2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl-, hydrochloride (1:1)

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:

May 2011 - Feb 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted with the base (labelled, BAY 73-4605 14-C) 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:

2012

Report date:

2012

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:

4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-Nmethylpyridine- 2-[14C]carboxamide

IUPAC Name:

4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-Nmethylpyridine- 2-[14C]carboxamide

Details on test material:

- Name of test material (as cited in study report): Regorafenib
- Analytical purity: 98.7%
- Lot/batch No.: GCM 1569-1-14C
- Radiochemical purity (if radiolabelling): 99.2%
- Specific activity (if radiolabelling): 2.47 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.:

200 other: uL

Based on:

test mat.

Results and discussion

% Degradation

% Degr.:

< 10

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.:

20 °C

Any other information on results incl. tables

Table 1: Mass balance of [14C]- regorafenib in two sediments after 100 days [% of initially introduced radioactivity]

Sediment system	Water	Sediment	CO2	Total mass balance
Nordhafen	0,4	112,5	0,3	113,3 *
Tegeler See	2	101,2	0,9	104,1

* Rounding resulted in slight differences to the individual values

Applicant's summary and conclusion

Validity criteria

Validity criteria fulfilled:

yes

Conclusions:

[14C]-regorafenib was removed rapidly from the water fraction and bound to the sediment in both sediment-systems.
Because of the lack of relevant biodegradation, the test item is assumed to accumulate in the sediment.

Executive summary:

The aerobic water/sediment metabolism (CO2 development) and the distribution of regorafenib (BAY 73-4506) was studied in two aerobic water/sediment-systems under laboratory conditions. Regorafenib is developed for cancer therapy. It is assumed that unlabeled regorafenib and 14C-labelled regorafenib behave identically in an aquatic sediment-system. Because the use of 14C-labelled test item is required in the study design, 14C-labelled regorafenib 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.

The 14C-labelled test item regorafenib was incubated in an aerobic system, which contained intact lake sediment and overlaying water. Two types of sediments were used, one with higher organic carbon content and fine particle size (sediment-system 1, Nordhafen), the other with lower content of organic carbon and coarse grain size (sediment-system 2, Tegeler See). The substance was incubated over a period of 100 days. 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) 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 sedimentsystem. Samples for analysis were taken after 2, 15, 29, 43, 64 and 100 days. Three test vessels for each time point were removed for analysis. On these days temperature, oxygen content and pH value were determined in one of the replicates. Additionally after day 15 the oxygen content was measured weekly in one vessel and in all test vessels when samples were taken. Radioactivity of [14C]-regorafenib in the test system (water, sediment and 14CO2 trap) was quantified by liquid scintillation counting (LSC). The concentration of extractable [14C]-regorafenib and of occurring transformation products were analysed by radio-HPLC. The distribution of [14C]-regorafenib 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]-regorafenib remained only to about 0.4 and 2 % 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 0.3 and 0.9 % of the radioactivity in sediment 1 and 2, respectively. The total mass balance ranged from 81.4 to 118.8 % of the total radioactivity (0.1 MBq) in sediment-system ¿Nordhafen¿ and from 67.5 to 114.7 % of the total radioactivity (0.1 MBq) in sediment-system ¿Tegeler See¿ without showing major differences between the sediment-systems.

The extraction of water and sediment did not show significant (>10%) transformation of regorafenib and no non-extractable radioactivity was found in sediments.