N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide

Short-term toxicity to aquatic invertebrates

Administrative data

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 2013 to March 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

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 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

not applicable

Remarks:

Light intensity ranged from 27 to 107 footcandles; slightly outside the acceptable range criteria. This deviation is not considered to have had an impact on the results or interpretation of this study.

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide

EC Number:

801-607-0

Cas Number:

302962-49-8

Molecular formula:

C22 H26 Cl N7 O2 S

IUPAC Name:

N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide

Test material form:

not specified

Remarks:

Purity grade not specified

Specific details on test material used for the study:

Powder form stored at -20 °C.

Sampling and analysis

Analytical monitoring:

yes

Details on sampling:

The number of immobilized daphnids in each replicate test vessel was recorded at 0, 24 and 48 hours of exposure. Biological observations and observations of the physical characteristics of each replicate exposure solution and control were also made and recorded at 0, 24 and 48 hours, if applicable. The pH, dissolved oxygen concentration and temperature were measured at 0, 24 and 48 hours in replicate A of each treatment level and control.

Test solutions

Vehicle:

yes

Remarks:

DMF

Details on test solutions:

Exposure was conducted at nominal concentrations of 0.097, 0.21, 0.47, 1.0, 2.3 and 5.0 mg/L.

Test organisms

Test organisms (species):

Daphnia magna

Details on test organisms:

Age: < 24 hours old at exposure initiation
Source: Smithers Viscient culture facility

Study design

Test type:

static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

48 h

Post exposure observation period:

Not specified

Test conditions

Hardness:

Total hardness of dilution water: CaCO3: 180 mg/L

Test temperature:

19 to 21 ºC

pH:

pH: 8.1

Dissolved oxygen:

c.a. 10mg/L

Salinity:

Freshwater

Conductivity:

c.a. 620 μS/cm,

Details on test conditions:

Nominal: 0.097, 0.21, 0.47, 1.0, 2.3 and 5.0 mg/L
Measured: 0.093, 0.21, 0.47, 1.0, 2.3 and 5.1 mg/L

Reference substance (positive control):

no

Results and discussion

Effect concentrations

Effect concentrations 1

Key result

Duration:

24 h

Dose descriptor:

NOEC

Effect conc.:

> 5.1 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

mobility

Effect concentrations 2

Key result

Duration:

48 h

Dose descriptor:

NOEC

Effect conc.:

ca. 3.7 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

mobility

Details on results:

Following 48 hours of exposure, 0, 0, 0, 15, 20 and 70% immobilization was observed in the 0.093, 0.21, 0.47, 1.0, 2.3 and 5.1 mg/L treatment levels, respectively. Several daphnids exposed to the 1.0 mg/L treatment level were observed to be lethargic following 48 hours of exposure. All surviving daphnids exposed to the 2.3 and 5.1 mg/L treatment levels were observed to be on the bottom of the test vessel following 48 hours of exposure. Following 48 hours of exposure 5% immobilization was observed among daphnids exposed to the control and no immobilization or adverse effects were observed among daphnids exposed to the solvent control.

Any other information on results incl. tables

Mean Measured Concentration (mg/L)	Cumulative Percent Immobilization (a)
	24-hour					48-hour
	A	B	C	D	Mean	A	B	C	D	Mean
Control	0	0	0	0	0	20	0	0	0	5b
	(0)	(0)	(0)	(0)		(1)	(0)	(0)	(0)
Solvent Control	0	0	0	0	0	0	0	0	0	0
	(0)	(0)	(0)	(0)		(0)	(0)	(0)	(0)
0.093	0	0	0	0	0	0	0	0	0	0
	(0)	(0)	(0)	(0)		(0)	(0)	(0)	(0)
0.21	0	0	0	0	0	0	0	0	0	0
	(0)	(0)	(0)	(0)		(0)	(0)	(0)	(0)
0.47	0	0	0	0	0	0	0	0	0	0
	(0)	(0)	(0)	(0)		(0)	(0)	(0)	(0)
1	0	0	0	0	0	0	20	20	20	15c
	(0)	(0)	(0)	(0)		(0)	(1)	(1)	(1)
2.3	0	0	0	0	0c	20	40	0	20	20d
	(0)	(0)	(0)	(0)		(1)	(2)	(0)	(1)
5.1	0	0	0	0	0c	80	60	80	60	70d
	(0)	(0)	(0)	(0)		(4)	(3)	(4)	(3)
a The actual number of immobilized daphnids is presented in parentheses.
b ASTM (2002) recognizes the limitations of acute toxicity testing, i.e., response less than or equal to 10% is allowable in a control population and is considered within the expected range of naturally occurring variability.
c Several daphnids were observed to be lethargic.
d All surviving daphnids were observed to be on the bottom of the test vessel.

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

Based on mean measured concentrations of dasatinib, the 48−hour EC50 value for dasatinib and Daphnia magna was determined to be 3.7 mg/L. The No-Observed-Effect Concentration (NOEC) was determined to be 0.47 mg/L. The highest concentration producing 0% toxicant-related immobilization was 0.47 mg/L. No concentration tested produced 100% immobilization.

Executive summary:

Based on mean measured concentrations of dasatinib, the 48−hour EC50 value for dasatinib and Daphnia magna was determined to be 3.7 mg/L. The No-Observed-Effect Concentration (NOEC) was determined to be 0.47 mg/L. The highest concentration producing 0% toxicant-related immobilization was 0.47 mg/L. No concentration tested produced 100% immobilization.