Reaction products of N6,N6'-hexane-1,6-diylbis[N2,N4-dibutyl-N2,N4,N6-tris(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4,6-triamine] and allylbromide, subsequently reacted with ethaneperoxoic acid, hydrogenated

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018

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
OASIS Catalogic v5.12.1

2. MODEL (incl. version number)
BCF base-line model v02.09 - July 2016

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See section 'Test Material'.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF.

5. APPLICABILITY DOMAIN
See attached QPRF.

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QMRF).
- The model estimates the Bioconcentration factor (BCF) as required information point according to Regulation (EC) No 1907/2006 [REACH], Annex IX, 9.3.2 Bioaccumulation in aquatic species (preferably fish);
further related predictions: Apparent effect of mitigating factors / Maximum bioconcentration factor (BCFmax) / Maximum diameter of energetically stable conformers / Whole body primary biotransformation half-life / Metabolic biotransformation rate constant Km / Metabolites and their quantitative distribution
- See attached QPRF for reliability assessment.

Principles of method if other than guideline:

Calculation using Catalogic v.5.12.1, BCF base-line model v.02.09

GLP compliance:

no

Details on estimation of bioconcentration:

BASIS FOR CALCULATION OF BCF
- Estimation software: OASIS Catalogic v5.12.1 [BCF base line model - v.02.09]

Key result

Type:

BCF

Value:

7.4 L/kg

Remarks on result:

other: considering all mitigating factors; the substance is not within the applicability domain of the model.

Type:

BCF

Value:

9.2 L/kg

Remarks on result:

other: without considering any mitigating factors; the substance is not within the applicability domain of the model.

Reference 2

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018

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
OASIS Catalogic v5.12.1

2. MODEL (incl. version number)
BCF base-line model v02.09 - July 2016

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See section 'Test Material'.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF.

5. APPLICABILITY DOMAIN
See attached QPRF.

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QMRF).
- The model estimates the Bioconcentration factor (BCF) as required information point according to Regulation (EC) No 1907/2006 [REACH], Annex IX, 9.3.2 Bioaccumulation in aquatic species (preferably fish);
further related predictions: Apparent effect of mitigating factors / Maximum bioconcentration factor (BCFmax) / Maximum diameter of energetically stable conformers / Whole body primary biotransformation half-life / Metabolic biotransformation rate constant Km / Metabolites and their quantitative distribution
- See attached QPRF for reliability assessment.

Principles of method if other than guideline:

Calculation using Catalogic v.5.12.1, BCF base-line model v.02.09

GLP compliance:

no

Details on estimation of bioconcentration:

BASIS FOR CALCULATION OF BCF
- Estimation software: OASIS Catalogic v5.12.1 [BCF base line model - v.02.09]

Key result

Type:

BCF

Value:

7.6 L/kg

Remarks on result:

other: considering all mitigating factors; the substance is not within the applicability domain of the model.

Type:

BCF

Value:

11.9 L/kg

Remarks on result:

other: without considering any mitigating factors; the substance is not within the applicability domain of the model.

Reference 3

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2018

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
OASIS Catalogic v5.12.1

2. MODEL (incl. version number)
BCF base-line model v02.09 - July 2016

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See section 'Test Material'.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF.

5. APPLICABILITY DOMAIN
See attached QPRF.

6. ADEQUACY OF THE RESULT
- The model is scientifically valid (see attached QMRF).
- The model estimates the Bioconcentration factor (BCF) as required information point according to Regulation (EC) No 1907/2006 [REACH], Annex IX, 9.3.2 Bioaccumulation in aquatic species (preferably fish);
further related predictions: Apparent effect of mitigating factors / Maximum bioconcentration factor (BCFmax) / Maximum diameter of energetically stable conformers / Whole body primary biotransformation half-life / Metabolic biotransformation rate constant Km / Metabolites and their quantitative distribution
- See attached QPRF for reliability assessment.

