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

Toxicity to soil macroorganisms except arthropods

Administrative data

Endpoint:

toxicity to soil macroorganisms except arthropods: short-term

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Feb 2011

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 207 (Earthworm, Acute Toxicity Tests)

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 (BAY 73-4605)
- Analytical purity: 100.2%
- Lot/batch No.: BXR3JPV

Sampling and analysis

Analytical monitoring:

no

Test substrate

Vehicle:

no

Test organisms

Test organisms (species):

Eisenia fetida

Animal group:

annelids

Study design

Study type:

laboratory study

Substrate type:

artificial soil

Limit test:

yes

Total exposure duration:

14 d

Results and discussion

Effect concentrations

Duration:

14 d

Dose descriptor:

LC50

Effect conc.:

> 100 mg/kg soil dw

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mortality

Any other information on results incl. tables

Table 1: LC50, NOEC and LOEC values for mortality on days 7 and 14 in the acute toxicity test with Regorafenib (BAY 73-4506

monohydrat).

	Based on nominal concentration
	(mg a.i./kg dry soil)
LC50 a (95% C.I.)	NOEC a LOEC a
Day 7	> 100 (NA)	¿ 100	> 100
Day 14	> 100 (NA)	¿ 100	> 100
C.I.	Confidence Interval.
NA	Not Applicable.
a	Empirical estimation.

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

The 7- and 14- day LC50 values were empirically estimated to be > 100 mg a.i./kg dry soil. Accordingly, Regorafenib is not harmful to the earthworm
Eisenia fetida.

Executive summary:

The objective of this study was to determine the acute toxicity of Regorafenib (BAY 73-4506 monohydrat) to the earthworm Eisenia fetida (Oligochaeta: Lumbricidae). In order to estimate an LC50 value, the NOEC and LOEC, the mortality was assessed 7 and 14 days after experimental start.

The toxicity test was performed according to the OECD Guideline # 207, Earthworm, Acute Toxicity Tests (OECD, 1984).

8 replicates for the control and 100 mg a.i./kg dry soil treatment and 1 replicate for the 1 and 10 mg a.i./kg dry soil

treatments (each replicate with 10 earthworms) was used. As test soil was used Artificial soil according to OECD Guideline # 207

On day 0: mean pH 6.14 and 41.0% mean moisture content.

After 7 and 14 days, earthworm mortality and health assessments were performed by testing their reaction to a mechanical stimulus. Mortality was defined as a lack of a visible movement after gentle mechanical stimulation. The general health of the earthworms was recorded by observing color changes, lethargy, lesions and the absence of burrowing. On days 0 and 14, individual earthworm weights were recorded.

On day 7 and 14, all worms were healthy and no mortality was observed in the control and the 1.0, 10 and 100 mg a.i./kg dry soil treatments, respectively. Therefore, the 7- and 14-day NOEC and LOEC values for mortality were empirically estimated to be ¿ 100 and > 100 mg a.i./kg dry soil, respectively. The 7- and 14- day LC50 values were empirically estimated to be > 100 mg a.i./kg dry soil.