4-trans-propenylveratrole

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

Run on 2015/09

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

1. SOFTWARE
ECOSAR

2. MODEL (incl. version number)
ECOSAR v1.11

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O(c(c(OC)cc(c1)C=CC)c1)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined Endpoint: short term toxicity to aquatic invertebrates (Daphnid).
- Unambigous algorithm: Linear regression QSAR; Log 48h-LC50 (mmol/L) = -0.858*log Kow + 1.3848. To convert the LC50 from mmol/L to mg/L, multiply by the molecular weight.
- Defined domain of applicability: Applicable to chemicals with log Kow less than 5.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of Neutral organics.
- Appropriate measures of goodness-of-fit and robustness and predictivity: N = 98+31 and the coefficient of determination R² = 0.7704.
- Mechanistic interpretation: related to the partitioning of the substance from water into the organisms lipid phase.

5. APPLICABILITY DOMAIN
Applicable to chemicals with log Kow less than 5.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of Neutral organics.

6. ADEQUACY OF THE RESULT
The substance falls within the applicability domain described above and therefore the predicted value can be considered reliable.
For more information, see Neutral organics SAR document in "Attached background material".

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6, May 2008

Deviations:

no

Principles of method if other than guideline:

See attached QPRF.

GLP compliance:

no

Remarks:

(not relevant)

Specific details on test material used for the study:

- log Kow : 2.9 (experimental result)

Details on sampling:

Not applicable

Details on test solutions:

Not applicable

Test organisms (species):

Daphnia sp.

Details on test organisms:

None

Test type:

not specified

Water media type:

not specified

Total exposure duration:

48 h

Remarks on exposure duration:

none

Post exposure observation period:

Not applicable

Hardness:

Not applicable

Test temperature:

Not applicable

pH:

Not applicable

Dissolved oxygen:

Not applicable

Salinity:

Not applicable

Nominal and measured concentrations:

Not applicable

Details on test conditions:

Not applicable

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

14 mg/L

Remarks on result:

other: ECOSAR Class: Neutral Organics

Details on results:

Validity of model:
1. Defined Endpoint: short term toxicity to aquatic invertebrates (Daphnid).
2. Unambigous algorithm: Linear regression QSAR; Log 48h-LC50 (mmol/L) = -0.858*log Kow + 1.3848.
To convert the LC50 from mmol/L to mg/L, multiply by the molecular weight.
3. Applicability domain: applicable to chemicals with log Kow less than 5.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of neutral organic.
4. Statistical characteristics: N = 98+31 and the coefficient of determination R² = 0.7704.
5. Mechanistic interpretation: related to the partitioning of the substance from water into the organisms lipid phase.

Adequacy of prediction: the substance falls within the applicability domain described above and therefore the predicted value can be considered reliable. For more information, see Neutral Organics SAR document in "Attached background material".

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

N = 98+31 and the coefficient of determination R² = 0.7704.

None

Validity criteria fulfilled:

yes

Conclusions:

The substance was predicted to have a LC50 value at 14.0 mg/L to aquatic invertebrates Daphnid after 48h of exposure. The substance falls within the applicability domain and therefore the predicted value can be considered reliable.

Executive summary:

The short term toxicity to daphnid was estimated using the ECOSAR v1.11 QSAR model available from the U.S. EPA.

The estimation 48h-LC50 was 14.0 mg/L (Neutral Organics class), calculated from a measured log Kow value at 2.9 and a linear regression:

Log 48h-LC50 (mmol/L) = -0.858*log Kow + 1.3848.

The substance falls within the applicability domain and therefore the predicted value can be considered reliable.

Reference 2

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2000-10-18 to 2000-10-20

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This study was conducted according to OECD guideline 202 with GLP statement. The test substance was only analytically verified at test beginning, with DOC analysis. No analytical verification of test concentrations was performed at the end of the test. The initial measured concentration at the nominal concentration of 25 mg/L was 23.5 mg/L, that means that the real measured EC50 value is expected at less than 23.5 mg/L. As this result goes in the same trend as QSAR results, this study is assess with a Klimisch score 4, instead of 3.

Qualifier:

according to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

yes

Remarks:

, analytical monitoring not performed at test end.

