2-(1-(3',3'-dimethyl-1'-cyclohexyl)ethoxy)-2-methyl propyl propanoate

Long-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

long-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 11 March 2002 to 6 November 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

This study was carried out according to international OECD Guideline No. 211 with GLP statement. All validity criteria were fulfilled.

Qualifier:

according to guideline

Guideline:

OECD Guideline 211 (Daphnia magna Reproduction Test)

Deviations:

yes

Remarks:

The number of adults with eggs in the brood pouch were recorded daily as opposed to only at media renewal time points. This deviation was considered to have no effect on the results of the test.

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

2000-04-26

Analytical monitoring:

yes

Details on sampling:

- Concentrations: Water samples were taken from the control and each surviving test group 0.030, 0.095, 0.30, 0.95 and 3.0 mg/L (replicates pooled) for quantitative analysis.
- Sampling method: A volume of test sample was extracted with dichloromethane (3 x 50 mL). The extracts were filtered through anhydrous sodium sulphate. The combined extracts were evaporated to dryness and the residue re-dissolved in ethyl acetate to give a final theoretical concentration
of approximately 10 mg/L.
- Sample storage conditions before analysis: Duplicate samples were taken and stored frozen at approximately -20°C for further analysis if necessary.

Vehicle:

no

Details on test solutions:

PREPARATION AND APPLICATION OF TEST SOLUTION (especially for difficult test substances)
- Method: An amount of test material (1100 mg) was dispersed in 11 litres of reconstituted water and stirred with a propeller stirrer (approximately 2000 rpm) for a period of 24 hours at 25°C. After 24 hours stirring the mixture was cooled to approximately 21°C prior to filtration (0.2 µm Gelman Suporcap, approximately 5 litres discarded in order to precondition the filter) to give a saturated solution of nominal test concentration 3.0 mg/l. Aliquots of the nominal 3.0 mg/l test concentration (20, 63.3, 200 and 633 ml) were each separately dispersed in a final volume of 2 litres of reconstituted water to give the nominal test concentrations of 0.030, 0.095, 0.30 and 0.95 mg/l.
- Eluate: reconstituted water
- Differential loading: no data
- Controls: 1 control
- Chemical name of vehicle (organic solvent, emulsifier or dispersant): not applicable
- Concentration of vehicle in test medium (stock solution and final test solution(s) including control(s)): not applicable
- Evidence of undissolved material (e.g. precipitate, surface film, etc): no data

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Common name: Daphnia magna
- Strain/clone: no data
- Justification for species other than prescribed by test guideline: not applicable
- Source: in-house laboratory cultures
- Age of parental stock (mean and range, SD): less than 24 hours old
- Feeding during test: yes
- Food type: a unicellular algal culture (Chlorella sp.)
- Amount: approximately 2.0 - 5.8 µL of a unicellular algal culture (approximately 0.1 - 0.2 mg carbon/daphnid/day, dependent on the age and size of the animals).
- Frequency: daily

ACCLIMATION
- Acclimation period: no data
- Acclimation conditions (same as test or not):same as test
- Type and amount of food: a suspension of algae (Chlorella sp.)
- Feeding frequency: daily
- Health during acclimation (any mortality observed): no data

QUARANTINE (wild caught)
not applicable

METHOD FOR PREPARATION AND COLLECTION OF EARLY INSTARS OR OTHER LIFE STAGES: no data

Test type:

semi-static

Water media type:

freshwater

Limit test:

no

Total exposure duration:

21 d

Remarks on exposure duration:

none

Post exposure observation period:

None

Hardness:

The water hardness was observed to be in the range 245 to 268 mg/L as CaCO3 in the control and the highest surviving test group throughout the test.

Test temperature:

Temperature was maintained at 21.0°C throughout the test

pH:

The pH varied between 7.8 to 8.0 throughout the study.

Dissolved oxygen:

The dissolved oxygen varied between 90 to 97 % Air Saturation Value throughout the study.

Salinity:

Not applicable

Nominal and measured concentrations:

Nominal concentrations: 0.030, 0.095, 0.30, 0.95 and 3.0 mg/L.
Measured concentrations: See tables in "Any other information on results incl. tables". The TWM measured concentrations were 0.032, 0.063, 0.20, 0.66, 2.0 mg/L. These concentrations were recalculated.

