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Short-term toxicity to fish

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Reference
Endpoint:
short-term toxicity to fish
Type of information:
(Q)SAR
Adequacy of study:
key 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 adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
The ECOSAR (ECOlogical Structure Activity Relationship) Class Programm for Microsoft Windows; U.S. Environmental Protection Agency; Office of Chemical Safety and Pollution Prevention (Kelly Mayo-Bean, June 19, 2012)
2. MODEL (incl. version number)
ECOSAR v 1.11
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS-No: 97-30-3
SMILES: C1(OC)C(O)C(O)C(O)C(CO)O1

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.
The studies collected for the training set chemicals in ECOSAR undergo an extensive data validation step to ensure appropriateness for inclusion in the model. 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. Using these resulting linear equations, toxicity values (mmol/L) for untested chemicals may then be calculated in a three-step process:
(1) select the appropriate class using the ECOSAR class definitions,
(2) input the measured or estimated log Kow value of the molecule into the mathematical regression equation to estimate the toxic effect concentration (mmol/L),
(3) use molecular weight of the subject chemical to convert the estimated effect concentration from mmol/L to mg/L for use in aquatic toxicity hazard profiles.
The computerized ECOSAR program is designed to automatically complete all three steps when providing estimates based on the users chemical input. The mode of toxic action for most neutral organic chemicals is narcosis, and many chemical classes present toxicity to organisms via narcosis (i.e ethers, alcohols, ketones). However, some organic chemical classes have been identified as having a more specific mode of toxicity. These are typically organics that are reactive and ionizable and exhibit excess toxicity beyond simple narcosis. In the ECOSAR output file the user will always be provided the neutral organics equation predictions, often referred to as "baseline toxicity", even when the compound falls into a separate class with excess toxicity. The purpose for providing baseline toxicity is to quantify the amount of excess toxicity to each species above baseline for the chemical class.
Endpoint 2012 Neutral Organics Equations
Fish 96hr LC50 Log Toxicity (mmol/L) = -0.8981(log Kow) + 1.7108
Daphnid 48hr LC50 Log Toxicity(mmol/L) = -0.8580(log Kow) + 1.3848
Green Algae 96hr EC50 Log Toxicity (mmol/L) = -0.6922(log Kow) + 0.9253
Fish Chronic (ChV) Log Toxicity (mmol/L) = -0.8508(log Kow) + 0.6063
Daphnid Chronic (ChV) Log Toxicity (mmol/L) = -0.7464(log Kow) + 0.1507
Green Algae Chronic (ChV) Log Toxicity (mmol/L) = -0.6029(log Kow) + 0.1648
Fish 96 hr - Salt Water Log Toxicity (mmol/L) = -0.8955(log Kow) + 1.8056
Mysid Shrimp 96hr - Salt Water Log Toxicity (mmol/L) = -1.1897(log Kow) + 2.2651
Fish Chronic (ChV) -Salt Water Log Toxicity (mmol/L) = -0.6303(log Kow) + 0.3108
Mysid Shrimp Chronic (ChV) - SW Log Toxicity (mmol/L) = -1.3184(log Kow) + 1.4592
Earthworm 14d Log Toxicity (mmol/L) = -0.1037(log Kow) + 0.4476

ECOSAR 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 reference listed below:
Meylan, WM; Howard, P. (1995) Atom/Fragment Contribution Method for Estimating Octanol-Water Partition Coefficients. J Pharm Sci 84: 83-92.
The water solubility is estimated with the WSKOWWIN program. The underlying predictive methodology is described in the references listed below:
Meylan, W.M., Howard, P.H. and R.S. Boethling. (1996) Improved method for estimating water solubility from octanol/water partition coefficient. Environ. Toxicol. Chem. 15: 100-106.

- 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.
Inorganic or organometallic chemicals are not represented in the training sets used to develop ECOSAR.
Polymers and chemicals with MW >1,000 also are not represented in the training sets used to develop ECOSAR. However, if the polymer is may be made up of dimers, trimers, and oligomers that have a molecular weight of less than 1,000 these smaller molecules can be run through the model.

Mixtures: ECOSAR requires a discrete structure be entered so mixtures can’t be profiled unless discrete representative structures of each constituent can be identified. Each substance can be run through the model separately. However this method does not account for synergistic effects.

