Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, (2R,3aR,10Z,11aS,12aR,14aR)-

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:

2015-12-18 to 2015-12-30

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method C.2 (Acute Toxicity for Daphnia)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylic acid

EC Number:

618-844-9

Cas Number:

923604-58-4

Molecular formula:

C35H42N4O6S

IUPAC Name:

(1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylic acid

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): JNJ-38940642-AAA (T003010)
- Physical state: solid
- Appearance: white powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I15AB0295
- Manufacture date: 22/01/2015
- Retest date: 22/1/2017
- Purity: 98.7%
- White powder

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability under test conditions: not indicated
- Solubility and stability of the test substance in the solvent/vehicle: solubility in water <0.01 g/L

Sampling and analysis

Analytical monitoring:

yes

Details on sampling:

- Sampling method: samples for possible analysis were taken form all test concentrations and the control at t=0 and t=48h. 2.0 mL of volume was taken from the approximate centre of the test vessels. At the end of the exposure period, the replicates were pooled at each concentration before sampling
- Sample storage conditions before analysis: the samples were stored in a freezer. Additionally, reserve samples of 2.0 mL were taken for possible analysis

Test solutions

Vehicle:

no

Details on test solutions:

PREPARATION AND APPLICATION OF TEST SOLUTION (especially for difficult test substances)
- Method: preparation of test solutions started with a loading rate of 100 mg/L applying 2 days of magnetic stirring at room temperature to ensure the maximum dissolution of the test item in the test medium. This resulted in a hazy dispersion that contained undissolved floating material and precipitate. The dispersion was consequently filtered through a 0.45 µm membrane filter (RC55, Whatman) to remove any non-dissolved material. The filter was preconditioned with a small volume of test solution that was discarded. The resulted SS was used as the highest test concentration. The lower test concentrations were prepared by subsequent dilutions of the SS in test medium.
- Evidence of undissolved material (e.g. precipitate, surface film, etc): final test solutions were clear and colourless

Test organisms

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Common name: Water-flea
- Source: in-house laboratory culture with a known history
- Age at study initiation (mean and range, SD): <24h (from parental daphnids of more than 2 weeks old)
- Method of breeding: 250 newborn daphnids (i.e. less than 3 days old) are placed into 5 litres of medium in an all-glass culture vessel.
- Medium: M7. After 7 days of cultivation half of the medium is renewed twice a week.
- Feeding during test: no

ACCLIMATION
- Acclimation period: max. 4 weeks
- Acclimation conditions (same as test or not): yes
- Type and amount of food: fresh water algae.
- Feeding frequency: daily
- Health during acclimation (any mortality observed): no

Study design

Test type:

static

Water media type:

freshwater

Limit test:

yes

Total exposure duration:

48 h

Test conditions

Hardness:

180 mg/L as CaCO3

Test temperature:

20°C

pH:

At t= 0h: 7.9
At t= 48h: 8.0-8.1

Dissolved oxygen:

At t= 0h: 9.2-9.9
At t= 48h: 9.0-9.1

Salinity:

not relevant

Nominal and measured concentrations:

Range finder:
Nominal concentrations (mg/L): 1.0, 10 and 100

Final test:
Nominal concentration tested (mg/L): 100
Measured concentrations (mg/L) at t=0h: 0.848
Measured concentrations (mg/L) at t=48h: 0.384

Details on test conditions:

TEST SYSTEM
- Test vessel: beaker
- Material, size, headspace, fill volume: 100 mL, glass beaker filled with 80mL
- Aeration: not during the test
- No. of organisms per vessel: 5
- No. of vessels per concentration (replicates): not reported
- No. of vessels per control (replicates): not reported

OTHER TEST CONDITIONS
- Photoperiod: 16h light daily

EFFECT PARAMETERS MEASURED (with observation intervals if applicable) : Immobility was defined as those organisms which are not able to swim within 15 seconds after gentle agitation of the test container and was monitored after 24 and 48 hours of continuous treatment with the test substance.

TEST CONCENTRATIONS
- Spacing factor for test concentrations: x10
- Range finding study: combined/range finding study was performed
- Test concentrations: 1.0, 10 and 100% of a SS prepared at a loading rate of 100 mg/L
- Results used to determine the conditions for the definitive study: yes

Reference substance (positive control):

yes

Remarks:

Potassium dichromate

Results and discussion

Effect concentrations

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

> 100 other: % v/v saturated solution

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mobility

Details on results:

- Mortality of control: none
- Other adverse effects control: no
- Abnormal responses: none
- Measured 24-h EC50 and 48-h EC50 > 0.57 mg/L.

Results with reference substance (positive control):

- Results with reference substance valid? yes (should lie between 0.3 and 1.0 mg/L)
- Mortality:
- EC50/LC50: 48-h EC50 = 0.38 mg/L with a 95% C.L. between 0.33 and 0.43 mg/L. The sensitivity of the daphnia was within the range determined with the historical data collected at WIL Research Europe.

Reported statistics and error estimates:

The average exposure concentrations were calculated as the geometric means of the concentrations of JNJ-38940642-AAA (T003010) measured in the samples taken at the start (t =0h) and the end of the test (t =48h).
The 24-h and 48-h EC50 could not be determined because no effect was observed at any of the tested concentrations.

Applicant's summary and conclusion

Validity criteria fulfilled:

yes

Conclusions:

The acute toxicity of T003010 to Daphnia magna was determined in a 48-hour static test according to the OECD guideline 202. The 48h-EC50 was beyond the concentration range tested, i.e. exceeded an average exposure concentration of 0.57 mg/L.
The results were therefore based on nominal concentrations, expressed as % v/v saturated solution (SS). The 48-h EC50 was determined to be > 100 % of the saturated solution at 100 mg/L test item. The NOErC was >= 100% v/v SS. The results of the test can be considered reliable without restriction.

In conclusion, the test item T003010 clearly had no toxic effect to Daphnia magna up to the maximum solubility in medium obtained with a loading rate of 100 mg/L.