Details on test conditions:

TEST SYSTEM
- Test vessel: glass flasks
- Type (delete if not applicable): covered with a plastic lid to reduce evaporation
- Material, size, headspace, fill volume: 150 mL
- Aeration: not aerated
- Type of flow-through (e.g. peristaltic or proportional diluter): not applicable
- Renewal rate of test solution (frequency/flow rate): the test preparations were renewed 3 times per week on days 2, 5, 7, 9, 12, 14, 16 and 19.
- No. of organisms per vessel: 1
- No. of vessels per concentration (replicates):10
- No. of vessels per control (replicates): 10
- No. of vessels per vehicle control (replicates): not applicable
- Biomass loading rate: no data

TEST MEDIUM / WATER PARAMETERS
- Source/preparation of dilution water: 25 ml of each of solutions (CaCl2.2H2O= 11.76 g/L; MgSO4.7H2O= 4.93 g/L; NaHCO3 = 2.59 g/L; KCL = 0.23 g/L) were added to each litre (final volume) of deionised water (conductivity <5µS cm-1). pH equal to 7.8 ± 0.2, adjust (if necessary) with NaOH or HCl. The reconstituted water was aerated until the dissolved oxygen concentration was approximately air-saturation value.
- Total organic carbon: no data
- Particulate matter: no data
- Metals: no data
- Pesticides: no data
- Chlorine: no data
- Alkalinity: no data
- Ca/mg ratio: no data
- Conductivity: <5µS cm-1
- Culture medium different from test medium: no
- Intervals of water quality measurement: no data

OTHER TEST CONDITIONS
- Adjustment of pH: if necessary
- Photoperiod: 16 hours light and 8 hours darkness with 20 minute dawn and dusk transition period for 21 days
- Light intensity: 416 to 565 lux

EFFECT PARAMETERS MEASURED (with observation intervals if applicable) : On a daily basis the numbers of live and dead of the "Parental" (PI) generation, the numbers of live and dead "Filial" (F1) Daphnia and the number of discarded unhatched eggs were counted. An assessment was also made of the general condition and size of the parental Daphnia as compared with the controls. The number of Daphnia with eggs or young in the brood pouch was determined daily. At the end of the test, the length of each surviving parent animal was determined.

VEHICLE CONTROL PERFORMED: not applicable

RANGE-FINDING STUDY
no

Reference substance (positive control):

no

Duration:

21 d

Dose descriptor:

LOEC

Effect conc.:

0.66 mg/L

Nominal / measured:

meas. (TWA)

Conc. based on:

test mat.

Key result

Duration:

21 d

Dose descriptor:

NOEC

Effect conc.:

0.2 mg/L

Nominal / measured:

meas. (TWA)

Conc. based on:

test mat.

Details on results:

- Lethal effects on the parental generation (P1):
Mortality (immobilisation) occurred predominantly at the highest test concentration of 3.0 mg/I resulting in 50% and 100% mortality by Days 7 and 12 respectively. Significant mortality (immobilisation) also occurred throughout the test in the 0.95 mg/l test group resulting in 30% and 100% mortality by Days 14 and 16 respectively indicating a prolonged toxic effect attributable to exposure of Daphnia magna to the test material.

- Sub-lethal effects on the parental generation (P1):
The surviving daphnids at the 3.0 mg/l test concentration were observed to be markedly smaller than the control animals on Days 2, 3 and 4 and smaller and paler than the control animals on Days 5, 6, 7, 8,9, 10 and 11 prior to the observation of 100% mortalities on Day 12. Some of the daphnids at the 0.95 mg/l test concentration were observed to be paler than the control animals prior to the observation of 100% mortalities on Day 16.
After 21 days there were no statistically significant differences between the control, 0.030, 0.095 and 0.30 mg/I test groups in terms of the number of live young produced per adult. The 0.95 and 3.0 mg/I test groups data were not included in the statistical analysis as exposure to the test
material eliminated all the daphnids prior to Day 21 of the test. The 21-Day ECso (reproduction) value based on nominal test concentrations was estimated to lie between 0.30 and 0.95 mg/l on the basis that at 0.30 mg/I there was no significant difference (P>=0.05) in terms of the number of young produced per adult when compared to the control and that the adult daphnids at 0.95 mg/l were eliminated from the test by Day 16 due to a prolonged toxic effect of the test material.
After 21 days the length of each surviving adult was determined. The results showed that there were no statistically significant differences (P>=0.05) between the control, 0.030, 0.095 and 0.30 mg/l test groups in terms of length of the daphnids after 21 days exposure to the test material. The 0.95 and 3.0 mg/l test group data was not included in this analysis as exposure to the test material eliminated all the daphnids prior to Day 21 of the test.

