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Environmental fate & pathways

Bioaccumulation: aquatic / sediment

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Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, regression-based method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
2. 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).
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Test organisms (species):
other: Fish
Route of exposure:
aqueous
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.01
- Result based on calculated log Kow of: 12.99 (estimated, KOWWIN v.1.68)
Type:
BCF
Value:
15.4 L/kg
Basis:
whole body w.w.
Type:
other: Log BCF
Value:
1.19 dimensionless
Basis:
whole body w.w.

For detailed information on the results please refer to the attached report.

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:
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
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, Arnot-Gobas method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Vehicle:
no
Test organisms (species):
other: Fish
Route of exposure:
other: aqueous and dietary
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: EPI Suite v4.11, BCFBAF v3.01
- Result based on calculated log Pow of: 12.99
Type:
BCF
Value:
0.893 L/kg
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic
Type:
other: log BCF
Value:
-0.049 dimensionless
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic

For detailed information on the results please refer to the attached report.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The main goal of this study is to describe the effect of molecular size on bioconcentration by accounting for conformational flexibility of molecules.
GLP compliance:
no
Radiolabelling:
not specified
Vehicle:
not specified
Test organisms (species):
other: fish
Route of exposure:
other: review article
Test type:
other: review article
Water / sediment media type:
not specified
Remarks on result:
other: Precise results cannot be given, see explanation in any other information on results incl. tables.

Results

The complexity of the effect of molecular geometry and flexibility on membrane permeation and subsequently on bioconcentration can be illustrated with n-pentadecane. The length of the n-pentadecane molecule, known also as the maximum diameter, is Dmax= 2.14 nm. The other two related dimensions, the effective and minimum cross-sections for this conformer, are Deff= 0.499 nm and Dmin= 0.492 nm, respectively. Due to the high hydrophobicity of n-pentadecane [log(Kow) = 7.71] and small effective cross-section of its lowest energy conformer, which is far below the critical 0.95 nm, one anticipates high bioconcentration for this chemical. The bioconcentration is in the range of 3.2 to 4.3 log units. Two other energetically reasonable conformers of n-pentadecane have got a heat formation of H°= –71.8 kcal/mol and H°= –68.5 kcal/mol, respectively. Based on the effective cross-section of the third conformer, Deff= 1.15 nm, a loss of membrane permeation may be expected, resulting in low bioconcentration. The experimentally measured BCF of n-pentadecane in carp, expressed as log (BCF), is in the range of 1.12 to 1.29. Two conclusions could be drawn from this simple example. First, molecular cross-sectional diameters appear to be strongly dependent on molecular flexibility Secondly, it is not clear which of the molecular dimensions controls the membrane permeation of chemicals.

The complex effect of molecular geometry and flexibility on the chemicals’ permeability is confirmed by superposition of the molecular effective cross-sectional diameters of the studied lipophilic chemicals with their experimentally measured BCFs.

The absence of any correlation indicates that this geometric characteristic is not related to the variation of BCF for highly hydrophobic chemicals. The hypothesis that the effective diameter controls permeability of chemicals assumes a strict spatial orientation of the molecules toward the cell membrane surface in a way that the molecular projection over the membrane does not exceed a certain threshold (anticipated to be around 0.95 nm). The appropriate orientation, however, is pre-vented by entropy (i.e., by chaotic movement of the molecules), which can explain the insufficiency of the effective cross-section of molecules to explain their permeability.

Two interesting features were displayed firstly, there is a well-outlined tendency of decreasing bioconcentration with the increase of the maximum cross-sectional areas of molecular conformers. The higher the molecular length (i.e., its Dmax value), the smaller are the chances of the molecule reaching the cell membrane at an appropriate angle. Secondly, most chemicals with Dmax under ~1.5 nm achieve high log (BCF)—in the range of 3 to 6, while the chemicals with Dmax greater than this threshold accumulate up to 3.3 units at most. The existence of such a transition point can be explained by a change in the mechanism of uptake of chemicals from passive diffusion through the phospholipid bilayer of the membrane to the more conservative passing of the membrane by the mechanism of exocytosis and endocytosis. Interestingly, the critical value of 1.5 nm for the threshold is comparable with the cell membrane architecture. The threshold of maximum diameter is comparable with the half thickness of leaflet constituting the lipid bilayer of the cell membrane.

