2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: "The test for the degree of bioconcentration in the bodies of fish and shellfish" (Kanpogyo No. 5, Yakuhatsu No. 615, 49-Kikyoku No. 392)

GLP compliance:

no

Radiolabelling:

no

Details on sampling:

- Sampling intervals for test medium samples: after 0, 3, 7, 14, 21, 28, 35, 42, 49 and 56 days (conc. of test substance, pH, temperature, dissolved oxygen)
- Analysis of test media samples: filtration, extraction, HPLC analysis
- Analysis of test organisms samples: homogenisation, filtration, extraction, HPLC analysis

Vehicle:

yes

Details on preparation of test solutions, spiked fish food or sediment:

PREPARATION AND APPLICATION OF TEST SOLUTION
- Method: 1.0 g test substance was dissolved by (HCO-40) 20 g. The mixture was blended to vaporize acetone. Separately, approximately 50 ml of boiling hot water was added to 20 g of sugar to dissolve. This solution was added to the mixture solution and blended. Distilled water was added to dissolve the mixture to adjust the final volume to 5000 mL to be used as a 200 ppm (W/V) stock solution.
- Chemical name of vehicle: hydrogenated castor oil (HCO-40)
- Concentration of vehicle in test medium: 6 ppm (high exposure), 0.6 ppm (low exposure)

Test organisms (species):

Oryzias latipes

Details on test organisms:

TEST ORGANISM
- Length at study initiation: 10.4 ± 0.3 cm (mean)
- Weight at study initiation: 23.9 g
- Weight at termination: 22.0 g
- Desinfection: bathing with 50 ppm of oxytetracycline hydrochloride (Terramycin) for 24 hours (performed twice)

ACCLIMATION
- Acclimation period: 20 days
- Temperature: 25 °C

Route of exposure:

aqueous

Test type:

flow-through

Water / sediment media type:

natural water: freshwater

Total exposure / uptake duration:

56 d

Test temperature:

25.0 ± 1.0 °C

pH:

7.1 - 7.4

Dissolved oxygen:

6.1 - 6.9

Details on test conditions:

TEST SYSTEM
- Test vessel:
- Material, volume: glass, 100 L
- Flowrate: 300 mL/min (432 L/day)
- Number of organisms per exposure time and concentration: 2

TEST MEDIUM / WATER PARAMETERS
- Intervals of water quality measurement: weekly

Nominal and measured concentrations:

Nominal: 0.3 ppm (w/v) (high exposure), 0.03 ppm (w/v) (low exposure)
Measured: 0.20 - 0.22 ppm (w/v) (high exposure), 0.022 - 0.024 (w/v) (low exposure)

Reference substance (positive control):

no

Lipid content:

ca. 4.2 %

Remarks on result:

other: chloroform-methanol extraction method

Type:

BCF

Value:

> 5.3 - < 10.1

Basis:

whole body w.w.

Remarks on result:

other: measured after 56 days

Remarks:

Conc.in environment / dose:0.3 ppm (w/v)

Type:

BCF

Value:

> 8 - < 10

Basis:

whole body w.w.

Remarks on result:

other: measured after 56 days

Remarks:

Conc.in environment / dose:0.03 ppm (w/v)

Details on results:

Recovery ratio:
Fish: 72% ± 0.8
0.33 ppm treatment group: 83.4% ± 3.7
0.03 ppm treatment group: 72.1% ± 6.8

Validity criteria fulfilled:

not specified

Conclusions:

The whole body BCF was determined to be >5.3 - <10.1 under the conditions of the test.