Nanomaterials: ECOSAR does not account for the unique physical properties of nanomaterials which may contribute to novel mechanisms of toxicity for this class of chemicals.

Log Kow Cutoffs: The limits of each QSAR must be understood if the results are to be interpreted properly. In general, when the log Kow is ≤5.0 for fish and daphnid, or ≤6.4 for green algae, ECOSAR provides reliable estimates for acute effects. If the log Kow exceeds those limits, empirical data indicate that the decreased solubility of these lipophilic chemicals results in “no effects at saturation” during a 48-hour to 96-hour test. For chronic exposures, the log Kow cut off is 8.0 or greater (indicating a poorly soluble chemical) and “no effects at saturation” are expected in saturated solutions even with long-term exposures. The user should always review these limits to determine when “no effects at saturation” may be expected for a chemical.

Water Solubility Considerations: For chemicals that are solids it is important to compare the toxicity estimates with the water solubility using the following decision logic:
Is the effect concentration below the water solubility of the solid chemical?
YES – Base the toxicity concern on the effect concentration
NO – Is the effect concentration ≥10x above the water solubility of the chemical?
YES – No effects at saturation (NES) (low concern)
NO – May have NES or effects may occur

Special Classes: Evaluating these special classes in ECOSAR can be problematic:
- Simple Salts: Use predicted log Kow for free acid or corresponding conjugate base for salts
- Larger Organic Salts: more difficult assessment
- Chemicals that rapidly hydrolyze (t1/2 <1 hour at 20 deg C, pH 7)
- Chemicals that undergo rapid photolysis, oxidation, or pyrolysis asess degradation products

Surfactants and Dyes: Some classes do not use log Kow in SAR predictions. For example, anionic surfactant SARs are typically non-linear and describe the relationship between the hydrophilic portion and hydrophobic portion of the chemical. An example is the anionic surfactants SAR:
log LC50 (mg/L) = [(avg. no. of carbons -16)² - 10.643]) - 12.9346

- 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. There have been numerous external validation exercises performed on ECOSAR by third parties and results are available in the public domain. The coefficient of determination (r²) is a statistically appropriate measure for the predictivity of a model; however, in some cases it may not reflect the true predictive power of a QSAR within a particular decision making framework. A list of supporting validation exercises performed in conjunction with EPA and other stakeholders on the ECOSAR model can be found within the ECOSAR methodology file.

- Mechanistic interpretation:

5. APPLICABILITY DOMAIN
- Descriptor domain: Water solubility, log Kow, molecular weight
- Structural and mechanistic domains: n/a; 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 reference listed below:
Meylan, WM; Howard, P. (1995) Atom/Fragment Contribution Method for Estimating Octanol-Water Partition Coefficients. J Pharm Sci 84: 83-92.
The water solubility is estimated with the WSKOWWIN Program. The underlying predictive methodology is described in the references listed below:
Meylan, W.M., Howard, P.H. and R.S. Boethling. (1996) Improved method for estimating water solubility from octanol/water partition coefficient. Environ. Toxicol. Chem. 15: 100-106.

- 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. Since the present structure is not considered to belong to one of the not-predictable chemical classes but rather to the neutral organics class of chemicals and its logKow as well as its molecular weight are in a similar range of that from the trainings set chemicals, the estimation is assumed to be reliable.

6. ADEQUACY OF THE RESULT
As outlined in the section above the test substance is assumed to belong to the neutral organics class of chemicals whose aquatic toxicity can be reliably estimated with the ECOSAR model. Furthermore, its molecular weight and its logKow are in the recommended range for acceptance of the prediction.
Qualifier:
no guideline followed
Principles of method if other than guideline:
QSAR estimation using ECOSAR (ECOlogical Structure Activity Relationship) Class Programm for Microsoft Windows; U.S. Environmental Protection Agency; Office of Chemical Safety and Pollution Prevention (Kelly Mayo-Bean, June 19, 2012).
GLP compliance:
no
Key result
Duration:
96 h
Dose descriptor:
LC50
Effect conc.:
1 770 000 mg/L
Nominal / measured:
nominal
Conc. based on:
test mat.
Basis for effect:
mortality
Remarks on result:
other: results from a QSAR prediction

ECOSAR Version 1.11 Results Page

     