- Chemical analysis:
The decline was due to the suspected volatile nature of the test material (Henry's Law Constant of 2218, thus indicating high potential for losses du to volatility) and possible adsorption of the test material to the algal feed, test organisms and/or their waste products over each period of media renewal. Given the variability shown in the measured test concentrations of the fresh test media and the marked decline shown in the old or expired test samples it was considered appropriate to base the results of the test on the time-weighted mean measured test concentrations.
The time-weighted mean measured concentrations were recalculated and some differences were observed based on the study report.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

See above in "Details on results".

Table 6.1.4/1: Measured concentrations

Nominal concentration (mg/L)	Control	0,03	0,095	0,30	0,95	3,00
Day 0, fresh medium	<LOQ	0,41	0,139	0,404	1,27	4,31
Day 2, old medium	<LOQ	0,0139	0,0482	0,121	0,461	1,32
Day 2, fresh medium	<LOQ	0,0394	0,123	0,32	1,33	3,73
Day 5, old medium	<LOQ	0,0108	0,0307	0,0757	0,212	0,636
Day 5, fresh medium	<LOQ	0,0361	0,0939	0,314	1,08	3,33
Day 7, old medium	<LOQ	0,0164	0,0457	0,117	0,422	1,1
Day 7, fresh medium	<LOQ	0,0373	0,118	0,387	1,27	3,72
Day 9, old medium	<LOQ	0,0128	0,0424	0,124	0,362	1,2
Day 9, fresh medium	<LOQ	0,043	0,117	0,362	1,21	3,81
Day 12, old medium	<LOQ	0,00674	0,015	0,0334	0,176	0,497
Day 12, fresh medium	<LOQ	0,041	0,113	0,4	1,29	-
Day 14, old medium	<LOQ	0,00985	0,0259	0,0852	0,272	-
Day 14, fresh medium	<LOQ	0,04	0,0906	0,409	1,22	-
Day 16, old medium	<LOQ	0,0176	0,0307	0,111	0,316	-
Day 16, fresh medium	<LOQ	0,0442	0,111	0,414	-	4,006
Day 19, old medium	<LOQ	0,0111	0,0242	0,0904	-	-
Day 19, fresh medium	<LOQ	0,0413	0,101	0,346	-	3,48
Day 21, old medium	<LOQ	0,0105	0,0374	0,103	-	-

Table 6.1.4/2: TWM measured concentrations

Nominal concentrations (mg/L)	TWM measured concentrations (mg/L)
0,03	0,032
0,095	0,063
0,3	0,2
0,95	0,66
3	2

Validity criteria fulfilled:

yes

Conclusions:

The LOEC and the NOEC based on the time-weighted mean measured test concentrations were 0.66 and 0.20 mg/L, respectively.

Executive summary:

This study was performed to assess the effect of the test material on the reproduction of Daphnia magna over a 21 -day period. The method followed that described in the OECD Guideline No. 211.

Daphnia magna were exposed (10 replicates of a single daphnid per group) to an aqueous solution of the test material over a range of nominal test concentrations of 0.030, 0.095, 0.30, 0.95 and 3.0 mg/L (the saturated solution was allocated a nominal test concentration of 3.0 mg/L) which corresponds to time-weighted mean measured test concentrations of 0.032, 0.063, 0.20, 0.66 and 2.0 mg/L for a period of 21 days. The test solutions were renewed 3 times per week. The numbers of live and dead adult Daphnia and young daphnids (live and dead) were determined daily. The Daphnia were fed daily with an algal suspension.