Reference 2

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Accepted calculation method

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Principles of method if other than guideline:

Calculated with SRC BCFBAF v3.01

GLP compliance:

no

Radiolabelling:

no

Test organisms (species):

other: calculation

Details on estimation of bioconcentration:

BASIS INFORMATION
- Measured/calculated logPow: calculated

BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF Program (v3.01) (part of EPI Suite v4.10)
- Result based on calculated log Pow of: 2.73

Type:

BCF

Value:

7.6 L/kg

Remarks on result:

other: log BCF: 0.88; regression-based estimate

Type:

BCF

Value:

24.77 L/kg

Remarks on result:

other: log BCF: 1.394; Arnot-Gobas BCF method (including biotransformation rate estimates; upper trophic level)

Type:

BCF

Value:

23.1 L/kg

Remarks on result:

other: log BCF: 1.364; Arnot-Gobas BCF method (including biotransformation rate estimates; mid trophic level)

Type:

BCF

Value:

22.01 L/kg

Remarks on result:

other: log BCF: 1.343; Arnot-Gobas BCF method (including biotransformation rate estimates; lower trophic level)

Summary Results:

Log BCF (regression-based estimate): 0.88 (BCF = 7.6 L/kg wet-wt)

Biotransformation Half-Life (days) : 0.114 (normalized to 10 g fish)

Log BAF (Arnot-Gobas upper trophic): 1.39 (BAF = 24.8 L/kg wet-wt)

 

Log Kow (experimental): not available from database

Log Kow used by BCF estimates: 2.73

 

Equation Used to Make BCF estimate:

Log BCF = 0.6598 log Kow - 0.333 + Correction

 

Correction(s):                   Value

Ketone (aromatic connection)  -0.585

 

Estimated Log BCF = 0.881 (BCF = 7.599 L/kg wet-wt)

Whole body primary biotransformation rate estimate for fish:
Type	Num	Log Biotransformation Fragment Description	Coeff	Value
Frag	1	Carbon with 4 single bonds & no hydrogens	-0.2984	-0.2984
Frag	1	Aliphatic ether [C-O-C]	-0.0232	-0.0232
Frag	1	Ketone  [-C-C(=O)-C-]	-0.1801	-0.1801
Frag	1	Tertiary amine	-0.7829	-0.7829
Frag	4	Aromatic-H	0.2664	1.0655
Frag	3	Methyl [-CH3]	0.2451	0.7353
Frag	4	-CH2- [cyclic]	0.0963	0.3850
Frag	1	Benzene	-0.4277	-0.4277
L Kow	*	Log Kow =  2.73 (KowWin estimate)	0.3073	0.8379
MolWt	*	Molecular Weight Parameter		-0.7165
Const	*	Equation Constant		-1.5058
Result		LOG Bio Half-Life (days)		-0.9422
Result		Bio Half-Life (days)		0.1142
Note		Bio Half-Life Normalized to 10 g fish at 15 deg C

Biotransformation Rate Constant:

kM (Rate Constant): 6.067 /day (10 gram fish)

kM (Rate Constant): 3.412 /day (100 gram fish)

kM (Rate Constant): 1.919 /day (1 kg fish)

kM (Rate Constant): 1.079 /day (10 kg fish)

 

Arnot-Gobas BCF & BAF Methods (including biotransformation rate estimates):

Estimated Log BCF (upper trophic) = 1.394 (BCF = 24.77 L/kg wet-wt)

Estimated Log BAF (upper trophic) = 1.394 (BAF = 24.77 L/kg wet-wt)

Estimated Log BCF (mid trophic)  = 1.364 (BCF = 23.1 L/kg wet-wt)

Estimated Log BAF (mid trophic)  = 1.364 (BAF = 23.1 L/kg wet-wt)

Estimated Log BCF (lower trophic) = 1.343 (BCF = 22.01 L/kg wet-wt)

Estimated Log BAF (lower trophic) = 1.343 (BAF = 22.03 L/kg wet-wt)

 

Arnot-Gobas BCF & BAF Methods (assuming a biotransformation rate of zero):

Estimated Log BCF (upper trophic) = 1.762 (BCF = 57.76 L/kg wet-wt)

Estimated Log BAF (upper trophic) = 1.795 (BAF = 62.33 L/kg wet-wt)

 

Reference 3

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Accepted calculation method

Principles of method if other than guideline:

Calculated with Catalogic v5.11.5 BCF base-line model v02.05.

