2-Buten-1-ol, 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-, (2E)-

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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

0. INTRODUCTION:
The analogue approach is based on it's structural similarity, with the only difference being in the terminal ethyl group of the source chemical instead of the methyl of the target chemical (as defined in this dossier section number 1). The read-across is based in the hypothesis that this difference will not affect significantly the toxicity towards aquatic organisms. This approach is supported by the ECOSAR prediction of both the source and the target substances, showing similar toxicities among both substances, and to the experimental data on the source substance

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read read-across is from a source substance with the same functional groups than the target but only with a different alkyl chain (ethyl instead of methyl), which is believed not to have a significant effect on the properties of the substance.
The hydrolisys products are predicted to be the same except for the methyl group, which is not expected to affect significantly.
The mechanisms of action both products are predicted to be the same. The physical properties are also very similar, including it’s characteristic odour which is very similar in both cases.
About the trans/cis isomerism: in the source substance such ratio is unfortunately not specified in the report (the CAS number refers to the mixture of cis & trans) and in the target substance is typically 95% trans and 1% cis. However this possible difference is also not believed to have affect the toxicity towards aquatic organisms of the substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both substances have a similar purity. In the source substance report, the purity is reported as 86.7%. In the target substance the typical purity content is 95%.

3. ANALOGUE APPROACH JUSTIFICATION
As can be seen in the data matrix detailed below, the physical properties of the target and source substances are very similar. As shown in the estimation results, in this case the differences in the water solubility and vapour pressure are not believed to have a relevant effect related to the toxicity to aquatic organisms.

4. DATA MATRIX
Appearance. Source substance: clear liquid at 20°C. Target substance: clear liquid at 20°C
Melting Point. Source substance: < - 20 °C. Target substance: < -20 °C
Boiling Point. Source substance: 279 °C. Target substance: 272 °C.
Relative density at 20°C. Source substance: 0.916 ± 0.001 Target substance: 0.921 ± 0.001
Vapour Pressure.
Source Substance: 1.71 * 10-2 Pa at 20°C; 4.24 * 10-2 Pa at 25°C.
Target Substance: 1.35* 10-01Pa at 20 °C; 2.08* 10-01Pa at °C.
Water Solubility. Source Substance: 25.83 mg/L at 20 °C. Target Substance: 59.36 at 20 °C

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Remarks:

QSAR on the same substance

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

> 1 - <= 10 mg/L

Remarks on result:

other:

Remarks:

derived from the read-across on the source substance together plus the QSAR prediction on the target substance

Validity criteria fulfilled:

not applicable

Conclusions:

The EC50(48h) toward daphnids on the registered substance is estimated to be in the range of 1 - 10 mg/L, based on a read across experimental study from a source substance plus a QSAR estimation on the target substance.
For risk assessment purposes the EC50(48h) used is the result from the source substance study as worst case. Therefore EC50(48h) = 1.4 mg/L

Reference 2

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29/10/1998 to 25/3/1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Remarks:

QSAR on the same substance

Qualifier:

according to guideline

Guideline:

EPA OPPTS 850.1010 (Aquatic Invertebrate Acute Toxicity Test, Freshwater Daphnids)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

Details on properties of test surrogate or analogue material (migrated information):
- Water solubility (under test conditions): 20 mg/L at 20°C

Analytical monitoring:

yes

Details on sampling:

- Concentrations: 0, 0.65, 1.3, 2.5, 5, 10 mg ai/L
- Sampling method: Samples were collected at day (-N), 0-hour (initiation) and 48-hour (termination). Control, vehicle control. chemical mixing box, diluter stock and 2 Super Radjanol fortified samples were alos acalyzed at each sample period. At each sampling event, 5mL samples were collected and composited to produce a 10mL sample for each test level. A 10 mL sample was taken from the chemical mixing box.
Quality control samples were prepared by fortifying control dilution water with Super Radjanol at concentration of 0.300 and 11.0 mg ai/L.
The samples with concentrations of Super Radjanol below 0.300 mg ai/L were diluted with a UV-grade ACN to a final concentration of 50%. Samples above 0.65 mg ai/L were diluted in appropriate volumes of UV-grade ACN such that the concentration of the analyte in the final solution was within the range of the standard reference curve.