    SMILES :              C1(OC)C(O)C(O)C(O)C(CO)O1

    CHEM   :              methyl-D-glucoside

    CAS Num:             97-30-3

    ChemID1:

    MOL FOR:            C7 H14 O6

    MOL WT :             194.19

    Log Kow:              -2.504     (EPISuite Kowwin v1.68 Estimate)

    Log Kow:            (User Entered)

    Log Kow:            (PhysProp DB exp value - for comparison only)

    Melt Pt:            (User Entered for Wat Sol estimate)

    Melt Pt: 168.00     (deg C, PhysProp DB exp value for Wat Sol est)

    Wat Sol: 1E+006   (mg/L, EPISuite WSKowwin v1.43 Estimate)

    Wat Sol:            (User Entered)

    Wat Sol: 3.87E+005  (mg/L, PhysProp DB exp value)

     

     

    --------------------------------------

    Values used to Generate ECOSAR Profile

    --------------------------------------

    Log Kow: -2.504     (EPISuite Kowwin v1.68 Estimate)

    Wat Sol: 3.87E+005  (mg/L, PhysProp DB exp value)

     

   

   

    --------------------------------------

    ECOSAR v1.11 Class-specific Estimations

    --------------------------------------

    Neutral Organics

                                                                        Predicted

    ECOSAR Class                 Organism            Duration  End Pt   mg/L (ppm)

    ===========================  ==================  ========  ======   ==========

    Neutral Organics           : Fish                96-hr     LC50    1.77e+006 *

    Neutral Organics           : Daphnid             48-hr     LC50    6.63e+005 *

    Neutral Organics           : Green Algae         96-hr     EC50    88454.055

    Neutral Organics           : Fish                          ChV     1.06e+005

    Neutral Organics           : Daphnid                       ChV     20315.576

    Neutral Organics           : Green Algae                   ChV      9175.284

    Neutral Organics           : Fish (SW)           96-hr     LC50    2.17e+006 *

    Neutral Organics           : Mysid               96-hr     LC50    3.41e+007 *

    Neutral Organics           : Fish (SW)                     ChV     15039.254

    Neutral Organics           : Mysid (SW)                    ChV     1.12e+007 *

    Neutral Organics           : Earthworm           14-day    LC50      989.629

   

     Note:  * = asterisk designates: Chemical may not be soluble enough to

            measure this predicted effect. If the effect level exceeds the

            water solubility by 10X, typically no effects at saturation (NES)

            are reported.

     

     

    ------------------------------

    Class Specific LogKow Cut-Offs

    ------------------------------

    If the log Kow of the chemical is greater than the endpoint specific cut-offs

    presented below, then no effects at saturation are expected for those endpoints.

     

    Neutral Organics:

    ----------------

    Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50, Mysid LC50)     Maximum LogKow: 6.0 (Earthworm LC50)

    Maximum LogKow: 6.4 (Green Algae EC50)

    Maximum LogKow: 8.0 (ChV)

     

   

Validity criteria fulfilled:
not applicable
Conclusions:
In the present report the short-term toxicity to fish for alpha methyl glucoside was estimated using the reliable ECOSAR model. The 96 h LC50 was predicted to be 1.77E6 mg/L.
Executive summary:

The present results for alpha methyl glucoside effects on acute toxicity to fish were generated from a reliable QSAR prediction using the EPISuite software and the ECOSAR model. The 96 h LC50 was predicted to be 1.77E6 mg/L.

Description of key information

- QSAR estimation using the Estimation Programs Interface (EPI) SuiteTM v4.1 containing the ECOlogical Structure Activity Relationship (ECOSAR) software, the substance falls within the applicability domain

Key value for chemical safety assessment

LC50 for freshwater fish:
1 770 000 mg/L

Additional information

Based on the reliable estimation using the Estimation Programs Interface (EPI) SuiteTM v4.1 containing the ECOlogical Structure Activity Relationship (ECOSAR) software, which reveals a LC50 value which is clearly above the limit concentration of 100 mg/L and further mitigating factors which indicate that the substance unlikely causes ecotoxicological effects, i.e. no toxic effects to fish up to the limit concentration of 100 mg/L, alpha methyl glucoside is not considered to generate toxic effects up to the limit concentration of 100 mg/L.