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Long-term toxicity to aquatic invertebrates

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Reference
Endpoint:
long-term toxicity to aquatic invertebrates
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
Ecological Structure Activity Relationships (ECOSAR) Class Program


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


3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: OC(C(O)C(=O)O)C(=O)O


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL (Please, see also the attached QMRF file)
- Defined endpoint:
Long term toxiciy to invertebrates (DAPHNID ChV)

- Unambiguous algorithm:
SAR for: Neutral Organics Class, Daphnid Chronic Value
Baseline Toxicity Equations
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).
Daphnid Chronic (ChV)
Log Toxicity (mmol/L) = -0.7464(log Kow) + 0.1507

- Defined domain of applicability:
Chemicals with Experimental Data: Chemicals with experimental data from a well conducted laboratory study should not be run through ECOSAR, unless it is for comparative purposes or a weight of evidence assessment.Experimental data should always be used in preference to estimations when identifying aquatic toxicity concerns.

Inorganic Chemicals: The computerized estimation methods currently programmed into the ECOSAR Class Program were designed and developed for organic chemicals. Inorganic chemicals will not provide reliable results and should not be profiled. It includes neutral species such as titanium dioxide (TiO2) and inorganic salts, such as sodium chloride (NaCl) or potassium permanganate (KMnO4). This class of chemicals also includes organo-metallic chemicals (chemicals that contain carbon bonded to a metal species). There is a current lack of good data and knowledge rules regarding toxicity pathways for these types of compounds, and the traditional estimation techniques used for organics have in some cases been found to be inappropriate for metal containing molecules. It is also difficult to distinguish oxidation states using the molecular descriptors employed for organics, which may play an important role in estimating toxicity for metals.

Hydrolytically Unstable or Highly Reactive Chemicals: Data or information on a chemical’s degradation rate can determine if other chemical degradates should be considered during the course of an ecotoxicity assessment. Guidance provided within the context of the U.S. EPA New Chemicals Program states that if a chemicals half-life in water is less than one hour, it is predominantly the degradation products that enter the aquatic environment and the focus of the ecotoxicity assessment should be on the degradates, not the parent. If the half-life is greater than one hour, but less than 14 days, then both the intact parent chemical and its degradates should be reviewed. If the half-life is greater than 14 days, then only the parent chemical is generally assessed. This 14 day criterion is based on the average residence time for a chemical to move through a waste water treatment facility before being released to surface water where it may be toxic to the aquatic life. The form a chemical takes after this 14-day window is important to consider when determining what the aquatic system will be exposed to (parent or degradate).

Complex Organic Salts: The properties and toxicity of a small number of organic salts are well documented in the environmental literature such as Sodium (Na) salts, Potassium (K) salts, Ammonium (NH4+) salts, and Lithium (Li) salts. Simple salts can be entered into the system and modeled by neutralizing the compounds (remove the salt, replace with a hydrogen atom) as the salts are typically treated as spectator ions (since they are considered dissociated at environmental conditions). Compounds with more complex organic cation and anion are difficult to model because the organic salt may in fact play a larger role depending on dissociation products.
High Molecular Weight Compounds (MW >1000): Polymers and chemicals with a molecular weight greater than 1,000 should not be profiled using ECOSAR.

Isomers: Three dimensional molecular properties or molecular conformation can be important as it relates to absorption, binding, and resulting toxicity potential of a chemical. Some QSAR models are unable to account for these three dimensional characteristics that in some cases can be important considerations since they can influence toxicokenetic (PBPK) processes. Often QSAR models do not distinguish between steroisomers, optical isomers, tautomers, or specific conformations because they are built using simple one or two-dimensional descriptors only, as is the case with the ECOSAR model. More advanced QSAR techniques and experts systems may be able to distinguish isomers either through advanced calculations or overlaid expert rules, but the user often sacrifices speed when using these tools.

Mixtures: ECOSAR does not have the ability to simultaneously assess multiple chemicals and all potential synergistic effects of that mixture. The model uses more simplistic structure-activity relationships based on a single, discrete chemical structure as its input. There are many CAS numbers that actually represent isomer mixtures, polymers (containing residual monomers), and unknown or variable composition substances. In general, mixtures cannot be run through QSAR models. If the chemical to be profiled is a mixture of discrete organic substances, then each substance can be run through the model separately and the result can be compared and contrasted. If there is one component of a mixture that predominates, then it may be used to represent the entire mixture (i.e., a representative structure can be entered).