Vehicle:

yes

Details on test solutions:

PREPARATION AND APPLICATION OF TEST SOLUTION (especially for difficult test substances)
- Chemical name of vehicle (organic solvent, emulsifier or dispersant): DMF
- Concentration of vehicle in test medium (stock solution and final test solution): 100 µL/L
- Evidence of undissolved material (e.g. precipitate, surface film, etc): no

Test organisms (species):

Daphnia magna

Details on test organisms:

TEST ORGANISM
- Common name: Water flea
- Source: ABC Laboratories in-house culture
- Age at study initiation (mean and range, SD): neonates (< 24 hours old)
The adults which produced the neonates were approximately 17 days old and had produced approximately 5 prior brood. The culture received a diet of algae (Selenastrum capricornatum and/or Ankistrodesmus falcatus) supplemented by a prepared artificial invertebrate food.

Test type:

flow-through

Water media type:

freshwater

Limit test:

no

Total exposure duration:

48 h

Hardness:

164 mg/L as CaCO3

Test temperature:

19.8 to 21.1°C in all control and test solutions

pH:

8.2 to 8.4 for all control and test solutions control

Dissolved oxygen:

5.3 to 8.8

Salinity:

non relevant

Nominal and measured concentrations:

nominal concentrations: 0, 0.65, 1.3, 2.5, 5, 10 mg a.i/L
measured concentrations (arithmetic means of T=0 and T=48h): 0, 0.38, 0.80, 1.7, 3.4, 8.1 mg a.i/L
Measured concentrations were outside the 80-120% range. Therefore the results are expressed as means of measured concentrations.

Details on test conditions:

TEST SYSTEM
- Test vessel: 1-L glass beaker
- Type (delete if not applicable): open
- Type of flow-through (e.g. peristaltic or proportional diluter): intermittent-flow proportional diluter
- No. of organisms per vessel: 10
- No. of vessels per concentration (replicates): 2
- No. of vessels per control (replicates): 2
- No. of vessels per vehicle control (replicates): 2


TEST MEDIUM / WATER PARAMETERS
- Source/preparation of dilution water: moderately hard freshwater prepared by blendind naturally hard well water with well water that was demineralized by reverse osmosis
- Total organic carbon: < 1 mg/L
- Metals: < 0.5 mg/L
- Suspended solids: 0 mg/L
- Alkalinity: 168 mg/L as CaCO3
- Conductivity: 323 µS


OTHER TEST CONDITIONS
- Adjustment of pH: no adjustement
- Photoperiod: 16-hour light and 8-hour dark photoperiod with 30-minute simulated dawn and dusk period
- Light intensity: 419 lux


EFFECT PARAMETERS MEASURED (with observation intervals if applicable) : mortality

TEST CONCENTRATIONS
- Spacing factor for test concentrations: 2
- Range finding study: conducted under static conditions
- Test concentrations: 0 (control and vehicle control), 0.65, 1.3, 2.5, 5, 10 mg a.i/L
- Results used to determine the conditions for the definitive study: Five daphnids were tested per treatment. After 48 hours of exposure, immobility/mortality was 0% at test concentrations < 1 mga.i/L, 40% at 10 mga.i/L and 100% at > 20 mg a.i/L. Three animals were quiescent at the 1à mg a.i/L treatment. Immobility/mortality was 0% in the dilution water control and the vehicle control.

Reference substance (positive control):

no

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

1.4 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

act. ingr.

Basis for effect:

mobility

Remarks on result:

other: 1.2-1.6 mg/L

Duration:

48 h

Dose descriptor:

NOEC

Effect conc.:

0.8 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

act. ingr.

Basis for effect:

mobility

see attached Table 1 and 2

Validity criteria fulfilled:

yes

Conclusions:

The 48-hour EC50 was 1.4 mg a.i/L with 95% confidence limits of 1.2 and 1.6 mg a.i/L.
The NOEC value was 0.80 mg a.i/L based upon immobility/mortality being < 10% and equivalent to the vehicle control immobility/mortality

Executive summary:

The 48–hr-acute toxicity of Super Radjanol to Daphnia magnawas studied under flow-through conditions. Daphnids were exposed to control, vehicle control, and test chemical at measured concentrations of 0, 0.38, 0.80, 1.7, 3.4, 8.1 mg a.i./L for 48 hr. Mortality/immobilization and sublethal effects were observed daily. The 48–hr EC₅₀ was 1.4 mg a.i./L. The 48–hr NOEC based on immobilization was 0.80 mg a.i./L.

 

This study is classified as acceptable and satisfies with the guidelines requirements for an acute toxicity study with freshwater invertebrates.

