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Diss Factsheets

Environmental fate & pathways

Bioaccumulation: aquatic / sediment

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Description of key information

The test substance does not accumulate in aquatic organisms.

Key value for chemical safety assessment

Additional information

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 the test substance (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.

 

In a bioaccumulation study according to OECD 305C, Carp (Cyprinus carpio) were exposed to two concentrations of the test substance for a period of 8 weeks. The determined BCF values are between < 4 and < 50 (Mitsubishi Chemical Safety Institute Ltd. 1994). An emulsifier (HCO-30) has been used and, therefore, the test is regarded as acceptable only in a weight-of-evidence since the test concentrations of 0.5 and 0.05 mg/l are both above the water solubility of the test substance (< 0.019 mg/L). Nevertheless, the results indicate that the test substance is not bioaccumulative within the weight-of-evidence.

However, the results are supported by the calculated logPow of > 11, the mol

ecular weight (639.89 - 653.91 g/mol) and the maximum diameter of the molecule that was calculated using CATALOGIC v5.11.15. It resulted in an average maximum diameter (Dmaxaver) of 2.51 nm. According to the guidance on information requirements and chemical safety assessment Chapter R.11 - PBT Assessment - another parameter that directly reflect the molecular size of a substance is the average maximum diameter (Dmaxaver). Very bulky molecules will less easily pass the cell membranes. This results in a reduced BCF of the substance. From a diverse set of chemicals it appeared that for compounds with a Dmaxaver larger than 1.7 nm the BCF value was less than 5000 L/kg. It can be assumed combining the maximum diameter of above 1.7 nm and the high molecular size of the test item that the test item will not easily pass the cell membranes, the uptake is reduced and bioaccumulation will not occur. Furthermore, the aquatic BCF of a substance is probably lower than 2000 L/kg if the calculated logKow is higher than 10. Therefore, due to the high molecular weight, the high Dmaxaver and the high calculated logPow it can be concluded that the test substance is not bioaccumulative.

Additionally, to support these findings four QSAR calculations have been conducted. The single models and their results are summarized in the table below:

Model

 

BCF

Log BCF

Remarks

Catalogic v5.11.15

 

7.413

0.87

all mitigating factors applied; 45.83 % in domain

T.E.S.T. v4.01

 

5.91

0.77

EPISuite v4.10

Regression-based estimate

63

1.8

The substance is within the applicability domain of the BCFBAF submodel: Bioconcentration factor

Arnot-Gobas upper trophic level

67.1

1.827

Including biotransformation rate estimates; MW is within the range of training set, but exceeds 600 g/mol. And Log Kow is outside of the range. Therefore, the estimate may be less accurate

Arnot-Gobas mid trophic level

92.77

1.967

Including biotransformation rate estimates; MW is within the range of training set, but exceeds 600 g/mol. And Log Kow is outside of the range. Therefore, the estimate may be less accurate

Arnot-Gobas lower trophic level

102.5

2.011

Including biotransformation rate estimates; MW is within the range of training set, but exceeds 600 g/mol. And Log Kow is outside of the range. Therefore, the estimate may be less accurate

 VEGA CAESAR v2.1.13   2  0.32 The test substance is out of model Applicability Domain

Regarding the results of the model calculation, the calculated BCF values range from 2 (VEGA) to 102.5 (Arnot-Gobas lower trophic level

).

Of these models, Catalogic, VEGA CAESAR and the Arnot-Gobas model from EPISuite v4.10 take into account mitigating factors, e.g. metabolism, water solubility and/or size.

Catalogic revealed a corrected BCF of 7.413 and the compound is 45.83% within the model’s applicability domain.

The Arnot-Gobas model from the EPISuite takes into account the biotransformation rate of the compound and calculates BCF values for the upper, mid and lower trophic levels. The values for the present compound range from 67.1 (upper trophic level) to 102.5 (lower trophic level). The model assumes default lipid contents of 10.7%, 6.85% and 5.98% for the upper, middle and lower trophic levels, respectively. Usually, in the context of REACH a default lipid value of 5% is assumed which represents the average lipid content of the small fish used in OECD 305 studies. Thus, the higher lipid values of the Arnot-Gobas model can be regarded as reasonable worst-case scenarios as higher lipid contents are usually associated with a higher potential for bioaccumulation. However, the MW is within the range of training set, but exceeds 600 g/mol. And Log Kow is outside of the range. Therefore, the estimate may be less accurate.

The regression-based estimate from the EPISuite revealed a BCF value of 63 based on a calculated logKow of 8.95 and the test substance is in the applicability domain of the model.

The T.E.S.T. package from the US EPA estimates BCF values using several different advanced QSAR methodologies. The recommended model of the T.E.S.T. package is the consensus method since it provides the most accurate prediction. This model estimates the BCF by taking an average of the predicted BCF values from the other applicable QSAR methods of the package. For the present substance the consensus method averaged the results from (1) the hierarchical clustering method, (2) the single model method, (3) the group contribution method, (4) the FDA method and (5) the nearest neighbor method. The resulting BCF value is 5.91.

The VEGA model was developed with several descriptors and is based on a dataset of 473 compounds. It offers detailed information on the applicability domain. In the present case, the calculation gave a BCF value of 2. Since the Global AD Index was calculated to be 0 the substance is out of the Applicability Domain of the model.

However, even though the test substance was out of the Applicability Domain of some programs, the QSAR results support the overall conclusion that the test substance is not bioaccumulative, since all QSAR models give a value far below a BCF of 2000 and the results of the models were the applicability domain is met are consistent with the results of all models.

Furthermore, regarding the toxicokinetics, the route of excretion is assumed to be via the bile using the glucuronic acid-conjugate pathway. Glucuronic acid conjugates are most likely formed either with phenolic -OH groups, or with secondary carboxylic acids formed in the course of the metabolism along the aliphatic side chain. It is considered rather unlikely, that water-soluble metabolites would be formed by oxidation along the sidechain and sulfation on the phenolic -OH. Glucuronidated metabolites are generally known to be rapidly excreted.

In the intestines, due to its very low solubility in water and the large molecular weight only a small amount of the article is expected to be absorbed. Almost the entire ingested test item is expected to pass the intestines unchanged and to be excreted directlyviafaeces. With respect to the very small part of the substance resorbed, most is expected to become directly glucuronidated in the liver and excretedviathe bile. This is likely as the substance has free phenolic hydroxy groups.

A bioaccumulation of the test substance is considered unlikely, due to the fact that in the course of a 28d study performed with a structural analogue at high doses, slight reversible liver induction was shown, which is indirect evidence that metabolism and excretion takes place.

In overall conclusion, considering the test results, the logPow, the high molecular weight, the high average maximum diameter, the QSAR calculations and the toxicokinetics conclusion it can clearly be stated that test substance is not bioaccumulative according to PBT-criteria.