Analysis of the old or expired test media showed a marked decline in the measured test concentrations. For this reason, it was considered appropriate to base the results of the test on the time-weighted mean measured test concentrations. The LOEC and the NOEC based on the time-weighted mean measured test concentrations were 0.66 and 0.20 mg/L, respectively.

Reference 2

Endpoint:

long-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Remarks:

QSAR result on the C6 isomers of the transformation product of the registered substance

Adequacy of study:

supporting study

Study period:

Run on 2016-01

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

Remarks:

(Q)SAR method with established scientific validity. The substance, C6 isomers of the transformation product of the registered substance, falls within the applicability domain of the model.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

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

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C6 isomers of the transformation product of the registered substance: C1C(C)(C)CCCC1C(C)OC(C)(C)COH
log Pow: 4.33 (experimental result)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Neutral Organics SAR document in "Attached background material".

5. APPLICABILITY DOMAIN
See attached QPRF

6. ADEQUACY OF THE RESULT
See attached QPRF

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 Pow: 4.33 (experimental result)

Details on sampling:

Not applicable

Details on test solutions:

Not applicable

Test organisms (species):

Daphnia sp.

Details on test organisms:

Not applicable

Test type:

not specified

Water media type:

not specified

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

Dose descriptor:

other: ChV

Effect conc.:

0.19 mg/L

Remarks on result:

other: ECOSAR Class: Neutral Organics

Details on results:

Validity of model:
1. Defined Endpoint: Long term toxicity to aquatic invertebrates (daphnid chronic value).
2. Unambigous algorithm: Linear regression QSAR; Log ChV (mmol/L) = -0.7464*log Kow + 0.1507.
To convert the ChV from mmol/L to mg/L, multiply by the molecular weight.
3. Applicability domain: applicable to chemicals with log Kow less than 8.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of neutral organic.
4. Statistical characteristics: N = 26+1 and the coefficient of determination R² = 0.8728.
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 = 26+1 and the coefficient of determination R² = 0.8728.

No additional information

Validity criteria fulfilled:

yes

Conclusions:

The C6 isomers of the transformation product of the registered substance was predicted to have a chronic value ChV of 0.19 mg/L to aquatic invertebrates daphnid. The substance falls within the applicability domain and therefore the predicted value can be considered reliable.

Executive summary:

The long term toxicity to aquatic invertebrates of the C6 isomers of the transformation product of the registered substance was estimated using the ECOSAR v1.11 QSAR model available from the U.S. EPA.

The estimation chronic value ChV was 0.19 mg/L (neutral organics class), calculated from a measured log Kow value (4.33) and a linear regression:

Log ChV (mmol/L) = -0.7464*log Kow + 0.1507

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

Reference 3

Endpoint:

long-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Remarks:

QSAR result on the C6 isomers of the transformation product of the registered substance

Adequacy of study:

supporting study

Study period:

From 2016-01-05 to 2016-01-06

Reliability:

1 (reliable without restriction)

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

Remarks:

QSAR value. The substance, the C6 isomers of the transformation product of the registered substance, falls into the applicability domain of the model QSAR

Justification for type of information:

1. SOFTWARE
iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity : Long-term toxicity to Daphnia magna

2. MODEL (incl. version number)
iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity v1.1.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C6 isomers of the transformation product of the registered substance: C1C(C)(C)CCCC1C(C)OC(C)(C)COH
Water solubility = 35.0 mg/L (KREATIS internal study, 2015), derived using the log Kow experimental value at 4.33

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 211 (Daphnia magna Reproduction Test)

Deviations:

not applicable

Remarks:

(QSAR model)

Principles of method if other than guideline:

The purpose of this QSAR model is to accurately predict the chronic toxicity to daphnid as would be expected in a laboratory experiment following OECD Guideline 211 for specific, named modes of action to provide a value that can effectively replace a 21-day NOEC 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 KREATiS QMRF identifier: KTS/QMRF/CHR/01 for further details).