Qualifier:

according to guideline

Guideline:

EU Method C.2 (Acute Toxicity for Daphnia)

Deviations:

yes

Remarks:

, analytical monitoring not performed at test end.

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected on March 24-25, 1997 / signed on July 07, 1997

Specific details on test material used for the study:

- ThTOC 69.4 %

Analytical monitoring:

yes

Details on sampling:

The test item was analytically verified via DOC analysis according to DIN 38409 part 3. DOC was measured in all concentration levels and control at test start (0 h, fresh media).

Vehicle:

yes

Details on test solutions:

PREPARATION AND APPLICATION OF TEST SOLUTION
- The solution (100 mg/L test item were weighed out) was prepared with dilution water one day prior to application and filtered before use (0.45 µm).
- Dispersion treatment: 24 h an a magnetic stirrer
- Test dilutions: 1:16, 1:8, 1:4, 1:2, 1:1
- Controls: Dilution water without test item tested under the same conditions as the test groups.

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Source: Institut für Wasser-, Boden- und Lufthygiene des Bundesgesundheitsamtes, Corrensplatz, D-14195 Berlin
- Age at study initiation: < 24 h (2-24 h)
- Culture medium: Elendt M4, according to Elendt (1990), modified to a total hardness of 160 to 180 mg CaCO3/L.
- Feeding: 5 times weekly ad libitum with a mix of Scenedesmus subspicatus and Chlorella vulgaris, with an algae cell density of > 10^6 cells/mL.

ACCLIMATION
- Acclimation period: 2 h in dilution water

Test type:

static

Water media type:

not specified

Limit test:

no

Total exposure duration:

48 h

Remarks on exposure duration:

none

Post exposure observation period:

None

Hardness:

268 mg/L as CaCo3

Test temperature:

20.7 °C (21 ± 1 °C)

pH:

7.68

Dissolved oxygen:

8.51 mg/L

Salinity:

Not applicable

Nominal and measured concentrations:

Nominal concentrations: 6.3, 12.5, 25, 50 and 100 mg/L
Measured concentrations: see table 6.1.3/2 in "Any other information on results incl. tables".

Details on test conditions:

TEST SYSTEM
- Test vessel: Glass beakers (5 cm ID x 8 cm H), 50 mL
- Aeration: No
- Type of flow-through (e.g. peristaltic or proportional diluter): Not applicable
- Renewal rate of test solution (frequency/flow rate): Not applicable
- No. of organisms per vessel: 5 (control and test material groups); 10 (reference item)
- No. of vessels per concentration (replicates): 4
- No. of vessels per vehicle control (replicates): 4
- No. of vessels per reference item (replicates): 2

TEST MEDIUM / WATER PARAMETERS
- Dilution water: According to EEC 92/69 L383A C.2.
- Alkalinity: 268 mg CaCO3/L
- Conductivity: 642 µs

OTHER TEST CONDITIONS
- Photoperiod: 16 h light/8 h dark cycle
- Light intensity: Diffuse light, Illumination range 1.5 - 5 µmol/m2/s

EFFECT PARAMETERS MEASURED:
- Prior to test start pH-values, dissolved oxygen concentration, conductivity, total hardness and temperature of the dilution water were measured.
- At the beginning of the test water parameters (pH value, oxygen concentration) were measured in one additional replicate per concentration and control groups. After 48 h the water parameters in the old media were measured in all replicates per concentration and control. The temperature was recorded throughout the test with a thermohygrograph.
- The percentage immobility was determined in all test and control groups after 24 h and 48 h.

TEST CONCENTRATIONS
- Range finding study
- Test concentrations: 1, 10 and 100 mg/L
- Results used to determine the conditions for the definitive study: After 48 h of exposure the total rate of immobilisation of daphnia was 100 % at the concentration of 100 mg/L. No biologically significant effect was seen at the concentration of 10 mg/L.

Reference substance (positive control):

yes

Remarks:

Potassium dichromate (0.58, 1.0, 1.8, 3.2 and 5.8 mg/L)

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

25 mg/L

Nominal / measured:

nominal

Conc. based on:

test mat.

Basis for effect:

mobility

Remarks on result:

other: 23-27 mg/L

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

16.26 mg/L

Nominal / measured:

meas. (initial)

Conc. based on:

test mat.

