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Environmental fate & pathways

Bioaccumulation: aquatic / sediment

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Reference
Endpoint:
bioaccumulation in aquatic species: fish
Type of information:
(Q)SAR
Adequacy of study:
key study
Study period:
2021
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
Individual model BCFBAF included in the Estimation Programs Interface (EPI) Suite.

2. MODEL (incl. version number)
BCFBAF v3.01 included in EPISuite v 4.11, 2000 - 2015

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
The SMILES CODE (n(c(c(s1)ccc2)c2)c1SNC(CCCC3)C3) was entered in the initial data entry screen. An experimental determined log Kow value was provided prior to estimation.
A searchable database of CAS RNs and corresponding SMILES structures are provided within the KOWWIN program. CAS RNs are available for approximately 112,000 organic chemicals. If a CAS RN is not available, a SMILES notation can be directly entered by the user. Alternatively, logKow values can be manually entered if available. The correction factors are linked to the presence of certain structural fragments or functional groups.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
a. Defined endpoint: Bioconcentration factor (BCF). As a coefficient the logBCF is given without unit. The BCF can be given with L/kg wet wt.
b. Explicit algorithm (OECD Principle 2): The BCF is usually estimated from regression equations of the general form logBCF= a logKow + b, whereas a and b are empirically determined constants and Kow is the n octanol/water partition coefficient. Therefore, logBCF values for the non-ionic and ionics were plotted separately against the respective logKow values yielding a linear relationship for certain logKow ranges. Furthermore, compounds sharing certain structural features were identified resulting in residuals that were relatively consistent in sing and magnitude. On this basis several compound classes were identified that seemed amenable to derivation of correction factors.

Non-ionic compounds:
(i) For LogKow 1.0 to 7.0 the derived QSAR estimation equation is:
Log BCF= 0.6598 LogKow - 0.333 + Σ correction factors
(ii) For LogKow > 7.0 the derived QSAR estimation equation is:
Log BCF= -0.49 LogKow + 7.554 + Σ correction factors
(iii) For LogKow < 1.0 the derived QSAR estimation equation is:
All compounds with a logKow of less than 1.0 are assigned an estimated log BCF of 0.50.

Ionic compounds:
logKow < 5.0: log BCF= 0.50
logKow 5.0 to 6.0: log BCF= 0.75
logKow 6.0 to 7.0: log BCF= 1.75
logKow 7.0 to 9.0: log BCF= 1.00
logKow > 9.0: log BCF= 0.50

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.
Metals (tin and mercury), long chain alkyls and aromatic azo compounds require special treatment (see Meylan et al., 1999).
For ionic substances with long alkyl chains (≥ 11 carbons) a general log BCF of 1.85 was assigned by the program.

c. Applicability domain: The minimum and maximum values for molecular weight are the following:
Training Set Molecular Weight:
Minimum MW (Non-Ionic): 68.08
Maximum MW (Non-Ionic): 959.17
Average MW (Non-Ionic): 513.63

Minimum MW (Ionic): 102.13
Maximum MW (Ionic): 991.80
Average MW (Ionic): 546.97

The minimum and maximum values for logKow are the following:
Training Set logKow:
Minimum LogKow (Non-Ionic): -1.37
Maximum LogKow (Non-Ionic): 11.26

Minimum LogKow (Ionic): -6.50
Maximum LogKow (Ionic): 7.86

d. Statistics for goodness-of-fit:
number in dataset = 527
correlation coef (r^2) = 0.833
standard deviation = 0.502
average deviation = 0.382

e. Predictivity – Statistics obtained by external validation:
number in dataset = 158
correlation coef (r2) = 0.82
standard deviation = 0.59
average deviation = 0.46

f. Mechanistic interpretation: The BCF is an inherent property used to describe the accumulation of a substance dissolved in water by an aquatic organism. The BCFBAF program estimates BCF of an organic compound using the compound's log octanol-water partition coefficient (Kow).
Measured BCFs and other experimental details were collected and analysed to derive subsets of data on non-ionic, ionic, aromatic and azo compounds, tin and mercury compounds. Because of the deviation from rectilinearity, different models were developed for different log Kow ranges, and a set of 12 correction factors and rules were introduced to improve the accuracy of the BCF predictions.

g. The uncertainty of the prediction (OECD principle 4): The rules applied for estimating the BCF of N-cyclohexylbenzothiazole-2-sulphenamide appear appropriate. An individual uncertainty for the investigated substance is not available.

h. The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5): Not applicable.

i. Limits of applicability: Model predictions may be highly uncertain for chemicals that have estimated log KOW values > 9. The model is not recommended at this time for chemicals that appreciably ionize, for pigments and dyes, or for perfluorinated substances.