Details on estimation of bioconcentration:

BASIS INFORMATION
- Measured/calculated logPow: calculated

BASIS FOR CALCULATION OF BCF
- Estimation software: BCF base-line model v02.05 of OASIS CATALOGIC v5.11.5

Type:

BCF

Value:

39.52

Remarks on result:

other: log BCF: 1.5968, all mitigating factors applied

Model domain similarity:

- Parametric domain: 100%

- Structural domain: 52.63% (47.37% unknown)

- Mechanistic domain: 100%

Effects of mitigating factors on BCF:

Acids	0.0000
Metabolism	0.0865
Phenols	0.0000
Size	0.3590
Water solubility	0.0616

The BCF base-line model estimates the log BCF for the test substance at 1.5968 (BCF 39.52).

The the average maximum diameter (Dmax_aver) was calculated to be 1.4 nm.

Reference 4

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented QSAR model for prediction of BCF, assesses applicability domain: "Compound is out of model applicability domain."

Principles of method if other than guideline:

The BCF is estimated based on several molecular descriptors. The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) calculated by grouping several other indices, e.g. by a similarity index that consider molecule's fingerprint and structural aspects (count of
atoms, rings and relevant fragments).

GLP compliance:

no

Details on estimation of bioconcentration:

BASIS INFORMATION
- Measured/calculated logPow: calculated

BASIS FOR CALCULATION OF BCF
- Estimation software: VEGA CAESAR v 2.1.13
- Result based on calculated log Pow of: 1.98 (calculated by VEGA)

Type:

other: log BCF

Value:

0.63

Type:

BCF

Value:

4 L/kg

Summary for Compound

Experimental value: -

Prediction: 0.63 [log(L/kg)]

Prediction: 4 [L/kg]

Prediction of model 1 (HM): 0.81 [log(L/kg)]

Prediction of model 2 (GA): 0.79 [log(L/kg)]

Structural Alerts: Moiety (SMILES: O=Cc1ccccc1) (SR 01); Carbonyl residue (SR 02); Thiobenzene residue (SR 04);

Tertiary amine (SR 05); >C=O group (PG 09)

Calculated LogP: 1.98 [log units]

Reliability: Compound is out of model Applicability Domain

Remarks for the prediction: none

 

Applicability Domain assessment details:

Global AD Index

AD Index = 0.261

Explanation: predicted substance is out of the the Applicability Domain of the model.

 

Similar molecules with known experimental value

Similarity index = 0.769

Explanation: only moderately similar compounds with known experimental value in the training set have been found.

 

Accuracy (average error) of prediction for similar molecules

Accuracy index = 0.615

Explanation: accuracy of prediction for similar molecules found in the training set is not optimal.

 

Concordance with similar molecules (average difference between target compound prediction and experimental values of similar molecules)

Concordance index = 0.13

Explanation: similar molecules found in the training set have experimental values that agree with the target compound predicted value.

 

Maximum error of prediction among similar molecules

Max error index = 1.15

Explanation: the maximum error in prediction of similar molecules found in the training set has a high value, considering the experimental variability.

 

Atom Centered Fragments similarity check

ACF matching index = 0.34

Explanation: 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.

 

Descriptors noise sensitivity analysis

Noise Sensitivity = 0.964

Explanation: predictions has a good response to noise scrambling, thus shows a good reliability.

 

Model descriptors range check

Descriptors range check = true

Explanation: descriptors for this compound have values inside the descriptor range of the compounds of the training set.

Reference 5

Endpoint:

bioaccumulation: aquatic / sediment

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Methods were validated by US EPA using statistical external validation

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Principles of method if other than guideline:

T.E.S.T. is a toxicity estimation software tool. The program requires only the molecular structure of the test item, all other molecular descriptors which are required to estimate the toxicity are calculated within the tool itself. The molecular descriptors describe physical characteristics of the molecule (e.g. E-state values and E-state counts, constitutional descriptors, topological descriptors, walk and path counts, connectivity, information content, 2d autocorrelation, Burden
eigenvalue, molecular property (such as the octanol-water partition coefficient), Kappa, hydrogen bond acceptor/donor counts, molecular distance edge, and molecular fragment counts). Each of the available methods uses a different set of these descriptors to estimate the toxicity.
The bioaccumulation factor (BCF) was estimated using several available methods: hierarchical method; FDA method, single model method; group contribution method; nearest neighbor method; consensus method. The methods were validated using statistical external validation using separate training and test data sets.
The experimental data set was obtained from several different databases (Dimitrov et al., 2005; Arnot and Gobas, 2006; EURAS; Zhao, 2008). From the available data set containing 643 chemicals salts, mixtures and ambiguous compounds were removed. The final data set contained 598 chemicals.

