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

Biodegradation in water: screening tests

Administrative data

Endpoint:

biodegradation in water: ready biodegradability

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sept - Oct 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted with the base (BAY 73-4506) 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:

2011

Report date:

2011

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 301 F (Ready Biodegradability: Manometric Respirometry Test)

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-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-3-fluorophenoxy)-N-methylpyridine-2- carboxamide

IUPAC Name:

4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-3-fluorophenoxy)-N-methylpyridine-2- carboxamide

Details on test material:

- Name of test material (as cited in study report): Regorafenib
- Analytical purity: 100.2%
- Lot/batch No.: BXR3JPV

Study design

Oxygen conditions:

aerobic

Inoculum or test system:

activated sludge, domestic (adaptation not specified)

Duration of test (contact time):

28 d

Initial test substance concentration

Initial conc.:

200 mg/L

Based on:

ThOD/L

Results and discussion

% Degradation

Parameter:

% degradation (O2 consumption)

Value:

0

Sampling time:

29 d

Details on results:

The reference compound sodium acetate was degraded to 90.0 % on day 29 (= 28 days of incubation). 60% degradation was reached on day 5.
In the toxicity control, the reference compound (sodium acetate) plus the test compound Regorafenib, was degraded to 43.0 % on day 29 (= 28 days of incubation), which reflected the
degradation in the individual sets.

Any other information on results incl. tables

Table 1: Biological degradation (cumulative) in percent corrected for blank O2 consumption (selected time-points)

		Day of sampling
Test compound	Concentration expressed in theoretical O2 demand	2	6	10	14	18	22	26	29
Regorafenib	200 mg/L	0*	0*	0*	0*	0*	0*	0*	0*
Reference (sodium acetate)	200 mg/L	12,8	68,2	81,3	85,7	88,9	89,8	90,3	90
Toxicity control (regorafenib + sodium acetate)	200 mg/L + 200 mg/L	4,4	29,4	39,2	40,8	42,2	42,9	43,2	43
* negative values are given as 0

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Interpretation of results:

under test conditions no biodegradation observed

Conclusions:

In accordance with the OECD 301F, the test compound regorafenib is not readily biodegradable under the conditions of the test and it was not toxic to the microbes of activated sludge.

Executive summary:

The purpose of this study was to determine the ready biodegradability of regorafenib (BAY 73-4506), which is developed for cancer therapy, in the manometric respiration test. The study was conducted in agreement with the OECD test guideline no. 301F.

The test substance regorafenib was incubated in an aqueous solution including nutrients with

microorganisms from a municipal sewage treatment plant for 28 days (start of treatment = day 1). The nutrient solutions were made up of phosphates, magnesium sulphate, iron chloride, ammonium chloride and calcium chloride.

The test substance regorafenib was incubated in triplicate at a concentration of 200 mg

theoretical oxygen demand (ThOD) per liter. Additionally, a reference substance (sodium

acetate) was tested in a single set according to the same procedure, in order to verify the viability

and activity of the degrading microorganisms. One further set was incubated with sodium acetate

at 200 mg ThOD/L (reference substance) plus regorafenib at 200 mg ThOD/L representing a

toxicity control. Furthermore, a blank control was tested in triplicate without any test or

reference substance.

The biological degradation of the test and reference substances was evaluated by measurement of

the O2 consumption during the test period. O2 consumption was continuously monitored and

recorded by an automated device. The O2 consumption was calculated as the percentage of total

O2 that the test material could theoretically have consumed, based on the molecular formula. The

blank O2 consumption was subtracted for correction.

The test compound regorafenib was not degraded on day 29 (= 28 days of incubation).

The reference compound sodium acetate was degraded to 90.0 % on day 29 (= 28 days of incubation). 60% degradation was reached on day 5. In the toxicity control, the reference compound (sodium acetate) plus the test compound

regorafenib, was degraded to 43.0 % on day 29 (= 28 days of incubation), which reflected the degradation in the individual sets.