5. APPLICABILITY DOMAIN
a. Descriptor Domains:
i. log Kow: With a log Kow value of 5.0, the substance is within the range of the training set (Non-Ionics: -1.37 – 11.26/ Ionics: -6.50 – 7.86).
ii. Molecular weight: With a molecular weight of 264.41 g/mol the substance is within the range of the training set (Non-Ionics 68.08 – 959.17/ Ionics 102.13 – 991.80).
iii. Structural fragment domain: Not applicable as the BCF is not estimated on the basis of fragments.
iv. Mechanism domain: No information available
v. Metabolic domain: not relevant
b. Structural analogues: Not relevant as the BCF is not estimated based on structural fragments.

6. ADEQUACY OF THE RESULT
a. Regulatory purpose: The data may be used for regulatory purpose.
b. Approach for regulatory interpretation of the model result: If no experimental data are available, the estimated value may be used to fill data gaps needed for hazard and risk assessment.
c. Outcome: The estimation of the bioconcentration factor (BCF) yields a useful result for further evaluation.
d. Conclusion: The result is considered as useful for regulatory purposes.
Guideline:
other:
Version / remarks:
REACH guidance on QSARs R.6, May 2008
Principles of method if other than guideline:
Calculated with BCF Program BCFBAF v.3.01 included in the Estimation Programs Interface (EPI)-Suite. The estimation methodology is based on the chemical structure of an organic compound and its log octanol-water partition coefficient (log Kow). Depending on chemical structure, structural correction factors are applied.
GLP compliance:
no
Radiolabelling:
no
Test organisms (species):
other: none, estimated by calculation
Key result
Type:
BCF
Value:
924.7 L/kg
Basis:
other: calculation

Any decomposition of the substance in water is not considered by the program.


 


Validity of model:


- Defined endpoint: bioconcentration of a substance in biota


- Unambiguous algorithm: linear regression QSAR. Because of the deviation from rectilinearity, different models were developed for different log Kow ranges. Metals (tin and mercury), long chain alkyls and aromatic azo compounds are specially treated.


- Applicability domain: the model is applicable to ionic as well as non-ionic compounds. It is applicable to substances with a logKow in the following range: -6.50 to 7.86 (ionic compounds) and -1.37 to 11.26 (non-ionic compounds). Applicable to substances with a molecular weight in the following range: 102.13 to 991.80 g/mol (ionic substances) and 68.08 and 959.17 g/mol (non-ionic compounds). ). Model predictions may be highly uncertain for chemicals that have estimated logKow values > 9. The model is not recommended at this time for chemicals that appreciably ionize, for pigments and dyes, or for perfluorinated substances.


 


- Statistical characteristics:


number in dataset = 527


correlation coef (r2) = 0.833


standard deviation = 0.502


 


- Mechanistic interpretation: The BCF is an inherent property used to describe the accumulation of a substance dissolved in water by an aquatic organism based on the lipophilicity of the compound.


 


Adequacy of prediction: N-cyclohexylbenzothiazole-2-sulphenamide falls within the applicability domain described above and, therefore, the predicted value can be considered reliable taking into account that the standard deviation error of prediction of the external test set is 0.59 (logBCF). 


Considering that error, the predicted value is not above or close to the criterion to consider a substance as potential bioaccumulative.

Description of key information

A BCF of 924.7 l/kg is estimated on the basis of log Pow of 5 (experimental value) using the EPI Suite program, v.4.11 (Currenta, 2021). This is indicating that N-cyclohexylbenzothiazole-2-sulphenamide (CBS) is not bioaccumulative (BCF ≤2000 L/kg). The described metabolites of CBS, MBT, BT, BTon, MBTS, MeSBT and MeBT are not also not bioaccumulative (BCF<100).


 


In order to fulfill the information requirements especially for the PBT properties of CBS, the registrant proposes to perform a bioaccumulation test according to OECD guideline 305 dependent on the outcome of the assessment of the P criterion. For this reason, the Registrant has already proposed to first perform a simulation study in soil.
1. If the outcome of the preceding simulation test leads to the conclusion that CBS is P/vP, a bioaccumulation test shall be performed.
2. If the conclusion is not P/vP, a bioconcentration test shall not be performed.


 


Should establishing stable conditions for CBS not prove feasible owing to the hydrolytic behaviour of CBS, the test will be performed with a degradation product which is potentially found to be P/vP in the soil simulation test and if it fulfills the screening criterion for the B assessment.

Key value for chemical safety assessment

BCF (aquatic species):
925 L/kg ww

Additional information

EU risk assessment 2008 reported a BCF of 3094 l/kg estimated by the equation log BCF = 0.85 log Pow - 0.70 (Veith et. al, 1979) with a log Pow of 4.93. This estimation is not taken into accout in current assessment, due to its limited training sets with only 55 diverse chemicals and its probabaly too broad application range of log Pow. The BCFBAF v3.02 from EPIWIN v4.11 was used instead as the most updated estimation program with more than 400 training sets. On the other hand, considering the fast hydrolysis property of CBS and the low bioaccumulativity of the metabolites, N-cyclohexylbenzothiazole-2-sulphenamide (CBS) should not be taken as PBT candidate.