Reference 3

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2016-04-07

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
ECOSAR (ECOlogical Structure Activity Relationship), U.S. Environmental Protection Agency

2. MODEL (incl. version number)
V1.11 (July 24, 2012)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: C1(C)C(C)(C)C(CC=C(CC)CO)CC=1
Besides, the experimental water solubility (27.23 mg/L) and partition coefficient (4.3) have been introduced in the software and considered in the calculations.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Ecological Structure - Activity Relationships Program (ECOSAR) Methodology Document v1.11. The document describing the underlying methods uses to derive the estimation techniques and equations used in the ECOSAR model can be found at:
https://www.epa.gov/tsca-screening-tools/ecological-structure-activity-relationships-program-ecosar-methodology-document

5. APPLICABILITY DOMAIN
This substance is within the domain of the ECOSAR model based on its molecular weight (less than 1000 g/mol) and the log Kow (less than 5). Furthermore, the model can be suitable for chemicals class of neutral organic.

6. ADEQUACY OF THE RESULT
This method of estimation is reliable as its results are very similar to the experimental test results (ECOSAR: EC50=1,0 mg/L versus an Experimental EC50 = 1.4 mg/L). Furthermore, to remark that the estimated EC50 is more conservative (i.e. lower EC50) than the experimental. Therefore this estimation method is regarded as reliable and useful to be used to predict this property for this substance and for similar substances.

Reason / purpose for cross-reference:

read-across: supporting information

Remarks:

QSAR on the same substance

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals

Version / remarks:

May 2008

GLP compliance:

no

Remarks:

not applicable for a QSAR result

Test organisms (species):

other: Daphnids

Details on test organisms:

No further details on the test organisms

Test type:

not specified

Total exposure duration:

48 h

Hardness:

no data

Test temperature:

no data

pH:

no data

Dissolved oxygen:

no data

Salinity:

no data

Conductivity:

no data

Nominal and measured concentrations:

not applicable

Reference substance (positive control):

not required

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

1.033 mg/L

Remarks on result:

other: ECOSAR Class: Neutral Organic SAR (Baseline toxicity)

Remarks:

the ECOSAR allocates this result in the class "Vinyl/Allyl Alcohols", and therefore also gives results using such model. However such results are very different from the experimental values and based on a very limited training set (just one value used to develop the model). Therfore the results based on this class are regarded as not reliable and the results based on Neutral Organic SAR are used instead.

Validity criteria fulfilled:

not applicable

Conclusions:

The short term toxicity to daphnid has been estimated using the ECOSAR v1.11 for the substance 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol (EC number: 248-908-8 | CAS number: 28219-61-6)
The result is LC50 after 48h = 1.03 mg/L

Executive summary:

The short term toxicity to daphnid has been estimated using the ECOSAR v1.11 (QSAR model from the U.S. EPA) for the substance 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol.

The result is LC50 after 48h = 1.033 mg/L (neutral organic SAR, baseline toxicity).

For the calculation, two experimental values of the same substance have been introduced to the model:

log Kow = 4.3

Water solubility = 25.8 mg/L

The substance falls within the applicability domain of the model

Reference 4

Endpoint:

short-term toxicity to aquatic invertebrates

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2016-08-29

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
ECOSAR (ECOlogical Structure Activity Relationship), U.S. Environmental Protection Agency

2. MODEL (incl. version number)
V1.11 (July 24, 2012)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: C1(C)C(C)(C)C(CC=C(C)CO)CC=1
Besides, the experimental water solubility (59 mg/L) and partition coefficient (4.0) have been introduced in the software and considered in the calculations.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
Ecological Structure - Activity Relationships Program (ECOSAR) Methodology Document v1.11. The document describing the underlying methods uses to derive the estimation techniques and equations used in the ECOSAR model can be found at:
https://www.epa.gov/tsca-screening-tools/ecological-structure-activity-relationships-program-ecosar-methodology-document

5. APPLICABILITY DOMAIN
This substance is within the domain of the ECOSAR model based on its molecular weight (less than 1000 g/mol) and the log Kow (less than 5). Furthermore, the model can be suitable for chemicals class of neutral organic.