From the present results, one could conclude that diffusion through the cell membrane is limited to molecules having a length not exceeding the threshold of about 1.5 nm. The latter could be assumed as the maximum tolerance of the cell membrane.

Conclusion

Analysis of the BCF data for narcotics with log (Kow) greater than 5.5 revealed that the maximum cross-sectional diameter can be used to explain the significant scatter around the maximum of the log (BCF)/log (Kow) curve. The chaotic collision of molecules with the cell membrane surface at different angles could explain the significance of this geometric characteristic, instead of generally accepted effective diameter. The drop in bioconcentration of chemicals at a maximum cross-sectional diameter of about 1.5 nm is an indication of a switch of the mechanism of uptake of chemicals into cells above this threshold. The value of this transition point can be used as an additional parameter of hydrophobicity for regression modeling of the BCF variation. Conformational flexibility tends to further increase the significance of entropy to cell permeability, which leads to additional decreases of BCF. The effect of this structural characteristic, however, needs to be further evaluated in order to be used for quantifying the bioconcentration of chemicals.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Literature study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Literature study addressing the effects of molecular size and lipid solubility on the bioaccumulation potential of environmental contaminants.
GLP compliance:
no
Test organisms (species):
other: Aquatic organisms
Route of exposure:
other: not applicable, review
Test type:
other: not applicable, review
Water / sediment media type:
not specified
Remarks on result:
other: Precise results cannot be given, see explanation in any other information on results incl. tables.

BCF measured values plotted against log Kow values

- Estimating bioconcentration factors (BCF) from octanol/water partition coefficients (log KOW) is well established and essentially valid for neutral organics of intermediate lipophilicity (0 < log Kow < 6).

- On the other hand, chemicals with log Kow > 6 often have measured BCFs lower than calculated from linear QSARs. Apparently, BCFs no longer increase in correspondence with log Kow. A maximum range in log BCF of approximately 6–7 for compounds with log Kow 6–8 is observed, followed by a plateau or a gradual decrease with further increase in log Kow. The maximum BCF

associated with a given lipophilicity can be described by a bilinear worst-case function:

log BCF = 0.99 log Kow - 1.47 log (4.97 x 10-8 KOW + 1) + 0.0135

The bilinear curve resumes a linearly increasing part between log Kow 0 and 6, where the empirically postulated coincidence of log Kow and log BCF is reflected by a near-unity slope (0.99) for the 1st-order log Kow term and the intercept of about 0. Maximum log BCF values of approximately 7 are obtained for compounds with log Kow between 7 and 8. Compounds that are more lipophilic are observed to be less accumulating, which corresponds to the negative slope derived for the second log Kow term of the bilinear function.

- The apparent loss in linear relationships for superlipophilic compounds has been attributed – in part – to experimental artefacts. Theoretical considerations substantiate curvilinear relationships for chemicals with log Kow > 6: - Aqueous phase diffusion control of water to lipid transfer - Differences in phase (solvent) properties of natural lipids and octanol - Influence of steric conformations - Differences in thermodynamic properties of partitioning, e.g. enthalpy changes To test established QSARs, BCF data were provided by Umweltbundesamt for 31 plant protection agents and for 18 new chemicals. These chemicals were selected by two criteria: molecular weight > 300 g/mol and bioaccumulation data available. Since this- 34 -data set includes no compounds with log BCF > 4 (range in BCF data: 1.5 to 14600), additional data for compounds with very high BCF were taken from the literature. Most BCF data from Umweltbundesamt were qualified as ‘valid data'. However, for two compounds Umweltbundesamt classified the measurements as ‘invalid’. Critical inspection of the available BCF data revealed major deficiencies in data quality of several superlipophilic compounds. For nine compounds, the accumulation experiments have been conducted at concentrations above the water solubility of the test compounds. Consequently, the resulting BCF values are too low artefacts due to invalid experiments. These data were excluded from further analyses. The remaining data set from Umweltbundesamt is considered not sufficiently representative, because it includes no compounds with log BCF > 4. It is too limited with regard to activity domain as to provide new insights to relationships between BCF and log Kow. New insights to relationships between BCF and log Kow could not be provided. The currently available database is insufficient to conclusively substantiate the effects of molecular size and lipid solubility on the bioaccumulation potential of environmental contaminants.