Basis for effect:

mobility

Details on results:

- Immobilization of daphnids for the definitive test was 0, 0, 0, 30, 95 and 100 % (24 h); 0, 0, 0, 55, 100 and 100 % (48 h) at 0, 6.3, 12.5, 25, 50 and 100 mg/L, respectively.
- Water quality parameters of pH-value and dissolved oxygen concentration measured at 0 and 48 h were determined to be within the acceptable limits.
- Analytical verification with DOC only at 0 h (65, 82, 94, 99 and 95 % at 6.3, 12.5, 25, 50 and 100 mg/L, respectively). See table 6.1.3/2 in "Any other information on results incl. tables".

Results with reference substance (positive control):

A reference test is carried out once per month with potassium dichromate as reference item and the reference toxicity determined. The EC50 -value of the reference item at 2.0 mg/L alter 24 h was within the prescribed concentration range of 1.0 to 2.5 mg/L according to AQS, DIN Guideline 38412 L 30.

Reported statistics and error estimates:

None

Table 6.1.3/1: Percentage of Daphnids Incapable of Swimming after 24 and 48 h of Exposure (n = 20)

 

Concentration (mg/L)	IMMOBILISATION [%]
	24 h					48 h
	1	2	3	4	MV	1	2	3	4	MV
100	100	100	100	100	100	100	100	100	100	100
50	100	100	100	80	95	100	100	100	100	100
25	60	20	20	20	30	60	60	60	40	55
12.5	0	0	0	0	0	0	0	0	0	0
6.3	0	0	0	0	0	0	0	0	0	0
Control	0	0	0	0	0	0	0	0	0	0

 

Validity criteria:

The validity criteria were fulfilled:

- In the control group no Daphnia were immobilised or trapped on the surface of the water.

- The EC50 -value after 24 h of the reference item was in the range of 1.0 to 2.5 mg/L.

- The dissolved oxygen concentration was > 5.21 mg/L (60 % of the air saturation value at the temperature used).

- The pH-value did not vary by more than 1 unit. Table 6.1.3/2: DOC Analysis at the start of the test

Table 6.1.3/2: DOC analysis at the start of the test

Test concentration (mg/L)	DOC (mg/L)			Recovery rate (%)
	Nominal*	Measured	Corrected**
100 50 25 12.5 6.3 Control	69.40 34.70 17.35 8.68 4.37 -	67.81 36.23 18.11 9.00 4.69 1.85	65.96 34.38 16.26 7.15 2.84 -	95 99 94 82 65 -

* Nominal DOC based on ThTOC (0.694 mg C/mg)

** Corrected against control

Validity criteria fulfilled:

yes

Conclusions:

Under the test conditions, the 48 h-EC50 for test item to Daphnia magna is 25 mg/L (95% CL: 23-27 mg/L), based on nominal concentrations. The test substance was only analytically verified at test beginning, with DOC analysis. No analytical verification of test concentrations was performed at the end of the test. The initial measured concentration at the nominal concentration of 25 mg/L was 16.26 mg/L. As some loss of test substance may be expected during the duration of the test, the mean measured 48h-EC50 value may be expected to be less than 16.26 mg/L.

Executive summary:

This study was performed according to OECD Guideline 202 with GLP statement, to assess the 48 h-acute toxicity of the of the test substance to Daphnia magna, under static conditions.

The daphnids were exposed to the test item at concentrations of 6.3, 12.5, 25, 50 and 100 mg/L for 48 hours. The control daphnids were exposed to dilution water only. There were four replicates per treatment with five daphnids per replicate, which provided a total of twenty daphnids per each treatment and control group at test initiation. All test solutions were prepared in dilution water. The test temperature was 20.7 °C. The test item solutions were clearly dissolved after filtration in all tested concentration levels throughout exposure. Before definitive test, a 48-hour static range-finding test was conducted at the nominal concentrations of 1, 10 and 100 mg/L and the percent immobilization was 100% at 100 mg/L; no biologically significant effect was seen at the concentration of 10 mg/L. Analytical verification with DOC was performed only at the start of the test. The recovery rate were 65, 82, 94, 99 and 95 % at 6.3, 12.5, 25, 50 and 100 mg/L, respectively.

