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

Toxicity to aquatic algae and cyanobacteria

Administrative data

Endpoint:

toxicity to aquatic algae and cyanobacteria

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug - Oct 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted with the base (BAY 73-4605) 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 201 (Alga, Growth Inhibition 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): BAY 73-4605
- Analytical purity: 100.0%
- Lot/batch No.: BXR4Z07

Sampling and analysis

Analytical monitoring:

yes

Test solutions

Vehicle:

no

Test organisms

Test organisms (species):

Desmodesmus subspicatus (previous name: Scenedesmus subspicatus)

Study design

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

72 h

Results and discussion

Effect concentrations

Effect concentrations 1

Duration:

72 h

Dose descriptor:

EC50

Effect conc.:

3.184 µg/L

Nominal / measured:

meas. (arithm. mean)

Conc. based on:

test mat.

Basis for effect:

growth rate

Effect concentrations 2

Duration:

72 h

Dose descriptor:

NOEC

Effect conc.:

0.15 µg/L

Nominal / measured:

meas. (arithm. mean)

Conc. based on:

test mat.

Basis for effect:

growth rate

Effect concentrations 3

Duration:

72 h

Dose descriptor:

LOEC

Effect conc.:

0.37 µg/L

Nominal / measured:

meas. (arithm. mean)

Conc. based on:

test mat.

Basis for effect:

growth rate

Any other information on results incl. tables

Table 1: Inhibition of the growth rate (%) of Desmodesmus subspicatus after 72 hours exposure to Regorafenib

Dilution	Concentration	Inhibition
of Regorafenib	of Regorafenib (¿g/L)1	in percent
in the test vessels	in the test vessels	Growth rate
0	0.0 (control)	0.0
1:100	0.037	-2.5
1:50	0.075	0.3
1:25	0.15	1.8
1:10	0.37	3.7
1:5	0.75	10.9
1:1.25	2,98	47.9
1) Calculated from measured saturated solution

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

Regorafenib had a concentration-depended inhibitory effect on the growth of Desmodesmus subspicatus. The ErC50 (growth rate) was
3.184 ¿g/L [95 % confidence limits: 2.946-3.475] on the basis of measured concentrations. The NOEC was 0.15 ¿g/L, the LOEC was 0.37 ¿g/L.

Executive summary:

The purpose of this study was to determine the effects of the test compound Regorafenib (BAY 73 -4506) on the growth of the green algae Desmodesmus subspicatus. Regorafenib is developed for cancer therapy. The study was conducted in agreement with the test guideline OECD no. 201.

The test substance Regorafenib was incubated in an aqueous solution including nutrients with an algae population of Desmodesmus subspicatus for a test duration of approximately 72 hours in an incubator shaker apparatus.

For the preparation of the test solutions a suspension with a nominal loading of 100 mg/L Regorafenib was suspended in demineralized water, ultrasonified for approximately 30 min and constantly stirred for approximately 24 hours. This suspension was filtered through a glass-fiber filter. The filtered solution was used for the preparation of the test solutions.

As a parameter for the growth of the algae population, the algae cells were measured with a coulter counter. The growth rate was calculated on the basis of the cell counts. The calculated growth rate of each concentration was compared to those of the controls, and the inhibition was calculated.

The growth rate was inhibited in a concentration-dependent manner. This was considered to be a compound related effect. The NOEC for growth rate inhibition was 0.15 ¿g/L, the LOEC was 0.37 ¿g/L and the ErC50 was 3.184 ¿g/L.