Endpoint:
bioaccumulation: aquatic / sediment
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles
Qualifier:
no guideline followed
Principles of method if other than guideline:
In this report, the application of selected physico-chemical and molecular attributes according to Lipinski's 'Rule of 5'* in the estimation of fish bioconcentration values is investigated.

*Lipinski et al. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, pp. 961-965).
GLP compliance:
no
Remarks:
No experimental study thus GLP standards are not relevant.
Test organisms (species):
other: Aquatic organisms
Route of exposure:
other: Not applicable, review
Test type:
other: Not applicable, review
Water / sediment media type:
not specified
Type:
BCF
Value:
< 2 000 L/kg
Calculation basis:
other: Review literature dataset
Remarks on result:
other: Substances log Kow < 3 and log Kow > 10

Molecular weight or size-related cut-off criteria

- No robust evidence was found for cut-offs for bioconcentration related to molecular size. A criterion in molecular weight of 650 mg/mol seems to be more appropriate that the 500 g/mol stated by Lipinski et al. (1997) as it was only exceeded by a few non-B compounds (BCF < 2000) in the dataset. Cut-offs in molecular weight are pragmatic due to readily available metrics, but they lack a mechanistic rationale. As often, the problem is multivariate in nature and there exists a multitude of parameters than jointly and simultaneously influence each other. The correlation between molecular weight and size is rather weak (r square= 0.36 -0.45). Other properties related to molecular weight, such as solubilities in various media, absorption kinetics and bioavailability are also influential.

Lipophility related cut-off (log Kow)

The results from the analysis of log BCF values plotted against log Kow values confirm the implication of non-linear log Kow-based QSARs that chemicals with either low (log Kow < 3) of very high lipophilicity (logKow > 10) may have rather low BCF (non B compounds). The maximum BCF associated with a given lipophilicity has been described by a bilinear worst-case function. The curve was constructed (without regression and thus without calibration statistics) to represent the upper border of the data distribution of log BCF versus log Kow:

logBCFmax = 0.99 log Kow – 1.47 log (4.97x10-08 Kow + 1) + 0.0135    (1)

Chemicals with log Kow > 6 often have measured BCFs lower than calculated from QSARs. Apparently, these BCFs no longer increase in correspondence with log Kow, but plateau or gradually decrease with further increase in log Kow. Arnot and Gobas identified sorption as the main reason that accumulation decreases with increasing log Kow for highly lipophilic chemicals: if accumulation were quantified as the ratio of the concentrations in the organisms and the freely dissolved chemical concentration in water the BCF of high Kow chemicals would rise to 107and the level off with a further increase Kow. The rationale is that for more hydrophobic chemicals (log Kow > 6) membrane permeation rates become increasingly controlled and ultimately dominated by aqueous boundary layer transport rather than phospholipid bilayer permeation.

Upward deviations relative to equation (1) only concern hydrophilic molecules (log Kow < 2), but their BCFs remain below 100. In the log Kow range between 3 and 10, many BCF values are lower than calculated by the QSAR, but the higher than the B (BCF > 2000) of vB (BCF > 5000) criteria. Above log Kow 10, none of the few available data in the test and validation datasets, exceeds the B criterion. Downward scatter relative to Equation (1) over several orders of magnitude increases for more lipophilic compounds, and many be attributed to mitigating factors such as ionization, degradation or metabolism of the test substances as well as to major errors particularly in very high log Kow values.

In the confirmation dataset, one bioaccumulative compound has a log Kow slightly above 10, octabromiddiphenyl ether, and two compounds bioaccumulating by different mechanisms have a log Kow < 3, methyl mercury and tetraethyl lead. The consequence of these observations is that in addition to polybrominated compounds, also alkylated heavy metals are excluded from the applicability domain of the classification scheme.

Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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 substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, regression-based method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
2. 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).
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Test organisms (species):
other: Fish
Route of exposure:
aqueous
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.01
- Result based on calculated log Kow of: 31.42 (estimated, KOWWIN v.1.68)
Type:
BCF
Value:
3.16 L/kg
Basis:
whole body w.w.
Type:
other: log BCF
Value:
0.5 dimensionless
Basis:
whole body w.w.