Principles of method if other than guideline:

Calculation using Catalogic v.5.12.1, BCF base-line model v.02.09

GLP compliance:

no

Details on estimation of bioconcentration:

BASIS FOR CALCULATION OF BCF
- Estimation software: OASIS Catalogic v5.12.1 [BCF base line model - v.02.09]

Type:

BCF

Value:

>= 7.4 - <= 23.4 L/kg

Remarks on result:

other: Metabolites from the main component. Considering all mitigating factors; only the smaller metabolites could be predicted. The substances are not within the applicability domain of the model.

Type:

BCF

Value:

>= 7.4 - <= 36.3 L/kg

Remarks on result:

other: Metabolites from the small alkylated side component. Considering all mitigating factors. The substances are not within the applicability domain of the model.

Type:

BCF

Value:

>= 7.4 - <= 263 L/kg

Remarks on result:

other: Metabolites from the small side component OH. Considering all mitigating factors. The substances are not within the applicability domain of the model.

Description of key information

Significant accumulation in organisms is not to be expected. Neither the components of the UVCB substance nor their relevant degradation products are expected to significantly accumulate in organisms.

Additional information

For the assessment of the bioaccumulative potential of the UVCB compound several lines of evidence have been considered in a weight-of-evidence approach. Both the substance itself and its possible degradation products have been considered.

 

Assessment for the substance itself

The substance is a UVCB and mainly consists of two 1,3,5-triazine-2,4,6-triamine groups connectedviaan alkyl chain and exhibiting six piperidine groups. The degree of O-alkylation is 84.9%. Individual components cannot be characterized and no purity of the single constituents can be given. The main constituent (fully O-alkylated) has a molecular weight of 1742 g/mol. Besides O-alkylation the amino groups can also be unsubstituted or substituted with OH-groups. Therefore, depending on the substitution, the molecular weight ranges between 1409 and 1742 g/mol. Besides these main components, constituents consisting of only one triazine-triamine group are present with differing degrees of O-alkylation. These constituents have molecular weights ranging from 785 to 886 g/mol.

The assessment of the bioaccumulative potential of the UVCB compound combined several lines of evidence for three representative structures. (1) The fully alkylated main component, (2) the fully alkylated constituent with one triazine-triamine group, and (3) the constituent with one triazine-triamine group constituted with OH groups. The structures are representative for the entire UVCB and have been chosen according to the results of the substance characterization and as worst case. Details of the structures can be found in Table 1.

If possible, QSAR estimations with Catalogic v5.12.1, BCF base-line model v.02.09 have been conducted. However, as the larger constituents are high-molecular weight substances a prediction was not always possible because the compounds did not fit into the QSAR tool. The following lines of evidence have been considered in the weight-of-evidence approach.

1.   QSAR estimation with Catalogic v5.12.1, BCF base-line model v.02.09 (if available)

2.   logKow

3.   molecular weight

4.   average maximum diameter (Dmax aver; if available)

 

Table 1: Representative structures of the UVCB compounds assessed in a weight-of-evidence approach.

No.	SMILES codes
1	CCCCN(C1CC(C)(C)N(OCCC)C(C)(C)C1)c2nc(nc(n2)N(CCCCCCN(C3CC(C)(C)N(OCCC)C(C)(C)C3)c4nc(nc(n4)N(CCCC)C5CC(C)(C)N(OCCC)C(C)(C)C5)N(CCCC)C6CC(C)(C)N(OCCC)C(C)(C)C6)C7CC(C)(C)N(OCCC)C(C)(C)C7)N(CCCC)C8CC(C)(C)N(OCCC)C(C)(C)C8
2	CCCCN(C1CC(C)(C)N(OCCC)C(C)(C)C1)c2nc(nc(n2)N(CCCC)C3CC(C)(C)N(OCCC)C(C)(C)C3)N(CCCC)C4CC(C)(C)N(OCCC)C(C)(C)C4
3	CCCCN(C1CC(C)(C)N(O)C(C)(C)C1)c2nc(nc(n2)N(CCCC)C3CC(C)(C)N(OCCC)C(C)(C)C3)N(CCCC)C4CC(C)(C)N(O)C(C)(C)C4

 

 

The principal assessment of the bioaccumulative potential of the UVCB compound has been conducted with the low molecular weight constituents as the main components (molecular weight from 1409 to 1742 g/mol) are two bulky to fit in the QSAR tool. This approach is considered as worst case as the smaller molecules are significantly more bioavailable and have a higher capacity to pass biological membranes. Nevertheless, all available data (also of the high-molecular weight constituents) have been considered in the weight-of-evidence approach. Table 2 gives an overview of the constituents and their relevant parameters.

