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Toxicity to aquatic algae and cyanobacteria

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Endpoint:
toxicity to aquatic algae and cyanobacteria
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because
- they are manufactured from similar precursors under similar conditions
- they share structural similarities with common functional groups: the substances start with an acetylene group as core structure; geminal hydroxyl groups on the alpha carbon atoms; distal to the geminal hydroxyl groups is an isobutyl group (methyl isopropyl); the target substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3) is further functionalised with ethylene oxide and has an ethoxylation degree of 1.3; the source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3.8) has an ethoxylation degree of 3.8
- they have similar physicochemical properties and thus, show a similar toxicokinetic behaviour
- they are expected to undergo similar metabolism: oxidation of the terminal methyl groups to result in alcohol, aldehyde and finally the corresponding acid

Therefore, read-across from the existing toxicity, ecotoxicity, environmental fate and physicochemical studies on the source substances is considered as an appropriate adaptation to the standard information requirements of REACH regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see “Justification for read-across” attached to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
see “Justification for read-across” attached to IUCLID section 13

4. DATA MATRIX
see “Justification for read-across” attached to IUCLID section 13
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Analytical monitoring:
yes
Test organisms (species):
Pseudokirchneriella subcapitata (previous names: Raphidocelis subcapitata, Selenastrum capricornutum)
Test type:
static
Total exposure duration:
72 h
Hardness:
Hardness (Ca+Mg) 0.24 mmol/l (24 mg CaCO3/l)
Test temperature:
23 +/- 2 °C
Duration:
72 h
Dose descriptor:
EC10
Effect conc.:
15 mg/L
Nominal / measured:
nominal
Conc. based on:
test mat.
Basis for effect:
growth rate
Remarks on result:
other: 95% c.i. 7 to 30 mg/L
Duration:
72 h
Dose descriptor:
EC50
Effect conc.:
82 mg/L
Nominal / measured:
nominal
Conc. based on:
test mat.
Basis for effect:
growth rate
Remarks on result:
other: 95% c.i. 39 to 170 mg/L
Validity criteria fulfilled:
yes
Conclusions:
72 h ErC10 = 15 mg/L (95% c.i. 7 to 30 mg/L)
72 h ErC50 = 82 mg/L (95% c.i. 39 to 170 mg/L)
Endpoint:
toxicity to aquatic algae and cyanobacteria
Type of information:
(Q)SAR
Adequacy of study:
supporting study
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

EpiSuite v4.11, US EPA, 2012

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

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL

CC(O)(C#CC(C)(O)CC(C)C)CC(C)C
CC(CC(C)C)(C#CC(C)(O)CC(C)C)OCCO
OCCOCCOC(C)(CC(C)C)C#CC(C)(O)CC(C)C
CC(CC(C)C)(C#CC(C)(CC(C)C)OCCO)OCCO
CC(C)CC(C)(O)C#CC(C)(CC(C)C)OCCOCCOCCO
OCCOCCOC(C)(CC(C)C)C#CC(C)(CC(C)C)OCCO
CC(C)CC(C)(O)C#CC(C)(CC(C)C)OCCOCCOCCOCCO
CC(C)CC(C)(OCCO)C#CC(C)(CC(C)C)OCCOCCOCCO
OCCOCCOC(C)(CC(C)C)C#CC(C)(CC(C)C)OCCOCCO