 

Immobilization of daphnids for the definitive test was 0, 0, 0, 30, 95 and 100 % (24 h); 0, 0, 0, 55, 100 and 100 % (48 h) at 0, 6.3, 12.5, 25, 50 and 100 mg/L, respectively. Based on nominal concentrations, the calculated 48-hour EC50 value was 25 mg/L (95% confidence interval of 23 to 27 mg/L). The EC50 -value of the reference item at 2.0 mg/L after 24 h was within the prescribed concentration range of 1.0 to 2.5 mg/L.

Under the test conditions, the 48 h-EC50 for test item to Daphnia magna is 25 mg/L (95% CL: 23-27 mg/L), based on nominal concentrations. The initial measured concentration at the nominal concentration of 25 mg/L was 16.26 mg/L. As some loss of test substance may be expected during the duration of the test, the mean measured 48h-EC50 value may be expected to be less than 16.26 mg/L.

Reference 3

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

From 2015-08-04 to 2015-08-05

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
iSafeRat® HA-QSAR toolbox v1.1

2. MODEL (incl. version number)
iSafeRat® High Accuracy QSAR – version 1.4

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O(c(c(OC)cc(c1)C=CC)c1)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF

5. APPLICABILITY DOMAIN
See attached QPRF

6. ADEQUACY OF THE RESULT
See attached QPRF

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test)

Deviations:

not applicable

Remarks:

(QSAR model)

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method C.2 (Acute Toxicity for Daphnia)

Deviations:

not applicable

Remarks:

(QSAR model)

Principles of method if other than guideline:

The purpose of this QSAR is to accurately predict the acute toxicity to daphnid as would be expected in a laboratory experiment following OECD Guideline 202 and EC method C.2 for specific, named modes of action (e.g. non-polar narcotics) to provide a value that can effectively replace a 48-hour EC50 value from an experimental study. The regression based method used to achieve this has been fully validated following the OECD (2004) recommendations (refer to the QMRF with JRC QMRF identifier: Q19-46-41-422 for further details).

GLP compliance:

no

Specific details on test material used for the study:

- Mode of action: non-polar narcotic (MOA 1)
- Water solubility: 297 mg/L (from experimental study)

Analytical monitoring:

no

Details on sampling:

Not applicable

Vehicle:

no

Details on test solutions:

Not applicable

Test organisms (species):

other: Daphnia magna, Daphnia pulex

Details on test organisms:

Results from the following species were used in the regression: Daphnia magna, Daphnia pulex.
Following the principles of Phase Equilibrium Thermodynamics, for narcotic substances, no difference in relationship between solubility and ecotoxicity between invertebrate (or indeed other) aquatic species is expected. Any observed differences may be attributed to lifestyle related parameters (e.g. shell closing in molluscs) and relative duration of study versus bodysize rather than to a specific toxic mechanism causing species differences. In this case, for MOA 1, no differences were observed in activity based toxicity for the 2 species used.

Test type:

other: QSAR

Water media type:

freshwater

Limit test:

no

Total exposure duration:

48 h

Remarks on exposure duration:

none

Post exposure observation period:

Not applicable

Hardness:

The QSAR is based on data from studies performed at acceptable hardness to ensure control survival.

Test temperature:

The temperatures varied from approximately 20 to 23 °C depending on the species used to construct the algorithm. This small difference is not expected to contribute to the variability of the EC50 values found in experimental data.

pH:

The QSAR is based on data from studies performed at acceptable pH between 6.0 - 9.0.

Dissolved oxygen:

The QSAR is based on data from studies performed at acceptable oxygen concentrations (generally >60%).

Salinity:

Not applicable.

Nominal and measured concentrations:

The QSAR is based on data from studies performed using measured concentrations or with acceptable stability.

Details on test conditions:

Not applicable

Reference substance (positive control):

no

Remarks:

QSAR model

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

13 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

mobility

Remarks on result:

other: 95% CL: 12-14 mg/L

Details on results:

The water solubility value given as input to the Ecotox module of the iSafeRat® Holistic HA-QSAR falls within the descriptor domain of the model between log water solubility (in log (mol/L)) of -4.70 to 0.87. Moreover the test substance is attributed to the class of non-polar narcotic compounds (MOA 1).