 

Table 2: Results of the representative constituents.

No.	BCF: Catalogic v5.12.1, BCF base-line model v.02.09	logKow [calculated]	Molecular weight [g/mol]	Dmax aver [nm]	Remarks
1	n/a	31.34	1742	n/a expected to be significantly larger than components #2 and 3.	Does not fit into the model.
2	7.4 (9.2)	16.3	886	2.3	Inside the parameter domain Outside the structural domain Inside the mechanistic domain.
3	7.6 (11.9)	12.7	802	2.0	Inside the parameter domain Outside the structural domain Inside the mechanistic domain.

 

The BCF base-line model v.02.09 integrated in OASIS Catalogic v5.12.1 reflects the current understanding of the process by which lipophilic organic chemicals are bioaccumulated in fish through the respiratory organs only. Chemicals bioaccumulating by other mechanisms (e.g., binding to proteins) are considered out of the mechanistic domain of the model. The model consists of two major components: a model for predicting the maximum potential for bioaccumulation based solely on chemicals’ lipophilicity (i.e., BCFmax model), and a set of mitigating factors that account for the reduction of the bioaccumulation potential of chemicals based on chemical (e.g., molecular size and ionization) and organism-dependent factors (e.g., metabolism). BCFmax model is a theoretical model based on the assumption that the only driving force of bioconcentration is lipophilicity and the effect of any other factors are insignificant. It mathematical formalism is derived considering multi-compartment diffusion. The bioconcentration predicted by BCFmax model could be limited by variety of mitigating factors that account for the reduction of the bioaccumulation potential of chemicals based on chemical and organism-dependent factors. The effect of mitigating factors mathematically is quantified by probabilities: to penetrate through the cell membrane, to be ionized, to be metabolized etc. In the BCF base-line model the tissue metabolism simulator is used to account for the effect of metabolism. It consists of a consequence of spontaneous abiotic and enzyme controlled steps. Probabilities of these molecular transformations are assessed by fitting the training set data. The CATALOGIC platform utilizes a multi-stage applicability domain that has been described by Dimitrov et al. (2005). The applicability domain of the BCF base-line model contains three layers: (1) General properties requirements. These requirements specify in the domain only those chemicals that fall in the range of variation of physicochemical properties that may affect significantly the quality of the measured endpoint. For the BCF base-line model attention is focused on lipophilicity (log KOW), molecular weight (MW) and water solubility (WS). Only correctly predicted chemicals from the training set are used to determine the range of variation of these properties. (2) The structural domain. It determines the maximum structural similarity between the target chemical and chemicals from the training set. The structural neighborhood of atom-centered fragments (ACF) accounting for 1st neighbors, atom type, hybridization and attached hydrogen atoms are used to determine this similarity. The target chemical could contain the following types of ACF:

-      Fragments present in correctly predicted training chemicals only (i.e. correct fragments)

-      Fragments found both in correctly and non-correctly predicted training chemicals (i.e. fuzzy fragments). These fragments are treated as correct fragments

-      Fragments present in non-correctly predicted training chemicals only (i.e. incorrect fragments),

-      Fragments not present in the training chemicals (i.e. unknown fragments).

(3) The mechanistic domain.It discriminates between modes of bioaccumulation - passive (partitioning in lipid phase) or active (based on protein binding). Only chemicals with expected passive diffusion driven bioaccumulation are considered to be in the mechanistic domain of the model.

