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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:
30 Jan - 3 Feb 2017
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
Qualifier:
according to
Guideline:
other: REACH guidance on QSARs, R.6, May/July 2008
Deviations:
no
Principles of method if other than guideline:
BCF base-line model v.02.09 implemented within OASIS Catalogic v5.11.17
GLP compliance:
no
Key result
Type:
BCF
Remarks on result:
not measured/tested
Remarks:
BCF estimate is based on a modeled value of log Kow which diverges from the measured value. Model supports lack of metabolism of the substance
Details on results:
3.1 Endpoint (OECD Principle 1):
a. Endpoint:
Bioconcentration factor (BCF) - the ratio of the chemical concentration in biota as a result of absorption
via the respiratory surface to that in the surrounding water at steady state.
Related predictions:
Maximum bioconcentration factor (BCFmax) - a theoretical bioconcentration for a given log Kow value
assuming that the only driving force of bioconcentration is lipophilicity and the effect of any other factors
is insignificant.
Apparent effect of mitigating factors
Maximum diameter of energetically stable conformers
Whole body primary biotransformation half-life
Metabolic biotransformation rate constant Km
Metabolites and their quantitative distribution
b. Dependent variable:
log BCF (L/kg wet weight)
3.2 Algorithm (OECD Principle 2):
a. Model or submodel name:
BCF base-line model
b. Model version:
v.02.09 - July2015
c. Reference to QMRF:
available in OASIS Catalogic v5.11.17
d. Predicted value (model result):
logBCF corrected 0.89 L/kg wet
Concomitant predictions :
logBCFmax = 1.116 L/kg wet
relative mitigating effect of Acids= 0.000
relative mitigating effect of Metabolism= 0.000
relative mitigating effect of Phenols= 0.000
relative mitigating effect of Size3= 0.611
relative mitigating effect of Watersolubility= 0.277
DiamMax Min value = 14.337 Å
DiamMax Max value = 24.099 Å
DiamMax Average = 18.414 Å
e. Predicted value (comments):
This value is based on a modeled value of log Kow which is not in accord with experimental results.
The model result is used to support lack of metabolism by organisms.
3.3 Applicability domain (OECD Principle 3):
a. Domain:
The applicability domain of the model consists of three layers:
• General properties requirements (log Kow, MW, WS)
• Structural domain (Atom Centered Fragments (ACFs))
• Mechanistic domain
Details can be found in:
• LMC QMRF BCF base-line model
• Dimitrov, S.; Dimitrova, G.; Pavlov, T.; Dimitrova, N.; Patlevisz, G.; Niemela, J.; Mekenyan, O. J. Chem.
Inf. Model. 2005, 45, 839-849.
•Dimitrov, S.; Dimitrova, N.; Georgieva, D.; , Vasilev, K.; Hatfield, T.; Straka, J.; Mekenyan, O. SAR QSAR
Environ. Res. 2011, 23, 7–36.
Log(Kow):
range = [ -4.05 .. 16.1 ]
calculated: 12.5 (In domain)
MOL._WEIGHT:
range = [ 16 .. 1130 ]Da
calculated: 950Da (In domain)
WaterSolubility_FR:
range = [ 0 .. 1000000 ]mg/L
calculated: 9.5E-7mg/L (In domain)
CONCLUSION:
The chemical fulfils the general properties requirements
ii. Structural fragment domain:
The following ACF are identified:
Fragments in correctly predicted training chemicals – 61.40%
Fragments in non-correctly predicted training chemicals – 10.53%
Fragments not present in the training chemicals – 28.07%
CONCLUSION:
The chemical is out of the interpolation structural space
iii. Mechanistic domain:
It is not expected that the uptake mechanism of the target chemical is passive diffusion across biological
membranes.
CONCLUSION:
The chemical is out of the mechanistic domain of the model.
b. Structural analogues:
The model training set does not contain appropriate structural analogs
3.4 The uncertainty of the prediction (OECD principle 4):
The model predicts an uncertainty of 0.11 for the predicted value
3.5 The chemical and biological mechanisms according to the model underpinning
the predicted result (OECD principle 5):
The model calculates a basic, maximum BCF value based on a diffusion limited model determined by
log Kow. The model then applies correction factors based on water solubility, molecular size, and
metabolisms. Two additional factors relate to highly polar/ionizable compounds and are not applicable
to the modeled compound.
Validity criteria fulfilled:
not applicable
Conclusions:
Metabolism is not expected to impact potential for bioaccumulation of this substance. The calculated average Dmax across conformers is 18.4 Å (range, 14.3 - 24.1 Å)
Executive summary:

The BCF base-line model v.02.09 within Catalogic v5.11.17 was used to model BCF for this substance. The model calculates a maximum BCF based on log Kow and applies correction factors for metabolism, molecular size, water solubility, and two other factors not relevant to this structure. The estimated log Kow used to calculate baseline BCF diverges from the log Kow value derived from an experimental water solubility:octanol solubility ratio, and therefore the predicted BCF is not reported. However, the model reports an average calculated Dmax across multiple conformers of 18.4 Å, and further supports lack of metabolic impact on potential bioaccumulation of the substance. Given this, the model is considered reliable with restrictions and can be used to support other arguments regarding bioaccumulation.

Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
weight of evidence
Study period:
1-6 Feb 2017
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Calculation using accepted method
Qualifier:
no guideline available
Principles of method if other than guideline:
Quantum chemical calculation using Spartan 2.0
GLP compliance:
no
Key result
Remarks on result:
not measured/tested
Remarks:
software calculates molecular geometry and energy levels, rather than BCF.

  Results after geometry optimization at DFT/6-31G(*) level (gas phase):
 Conformer index  Structure 1  Structure 2  Structure 3  Structure 4  Structure 5
 E (kCal/mole)  -2835636.74  -2835636.99  -2835637.18  -2835637.18  -2835637.18
 Dmax (nm)  2.19  1.74  1.51  1.52  1.41
 Result  linear, most favorable        least favorable


The gas-phase reorganization energies are within the range of bond rotation of a methyl group eclipsing another methyl group. However, conformational reorganization of dissolved substances involves the reorganization of the solvation sphere surrounding the molecule in addition to the conformational change of the molecule itself. In thermodynamic terms, the energy required to reorganize a structure is the sum of the gas phase reorganization energy plus the energy required to reorganize the water solvation sphere. Bending the molecule moves three to four waters per carbon, with an energy requirement far higher than the rotational energies presented above (1). For this reason, alkanes up to 16 carbons in length remain linear in water (2). Structure 1, with a Dmax of 2.19 nm, is the most favorable.

1. Mountain, R.D.; Thirumalai, D. Hydration Sphere for a Series of Hydrocarbons, Proc. Natl. Acad. Sci., 95, 1998, 8436

2. Ferguson, A.L.; Debeneditti, P.G.; Panaglotopoulos, A.Z. Solubilty and Molecular conformations of n-Alkane Chains in Water, J. Phys. Chem. B, 113, 2009, 6405

Validity criteria fulfilled:
not applicable
Conclusions:
TFEE-5 has a Dmax of 2.19 nm for its most favorable structure in water.
Executive summary:

Molecular conformation and energy levels for TFEE-5 were calculated using SPARTAN v2.0, an ab initio quantum chemical calculation program. After generation and optimization of structures, the most energetically favorable is the linear structure having a Dmax of 2.19 nm. Other conformations have a Dmax ranging from 1.74 down to 1.41 nm, in decreasing order of favorability. Conformational shifts away from linearity in solution are expected to be inhibited by the energy requirements of solvent sphere rearrangement. The software is a commonly-accepted tool used in quantum chemical research, with basis set universally defined for all atoms. The resulting variable, Dmax and conformation energy, speak to the ability or lack thereof for a molecule in a certain conformation to pass a membrane, and to remain in that conformation. The results are therefore deemed reliable with restriction and suitable for use in a weight of evidence argument on bioaccumulation.

Description of key information

TFEE-5 is not expected to bioaccumulate.

Key value for chemical safety assessment

Additional information

TFEE-5 is a large and almost completely perfluorinated polyether. TFEE-5 is not ionic, it is not a surfactant, and, therefore, studies and properties of perfluochemical acids and sulfonates should not be equated to TFEE-5. Rather, TFEE-5 must be evaluated using the best available data on this extremely hydrophobic chemistry.

The adsorption and excretion of TFEE-5 was investigated (see section Toxicokinetics, metabolism, and distribution: basic toxicokinetics) in a single dose study (907 mg/kg, oral gavage) in male Sprague Dawley rats, where it was determined that all of the administered dose was recovered in the feces. The complete recovery indicates that TFEE-5 was not taken up from the digestive tract. It is widely understood that if a substance is not taken up by mammals, then it is also likely that the substance will not easily pass across fish gill membranes and therefore may not have a high bioconcentration factor (BCF) in fish (1). Support for this conclusion, the total lack of transport from the digestive tract, is provided by examinations of molecular size using both SPARTAN molecular modeling (an ab initio quantum mechanical calculation) and OASIS Catalogic (CATABOL), which demonstrate that TFEE-5 is too large to cross biological membranes. Spartan calculated that the lowest energy conformer had a Dmax of 2.18 nm followed by a molecule with a Dmax 1.74 nm. Three additional and energetically unfavorable conformers were found with Dmax values ranging from 1.40-1.52 nm. Estimations of the molecular size using the ECHA recommended Catalogic software showed an average Dmax of 1.81 nm (range, 1.43 - 2.41 nm). The two calculated values are in substantive agreement despite using different calculation methodologies. Using the guidance value of 1.7 nm as the limit for transport through membranes (1), we conclude that TFEE-5 exists in stable conformation(s) that are too large to pass through biological membranes and will therefore not bioconcentrate. BCF modeling using Catalogic showed little potential for TFEE-5 to bioconcentrate. However, that estimate utilized an EPISuite calculation for the log Kow which is higher than the key study log Kow value estimated using the solubilities of TFEE-5 in water-saturated octanol and octanol-saturated water (see section Physical and chemical properties: partition coefficient). The bioconcentration data from Catalogic should be treated as indicative rather than definitive. We therefore conclude TFEE-5 is not bioconcentrating in fish.

1) ECHA. 2014. Guidance on Information Requirements and Chemical Safety Assessment Chapter R.11: PBT/vPvB assessment Version 2.0