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Bioaccumulation: aquatic / sediment

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Reference
Endpoint:
bioaccumulation: aquatic / sediment
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 and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
EPIWIN software by US-EPA

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

3. SMILES
CCOc1ccc2NC(C)(C)C=C(C)c2c1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Bioconcentration Factor (BCF)

- The measured BCF values used in the revised regressions were selected from a quality reviewed BCF database (Arnot and Gobas, 2006); details of the data quality review methods are described in Arnot and Gobas (2006). Single BCF values were selected for each compound (median values were generally selected for compounds with multiple values).
The BCF values selected for the BCFBAF training and validation datasets are available via Internet download at:
http://esc.syrres.com/interkow/EpiSuiteData.htm ... A substructure searchable version of the data can be downloaded at: http://esc.syrres.com/interkow/EpiSuiteData_ISIS_SDF.htm

The BCFBAF method classifies a compound as either ionic or non-ionic.  Ionic compounds include carboxylic acids, sulfonic acids and salts of sulfonic acids, and charged nitrogen compounds (nitrogen with a +5 valence such as quaternary ammonium compounds).  All other compounds are classified as non-ionic.
Training Dataset Included:
  466 Non-Ionic Compounds
  61  Ionic Compounds (carboxylic acids, sulfonic acids, quats)

Methodology for Non-Ionic was to separate compounds into three divisions by Log Kow value as follows:
  Log Kow  <  1.0
  Log Kow  1.0  to  7.0
  Log Kow  > 7.0

For each division, a "best-fit" straight line was derived by common statistical regression methodology. The regression methodology includes derivation of correction factors based on specific structural features. Non-ionic compounds are predicted by the following relationships:

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)

Certain super-hydrophobic chemicals (Log Kow >7.0) selected from the empirical database had reported BCF values with measured water concentrations that exceed water solubility limits. These BCF values were corrected based on estimates of water solubility limits (Arnot and Gobas, 2006).

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 (same as in BCFWIN).

Ionic compounds are predicted as follows:

  log BCF  =  0.50    (log Kow  <  5.0)
  log BCF  =  1.00    (log Kow  5.0 to 6.0)
  log BCF  =  1.75    (log Kow  6.0 to 8.0)
  log BCF  =  1.00    (log Kow  8.0 to 9.0)
  log BCF  =  0.50    (log Kow   >  9.0)

- Defined domain of applicability:
The minimum and maximum values for molecular weight and logKow are listed below. Currently there is no universally accepted definition of model domain. However,the possibility should be considered that bioconcentration factor estimates are less accurate for compounds outside the MW and logKow ranges of the training set compounds, and/or that have more instances of a given correction factor 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. In the latter case, predictions are based on molecular weight alone.

Training Set (527 Compounds):
Molecular Weight:
 Minimum MW:  68.08  (Furan)
 Maximum MW:  991.80   Ionic: (2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3,6-
            bis[[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]azo]-, tetrasodium salt)
 Maximum MW:  959.17   Non-Ionic: (Benzene, 1,1 -oxybis[2,3,4,5,6-pentabromo-)
Average MW:  244.00

Log Kow:
 Minimum LogKow:  -6.50   Ionic: (2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3,6-bis[[4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]azo]-, tetrasodium salt)
 Minimum LogKow:  -1.37   Non-Ionic: (1,3,5-Triazine-2,4,6-triamine)
 Maximum LogKow:  11.26 (Benzenamine, ar-octyl-N-(octylphenyl)-)

5. APPLICABILITY DOMAIN
- The substance is non-ionic
- The substance is within the MW range (217.31)
- The substance is within the logPow range (3.39)
- Maximum number of instances of correction factor in any of the training set compounds not exceeded (no corrections)
-> applicability domain fulfilled

