 0.3073 | 3.3900
MolWt| * | Molecular Weight Parameter | | -2.7587
Const| * | Equation Constant | | -1.5371
============+============================================+=========+=========
RESULT | LOG Bio Half-Life (days) | | -1.5439
RESULT | Bio Half-Life (days) | | 0.02858
NOTE | Bio Half-Life Normalized to 10 g fish at 15 deg C |
============+============================================+=========+=========

In regard to the (3) Arnot-Gobas BAF-BCF model, the calculated BCF and BAF values for 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) will not be accurate, as the logKow of the molecule is greater than 9. But considering that 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) is expected to be subject to rapid metabolic biotransformation, the estimates will therefore be overly conservative and will most likely overestimate the bioaccumulation potential.
Arnot-Gobas BCF & BAF Methods (including biotransformation rate estimates):
Estimated Log BCF (upper trophic) = -0.049 (BCF = 0.8935 L/kg wet-wt)
Estimated Log BAF (upper trophic) = -0.049 (BAF = 0.8935 L/kg wet-wt)
Estimated Log BCF (mid trophic) = -0.030 (BCF = 0.9322 L/kg wet-wt)
Estimated Log BAF (mid trophic) = -0.030 (BAF = 0.9328 L/kg wet-wt)
Estimated Log BCF (lower trophic) = -0.026 (BCF = 0.941 L/kg wet-wt)
Estimated Log BAF (lower trophic) = -0.019 (BAF = 0.957 L/kg wet-wt)
Arnot-Gobas BCF & BAF Methods (assuming a biotransformation rate of zero):
Estimated Log BCF (upper trophic) = 0.945 (BCF = 8.821 L/kg wet-wt)
Estimated Log BAF (upper trophic) = 4.605 (BAF = 4.029e+004 L/kg wet-wt)
Thus the results can be considered indicative for low or no bioaccumulation potential.

6. ADEQUACY OF THE RESULT
The above specified correlation coefficients indicate the calculated results are equivalent to those generated experimentally and are, hence, adequate for the purpose of classification and labelling and/or risk assessment. Taking into account the molecular structure and respective degradability and metabolism, the obtained results can be considered indicative for low or no bioaccumulation potential.
The BCFBAF predicted bioaccumulation values are therefore considered valid and fit for purpose.

Documentation of the BCFBAF model is provided in the following references:
Arnot JA, Mackay D, Bonnell M. 2008b. Estimating metabolic biotransformation rates in fish from laboratory data. Environmental Toxicology and Chemistry 27: 341-351.
Arnot JA, Gobas FAPC. 2003. A generic QSAR for assessing the bioaccumulation potential of organic chemicals in aquatic food webs. QSAR and Combinatorial Science 22: 337-345.
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. Environmental reviews 14(4): 257-297.
Arnot JA, Meylan W, Tunkel J, Howard PH, Mackay D, Bonnell M, Boethling RS. 2009. A QSAR for predicting metabolic biotransformation rates for organic chemicals in fish. Environmental Toxicology and Chemistry. 28: in press.
Meylan, W.M., Howard, P.H, Aronson, D., Printup, H. and S. Gouchie. 1997. "Improved Method for Estimating Bioconcentration Factor (BCF) from Octanol-Water Partition Coefficient", SRC TR-97-006 (2nd Update), July 22, 1997; prepared for: Robert S. Boethling, EPA-OPPT, Washington, DC; Contract No. 68-D5-0012; prepared by: ; Syracuse Research Corp., Environmental Science Center, 6225 Running Ridge Road, North Syracuse, NY 13212.
Meylan,WM, Howard,PH, Boethling,RS et al. 1999. Improved Method for Estimating Bioconcentration / Bioaccumulation Factor from Octanol/Water Partition Coefficient. Environ. Toxicol. Chem. 18(4): 664-672 (1999).ECHA (2012) “Guidance on information requirements and chemical safety assessment Chapter R.7b: Endpoint specific guidance”.
McFarland, M. et al. 2007. “Science Advisory Board (SAB) Review of the Estimation Programs Interface Suite (EPI SuiteTM)”.

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

The BCFBAF v3.01 module embedded within the EPISuite v4.11) computer model was used.
Arnot JA, Mackay D, Bonnell M. 2008b. Estimating metabolic biotransformation rates in fish from laboratory data. Environmental Toxicology and Chemistry 27: 341-351.
Arnot JA, Gobas FAPC. 2003. A generic QSAR for assessing the bioaccumulation potential of organic chemicals in aquatic food webs. QSAR and Combinatorial Science 22: 337-345.
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. Environmental reviews 14(4): 257-297.
Arnot JA, Meylan W, Tunkel J, Howard PH, Mackay D, Bonnell M, Boethling RS. 2009. A QSAR for predicting metabolic biotransformation rates for organic chemicals in fish. Environmental Toxicology and Chemistry. 28: in press.
Meylan, W.M., Howard, P.H, Aronson, D., Printup, H. and S. Gouchie. 1997. "Improved Method for Estimating Bioconcentration Factor (BCF) from Octanol-Water Partition Coefficient", SRC TR-97-006 (2nd Update), July 22, 1997; prepared for: Robert S. Boethling, EPA-OPPT, Washington, DC; Contract No. 68-D5-0012; prepared by: ; Syracuse Research Corp., Environmental Science Center, 6225 Running Ridge Road, North Syracuse, NY 13212.
Meylan,WM, Howard,PH, Boethling,RS et al. 1999. Improved Method for Estimating Bioconcentration / Bioaccumulation Factor from Octanol/Water Partition Coefficient. Environ. Toxicol. Chem. 18(4): 664-672 (1999).ECHA (2012) “Guidance on information requirements and chemical safety assessment Chapter R.7b: Endpoint specific guidance”.
McFarland, M. et al. 2007. “Science Advisory Board (SAB) Review of the Estimation Programs Interface Suite (EPI SuiteTM)”.

Specific details on test material used for the study:

SMILES : CCCCCC(CCCCCCCC)C(=O)OCC(COC(=O)C(CCCCCCCC)CCCCCC)(COC(=O)C(CCCCCCCC)CCCCCC)COC(=O)C(CCCCCCCC)CCCCCC

Details on estimation of bioconcentration:

- Estimation software: EPISuite
- Result based on measured logKow of: 11.03

Key result

Type:

BCF

Value:

35.7 L/kg

Basis:

other: wet weight

Remarks on result:

other: QSAR predicted value

BIOWIN predicted that 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate) has no or low bioaccumulation potential with an BCF of 35.7 L/kg wet-weight.

Conclusions:

A reliable QSAR model was used to calculate the bioaccumulation potential of 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate). BCF values were calculated using the BCFBAF v3.01 module embedded within the EPISuite v4.11 computer model. The calculated BCF (regression-based model) was 35.7 L/kg wet-wt., hence indicating low or no bioaccumulation potential.

Description of key information

A reliable QSAR model was used to calculate the bioaccumulation potential of 2,2-bis[[(2-hexyl-1-oxodecyl)oxy]methyl]-1,3-propanediyl bis(2-hexyldecanoate). BCF values were calculated using the BCFBAF v3.01 module embedded within the EPISuite v4.11 computer model.  The calculated BCF (regression-based model) was 35.7 L/kg wet-wt., hence indicating low or no bioaccumulation potential.

Key value for chemical safety assessment

BCF (aquatic species):

35.7 L/kg ww