Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate

Bioaccumulation: aquatic / sediment

Description of key information

Accumulation of the substance in organisms is not to be expected due to the log Kow of 0.35 and the Epi Suite calculation for the BCF of 197,1 L7kg ww..

Key value for chemical safety assessment

BCF (aquatic species):

197.1 L/kg ww

Additional information

QSAR-disclaimer:

In Article 13 of Regulation (EC) No 1907/2006, it is laid down that information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI (of the same Regulation) are met. Furthermore, according to Article 25 of the same Regulation testing on vertebrate animals shall be undertaken only as a last resort.

According to Annex XI of Regulation (EC) No 1907/2006 (Q)SAR results can be used if (1) the scientific validity of the (Q)SAR model has been established, (2) the substance falls within the applicability domain of the (Q)SAR model, (3) the results are adequate for the purpose of classification and labeling and/or risk assessment and (4) adequate and reliable documentation of the applied method is provided.

For the assessment of Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (CAS 52829-07-9) (Q)SAR results were used for aquatic bioaccumulation. The criteria listed in Annex XI of Regulation (EC) No 1907/2006 are considered to be adequately fulfilled and therefore the endpoint(s) sufficiently covered and suitable for risk assessment.

Therefore, and for reasons of animal welfare, further experimental studies on aquatic bioaccumulation are not provided.

Assessment:

In accordance with column 2 of REACH Annex IX, the study need not be conducted since the substance has a log Kow ≤ 3. The estimation model CATALOGIC BCF base-line model v03.10 (OASIS Catalogic v5.13.1) calculated for the parent compound Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (CAS 52829-07-9) a log Kow of 6.5, while in a test according to OECD 107 a log Kow of 0.35 at pH 7 was measured (BASF SE 1988, see IUCLID Ch. 4.7). However, the substance is predominantly positively charged at environmentally relevant pH conditions (pKa = 9.5 – 11 at 25°C, see IUCLID Ch. 4). Since the substance occurs as charged species in aqueous media at environmentally relevant pH (pH 4-9), all results for physico-chemical properties and environmental fate that were obtained by QSAR modeling have to be regarded with caution because the calculations only consider the uncharged species which occurs only under high pH conditions (pH > 10). Therefore, the experimental log Kow value of 0.35 is considered to be more accurate for the environmental conditions (pH 4 – 9), thereby identifying a low potential for accumulation in aquatic organisms.

Moreover, in order to assess the bioaccumulation potential of the test substance, the BCF was calculated with several estimation models. The table below lists the applied (Q)SAR models, the estimated BCF values and basic information on the applicability domain (AD). Detailed information on the model’s results and the AD are given in the endpoint study records of IUCLID Chapter 5.3.1. The selected models comply with the OECD principles for (Q)SAR models.

Table 1. Summary of relevant information on aquatic bioaccumulation: Predicted BCF values for applied QSAR models (AD = Applicability Domain)

