4-(4-((((4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)AMINO)CARBONYL)AMINO)PHENOXY)-N-METHYL-2-PYRIDINECARBOXAMIDE

Biodegradation in water and sediment: simulation tests

Administrative data

Endpoint:

biodegradation in water: sediment simulation testing

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Dec 2013 - Jul 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted with sorafenib tosylate according to OECD guideline under GLP

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 308 (Aerobic and Anaerobic Transformation in Aquatic Sediment Systems)

Deviations:

no

Principles of method if other than guideline:

not relevant

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

475207-59-1

Cas Number:

475207-59-1

IUPAC Name:

475207-59-1

Details on test material:

- Name of test material (as cited in study report): [14C]-Sorafenib tosylate
- Analytical purity: 99.9/99.4 % (radiochemical) 99.2/99.0 % (chemical)
- Lot/batch No.: PLS 0356-1-21 A
- Specific activity (if radiolabelling): 3.09 MBq/mg

Radiolabelling:

yes

Study design

Oxygen conditions:

aerobic

Inoculum or test system:

natural water / sediment

Duration of test (contact time):

100 d

Initial test substance concentration

Initial conc.:

0.22 mg/L

Based on:

test mat.

Results and discussion

% Degradation

% Degr.:

>= 0.7 - <= 1.1

Parameter:

radiochem. meas.

Sampling time:

100 d

Half-life of parent compound / 50% disappearance time (DT50)

Compartment:

water

DT50:

< 1 d

Type:

(pseudo-)first order (= half-life)

Temp.:

22 °C

Transformation products:

yes

Any other information on results incl. tables

After 100 days [14C]-sorafenib tosylate remained only to about 0.8 and 0.6 % in the water

phase of sediment location 1 and 2, respectively. After less than one day more than 50 % of

the test item were removed from the water fraction.

The extraction of water and sediment did not show significant (>10%) transformation of

[14C]- sorafenib tosylate and no non-extractable radioactivity was found in sediments.

Degradation of [14C]-sorafenib tosylate (active form BAY 43-9006) is only observed to a

limited amount leading to M-4 (BAY 43-9007).

Applicant's summary and conclusion

Validity criteria

Validity criteria fulfilled:

yes

Conclusions:

[14C]-sorafenib tosylate was removed rapidly from the water fraction and bound to the
sediment in both sediment-systems.
The sum of transformation products which were detected in sediment 1 and 2, was less than
10 % of the total radioactivity as determined by HLPC.

Executive summary:

The aerobic water/sediment metabolism (CO2 development) and the distribution of sorafenib

tosylate was studied in two aerobic water/sediment-systems under laboratory conditions.

Sorafenib tosylate is the active component of Nexavar, which is developed for tumor therapy.

It is assumed that unlabeled sorafenib tosylate and 14C-labelled sorafenib tosylate behave

identically in an aquatic sediment-system. Because the use of 14C-labelled test item is required

in the study design, 14C-labelled sorafenib tosylate was employed and the results of this study

utilized for the assessment.

The study was conducted in agreement with the test guideline OECD no. 308, aerobic part. It

was a repeat of a previous study but including a more detailed chromatographic analysis of

the potential transformation products.

For the preparation of the test vessels 50 g of intact sediment and 150 g sample water were

filled in each washing flask and 200 ¿L (equivalent to 0.1 MBq / 32.4 ¿g) of a stock solution

(total radioactivity: 5 MBq/10 mL ethanol) were applied. In order to absorb evolving 14CO2 a

trap of soda lime was put on each washing flask. 18 test vessels were prepared for each

sediment-system.

Samples for analysis were taken on day 2, 15, 29, 43, 64 and 100. Three test vessels for each

time point were removed for analysis. On these days oxygen content and pH value were

determined in one of the replicates. Additionally the oxygen content was measured weekly in

one vessel.

Radioactivity of [14C]-sorafenib tosylate in the test system (water, sediment and 14CO2 trap)

was quantified by liquid scintillation counting (LSC).

The concentration of extractable [14C]-sorafenib tosylate and of occurring transformation

products were analyzed by radio-HPLC.

The distribution of [14C]-sorafenib tosylate to the sediment compartment and the

disappearance from the water fraction was determined by plotting the radioactivity over time.

The disappearance time (DT50) was determined by empirical extrapolation.

The mass balance (recovery of radioactivity) was calculated by summing the total

radioactivity determined in soda lime, in the aqueous fraction and in the sediment.

After 100 days [14C]-sorafenib tosylate remained only to about 0.8 and 0.6 % in the water

phase of sediment location 1 and 2, respectively. After less than one day more than 50 % of

the test item were removed from the water fraction. Ultimate biodegradation was low and

accounted for 0.7 and 1.1 % of the radioactivity in sediment 1 and 2, respectively. Because of

the lack of relevant biodegradation, the test item is assumed to accumulate in the sediment.

The total mass balance ranged from 83.9 to 97.8 % of the total radioactivity (0.1 MBq) in

sediment-system 1 ¿TeK km 21.7/M11¿ and from 93.0 to 99.8 % of the total radioactivity

(0.1 MBq) in sediment-system 2 ¿TeK km 25.0¿ without showing major differences between

the sediment-systems.