In the present case, component #1 does not fit into the model due to its size. It cannot be predicted by the model. Components #2 and 3 fulfill the general properties requirements, i.e. their logKow, molecular weight and water solubility are within the ranges of the model. Furthermore, they are within the mechanistic domain, i.e. they are expected to be taken up by passive diffusion only. However, they are not in the structural domain. Around 69% of the fragments could be found in correctly predicted training set chemicals. The remaining fragments are not present in the training set chemicals. If a chemical is out of at least one of the specified layers mentioned above, it will be classified as out of the applicability domain. This classification means that the prediction falls in the extrapolation space but the prediction still could be reliable. The estimated BCFs for components #2 and 3 (all mitigating factors applied) were determined to be 7.4 and 7.6 L/kg, respectively. 

Although components #2 and 3 are not within the applicability domain of the model, the results are in line with the additional information (extremely high logKow, high molecular weight and large Dmax aver indicating low bioaccumulative potential) and therefore adequate for the use in a weight-of-evidence approach.

According to ECHA’s Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.11: PBT/vPvB assessment information on molecular size can be an indicator to strengthen the evidence for a limited bioaccumulation potential of a substance. Very bulky molecules will less easily pass the cell membranes. This results in a reduced BCF of the substance. The DiamMax-Average for the smallest component is already 2.0 nm and the molecular weight 802 g/mol. This is clear evidence of a low bioaccumulative potential which is reflected by the QSAR prediction of the BCF. The DiamMax-Average of the main component is unknown as it does not fit into the respective modelling tools. However, as it is significantly bigger than the small component, i.e. significantly larger than 2.0 nm, its capacity to pass cell membranes is expected to be negligible and a significant potential to bioaccumulate is not expected. 

The logKow is another indicator of the bioaccumulative potential. According to ECHA’s Guidance R.11 the aquatic BCF of a substance is probably lower than 2000 L/kg if the calculated logKow is higher than 10. For the smaller components the calculated logKow values are 12.7 and 16.33 (calculated within Catalogic). It can therefore be assumed that the small components have a BCF below 2000 L/kg. For the main component the calculated logKow is 31.34. Therefore, the main component is expected to have a BCF below 2000 L/kg.

In summary, none of the representative components are expected to pass cell membranes to a significant extent due to their sizes and weights. Therefore, their BCF values are expected to be below 2000 L/kg.

 

Assessment for the degradation products

In addition to the representative components of the UVCB compound, their relevant degradation products were assessed. The degradation products were identified with Catalogic v5.12.1, CATALOGIC 301 C v10.14 and filtered for quantity and logKow. Only metabolites with a quantity≥0.1% and a logKow≥4.0 were assessed. The logKow threshold of 4.0 instead of 4.5 which is the B screening criterion was chosen to avoid borderline cases. A complete list of the metabolites can be found in the summary of IUCLID chapter 5.2.1 and in the QPRF documents attached to the endpoint study records of IUCLID chapter 5.3.1.

Degradant of component #1

As most of the metabolites of component #1 are also too large to fit into the model, no BCF prediction was possible. However, due to their size and logKow values significant accumulation is not expected. For the smaller metabolites of component #1 the BCF values ranged from 7.4 to 23.4. According to these results, no significant accumulation is expected and the degradant of component #1 are not expected to fulfill the B criterion.

Degradants of component #2

The BCF values of the degradants of component #2 range from 7.4 to 36.3. Their average maximum diameter ranges from 1.7 to 1.8 nm. According to these results a significant accumulation is not expected. The B criterion is not expected to be fulfilled for any of the degradants.

Degradants of component #3

The BCF values of the degradants of component #3 range from 7.4 to 263. Their average maximum diameter ranges from 1.7 to 1.9 nm. According to these results a significant accumulation is not expected. The B criterion is not expected to be fulfilled for any of the degradants.

 

Overall conclusion

Neither the UVCB compound (its components) nor the degradants are expected to significantly accumulate in organisms. The components are too bulky to pass biological membranes.