For detailed information on the results please refer to the attached report.

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:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, Arnot-Gobas method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Vehicle:
no
Test organisms (species):
other: Fish
Route of exposure:
other: aqueous and dietary
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: EPI Suite v4.11, BCFBAF v3.01
- Result based on calculated log Pow of: 31.42
Type:
BCF
Value:
0.893 L/kg
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic
Type:
other: log BCF
Value:
-0.049 dimensionless
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic

For detailed information on the results please refer to the attached report.

Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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 substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, regression-based method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
2. 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).
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Test organisms (species):
other: Fish
Route of exposure:
aqueous
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.01
- Result based on calculated log Kow of: 35.35 (estimated, KOWWIN v.1.68)
Type:
BCF
Value:
3.16 L/kg
Basis:
whole body w.w.
Type:
other: log BCF
Value:
0.5 dimensionless
Basis:
whole body w.w.

For detailed information on the results please refer to the attached report.

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:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, Arnot-Gobas method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Vehicle:
no
Test organisms (species):
other: Fish
Route of exposure:
other: aqueous and dietary
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: EPI Suite v4.11, BCFBAF v3.01
- Result based on calculated log Pow of: 35.35
Type:
BCF
Value:
0.893 L/kg
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic
Type:
other: log BCF
Value:
-0.049 dimensionless
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic

For detailed information on the results please refer to the attached report.

Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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 substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, regression-based method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
2. 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).
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Test organisms (species):
other: Fish
Route of exposure:
aqueous
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.01
- Result based on calculated log Kow of: 22.13 (estimated, KOWWIN v.1.68)
Type:
BCF
Value:
3.16 L/kg
Basis:
whole body w.w.
Type:
other: log BCF
Value:
0.5 dimensionless
Basis:
whole body w.w.

For detailed information on the results please refer to the attached report.

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:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Remarks:
The substance is not fully compliant with the applicability domain of the model. However, this calculation is used in a weight of evidence approach, in accordance to the REACh Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2. It is adequately documented and justified: the prediction is evaluated on the basis of the model performance on similar substances. For more details see section `overall remarks, attachments´.
Justification for type of information:
1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.01, Arnot-Gobas method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.01
Full reference and details of the used formulas can be found in:
1. 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.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'
GLP compliance:
no
Vehicle:
no
Test organisms (species):
other: Fish
Route of exposure:
other: aqueous and dietary
Test type:
other: calculation
Water / sediment media type:
natural water: freshwater
Details on estimation of bioconcentration:
BASIS FOR CALCULATION OF BCF
- Estimation software: EPI Suite v4.11, BCFBAF v3.01
- Result based on calculated log Pow of: 22.13
Type:
BCF
Value:
0.893 L/kg
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic
Type:
other: log BCF
Value:
-0.049 dimensionless
Basis:
whole body w.w.
Remarks on result:
other: including biotransformation, upper trophic

For detailed information on the results please refer to the attached report.

Description of key information

Key value for chemical safety assessment

Additional information

Experimental bioaccumulation data are not available for Fatty acids lanolin, di, tri- and tetraesters with pentaerythritol and rape fatty acid. The high log Kow (> 10) as an intrinsic chemical property of the substance indicates a potential for bioaccumulation. However, the information gathered on environmental behaviour and metabolism, in combination with QSAR-estimated values, provide enough evidence (in accordance to the Regulation (EC) No 1907/2006, Annex XI General rules for adaptation of the standard testing regime set out in Annexes VII to X, 1.2), to cover the data requirements of Regulation (EC) No 1907/2006, Annex VIII to state that the substance is likely to show negligible bioaccumulation potential. The following individual constituents were chosen for QSAR calculation to represent the target substance in the best-possible manner: Pentaerythritol diesters of C16 fatty acids, Pentaerythritol tetraesters of C18:1 fatty acids, Pentaerythritol triesters of C18:2 fatty acids, and Pentaerythritol tetraesters of C20:1 fatty acids.