GLP compliance:

no

Specific details on test material used for the study:

- Mode of action: non-polar narcotic (MOA 1 or MechoA 1.1)
- Log Kow = 4.33 (from experimental study)
- Water solubility = 35.0 mg/L (KREATIS internal study, 2015)

Analytical monitoring:

no

Details on sampling:

Not applicable

Vehicle:

no

Details on test solutions:

Not applicable

Test organisms (species):

Daphnia magna

Details on test organisms:

None

Test type:

other: QSAR

Water media type:

freshwater

Limit test:

no

Total exposure duration:

21 d

Post exposure observation period:

None

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. This small difference is not expected to contribute to the variability of the NOEC values found in experimental data.

pH:

Test results were taken from studies with measured pHs between 6 - 9.

Dissolved oxygen:

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

Salinity:

Not applicable

Nominal and measured concentrations:

Studies were used only where analytical measurements were made on the control and all relevant test concentrations whenever possible. Any exceptions (initial concentrations measured only or NOEC based on nominal values) were used only when sufficient justification for stability of the test was determined.

Details on test conditions:

Only results from semi-static studies were used. For suspected volatile substances only tests performed in closed vessels were accepted unless accompanying analytical monitoring proved such a design was not necessary.

Reference substance (positive control):

no

Remarks:

(QSAR model)

Key result

Duration:

21 d

Dose descriptor:

NOEC

Effect conc.:

0.23 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

reproduction

Remarks on result:

other: 95% CL: 0.18-0.31 mg/L

Details on results:

The predicted value is reliable since the test substance falls within the applicability domain of the model. The water solubility value of the test substance is within descriptor domain of the model between log water solubility (in log (mol/L)) of -5.91 to -0.09. Moreover the test substance is attributed to the class of non-polar narcotic compounds.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% CL: 0.18-0.31 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 domain of the QSAR model.

Conclusions:

The 21-day NOEC of the C6 isomers of the transformation product of the registered substance to daphnids, based on reproduction and measured concentrations, was determined to be 0.23 mg/L with 95%-Confidence Limit between 0.18 and 0.31 mg/L.

Executive summary:

A QSAR model was used to calculate the chronic toxicity of the test item to daphnid. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following OECD Guideline 211. The criterion predicted was the NOEC (No Observed Effect Concentration), a tested concentration which is expected to cause no effect on reproducibility within a period of 21 days.

The chronic toxicity of the daphnids was determined using a validated QSAR model for the Mode of Action in question (MOA 1 or MechoA 1.1, non-polar narcosis). The QSAR is based on validated data for a training set of 30 chemicals derived from 21-day test on daphnids, for which the concentrations of the test item had been determined by chemical analyses over the test period. The water solubility of the substance given as input was predicted by the iSafeRat® solubility module using the experimental log Kow value of the substance, measured at 4.33. The substance falls within the applicability domain of the model as demonstrated in the QPRF.

The 21-day NOEC of the C6 isomers of the transformation product of the registered substance to daphnids, based on reproduction and measured concentrations, was determined to be 0.23 mg/L with 95%-Confidence Limit between 0.18 and 0.31 mg/L.

Reference 4

Endpoint:

long-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Remarks:

QSAR result on the C7 isomer of the transformation product of the registered substance

Adequacy of study:

supporting study

Study period:

Run on 2016-03

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

Remarks:

(Q)SAR method with established scientific validity. The substance, the C7 isomer of the transformation product of the registered substance, falls within the applicability domain of the model.

Justification for type of information:

1. SOFTWARE
EPISUITE v4.1

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

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C7 isomer of the transformation product of the registered substance: OCC(C)(C)OC1CC(C)(C)CCCC1C
log Pow: 4.40 (KREATIS QSAR - iSafeRat v1.5, 2016)

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Neutral Organics SAR document in "Attached background material".

5. APPLICABILITY DOMAIN
See attached QPRF

6. ADEQUACY OF THE RESULT
See attached QPRF

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 Pow: 4.40 (KREATIS QSAR - iSafeRat v1.5, 2016)

Details on sampling:

Not applicable

Details on test solutions:

Not applicable

Test organisms (species):

Daphnia sp.

