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Short-term toxicity to aquatic invertebrates

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Reference
Endpoint:
short-term toxicity to aquatic invertebrates
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
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:
QMRF report has been attached
Qualifier:
according to
Guideline:
other: Estimated data
Principles of method if other than guideline:
Prediction was done using the OECD QSAR toolbox version 3.4.
GLP compliance:
not specified
Specific details on test material used for the study:
- Name of test material : pyridine-2,4-dicarboxylic acid
-IUPAC name: 2,4-Pyridinedicarboxylic acid
- Molecular formula : C7H5NO4
- Molecular weight : 167.12 g/mol
- Smiles notation : c1(cc(ncc1)C(O)=O)C(O)=O
- InChl : 1S/C7H5NO4/c9-6(10)4-1-2-8-5(3-4)7(11)12/h1-3H,(H,9,10)(H,11,12)
- Substance type: Organic
- Physical state: Solid
Analytical monitoring:
not specified
Vehicle:
not specified
Test organisms (species):
Daphnia magna
Details on test organisms:
- Common name: Water flea
Test type:
static
Water media type:
freshwater
Total exposure duration:
48 h
Hardness:
230 mg CaCO3/L
Test temperature:
20-21°C
pH:
7.5 and 7.8
Dissolved oxygen:
8.2 - 9.6 mg O2/L
Nominal and measured concentrations:
Estimated
Reference substance (positive control):
not specified
Key result
Duration:
48 h
Dose descriptor:
EC50
Effect conc.:
230.75 mg/L
Nominal / measured:
estimated
Conc. based on:
test mat.
Basis for effect:
other: Intoxication
Remarks on result:
other: Other details not known
Details on results:
The EC50 was 230.749 mg/l.

The prediction was based on dataset comprised from the following descriptors: EC50
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and ( not "z") )  )  and ("aa" and "ab" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aromatic compound OR Carbonic acid derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid, aromatic attach [-COOH] OR Alcohol, olefinic attach [-OH] OR Aromatic Carbon [C] OR Aromatic Nitrogen OR Carbonyl, olefinic attach [-C(=O)-] OR Carbonyl, one aromatic attach [-C(=O)-] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] OR Pyridine, non fused rings  by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid OR Overlapping groups OR Pyridine/ Pyridinium ion by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aryl OR Carboxylic acid OR Pyridine/ Pyridinium ion by Organic Functional groups ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> Alpha, Beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> Alpha, Beta-Unsaturated Aldehydes OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Organic Azides OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR Radical OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Organic Azides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN1 >> Nucleophilic attack after nitrene formation OR SN1 >> Nucleophilic attack after nitrene formation >> Organic Azides OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael addition to activated double bonds OR AN2 >> Michael addition to activated double bonds >> alpha,beta-Unsaturated Carbonyls and Related Compounds OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha,beta-Unsaturated Carboxylic Acids and Esters OR AN2 >> Nucleophilic addition to alpha, beta - unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta - unsaturated carbonyl compounds >> Propargyl Alcohol derivatives OR Michael addition OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups  OR SN2 OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Isothiazolone derivatives  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.4

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Esters OR Inorganic Compound by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Melamines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as SHOULD NOT BE PROFILED by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Triazines, Aromatic by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Neutral Organics by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Acid moiety AND Pyridine-alpha by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Alkoxy Silanes by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Halogens OR Metalloids by Groups of elements

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.74

Domain logical expression index: "ab"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.87

Validity criteria fulfilled:
not specified
Conclusions:
Based on the intoxication of daphnia magna due to the chemical 2,4-Pyridinedicarboxylic acid the EC50 was 230.749 mg/l.
Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the closest seven read across substances, toxicity on daphnia magna was predicted for 2,4-Pyridinedicarboxylic acid (499 -80 -9). Based on the immobility of test organism the EC50 value was estimated to be 230.749 mg/l when 2,4-Pyridinedicarboxylic acid exposed to daphnia magna for 48 hrs.       

Based on this value it can be concluded that the substance 2,4-Pyridinedicarboxylic acid is considered to be not toxic to aquatic environment and not classified as per the criteria mentioned in CLP regulation.    

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the closest seven read across substances, toxicity on daphnia magna was predicted for 2,4-Pyridinedicarboxylic acid (499 -80 -9). Based on the immobility of test organism the EC50 value was estimated to be 230.749 mg/l when 2,4-Pyridinedicarboxylic acid exposed to daphnia magna for 48 hrs. Based on this value it can be concluded that the substance 2,4-Pyridinedicarboxylic acid is considered to be not toxic to aquatic environment and not classified as per the criteria mentioned in CLP regulation.    

Key value for chemical safety assessment

EC50/LC50 for freshwater invertebrates:
230.749 mg/L

Additional information

The aim of the study was to determine the behavior of chemical when it comes in contact with the aquatic invertebrates directly or indirectly. For the determination purpose predicted study for the target chemical and experimental study for the read across was used which was selected on the basis of structural and functional similarity were reviewed are summarized as below:

 

In a prediction done by SSS (2017), based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the closest seven read across substances, toxicity on daphnia magna was predicted for 2,4-Pyridinedicarboxylic acid (499 -80 -9). Based on the immobility of test organism the EC50 value was estimated to be 230.749 mg/l when 2,4-Pyridinedicarboxylic acid exposed to daphnia magna for 48 hrs. Based on this value it can be concluded that the substance 2,4-Pyridinedicarboxylic acid is considered to be not toxic to aquatic environment and not classified as per the criteria mentioned in CLP regulation.    