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% CL: 12-14 mg/L
QSAR statistical parameters are given in the QMRF and the QPRF

No additional information

Validity criteria fulfilled:

yes

Remarks:

The substance falls into the applicability domains of the QSAR model.

Conclusions:

The 48-h EC50 based on mobility and measured concentrations was determined to be 13 mg/L with 95%-Confidence Limit between 12 and 14 mg/L.

Executive summary:

A QSAR prediction was performed to assess the acute toxicity of the test substance to daphnid. This QSAR has been validated to be compliant with the OECD recommendations for QSAR modelling (OECD, 2004) and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following OECD Guideline 202. The criterion predicted was the EC50 (Median Effective Concentration), a statistically derived concentration which is expected to cause immobility in 50% of test animals within a period of 48 hours.

 

The immobility of the daphnids was determined using a validated QSAR for the Mode of Action in question, (MOA 1, non-polar narcosis). The QSAR is based on validated data for a training set of 58 chemicals derived from 48-hour tests on daphnids, for which the concentrations of the test substance had been determined by chemical analyses over the test period. The water solubility of the substance given as input was experimentally measured at 297 mg/L. The substance falls within the applicability domain of the model as demonstrated in the QPRF.

The 48-h EC50 based on mobility and measured concentrations was determined to be 13 mg/L with 95%-Confidence Limit between 12and 14 mg/L.

Description of key information

Geometric mean of QSARs data (iSafeRat v1.4 and ECOSAR v1.11) and experimental study (OECD Guideline 202, GLP):

48h-EC50 = 14.4 mg/L.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

14.4 mg/L

Additional information

To assess the short-term toxicity of the registered substance, (E)-1 ,2 -Dimethoxy-4 -prop-1 -en-1 -ylbenzene, to aquatic invertebrates, a weight of evidence approach with two reliable QSAR results and one experimental study performed on the registered substance is used.

The first prediction data (KREATiS, 2015) is a QSAR. This QSAR prediction (iSafeRat holistic approach v1.4) was performed on the registered substance, to assess the acute toxicity of the substance to daphnids. This QSAR has been validated to be compliant with the OECD recommendations for QSAR modelling (OECD, 2004) and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following OECD Guideline 202. The immobility of the daphnids was determined using a validated QSAR for the Mode of Action in question, (MOA 1, non-polar narcosis). This QSAR is based on validated data for a training set of 58 chemicals derived from 48-hour tests on daphnids, for which the concentrations of the test substance had been determined by chemical analyses over the test period. The substance falls within the applicability domain of the model. The 48h-EC50 value based on mobility and measured concentrations was determined to be 13 mg/L (95% CL: 12 - 14 mg/L).

The second prediction data (ECOSAR, 2015) is also a QSAR. This QSAR prediction used the ECOSAR v1.11 QSAR model available from the U.S. EPA to assess the acute toxicity of the registered substance to daphnids. The substance falls within the applicability domain of the model. The estimation 48h-LC50 was determined at 14.0 mg/L using the chemical class of Neutral Organics.

The experimental study (NOACK, 2000), performed on the registered substance, was conducted according to OECD Guideline 202 with GLP statement. In this study, the test substance was exposed to Daphnia magna at the concentrations of 0 (control with dilution water only), 6.3, 12.5, 25, 50 and 100 mg/L for 48 hours, under static conditions (four replicates per treatment; five daphnids per replicate). According to the results of this study, the 48h-EC50 value was determined at 25 mg/L (95% CL: 23 - 27 mg/L), based on nominal concentrations. The test substance was only analytically verified at test beginning, with DOC analysis. No analytical verification of test concentrations was performed at the end of the test. The initial measured concentration at the nominal concentration of 25 mg/L was 16.26 mg/L. As some loss of test substance may be expected during the duration of the test, the mean measured 48h-EC50 value may be expected to be less than 16.26 mg/L. This result is completely in line with the QSAR results on aquatic invertebrates performed on the registered substance which are both very close to the measured value from the daphnid study.

In conclusion, according to this weight of evidence approach, the key 48h-EC50 value on daphnids, used for chemical safety assessment, is determined at 14.4 mg/L, corresponding to a geometric mean of predicted EC50 values (13 mg/L for iSafeRat holistic approach v1.4; 14.0 mg/L for ECOSAR v1.11) and experimental EC50 value (16.26 mg/L).