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Aquatic toxicity
- Unambiguous algorithm: The QSARs in ECOSAR for both neutral organics and classes with excess toxicity are based on a linear mathematical relationship between the measured log Kow values and the corresponding log of the measured toxicity values (mmol/L) for a suite of training set chemicals within each class of interest. After collecting the training set information for each chemical including estimated log Kow and valid toxicity results, regression techniques are applied to the class-specific data sets to derive mathematical relationships between log Kow and toxicity (often called the resulting algorithm). These resulting class-specific equations typically take the form of y = mx + b, where “y” represents the toxic effect concentration (i.e. log LC50 in mmol/L) and “x” represents the log Kow value.
- Defined domain of applicability:
Currently there is no universally accepted definition of model domain. However, it should be considered that the estimates may be less accurate for compounds outside the molecular weight range of the training set compounds, and/or that have strongly differing log Kow as compared to training set compounds. Although the training set of the model contains a large number of diverse molecules and can be considered abundant, it is also possible that a compound may be characterised by structural features (e.g. functional groups) not represented in the training set, with no respective correction coefficient developed. These points should be taken into consideration when interpreting model results. In the development of the ECOSAR equations for neutral organics and classes with excess toxicity, the training sets generally include chemicals with log Kow values in the range of -3 to 8 and molecular weights less than 1000.
- Appropriate measures of goodness-of-fit and robustness and predictivity:
In its most simple design, an external evaluation uses chemicals not employed in the development of the model and takes the form of a direct comparison between the experimental and estimated values for the chemicals. When the predicted endpoint is quantitative (provides a numeric value), a regression analysis is performed comparing the experimental and estimated data to ascertain the coefficient of determination (r²) for the model. This coefficient of determination is used as a surrogate measure for the predictivity. The higher the r² value, the greater the correlation between experimental and estimated values, the better the predictive accuracy of the model.
- Mechanistic interpretation: The underlying predictive methodology is described in the following publication: Meylan, WM; Howard, P. (1995) Atom/Fragment Contribution Method for Estimating Octanol-Water Partition Coefficients. J Pharm Sci 84: 83-92.

5. APPLICABILITY DOMAIN
- Descriptor domain: Water solubility, log Kow, molecular weight
- Structural and mechanistic domains: ECOSAR estimates estimates the log of the octanol/water partition coefficient using methodology developed by the U.S. EPA and currently used in the U.S. EPA/OPPT EPISuite model for evaluation of physical-chemical properties and environmental fate of chemicals (the KOWWIN program). The underlying predictive methodology is described in the following publication: Meylan, WM; Howard, P. (1995) Atom/Fragment Contribution Method for Estimating Octanol-Water Partition Coefficients. J Pharm Sci 84: 83-92.
- Similarity with analogues in the training set: The HELP menu in the ECOSAR Class Program contains QSAR Equation Documents for all QSARs within each chemical class to provide transparency in the QSAR methods and supporting measured data.

6. ADEQUACY OF THE RESULT
The substance falls within the applicability domain with respect to water solubility, log Kow, molecular weight. The data are used as supporting data. Experimental data are available for one of the constituents (2,4,7,9-Tetramethyl-5-decyne-4,7-diol, monomer). The results of this QSAR demonstrate, that 2,4,7,9-Tetramethyl-5-decyne-4,7-diol represents the worst case and can be used to cover the endpoint in a read-across approach (see also Justification for read-across attached to IUCLID chapter 13).
Principles of method if other than guideline:
Estimation of ecotoxicity using EpiWeb v4.11, ECOSAR v1.11
GLP compliance:
no
Remarks:
not applicable for in silico study
Water media type:
freshwater
Total exposure duration:
96 h
Duration:
96 h
Effect conc.:
>= 6.053 - <= 61.91 mg/L
Nominal / measured:
nominal
Conc. based on:
test mat.
Basis for effect:
growth rate

 

SMILES

Algae

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, monomer

CC(O)(C#CC(C)(O)CC(C)C)CC(C)C

 

6.053

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1/0)

CC(CC(C)C)(C#CC(C)(O)CC(C)C)OCCO

 

9.983

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (2/0)

OCCOCCOC(C)(CC(C)C)C#CC(C)(O)CC(C)C

 

19.712

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1/1)

CC(CC(C)C)(C#CC(C)(CC(C)C)OCCO)OCCO

 

19.712

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3/0)

CC(C)CC(C)(O)C#CC(C)(CC(C)C)OCCOCCOCCO

 

35.603

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (2/1)

OCCOCCOC(C)(CC(C)C)C#CC(C)(CC(C)C)OCCO

 

35.603

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (4/0)

CC(C)CC(C)(O)C#CC(C)(CC(C)C)OCCOCCOCCOCCO

 

61.910

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (3/1)

CC(C)CC(C)(OCCO)C#CC(C)(CC(C)C)OCCOCCOCCO

 

61.910

2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (2/2)

OCCOCCOC(C)(CC(C)C)C#CC(C)(CC(C)C)OCCOCCO

 

61.910

Conclusions:
The 96 h EC50 values for the constituents of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated range from 6.05 (2,4,7,9-Tetramethyl-5-decyne-4,7-diol, monomer) to 61.91 mg/L (2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (4/0)), demonstrating, that with increasing degree of ethoxylation the toxicity decreases (ECOSAR v1.11).