Model	BCF [L/kg]	In AD	Restraints
CAESAR v2.1.14 (VEGA v1.1.3)	2	No	- only moderately similar compounds with known experimental value in the training set have been found - 1 descriptor(s) for this compound have values outside the descriptor range of the compounds of the training set.
BCF KNN/Read-Across v1.1.0 (VEGA v1.1.3)	4.47	No	- the maximum error in prediction of similar molecules found in the training set has a moderate value, considering the experimental variability
BCF baseline model v.03.10 (OASIS Catalogic v5.13.1): incl. mitigating factors	6.31	yes	-
US EPA T.E.S.T. v4.2.1: Bioaccumulation: Consensus method	24.99	Yes	Based on the mean absolute errors of the models the confidence in the predicted results is low
BCFBAF v3.01 (EPI Suite v4.11): Arnot-Gobas BCF, upper trophic, incl. biotransformation	197.1	No	- the substance ionizes at physiologically relevant pH - the number of occurrences of one fragment exceeded those of the training set data
BCFBAF v3.01 (EPI Suite v4.11): Meylan et al. (1997/1999)	382	Yes	-
Meylan v1.0.3 (VEGA v1.1.3)	2144	No	- only moderately similar compounds with known experimental value in the training set have been found - accuracy of prediction for similar molecules found in the training set is not optimal - similar molecules found in the training set have experimental values that disagree with the predicted value - the maximum error in prediction of similar molecules found in the training set has a high value, considering the experimental variability - reliability of logP value used by the model is not adequate - a prominent number of atom centered fragments of the compound have not been found in the compounds of the training set or are rare fragments (1 unknown fragment found)
BCFBAF v3.01 (EPI Suite v4.11): Arnot-Gobas BCF, upper trophic, incl. biotransformation of zero	18660	No	- the substance ionizes at physiologically relevant pH - the number of occurrences of one fragment exceeded those of the training set data
BCF baseline model v.02.09 (OASIS Catalogic v5.11.19): not considering mitigating factors	31769	yes	-

- Catalogic v5.13.1 – BCF base-line model v.03.10: Several BCF calculations using the CATALOGIC v.5.13.1 BCF base-line model v03.10 are available for the substance. The BCF model calculates the BCF implicating the log Kow value and the water solubility. Furthermore, the influence of mitigating factors like ionization of the molecule, water solubility, size and metabolism are also considered by the model. Taking into account a calculated log Kow of 6.5 and an estimated water solubility of 0.63 mg/L (BASF SE, 2019), the BCF is reduced from 31769 to 6.31. Metabolism and molecular size and to a minor part also water solubility reduce the overall bioaccumulation. The reduction of the BCF is mainly due to metabolism. Besides metabolism also the low water solubility and the molecular size reduce the log BCF as estimated by the model. Both parameters are discussed within the literature whether certain threshold values are suitable as cut-off criteria for indication of limited bioaccumulation. Regarding molecular size, the PBT working group on hazardous substances discussed a maximum diameter of > 17.4 Å (Comber et al., 2006).The average diameter of the molecules is higher than the critical value (20.643 Å) indicating the bioaccumulation potential of the substance possibly to be reduced as the molecules may pass less easily through cell membranes. All in all, based on the predicted BCF of 7-8 L/kg significant bioaccumulations is not to be expected in animal tissues. The test substance meets the structural domain requirements of the BCF baseline model. According to OECD 305 protocol, the transformation of the parent (i.e., parent quantity) is decisive for the effect of metabolism (i.e.. the reproduction of subsequent step is less critical for the prediction of BCF). Hence, the disappearance of parent could be assumed to be reflected adequately by the model - EPISuite v4.11 - BCFBAFv3.01: According to Meylan et al. 1997/1999, a BCF value of 382 was estimated based on a log Kow of 6. Using the Arnot-Gobas method including biotransformation, the BCF for the upper trophic level was estimated to be 197.1 (BASF SE, 2019). The substance is within the applicability domain of the Meylan method, but as it appreciably ionizes at physiological relevant pH, it is not within the applicability domain of the Arnot-Gobas method; therefore the estimate may be less accurate. - T.E.S.T. v4.1 (US EPA model): The Consensus method averages the reasonable results from all applicable models (<= 5). The model shows only results which are within the applicability domain. Based on a comparison of the mean absolute error between the entire dataset and a reduced dataset using only similar chemicals, the confidence in the results is evaluated. Following EPA, the Consensus method yields the best results in terms of prediction accuracy and coverage. Regarding the test item, the BCF result of the Consensus method was 25 (BASF SE, 2019). Following the calculated log Kow values of 6.5 (uncharged molecule), bioaccumulation in organisms may not be excluded. However, a log Kow of 0.35 at pH 7 was measured in a test according to OECD 107 (BASF SE 1988, see IUCLID Ch. 4.7). Since the substance occurs as charged species in aqueous media at environmentally relevant pH (pH 4-9), all results for physico-chemical properties and environmental fate that were obtained by QSAR modeling have to be regarded with caution because the calculations only consider the uncharged species which occurs only under high pH conditions (pH > 10). Therefore, the experimental log Kow value of 0.35 is considered to be more accurate for the environmental conditions (pH 4 – 9), thereby identifying a low potential for accumulation in aquatic organisms. In addition, the different estimation models (CATALOGIC v5.13.1 BCF base-line model v2.08, BCFBAF v3.01 and T.E.S.T v4.2.1) calculated BCF values between 2 and 31769. The geometric mean was calculated based on environmentally relevant models which consider mitigating factors like biotransformation, molecular size and/or water solubility. In addition, only values from models was considered where the substance was within the applicability domain and the results seemed reliable.