6. ADEQUACY OF THE RESULT
As proved in the source substance (2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol ; EC number: 248-908-8; CAS number: 28219-61-6), this method of estimation is reliable as its results are are very similar to the experimental test results (ECOSAR: EC50=1,0 mg/L versus an Experimental EC50 = 1,4 mg/L). Furthermore, the estimated EC50 is more conservative (i.e. lower EC50) than the experimental.
Similarly, it can be expected that for the registered substance the same occurs: the estimation result is reliable and any possible difference between the calculated and experimental result would likely be in a more conservative outcome for the estimation result. Therefore the estimation result can be used as a reasonable worst case.
Concluding that the result of the estimation for the registered substance is regarded as reliable and useful to demonstrate the EC50 (48h) to daphnia magna is in the range 1-10 mg/L

Reason / purpose for cross-reference:

read-across: supporting information

Remarks:

QSAR with the same substance

Qualifier:

according to guideline

Guideline:

other: ECHA Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals

Version / remarks:

May 2008

GLP compliance:

no

Remarks:

not applicable for a QSAR result

Specific details on test material used for the study:

Properties used for the calculation
- log Kow : 4 (experimental result)
- Water solubility : 59 mg/L (experimental result)

Test organisms (species):

other: Daphnids

Details on test organisms:

No further details on the test organisms

Test type:

not specified

Total exposure duration:

48 h

Hardness:

no data

Test temperature:

no data

pH:

no data

Dissolved oxygen:

no data

Salinity:

no data

Conductivity:

no data

Nominal and measured concentrations:

not applicable

Details on test conditions:

no data

Reference substance (positive control):

not required

Key result

Duration:

48 h

Dose descriptor:

LC50

Effect conc.:

1.743 mg/L

Remarks on result:

other: ECOSAR Class: Neutral Organic SAR (Baseline toxicity)

Remarks:

the ECOSAR allocates this result in the class "Vinyl/Allyl Alcohols", and therefore also gives results using such model. However such results are very different from the experimental values and based on a very limited training set (just one value used to develop the model). Therfore the results based on this class are regarded as not reliable and the results based on Neutral Organic SAR are used instead.

Validity criteria fulfilled:

not applicable

Conclusions:

The short term toxicity to daphnid has been estimated using the ECOSAR v1.11 for the registered substance
The result is LC50 after 48h = 1.74 mg/L

Executive summary:

The short term toxicity to daphnid has been estimated using the ECOSAR v1.11 (QSAR model from the U.S. EPA) for the registered substance.

The result is LC50 after 48h = 1.74 mg/L (neutral organic SAR, baseline toxicity).

For the calculation, two experimental values of the same substance have been introduced to the model:

log Kow = 4.0

Water solubility = 59 mg/L

The substance falls within the applicability domain of the model

Description of key information

Three studies are available to evaluate the acute toxicity to aquatic invertebrates
1) Key Study on a similar substance: Experimental study, guideline EPA OPPTS 850.1010, performed under GLP conditions. 
The test item is the substance 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol (CAS 28219-61-6; EC 248-908-8).
Result is EC50(48h) = 1.4 mg/L
2) Supporting QSAR estimation on a similar substance: Estimation done with  ECOSAR v1.11 (QSAR model from the U.S. EPA)
The substance used for the calculation is 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol (CAS 28219-61-6; EC 248-908-8).
Result is EC50(48h) = 1.03 mg/L
3) Supporting QSAR estimation on the substance under registration (i.e as defined in section 1 of this dossier). 
Estimation done with  ECOSAR v1.11 (QSAR model from the U.S. EPA)
Result is EC50(48h) = 1.7 mg/L

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

1.4 mg/L

Additional information

The toxicity towards aquatic invertebrates EC50(48h) is estimated to be in the range of 1 -10 mg/L.

This toxic concentration estimation is based on a read-across from an experimental study conducted with a very similar substance (2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol ; EC number: 248-908 -8; CAS number: 28219-61-6) plus a QSAR estimation on the target substance. Both are giving similar and consistent results in the range of 1 -10 mg/L.

Besides, the read-across is supported with a QSAR estimation on the source substance, which gives very similar results to the experimental study, confirming the QSARs estimation for this endpoint and for this substances are reliable.

Further arguments supporting the validity of the read-across:

1) comparing the QSAR estimation of the source substance with the experimental result of the source substance: the estimated EC50 is slightly more conservative (i.e. lower EC50) than the experimental.

Similarly, it can be expected that for the target substance the same occurs: the estimation result is reliable and any possible difference between the calculated and experimental result would be in a more conservative outcome for the estimation result. Therefore the estimation result can be used as a reasonable worst case.

2) comparing the QSAR estimation of the source substance with the QSAR estimation of the target substance: the predicted EC50 is lower for the source substance. Therefore the target substance is expected to be less toxic than the source substance (i.e. EC50(48h) > 1,4 mg/L)

For risk assessment purposes the EC50(48h) that will be used is the result from the source substance study as worst case.