The first study was supported by the second predicted weight of evidence study using ACD labs predicted median Lethal Concentration (LC50) of daphnia magna using v5.0.0.184. The value is supported by estimated Reliability Index (RI). Based on this, the LC 50 value for test item 2,4-Pyridinedicarboxylic acid (499 -80 -9) was predicted to be 7100 mg/l for Daphnia magna.On the basis of predicted value it can be concluded that the substance 2,4-Pyridinedicarboxylic acid is considered to be not toxic to aquatic environment as per the criteria mentioned in CLP regulation.

 

Similarly the third predicted study was used from Danish QSAR database, 2017. Based on the average value of both models (Leadscope Enterprise model and SciMatics SciQSAR model), the result were predicted in Battery model. Based on the Danish (Q)SAR Database, the 48 hours EC50 was estimated to be 103.6029 mg/l on Daphnia Magna for substance 2,4-Pyridinedicarboxylic acid with immobilization effects. Thus based on this value it can be concluded that the substance 2,4-Pyridinedicarboxylic acid cannot be classified as toxic as per the criteria of CLP regulation.

 

The fourth weight of evidence study for the target chemical 2,4-Pyridinedicarboxylic acid (499-80-9) done based on the prediction done by EPI suite, ECOSAR version 1.1, on the basis of similarity of structure to chemicals for which the aquatic toxicity has been previously measured by structure-activity relationships (SARs) program, the LC 50 value for short term toxicity to aquatic invertebrates was predicted. On the basis of this program, the LC 50 value for short term toxicity to aquatic invertebrates was predicted to be 1321.51 mg/l for 2,4-Pyridinedicarboxylic acid in 48 hrs. Based on this value it can be concluded that the substance is considered to be not toxic to aquatic environment and cannot be classified as per the criteria mentioned in CLP regulation.

Similarly the above predicted study was supported by the experimental studies for the read across chemicals which was structurally and functionally similar to the target chemical. First Terephthalic acid (100-21-0) from j-check, 2017, An acute immobilization test was used to test how a range of concentrations of Terephthalic acid exerts different degrees of toxic effects on the swimming capability of Daphnia magna under otherwise identical test conditions. A short term study in a semi-static test design was performed according to guidelines OECD Guideline 202 (Daphnia sp., Acute Immobilisation Test and Reproduction Test). Analytical method conducted by using HPLC method. 100 microL/L vehicle were used. 100 mL per vessel test solution volume added. Test conducted on 20 daphnia per concentration, where test performed in 4 replicates. Dechlorinated tap water collected from Tsukuba City, Ibaraki Prefecture were used. Based on the immobility of daphnia magna due to the chemical Terephthalic acid, the EC50 was ≥ 20 mg/l. Thus based on the effect concentration and readily biodegradability of chemical Terephthalic acid, it can be concluded that the chemical was nontoxic and can be consider to be not classified as toxic as per the CLP classification criteria.

 

In the sixth weight of evidence study from HSDB and OECD SIDS report, for the read across chemical (121-91-5) study was conducted to determine the toxic effect of chemical 1,3 Benzene dicarboxylic acid (Isophthalic acid) on the mobility of daphnia magna for 48hrs. Standards methods as per the OECD guideline were used in the test. 5 daphnids per concentration added in the test solution. Test performed in the 4 replicates, were observation of pH, effect on growth and other effects were measured. Based on the immobility of daphnia magna for 48hrs of exposure duration with the chemical, the EC0 was 876 mg/l. Based on the effect of chemical 1,3 Benzene dicarboxylic acid (Isophthalic acid) on the growth of daphnia magna, it can be concluded that the chemical was nontoxic and can be consider to be not classified as per the CLP classification criteria.

 

Similarly another read across chemical (59-67-6) from Fisheries Science 1994 also supports the nontoxic nature and classification of target chemical, Inhibitory effect was measured for B. Amphitrite by nicotinic acid. The test sample in the Petri dish was dissolved or dispersed in 5 m/ of filtered sea water. Ten cyprid larvae of B. amphitrite were transferred to each Petri dish and incubated in a darkroom at 23°C for 24h, The number of B. amphitrite settled and metamorphosed on the bottom of each Petri dish was counted to evaluate the effect of the test sample. TBTO and CuSO4 which are known to be antifouling chemicals were also applied as the positive controls in the assay. The highly active fractions were lyophilized, chromatographed and purified by HPLC. After that the minimum inhibitory concentration (MIC) or LOEC for nicotinic acid (59-67-6) was determined to be 20 mg/l. Based on the value, the nicotinic acid was considered to be toxic to aquatic invertebrates but as it was readily biodegradable it can considered to be not classified as per the CLP regulations.

 

Thus on the basis of all studies including predicted for the target chemical 2,4-Pyridinedicarboxylic acid (Pyridine-2,4-dicarboxylic acid) (499-80-9) (from QSAR toolbox version 3.4, ACD lab, Danish QSAR, EPIsuite) and experimental for the read across chemicals from (j-check, HSDB, OECD SIDS report and Fisheries Science 1994), it can be concluded that the target chemical was nontoxic and can be consider to be not classified as toxic to aquatic invertebrates as per the CLP classification criteria.