Details on test organisms:

Not applicable

Test type:

not specified

Water media type:

not specified

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

Dose descriptor:

other: ChV

Effect conc.:

0.17 mg/L

Remarks on result:

other: ECOSAR Class: Neutral Organics

Details on results:

Validity of model:
1. Defined Endpoint: Long term toxicity to aquatic invertebrates (daphnid chronic value).
2. Unambigous algorithm: Linear regression QSAR; Log ChV (mmol/L) = -0.7464*log Kow + 0.1507.
To convert the ChV from mmol/L to mg/L, multiply by the molecular weight.
3. Applicability domain: applicable to chemicals with log Kow less than 8.0 and molecular weight less than 1000 g/mol. The model can be suitable for chemicals class of neutral organic.
4. Statistical characteristics: N = 26+1 and the coefficient of determination R² = 0.8728.
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 = 26+1 and the coefficient of determination R² = 0.8728.

No additional information

Validity criteria fulfilled:

yes

Conclusions:

The C7 isomer of the transformation product of the registered substance was predicted to have a chronic value ChV of 0.17 mg/L to aquatic invertebrates daphnid. The substance falls within the applicability domain and therefore the predicted value can be considered reliable.

Executive summary:

The long term toxicity to aquatic invertebrates of the C7 isomer of the the transformation product of the registered substance was estimated using the ECOSAR v1.11 QSAR model available from the U.S. EPA.

The estimation chronic value ChV was 0.17 mg/L (neutral organics class), calculated from an estimated log Kow value (4.40) and a linear regression:

Log ChV (mmol/L) = -0.7464*log Kow + 0.1507

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

Reference 5

Endpoint:

long-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Remarks:

QSAR result on the C7 isomer of the transformation product of the registered substance

Adequacy of study:

supporting study

Study period:

From 2016-03-14 to 2016-03-16

Reliability:

1 (reliable without restriction)

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

Remarks:

QSAR value. The substance, the C7 isomer of the transformation product of the registered substance, falls into the applicability domain of the model QSAR

Justification for type of information:

1. SOFTWARE
iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity : Long-term toxicity to Daphnia magna

2. MODEL (incl. version number)
iSafeRat® High Accuracy QSAR to predict the chronic aquatic toxicity v1.1.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
C7 isomer of the transformation product of the registered substance: OCC(C)(C)OC1CC(C)(C)CCCC1C
Water solubility = 29.1 mg/L (KREATiS – Internal Study (2016))

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 211 (Daphnia magna Reproduction Test)

Deviations:

not applicable

Remarks:

(QSAR model)

Principles of method if other than guideline:

The purpose of this QSAR model is to accurately predict the chronic toxicity to daphnid as would be expected in a laboratory experiment following OECD Guideline 211 for specific, named modes of action to provide a value that can effectively replace a 21-day NOEC 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 KREATiS QMRF identifier: KTS/QMRF/CHR/01 for further details).

GLP compliance:

no

Specific details on test material used for the study:

- Mode of action: non-polar narcotic (MOA 1 or MechoA 1.1)
- log Kow : 4.40 (KREATIS, 2016)
- Water solubility = 29.1 mg/L (KREATIS internal study, 2016)

Analytical monitoring:

no

Details on sampling:

Not applicable

Vehicle:

no

Details on test solutions:

Not applicable

Test organisms (species):

Daphnia magna

Details on test organisms:

None

Test type:

other: QSAR

Water media type:

freshwater

Limit test:

no

Total exposure duration:

21 d

Post exposure observation period:

None

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. This small difference is not expected to contribute to the variability of the NOEC values found in experimental data.

pH:

Test results were taken from studies with measured pHs between 6 - 9.

Dissolved oxygen:

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

Salinity:

Not applicable

Nominal and measured concentrations:

Studies were used only where analytical measurements were made on the control and all relevant test concentrations whenever possible. Any exceptions (initial concentrations measured only or NOEC based on nominal values) were used only when sufficient justification for stability of the test was determined.

Details on test conditions:

Only results from semi-static studies were used. For suspected volatile substances only tests performed in closed vessels were accepted unless accompanying analytical monitoring proved such a design was not necessary.