Chemicals with Unknown or Variable Composition: If the material has a variable composition, (such as oligomers, natural fats, or a product mixture that changes composition depending on the reaction conditions), then the results provided by models where a representative structure was used may not accurately reflect the true nature of the commercial product. Because of the complexity of structural identification, the assessor may need to complete a review of the CAS, name, reaction mechanism, and representative structure(s) to determine appropriateness of the structural input used to generate the model estimates. If this procedure is performed, the results should be interpreted with caution, as other components of the product may possess significantly different toxicities.

Maximum Kow: 8.0
Maximum MW: 1000

- Appropriate measures of goodness-of-fit and robustness and predictivity:
y = -0.7464x + 0.1507
R2 = 0.8728
n = 26 + 1

- Mechanistic interpretation:
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).

5. APPLICABILITY DOMAIN
- Descriptor domain:
Organic substance
MW = 150.09
logKow (used for prediction) = -1.002 (Maximum LogKow: 8.0 (ChV))
water solubility (used for prediction) = 2.46E+005 mg/L
- Structural and mechanistic domains: Organic substance and Neutral Organics

6. ADEQUACY OF THE RESULT
Predictions can be used for the risk assessment.
Qualifier:
according to guideline
Guideline:
other: ECHA Guidance on information requirements and chemical safety assessment - Charpter R.06: QSAR and grouping of chemicals - May 2008
Qualifier:
according to guideline
Guideline:
other: How to prepare registration and PPORD dossiers - version 2.0 - September 2016.
Principles of method if other than guideline:
The Quantitative Structure Activity Eelationships (QSARs) presented in this program are used to predict the aquatic toxicity of chemicals based on their similarity of structure to chemicals for which the aquatic toxicity has been previously measured.  Most QSAR calculations in the ECOSAR Class Program are based upon the octanol/water partition coefficient (Kow).
Specific details on test material used for the study:
OC(C(O)C(=O)O)C(=O)O
Key result
Dose descriptor:
NOEC
Effect conc.:
11.88 g/L
Nominal / measured:
estimated
Remarks on result:
other: QSAR predictions of daphnid ChV

ECOSAR has estimated a Daphnid ChV of 11877.286 mg/L.

Conclusions:
For tartaric acid ECOSAR has estimated a Daphnid ChV of 11877.286 mg/L.
Executive summary:

For tartaric acid ECOSAR has estimated a Daphnid ChV of 11877.286 mg/L.

Even if the predictions were performed on tartaric acid it is valid also for calcium tartrate, since:

  1. the properties and toxicity of a small number of organic salts (like Ca) are well documented in the environmental literature
  2. Simple salts (like calcium tartate) can be entered into the system and modeled by neutralizing the compounds (remove the salt, replace with a hydrogen atom) as the salts are typically treated as spectator ions
  3. we can consider compounds and dissociation at environmental conditions
  4. logKow for calcium tartrate and tartaric acid are similar (-1.46 vs -1.002)
  5. moreover, since logKow of calcium tartrate is lowest than logKow o tartaric acid, the estimated toxicity is too conservative.

Description of key information

For tartaric acid ECOSAR has estimated a Daphnid ChV of 11877.286 mg/L.

Even if the predictions were performed on tartaric acid it is valid also for calcium tartrate, since:

  1. the properties and toxicity of a small number of organic salts (like Ca) are well documented in the environmental literature
  2. Simple salts (like calcium tartate) can be entered into the system and modeled by neutralizing the compounds (remove the salt, replace with a hydrogen atom) as the salts are typically treated as spectator ions
  3. we can consider compounds and dissociation at environmental conditions
  4. logKow for calcium tartrate and tartaric acid are similar (-1.46 vs -1.002)
  5. moreover, since logKow of calcium tartrate is lowest than logKow o tartaric acid, the estimated toxicity is too conservative.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates
Effect concentration:
11.877 g/L

Additional information

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