Environmental behaviour

Due to the high potential for adsorption, the substance can be effectively removed in conventional sewage treatment plants (STPs) by sorption to biomass. The low water solubility (< 0.15 mg/L at 20 °C) and high estimated log Kow (> 10, KOWWIN v1.68) indicate that the substance is highly lipophilic. If released into the aquatic environment, the substance undergoes extensive sorption to organic matter. Thus, the bioavailability in the water column is reduced rapidly. The relevant route of uptake of the substance in aquatic organisms is expected to be predominantly by ingestion of particle bound substance. 

Uptake/Absorption

If the substance is taken up by ingestion, absorption is expected to be low based on the molecular weight, size and structural complexity of the substance. These large and complex structures assume ahigh degree of conformational flexibility. Dimitrov et al. (2002) revealed a tendency of decreasing logBCF with an increase in conformational flexibility of molecules. They suggest that this effect is related to the enhancement of the entropy factor on membrane permeability of chemicals. This concludes a high probability that the substance may encounter the membrane in a conformation which does not enable the substance to permeate. Furthermore, the substance has a high molecular weight (> 600 g/mol for the smallest representative constituent, > 900 g/mol for the three other representative constituents). Thus, it is unlikely that it is readily absorbed, due to the steric hindrance of crossing biological membranes. Following the ‘rule of 5’ (Lipinski et al., 2001), developed to identify drug candidates with poor oral absorption based on criteria regarding partitioning (log Kow > 5) and molecular weight (> 500 g/mol), the substance is considered to be poorly absorbed after oral uptake (also see Hsieh & Perkins, 1976).

This interaction between lipophilicity, bioavailability and membrane permeability is considered to be the main reasons why the relationship between the bioaccumulation potential of a substance and its hydrophobicity is commonly described by a relatively steep Gaussian curve with the bioaccumulation peak approximately at log Kow of 6-7 (e.g., see Dimitrov et al., 2002; Nendza & Müller, 2007; Arnot and Gobas 2003). Substances with log Kow values above 10, which have been calculated for the test substance, are considered to have a low bioaccumulation potential (e.g., Nendza & Müller, 2007; 2010). Furthermore, for those substances with a log Kow value > 10 it is unlikely that they reach the pass level of being bioaccumulative according to OECD criteria for the PBT assessment (BCF > 2000; ECHA, 2017).

This assumption is supported by QSAR calculations using BCFBAF v3.01 performed for four representative individual constituents (see above) of Fatty acids lanolin, di, tri- and tetraesters with pentaerythritol and rape fatty acid. A value of 0.893 L/kg (BCF and BAF) was obtained for all four constituents using Arnot-Gobas estimate (including biotransformation, upper trophic). Values of 3.16-15.4 L/kg (BCF and BAF) were obtained using the regression-based approach. Even though Fatty acids lanolin, di, tri- and tetraesters with pentaerythritol and rape fatty acid is outside the applicability domain of the model, the estimation can be used as supporting indication of low bioaccumulation potential. The model training set consists only of substances with log Kow values of 0.31 - 8.70. However, it supports the tendency that substances with high log Kow values (> 10) have a lower potential for bioconcentration as summarized in the ECHA Guidance R.11 and they are not expected to meet the B/vB criterion (ECHA, 2017).

Conclusion

Fatty acids lanolin, di, tri- and tetraesters with pentaerythritol and rape fatty acid is characterized by a low water solubility (< 0.15 mg/L at 20 °C), high log Kow (> 10, KOWWIN v1.68) and high molecular weight (>600 g/mol). Based on the physico/chemical properties such as low water solubility and high potential for adsorption a reduced availability in water is expected. The high molecular weight of the substance significantly reduces the absorption due to steric hindrance to cross biological membranes. It can be concluded that the bioaccumulation potential of Fatty acids lanolin, di, tri- and tetraesters with pentaerythritol and rape fatty acid is negligible. BCF/BAF values estimated by QSAR (BCFBAF v3.01) also support this assumption (BCF values all well below 2000 L/kg).

Taking all these information into account, it can be concluded that bioaccumulation of Fatty acids lanolin, di, tri- and tetraesters with pentaerythritol and rape fatty acid is unlikely to occur.

A detailed reference list is provided in the CSR.