6. ADEQUACY OF THE RESULT
The organic substance Quinoline, 6-ethoxy-1,2-dihydro-2,2,4-trimethyl- lies within the applicability domain as shown under 5. Hence, the result seems reasonable and is considered as adequate and acceptable to use this result for risk assessment purposes.
Reference:
Composition 0
Guideline:
other: REACH guidance on QSARs Chapter R.6
Version / remarks:
May 2008
Principles of method if other than guideline:
The BCFBAF Program is an update and expansion of the previous BCFWIN Program that was part of the EPI Suite version 3.20. The update pertains to estimation of Bioconcentration Factor (BCF). The BCFBAF program estimates BCF of an organic compound using the compound's log octanol-water partition coefficient (Kow). For the update, a more recent and better evaluated database of BCF values was used for both training and validation.  The BCF data were re-regressed using the same methodology as in the original BCFWIN program.
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 methodology is described in the Bioconcentration Factor Estimation section.
BCFBAF has been expanded to include estimation of the Biotransformation Rate (kM) in fish and estimation of Bioaccumulation Factor (BAF) by the Arnot-Gobas method (Arnot and Gobas, 2003).
GLP compliance:
no
Remarks:
(not applicable)
Test material information:
Composition 1
Specific details on test material used for the study:
SMILES: CCOc1ccc2NC(C)(C)C=C(C)c2c1
Test organisms (species):
other: Fish, not further specified
Route of exposure:
other: estimated value
Test type:
other: QSAR
Water / sediment media type:
natural water: freshwater
Reference substance (positive control):
not required
Remarks:
(not applicable)
Details on estimation of bioconcentration:
The estimation for the Bioconcentration factor of the test material was performed with US-EPA software EPWIN/BCFBAF v3.01. The BCFBAF program estimates BCF of an organic compound using the compound's log octanol-water partition coefficient (Kow). BCFBAF has been expanded to include estimation of the Biotransformation Rate (kM) in fish and estimation of Bioaccumulation Factor (BAF) by the Arnot-Gobas method (Arnot and Gobas, 2003).
Type:
BCF
Value:
167.3 L/kg
Basis:
whole body w.w.
Remarks on result:
other: Regression-based estimate
Type:
BCF
Value:
455.8 L/kg
Basis:
whole body w.w.
Remarks on result:
other: Arnot-Gobas method, based on mechanistic first principles
Details on kinetic parameters:
Not applicable
Metabolites:
Not applicable
Results with reference substance (positive control):
Not applicable
Details on results:
--------------------------------- BCFBAF v3.01 --------------------------------
Summary Results:
Log BCF (regression-based estimate): 2.22 (BCF = 167 L/kg wet-wt)
Biotransformation Half-Life (days) : 2.58 (normalized to 10 g fish)
Log BAF (Arnot-Gobas upper trophic): 2.66 (BAF = 457 L/kg wet-wt)

Biotransformation Rate Constant:
kM (Rate Constant): 0.2683 /day (10 gram fish)
kM (Rate Constant): 0.1509 /day (100 gram fish)
kM (Rate Constant): 0.08486 /day (1 kg fish)
kM (Rate Constant): 0.04772 /day (10 kg fish)

Arnot-Gobas BCF & BAF Methods (including biotransformation rate estimates):
Estimated Log BCF (upper trophic) = 2.659 (BCF = 455.8 L/kg wet-wt)
Estimated Log BAF (upper trophic) = 2.660 (BAF = 456.9 L/kg wet-wt)
Estimated Log BCF (mid trophic) = 2.580 (BCF = 380 L/kg wet-wt)
Estimated Log BAF (mid trophic) = 2.585 (BAF = 384.8 L/kg wet-wt)
Estimated Log BCF (lower trophic) = 2.545 (BCF = 350.9 L/kg wet-wt)
Estimated Log BAF (lower trophic) = 2.560 (BAF = 363 L/kg wet-wt)

