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

Toxicity to terrestrial arthropods

Administrative data

Endpoint:

toxicity to terrestrial arthropods: long-term

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Feb - Mar 2011

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted with the base (BAY 73-4605) accordind 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:

other: OECD No. 232 Collembolan Reproduction Test in Soil

Deviations:

no

Principles of method if other than guideline:

not relevant

GLP compliance:

yes (incl. QA statement)

Application method:

soil

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):

Folsomia candida

Animal group:

Collembola (soil-dwelling springtail)

Study design

Study type:

laboratory study

Limit test:

yes

Total exposure duration:

28 d

Results and discussion

Effect concentrations

Effect concentrations 1

Duration:

28 d

Dose descriptor:

NOEC

Effect conc.:

> 100 mg/kg soil dw

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mortality

Effect concentrations 2

Duration:

28 d

Dose descriptor:

NOEC

Effect conc.:

> 100 mg/kg soil dw

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

reproduction

Any other information on results incl. tables

Table 1: Number of alive adults, percent mortality and number of juveniles per replicate in the reproduction toxicity test exposing Folsomia candida to Regorafenib (BAY 73-4506 monohydrat).

Treatments (mg a.i./kg dry soil)	Replicate	# Alive Adults	% Mortality Adults	# Juveniles
Control	1	6	40	404
	2	10	0	812
	3	10	0	529
	4	9	10	470
	5	10	0	527
	6	10	0	864
	7	10	0	536
	8	10	0	559
1	1	9	10	388
10	1	9	10	525
100	1	8	20	466
	2	10	0	473
	3	9	10	435
	4	9	10	562
	5	9	10	528
	6	10	0	820
	7	10	0	573
	8	10	0	604
Toxic Standard	1	7	30	221
	2	8	20	226
	3	8	20	364
	4	8	20	253
	5	9	10	346
	6	7	30	315
	7	10	0	282
	8	8	20	285

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

The NOEC and LOEC values for mortality and reproduction were determined to be ¿ 100 and > 100 mg a.i./kg dry soil, respectively. Therefore, the test item was not considered to be harmful to Folsomia candida.

Executive summary:

The objective of this study was to determine the potential effects of Regorafenib (BAY 73-4506 monohydrat) on the reproduction of the springtail Folsomia candida (Collembola). In order to estimate a NOEC and LOEC, the mortality and number of offspring was assessed 28 days after experimental start.

This study was performed according to the OECD guideline # 232 Collembolan reproduction test in soil (2009).

Folsomia candida were obtained from cultures maintained at Smithers Viscient AG originally initiated with organisms obtained from Cecotox, EPFL, Lausanne, Switzerland. During culturing, the organisms were fed ad libitum with granulated yeast. Springtails used in this study were 11 to 12 days old.

Artificial soil was used as test substrate (OECD # 207, 1984). The test substrate consisted of 70% industrial sand with more than 50% of particles between 80 and 200 ¿m, 20% kaolin clay with more than 30% kaolinite content and 10% sphagnum peat moss finely ground. The pH was adjusted with CaCO3. Prior to the test start, the soil moisture content (based on dry weight) was 20.4% and the pH 6.26. The total water holding capacity of the artificial soil was determined to be 60.3%.

A limit test with a definitive test concentration of 100 mg a.i./kg dry soil was selected. Two additional range-finding concentrations (i.e., 10 and 1.0 mg a.i./kg dry soil) were included to determine the range of test item concentrations, if a following definitive test needed to be conducted. Additionally, a control with quartz sand was prepared. The toxic standard with boric acid was applied at a concentration of 100 mg product/kg dry soil.

Four weeks after the experimental start, the number of adult and juvenile springtails per test vessel was counted as follows: water was added to each test vessel and the adult organisms, floating on the water surface, were counted.

The differences between the control and the 100 mg a.i./kg dry soil test item treatment were not statistically significant different (Fisher¿s Exact test p > 0.05). Therefore, the NOEC and LOEC values for mortality were determined to be ¿ 100 and > 100 mg a.i./kg dry soil, respectively. No statistical significant differences between the control and the 100 mg a.i./kg dry soil test item treatment were found (Dunnett t test p > 0.05). Therefore, the NOEC and LOEC values for mortality were determined to be ¿ 100 and > 100 mg a.i./kg dry soil, respectively.