Based on a log Kow of 6.5, the geometric mean of the BCF is 39 (BCFBAF – Meylan; BCF base-line model, T.E.S.T).

Assessment of relevant metabolites:

CATALOGIC BCF base-line model v03.10 (OASIS Catalogic v5.13.1) predicted 3 metabolites, identifying these metabolites as relevant degradation products in terms of PBT/vPvB assessment, with an estimated quantity of ≥ 0.1% (equivalent to ≥ 0.001 mol/mol parent; for details see ‘Attached background material’ of the respective Endpoint Study Record). One of the 3 modelled degradation products of the test substance were estimated to exhibit log Kow values of ≥ 4.5 (see Table 1). Since, the CATALOGIC BCF base-line model v03.10 (OASIS Catalogic v5.13.1) predicts log Kow value for uncharged molecules (pH > 10), the log Kow value of the predicted metabolite might be lower under environmental conditions (pH 4 – 9). However, based on the available calculated log Kow value the CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(CO)C2)CC(C)(C)N1 could be considered as ‘’B’’ or ‘’vB’’, according to screening criterion for bioaccumulation (B/vB). The calculated log BCF values for the predicted metabolites range from 0.46 to 0.80. Thus, they are clearly under 2000, thereby not fulfilling the screening criteria for bioaccumulation (B/vB) as laid down in Section 3.1 of REACH Annex XIII.

Based on the estimation data available for the modelled metabolites, all relevant metabolites of CAS 52829-07-9 are concluded to be “not B” and “not vB”.

Table 2. QSAR prediction for CAS-#52829 -07 -9 using CATALOGIC BCF base-line model v03.10 – July 2018 (OASIS CATALOGIC v5.13.1; metabolites with a quantity > 0.001 mol/mol are highlighted by grey background and bold type; metabolite no: according to (Q)SAR model Catalogic v03.10 – July 2018 (OASIS CATALOGIC v5.13.156))

#	Smiles	Quantity [mol/mol parent]	log Kow	logBCF corrected	Total Domain
Parent	CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1	0.0002561	6.5004	0.80	In domain
2	CC1(C)CC(OC(=O)CCCCCCCCC(O)=O)CC(C)(C)N1	0.5456	1.4396	0.68	Out of Domain
3	CC1(C)CC(O)CC(C)(C)N1	0.5456	0.9422	0.46	In domain
4	CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(CO)C2)CC(C)(C)N1	0.4542	5.0356	0.72	Out of Domain

 

(metabolites which are predicted at quantity >0.001 are highlighted in grey and written in bold letters)

(metabolite no: according to (Q)SAR model CATALOGIC BCF model v103.10 – July 2018 (OASIS CATALOGIC v5.13.1))

AD: applicability domain

Conclusion:

Summing up the available estimated data on the bioaccumulation potential of the parent item and its predicted metabolites evolving from bioaccumulation, and taking into consideration mitigation factors like metabolism by organisms and the molecular size of the target substance that additionally reduce the BCF, it can be concluded that significant bioaccumulation in organisms is not to be expected.