Reference substance (positive control):

no

Remarks:

(QSAR model)

Key result

Duration:

21 d

Dose descriptor:

NOEC

Effect conc.:

0.2 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

reproduction

Remarks on result:

other: 95% CL: 0.15-0.27 mg/L

Details on results:

The predicted value is reliable since the test substance falls within the applicability domain of the model. The water solubility value of the test substance is within descriptor domain of the model between log water solubility (in log (mol/L)) of -5.91 to -0.09. Moreover the test substance is attributed to the class of non-polar narcotic compounds.

Results with reference substance (positive control):

Not applicable

Reported statistics and error estimates:

95% CL: 0.15-0.27 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 domain of the QSAR model.

Conclusions:

The 21-day NOEC of the C7 isomer of the transformation product of the registered substance to daphnids, based on reproduction and measured concentrations, was determined to be 0.20 mg/L with 95%-Confidence Limit between 0.15 and 0.27 mg/L.

Executive summary:

A QSAR model was used to calculate the chronic toxicity of the test item to daphnid. This QSAR model has been validated to be compliant with the OECD recommendations for QSAR modeling (OECD, 2004) and predicts the endpoint value which would be expected when testing the substance under experimental conditions in a laboratory following OECD Guideline 211. The criterion predicted was the NOEC (No Observed Effect Concentration), a tested concentration which is expected to cause no effect on reproducibility within a period of 21 days.

The chronic toxicity of the daphnids was determined using a validated QSAR model for the Mode of Action in question (MOA 1 or MechoA 1.1, non-polar narcosis). The QSAR is based on validated data for a training set of 30 chemicals derived from 21-day test on daphnids, for which the concentrations of the test item had been determined by chemical analyses over the test period. The water solubility of the substance given as input was predicted by the iSafeRat® solubility module. The substance falls within the applicability domain of the model as demonstrated in the QPRF.

The 21-day NOEC of the C7 isomer of the transformation product of the registered substance to daphnids, based on reproduction and measured concentrations, was determined to be 0.20 mg/L with 95%-Confidence Limit between 0.15 and 0.27 mg/L.

Description of key information

OECD Guideline 211, GLP, key study, validity 1:

21d-NOEC (Daphnia magna) = 0.20 mg/L, based on time-weighted mean measured concentrations.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

0.2 mg/L

Additional information

One valid key study, according to OECD Guideline 211 with GLP standards, is available to assess the effect of the registered substance on the reproduction of Daphnia magna over a 21-day period. For this, Daphnia magna were exposed (10 replicates of a single daphnid per group) to an aqueous solution of the test substance over a range of nominal test concentrations of 0.030, 0.095, 0.30, 0.95 and 3.0 mg/L which corresponds to time-weighted mean measured test concentrations of 0.032, 0.063, 0.20, 0.66 and 2.0 mg/L for a period of 21 days. The numbers of live and dead adult daphnids and young daphnids (live and dead) were determined daily. The results were based on the time-weighted mean measured test concentrations. The LOEC and the NOEC were 0.66 and 0.20 mg/L, respectively.

In addition, the chronic toxicity of the transformation product (C6 and C7 isomers) of the registered substance to daphnids was estimated using two QSAR models. The two QSAR models were ECOSAR v1.11 and iSafeRat High Accuracy QSAR v1.1. Both QSAR results were considered reliable as the substances, the C6 and C7 isomers of the transformation product of the registered substance, fall within the applicability domain of the models. The estimated chronic values for the C6 isomers were 0.19 mg/L (ChV) and 0.23 mg/L (21d-NOEC), using ECOSAR v1.11 and iSafeRat High Accuracy QSAR v1.1, respectively. The estimated chronic values for the C7 isomer were 0.17 mg/L (ChV) and 0.20 mg/L (21d-NOEC), using ECOSAR v1.11 and iSafeRat High Accuracy QSAR v1.1, respectively. The worst case endpoint value, estimated at 0.17 mg/L for the C7 isomer is chosen as key data for the long-term toxicity of the transformation product to aquatic invertebrates.

These data demonstrate that the transformation product of the registered substance is not Toxic (T) in the context of PBT assessment.