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

Biodegradation in water and sediment: simulation tests

Link to relevant study record(s)

Reference

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:

guideline study

Justification for type of information:

Sorafenib Tosylate was used as an analogue.

Reason / purpose for cross-reference:

read-across: supporting information

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)

Radiolabelling:

yes

Oxygen conditions:

aerobic

Inoculum or test system:

natural water / sediment

Duration of test (contact time):

100 d

Initial conc.:

0.22 mg/L

Based on:

test mat.

% Degr.:

>= 0.7 - <= 1.1

Parameter:

radiochem. meas.

Sampling time:

100 d

Key result

Compartment:

water

DT50:

< 2.5 d

Type:

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

Temp.:

12 °C

Remarks on result:

other: Value according to temperature correction by using the Arrhenius equation with the generic Ea-value (ECHA Guidance R.7b)

Compartment:

water

DT50:

< 1 d

Type:

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

Temp.:

22 °C

Transformation products:

not specified

Details on transformation products:

The transformation products are not specifically determined.

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).

Validity criteria fulfilled:

yes

Conclusions:

[14C]-sorafenib tosylate was removed rapidly from the water fraction (DT50<1d at 22 °C corresponding to <2.5 d at 12°C) and bound to the sediment in both sediment-systems. The test substances accumulated in the sediment fraction with an average recovery of 87.0 to 91.4%. The extraction of water and sediment did not show significant (>10%) transformation of [14C]- sorafenib tosylate. 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) as 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.

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.

Description of key information

A guideline study according to OECD 308 (Aerobic and Anaerobic Tranformation in Aquatic Sediment Systems) was conducted to assess the biodegradation of [14C]-sorafenib tosylate in water over 100 days. The aerobic water/sediment metabolism (CO2 development) and the distribution of the test substance was studied in two aerobic water/sediment-systems under laboratory conditions. Test vessels were exposed to a start concentration of 0.22 mg/L in water phase (nominal concentration). Samples for analysis were taken on day 2, 15, 29, 43, 64 and 100. The test substance was removed rapidly from the water fraction and bound to the sediment in both sediment-systems (DT50 for water was < 1 day at 22°C corresponding to <2.5 d at 12°C). 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. 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.