References:
- Dimitrov, S., N. Dimitrova, T. Parkerton, M. Combers, M. Bonnell, and O. Mekenyan. 2005. Base-line model for identifying the bioaccumulation potential of chemicals. SAR and QSAR in Environmental Research 16:531-554.
- Arnot, J.A., and F.A.P.C. Gobas. 2006. A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms. Environ. Rev. 14:257-297.
- EURAS. Establishing a bioconcentration factor (BCF) Gold Standard Database. EURAS [cited 5/20/09]. Available from http://www.euras.be/eng/project.asp?ProjectId=92.
- Zhao, C.; Boriani, E.; Chana, A.; Roncaglioni, A.; Benfenati, E. 2008. A new hybrid system of QSAR models for predicting bioconcentration factors (BCF). Chemosphere 73:1701-1707.

GLP compliance:

no

Test organisms (species):

other: fish

Details on estimation of bioconcentration:

BASIS FOR CALCULATION OF BCF
- Estimation software: US EPA T.E.S.T. v4.0.1

Applied estimation methods:
- Hierarchical method : The toxicity for a given query compound is estimated using the weighted average of the predictions from several different cluster models.
- FDA method : The prediction for each test chemical is made using a new model that is fit to the chemicals that are most similar to the test compound. Each model is generated at runtime.
- Single model method : Predictions are made using a multilinear regression model that is fit to the training set (using molecular descriptors as independent variables).
- Group contribution method : Predictions are made using a multilinear regression model that is fit to the training set (using molecular fragment counts as independent variables).
- Nearest neighbor method : The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical.
- Consensus method : The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains; recommended method by T.E.S.T. for providing the most accurate predictions).

Type:

BCF

Value:

116.91

Remarks on result:

other: method: consensus

Type:

other: log BCF

Value:

2.07

Remarks on result:

other: method: consensus

Description of key information

The key study was conducted to national guidelines, with additional support and verification from QSAR results.

Key value for chemical safety assessment

BMF in fish (dimensionless):

10.1

Additional information

In a bioaccumulation study according to Japanese protocol procedures, individuals of Oryzias latipes were exposed to two concentrations of the test substance for a period of 56 days. The determined BCF values are between 5.3 and 10.1 (Gakushuin University, 1984). Even though an emulsifier has been used the test is regarded a valid since the test concentrations of 0.3 and 0.03 mg/l are both way below the water solubility of the test substance (17 mg/L). Additionally, the logPow was determined to be 3.02 in a study according to EEC Directive 79/831, ANNEX V, Part A, 3.8 and, therefore, the test substance is considered not bioaccumulative.

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

Model		BCF	Log BCF	Remarks
Catalogic v5.11.5		39.52	1.5968	all mitigating factors applied; 52.63 % in domain
T.E.S.T. v4.01		116.91	2.07
EPISuite v4.10	Regression-based estimate	7.6	0.88
	Arnot-Gobas upper trophic level	24.77	1.394	Including biotransformation rate estimates
	Arnot-Gobas mid trophic level	23.1	1.364	Including biotransformation rate estimates
	Arnot-Gobas lower trophic level	22.01	1.343	Including biotransformation rate estimates
VEGA CAESAR v2.1.13		4	0.63	is out of model Applicability Domain

Regarding the results of the model calculation, the calculated BCF values range from 4 (VEGA) to 116.91 (T.E.S.T.).

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 39.52 and the compound is 52.63% 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 24.77 (upper trophic level) to 22.01 (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. The regression-based estimate from the EPISuite revealed a BCF value of 7.6 based on a calculated logKow of 2.73.

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 116.91.

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 4. Since the Global AD Index was calculated to be 0.261 the substance is out of the Applicability Domain of the model.

However, in an overall conclusion, considering the test results, the logPow and the QSAR calulations the test substance is not bioaccumulative according to PBT-criteria.