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

Toxicity to terrestrial plants

Administrative data

Endpoint:

toxicity to terrestrial plants: short-term

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Mar - Apr 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 208 (Terrestrial Plants Test: Seedling Emergence and Seedling Growth 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

Sampling and analysis

Analytical monitoring:

yes

Test substrate

Vehicle:

no

Test organisms

1

Species:

Pisum sativum

Plant group:

Dicotyledonae (dicots)

Details on test organisms:

Pisum sativum, pea, Douce de Provence, Sativa Rheinau AG, Switzerland

2

Species:

Raphanus sativus

Plant group:

Dicotyledonae (dicots)

Details on test organisms:

Rhaphanus sativus, radish, Sora, Sativa Rheinau AG, Switzerland

3

Species:

Zea mays

Plant group:

Monocotyledonae (monocots)

Details on test organisms:

Zea mays, corn, sh2 mittelspät, Sativa Rheinau AG, Switzerland

Study design

Test type:

seedling emergence toxicity test

Study type:

laboratory study

Substrate type:

artificial soil

Limit test:

yes

Total exposure duration:

21 d

Results and discussion

Effect concentrations

Effect concentrations 1

Species:

Zea mays

Duration:

21 d

Dose descriptor:

NOEC

Effect conc.:

>= 100 mg/kg soil dw

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

seedling emergence

Effect concentrations 2

Species:

Raphanus sativus

Duration:

21 d

Dose descriptor:

NOEC

Effect conc.:

>= 100 mg/kg soil dw

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

seedling emergence

Effect concentrations 3

Species:

Pisum sativum

Duration:

21 d

Dose descriptor:

NOEC

Effect conc.:

>= 100 mg/kg soil dw

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

seedling emergence

Any other information on results incl. tables

Table 1	Concentrations of Regorafenib measured in the soil samples.	(BAY	73-4506 monohydrat)
Nominal Concentration (mg a.i./kg dry soil)	Measured Concentration (mg a.i./kg dry soil)	% Recovery		Mean Measured Concentration (mg a.i./kg dry soil)	Mean % Recovery
Control	<LOQ	NA		NA	NA
1	1,13	113		1,22	122
	1,32	132
10	9,21	92,1		9,65	96,5
	10,1	101
100	91,2	91,2		92,7	92,7
	94,2	94,2
QC#1 (0,873)	0,902	103		NA	NA
QC#2 (147)	131	89,5		NA	NA
LOQ NA QC	Limit of quantification. (Determined as  0,780 mg a.i./kg dry soil). Not Applicable. Quality Control sample.

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

For all species, effects on emergence and shoot fresh weight data were not statistically significant at the 100 mg a.i. /kg dry soil treatment level, i.e.,
the NOEC and LOEC were >- 100 and >100 mg/kg dry soil for all species respectively.

Executive summary:

The purpose of this study was to estimate the potential effects of Regorafenib (BAY 73-4506 monohydrat) on the emergence and seedling growth of three non-target plants species according to OECD test guideline No. 208. Toxic endpoints were the emergence of seedlings and visual assessments 14 and 21 days after 50% control emergence. Additionally, shoot fresh weights were taken 21 days after 50% control emergence.

Seeds of corn, radish and pea were used during this study. Only untreated seeds were used. A standard soil, type 5M from Lufa, Speyer, Germany, was used as plant growth medium. The soil was a sandy loam (according to USDA) with 10.9 % clay, 27.7 % silt and 61.5 % sand. The pH (CaCl2) was 7.2 and the organic carbon content was with 0.98% within the required < 1.5%.

No pesticides or organic fertilizer were applied to the collecting site over the last three years, which was used as a meadow.

Based on the results of the preliminary test and at the request of the Study Sponsor, this test was conducted as a single concentration limit test (i.e., 100 mg a.i./kg dry soil), but included two additional concentrations (i.e., 10 and 1 mg a.i./kg dry soil). Additionally, an untreated control was performed.

On day 21 after 50% of control emergence, the fresh weight of each plant shoot was recorded. All soil and quality control (QC) samples were extracted and analyzed for Regorafenib (BAY 73-4506 monohydrat) by HPLC based on a validated method.

Emergence rates in the controls and test item concentrations were higher than 70%. All emerged plants of all three tested species survived at concentrations up to 100 mg a.i./kg dry soil. For all species, effects on emergence and shoot fresh weight data were not statistically significant at the 100 mg a.i./kg dry soil treatment level, i.e. the NOEC and LOEC were ¿100 and >100 mg a.i./kg dry soil for all species, respectively.