Arnot-Gobas BCF & BAF Methods (assuming a biotransformation rate of zero):
Estimated Log BCF (upper trophic) = 2.893 (BCF = 781.9 L/kg wet-wt)
Estimated Log BAF (upper trophic) = 3.186 (BAF = 1535 L/kg wet-wt)
Reported statistics:
Not applicable
Validity criteria fulfilled:
yes
Remarks:
(Scientifically accepted calculation method.)
Conclusions:
The study report describes a scientifically accepted calculation method for the Bioconcentration factor estimation using the US-EPA software BCFBAF v3.01. No GLP criteria are applicable for the usage of this tool and the QSAR estimation is easily repeatable. The result (regression based estimated BCF = 167 L/kg wet-wt; Arnot-Gobas method based estimate BCF (higher trophic level) = 455.8 L/kg wet-wt) is adequate for the regulatory purpose.
Executive summary:

The prediction for the bioconcentration factor (BCF) of the test substance was determined by the computer program BCFBAF v3.01 (EPIWIN software) by US-EPA . Furthermore the whole body primary biotransformation rate estimation for fish was calculated with the notation that the bio half-life normalized to 10 g fish at 15 °C. It is possible to predict the apparent metabolism half-life in fish for three different trophic levels (lower, mid and upper). In general, the bioconcentration factor of a substance describes the accumulation potential of a substance dissolved in water by an aquatic organism. BCFBAF v3.01 calculates also the BAF (Bioaccumulation factor) of the chemical, which is defined as the steady-state (equilibrium) ratio of the substance concentration in an organism to the concentration in the surrounding medium. However, this value is not taken into account for the risk assessment and is not relevant for a registration under REACH Regulation (EC) 1907/2006.

Using the regression-based estimate (traditional method) a BCF of 167 L/kg wet-wt was calculated. Using the Arnot-Gobas method, which is based on the mechanistic first principles, the BCF results in a value of 455.8 L/kg wet-wt (upper trophic). The whole body primary biotransformation rate estimate for fish gives a half-life of 2.583 days, whereby the rate constant (kM) for 10 g fish is designated as 0.2683/day. This is taken into account to predict the apparent metabolism half-life in fish for the substance. For the lower trophic level a BCF of 350.9 L/kg wet-wt is calculated, whereas for the mid trophic level the BCF will result in 380 L/kg wet-wt and the upper trophic level gives a value of 455.8 L/kg wet-wt.

All values are below the lowest BCF value regarded as critial during the PBT Assessment (B criteria BCF ≥ 500; vB criteria: BCF ≥2000).

Description of key information

BCF Calculation with BCFBAF v3.01 (EPIWIN software by US-EPA): 167 L/kg wet wt (regression based estimate); 455.8 (Arnot-Gobas method, including biotransformation rate estimates, upper trophic level)

Key value for chemical safety assessment

BCF (aquatic species):
455.8 L/kg ww

Additional information

The prediction for the bioconcentration factor (BCF) of the test substance was determined by the computer program BCFBAF v3.01 (EPIWIN software) by US-EPA . Furthermore the whole body primary biotransformation rate estimation for fish was calculated with the notation that the bio half-life normalized to 10 g fish at 15 °C. It is possible to predict the apparent metabolism half-life in fish for three different trophic levels (lower, mid and upper).

Using the regression-based estimate (traditional method) a BCF of 167 L/kg wet-wt was calculated. Using the Arnot-Gobas method, which is based on the mechanistic first principles, the BCF results in a value of 455.8 L/kg wet-wt (upper trophic). The whole body primary biotransformation rate estimate for fish gives a half-life of 2.583 days, whereby the rate constant (kM) for 10 g fish is designated as 0.2683/day. This is taken into account to predict the apparent metabolism half-life in fish for the substance. For the lower trophic level a BCF of 350.9 L/kg wet-wt is calculated, whereas for the mid trophic level the BCF will result in 380 L/kg wet-wt and the upper trophic level gives a value of 455.8 L/kg wet-wt.

Even the highest value is below the lowest BCF value regarded as critial during the PBT Assessment (B criteria BCF ≥ 500; vB criteria: BCF ≥2000).