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

Toxicity to microorganisms

Administrative data

Endpoint:

activated sludge respiration inhibition testing

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Oct 2010

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:

2011

Report date:

2011

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 209 (Activated Sludge, Respiration 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: 100.2%
- Lot/batch No.: BXR3JPV

Sampling and analysis

Analytical monitoring:

no

Test solutions

Vehicle:

no

Test organisms

Test organisms (species):

activated sludge of a predominantly domestic sewage

Study design

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

3 h

Results and discussion

Effect concentrations

Duration:

3 h

Dose descriptor:

EC50

Effect conc.:

> 40 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

inhibition of total respiration

Remarks:

respiration rate

Any other information on results incl. tables

Table 1: Inhibition of the respiration rate (%) of the activated sludge after 3 hours incubation with exposure to Regorafenib

Concentration of BAY 73-4506 in test vessel (mg/L)	Inhibition in percent
control	0
8	5,8
16	-36
24	13,1
32	7,4
40	-3,1

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

Regorafenib (BAY 73-4506) had no concentration-depended inhibitory effect on the respiration rate of activated sludge.

Executive summary:

The purpose of this study was to determine the effects of the test compound Regorafenib (BAY 73-4506) on the activity of activated sludge micro-organisms. Regorafenib is a multikinase inhibitor for cancer therapy. The study was conducted in agreement with the test guideline OECD no. 209.

The test substance Regorafenib was incubated in a test system consisting of aerated activated sludge with microorganisms from a municipal sewage treatment plant including synthetic sewage feed for approximately 3 hours followed by the measurement of the respiration rate by an oxygen probe. The synthetic sewage feed solution was made up of mainly peptone, meat extract and urea. Regorafenib is only slightly soluble, therefore the substance was introduced directly into the test vessel. 2, 4, 6, 8 and 10 mg substance were suspended in 42 mL demineralized water, ultrasonified and constantly stirred each for approximately 30 min. To each vessel the synthetic feed and inoculum was added. The resulting nominal concentrations were 8, 16, 24, 32 and 40 mg/L. Additionally, a reference substance (3.5-Dichlorophenole) in three concentrations (5, 15 and 30 mg/L in test vessel) was prepared. For the control two vessels with tap water were used. The activated sludge and the positive control were exposed to each concentration in single vessels. Two vessels were prepared for the control. The activated sludge was incubated under standardized conditions (constant stirring, aerated and at room temperature). As a parameter for the activity of the sludge, the respiration rate was measured with an oxygen probe. The decrease of the respiration rate was calculated on the basis of the oxygen consumption per hour. The inhibitory effect of the test and the reference substance at a particular concentration was expressed as a percentage of the mean respiration rate of the controls.

The respiration rate in the test vessels was not relevantly inhibited.