Description of key information

72 h ErC10 = 15 mg/L (95% c.i. 7 to 30 mg/L)

72 h ErC50 = 82 mg/L (95% c.i. 39 to 170 mg/L)

(OECD TG 201, Selenastrum capricornutum, read-across:  2,4,7,9-Tetramethyl-5-decyne-4,7-diol)

Key value for chemical safety assessment

EC50 for freshwater algae:
82 mg/L
EC10 or NOEC for freshwater algae:
15 mg/L

Additional information

Experimental data on toxicity to algae of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3) are not available. However, studies were conducted with the structurally related source substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol. In addition, a QSAR calculation (ECOSAR) was performed for the components of the target substance. A justification for read-across is attached to iuclid section 13.

 

2,4,7,9-Tetramethyl-5-Decyne-4,7-Diol affected growth of the fresh-water algae species Selenastrum capricornutum significantly at 2.2 mg/l and higher. The NOEC for cell growth inhibition and growth rate reduction was 1.0 mg/l. However, a recovery of growth was observed during the last 48 hours of exposure with a NOEC of 4.6 mg/l for growth rate. After a range-finding test, a final test was performed exposing exponentially growing algal cultures to 2,4,7,9-Tetramethyl-5-Decyne-4,7-Diol concentrations ranging from 1 to 100 mg/l, increasing with a factor of 2.2. The initial cell density was 104 cells/ml. The total test period was 72 hours. Samples for analysis were taken at 1.0, 10 and 100 mg/l at the start and the end of the test. Measured concentrations were greater than 100 percent of nominal in all samples analysed. Based on a recovery experiment simultaneously performed, the measured values indicated that the actual concentrations were in agreement with nominal and remained stable during the test period. The EC50 for cell growth inhibition (EBC50: 0-72h) was 15 mg/l with a 95 percent confidence interval ranging from 9 to 23 mg/l. The EC10 for cell growth inhibition (EBC10: 0-72h) was 1.8 mg/l with a 95 percent confidence interval ranging from 1.1 to 3.0 mg/l. A more time related response appeared by comparison of the reduction of growth rate for different time intervals. For the total test period, the EC50 for growth rate reduction (ERC50: 0-72h) was 82 mg/l with a 95 percent confidence interval ranging from 39 to 170 mg/l. The EC10 for growth rate reduction (ERC10: 0-72h) was 15 mg/l with a 95 percent confidence interval ranging from 7 to 30 mg/l. However, based on the data recorded during the last 48 hours of exposure (24-72h) the EC50 for growth rate reduction (ERC50: 24-72h) was 39 mg/l with a 95 percent confidence interval ranging from 19 to 81 mg/l. The EC10 for growth rate reduction (ERC10: 24-72h) was not different from the (ERC10: 0-72h): 15 mg/l with a 95 percent confidence interval ranging from 7 to 31 mg/l. 

 

The 96 h EC50 values for the constituents of 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated range from 6.05 (2,4,7,9-Tetramethyl-5-decyne-4,7-diol, monomer) to 61.91 mg/L (2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (4/0)), demonstrating, that with increasing degree of ethoxylation the toxicity decreases (ECOSAR v1.11).

 

Overall, 72 h ErC10 = 15 mg/L (95% c.i. 7 to 30 mg/L) and 72 h ErC50 = 82 mg/L (95% c.i. 39 to 170 mg/L) are used for chemical safety assessment of the target substance 2,4,7,9-Tetramethyl-5-decyne-4,7-diol, ethoxylated (1.3).