2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sep - Dec 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

The study was conducted in accordance with OECD 305 (1996) and meet respective guideline criteria. According to the newest version of OECD 305 (2012) the fish lipid content should be measured so that BCF can be expressed on a 5% lipid content basis. Furthermore, the fish weight should be measured so that the BCF can be corrected for growth dilution. These requirements are not met by the study because the lipid content was not measured, and the fish weight was measured but not reported in the study. Additionally, the new version of OECD 305 (2012) put a greater emphasis on estimating the BCF at steady state, which was not reached at the lower dosed group in this study. For more details, please refer to the executive summary. In general, for the interpretation of the results those deviations do not influence the outcome of this study. Therefore, the values obtained within this study are considered reliable with restrictions.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

OECD Guideline 305 (Bioconcentration: Flow-through Fish Test)

Version / remarks:

1996

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Radiolabelling:

yes

Vehicle:

yes

Test organisms (species):

Lepomis macrochirus

Route of exposure:

aqueous

Test type:

flow-through

Water / sediment media type:

natural water: freshwater

Total exposure / uptake duration:

26 d

Total depuration duration:

16 d

Test temperature:

23.2 to 24.6 °C

pH:

7.7 to 8.1

Dissolved oxygen:

4.6 to 8.4 mg/L

Nominal and measured concentrations:

In group 2 the mean value in water was 0.32 µg/L. At steady state, i.e. at sampling day 22 and 26
in group 2, the mean concentration in fish was 1.71 mg/kg.
For group 3 no steady state was reached. The mean water concentration was determined with
0.04 µg/L, the concentration in fish at day 26 was determined with 0.29 mg/kg

Key result

Type:

BCF

Value:

5 300 dimensionless

Basis:

whole body w.w.

Time of plateau:

22 d

Calculation basis:

steady state

Remarks on result:

other: Conc.in environment / dose:0.32 µg/L

Key result

Type:

BCF

Value:

> 7 300 dimensionless

Basis:

whole body w.w.

Time of plateau:

26 d

Calculation basis:

steady state

Remarks on result:

other: Steady state not reached at end of uptake phase

Remarks:

Conc.in environment / dose:0.04 µg/L

Elimination:

yes

Parameter:

DT50

Depuration time (DT):

6 d

Validity criteria fulfilled:

yes

Conclusions:

No substance related mortality or abnormal behavior was observed neither in the test nor in the
control solution during the whole experimental period. Thus, it was documented that the
exposure had no toxic effect on the fish at the concentration tested.
The BCF was greater than 10, the uptake of the substance is established to be significant
according to the guideline.

Executive summary:

The fish species Lepomis macrochirus were exposed to 14C labeled sorafenibtosylate and additionally to the vehicle control for a period of 26 days. Two replicate tanks for each test concentrations and one replicate tanks for the vehicle control were used. For the preparation of each stock solution, the labeled test compound was dissolved in ethanol. 20 fish were used for each test solution and 20 for the control group. A stock solution with a nominal concentration of sorafenibtosylate of 10 mg/L ethanol for group 2 and 1 mg/L ethanol for group 3 were prepared. The stock solutions were mixed with tap water and delivered continuously to the tanks. The nominal concentrations of sorafenibtosylate in the water were 1.0 (group 2) and 0.1 µg/L (group 3). Both treatment groups were run in duplicate. The concentration of the test substance in the fish and in the water was determined through both phases of the test by measurement of the radioactivity. The 14C concentration in the fish was analyzed by liquid scintillation after degradation of the fish by oxidation (SOLUENE-350) in samples taken on day 7, 14, 22 and 26 (uptake phase) and on day 35 and 42 (post-exposure phase). The 14C concentration in the water was analyzed by liquid scintillation in samples taken on day 1, 5, 7, 14, 19, 22, 26, 35 and 42. The concentration factor in fish (BCF) was calculated as the ratio of the mean values of the 14C concentration in fish and in water, taken at steady state.
In group 2 the mean concentration in water was measured to be 0.32 µg/L. At steady state, i.e., at sampling day 22 and 26, the mean concentration in fish (in group 2) was 1.71 mg/kg. For group 3 no steady state was reached. The mean water concentration was determined with 0.04 µg/L and the concentration in fish at day 26 was determined with 0.29 mg/kg. No substance related mortality or abnormal behavior was observed in the test concentration or the control during the whole experimental period. The BCF values for group 2 (high concentration) was 5300 (rounded). For group 3 (low concentration) no steady state was reached. However, at the last measurement point of the exposure phase, the BCF was calculated with 7300. Due to the lack of information about the lipid content of the fish. the standard lipid content was assumed. For group 2, the rate constant for uptake (k1) was determined with 0.098, the rate constant for depuration (k2) was determined with -0.095. For group 3, k1 and k2 were determined with 0.012 and -0.018, respectively.
The study was conducted in accordance with OECD 305 (1996) and meet respective guideline criteria. According to the newest version of OECD 305 (2012) the fish lipid content should be measured so that BCF can be expressed on a 5% lipid content basis. Within this study the lipid content of the fish were not considered to be reliable due to partial degradation of the plastic material in contact with the solvents. However, the standard lipid content was assumed but not reported. Furthermore, the fish weight should be measured so that the BCF can be corrected for growth dilution. These requirements are not met by the study because the fish weight was measured but not reported in the study. Additionally, the new version of OECD 305 (2012) put a greater emphasis on estimating the BCF at steady state, which was not reached at the lower dosed group in this study. However, it was reached for the higher dose group for which the BCF value was 5300. For the general interpretation of the results those deviations do not influence the outcome of this study since additional measures are not expected to substantially influence the dimension of BCF values. Therefore, the values obtained within this study are considered reliable with restrictions.

Description of key information

Within a study on the bioconcentration according to OECD 305 sorafenib tosylate (as analogue of the test substance) was tested in a flow-through fish test. The BCF was determined to be 5300 at a concentration of 0.32 µg/L after 22 d and >7300 at a concentration of 0.04 µg/L after 26 d (but no steady state was reached). These values are greater than the threshold for the vB criterion that is 5000 and show that the test substance has a high bioaccumulation potential.
In addition, a QSAR derived bioaccumulation factor was calculated based on the logKow=3.3 of the test substance. The bioaccumulation factor of the test substance was calculated to be 69.9 L/kg (ww) using the BCFBAF model included in the EPI-Suite Program. According to this value the test substance has a low potential to bioaccumulate in biota. The findings from the OECD 305 study are rather surprising as these deviate significantly from the behavior expected from QSAR that is based on physico-chemical properties.
QSAR applications reflect established relationships between molecular structures, physico-chemical properties, and biological activities of the test substance. However, bioconcentration of a substance is the result of lipid-water partitioning (Know) and other processes, e.g., metabolism and interactions with specific tissues. The QSAR can be adapted to include such processes to a certain degree. Nevertheless, BCF estimates from QSAR applications can differ from real BCF values when the test substance, e.g., accumulates in specific target tissues or body fluids, such as blood. Therefore, BCF values derived from the bioconcentration study (OECD 305) are used to assess the bioaccumulation potential and the test substance is assigned to be very bioaccumulative (vB).

Key value for chemical safety assessment

BCF (aquatic species):

7 300 dimensionless

Additional information

Based on the bioaccumulation study in fish the compound has a high bioaccumulation potential.