Pyridine-2,4-dicarboxylic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 871.5 mg/kg bw when rats were orally exposed with Pyridine-2,4-dicarboxylic acid.  

Thus, as per criteria of CLP regulation, Pyridine-2,4-dicarboxylic acid can be not classified for reproductive toxicity.   

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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:

Data is predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: 2,4-Pyridinedicarboxylic acid
InChI: 1S/C7H5NO4/c9-6(10)4-1-2-8-5(3-4)7(11)12/h1-3H,(H,9,10)(H,11,12)
Smiles: c1(cc(ncc1)C(O)=O)C(O)=O
- Molecular formula (if other than submission substance):C7H5NO4
- Molecular weight (if other than submission substance):167.12 g/mol
- Substance type:Organic

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Remarks on MMAD:

not specified

Vehicle:

water

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

Once a day

Details on study schedule:

not specified

Dose / conc.:

871.5 mg/kg bw/day

No. of animals per sex per dose:

10 per sex and dose

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

not specified

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

871.5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 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 ("j" and ( not "k") )  )  and "l" )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

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 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinone methides OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR Radical OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides 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 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 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 Protein binding by OASIS v1.4

Domain logical expression index: "h"

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 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 >> alpha,beta-Carbonyl compounds with polarized double bonds  OR SN2 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: "i"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Carboxylic acids (Hepatotoxicity) No rank OR Ethionine (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "l"

Similarity boundary:Target: OC(=O)c1ccnc(C(O)=O)c1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.28

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.18

Conclusions:

NOAEL was estimated to be 871.5 mg/kg bw when rats were orally exposed with Pyridine-2,4-dicarboxylic acid.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Pyridine-2,4-dicarboxylic acid. The NOAEL was estimated to be 871.5 mg/kg bw when rats were orally exposed with Pyridine-2,4-dicarboxylic acid.  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

871.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity:

In different studies, Pyridine-2,4-dicarboxylic acid has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Pyridine-2,4-dicarboxylic acid along with the study available on structurally similar read across substance Terephtalic acid (CAS no 100-21-0) and Trimellitic acid (CAS no 528-44-9). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Pyridine-2,4-dicarboxylic acid. The NOAEL was estimated to be 871.5 mg/kg bw when rats were orally exposed with Pyridine-2,4-dicarboxylic acid.  

In another experimental study given by European Commission (European Chemicals Bureau, 22–FEB–2000), NTRL (National Technical Reports Library (NTRL), OTS94820190, 1982) and OECD SIDS (OECD SIDS, 2001) on structurally similar read across substance Terephtalic acid (CAS no 100-21-0), Wistar male and female rats treated with Terephtalic acid in the concentration of 0, 15, 62.5, 250, 1000 and 2500 mg/kg/day orally in feed for 90 days. Diarrhea was observed in some of the rats at 2500 mg/kg bw. Five unscheduled deaths occurred between 4 and 13 weeks in animals at 2500 mg/kg bw. Dose-related decreases in body weight and weight gain and food consumption were observed in all dose groups. No effect on reproductive parameters such as fertility and litter size were observed in treated rats. No bladder stones were observed in dead animals. In addition, Decrease in pup viability and Significant decrease in body weight were observed at 1000 and 2500 mg/kg bw. No gross anomalies and fetal malformations were observed. Therefore, NOAEL was considered to be 1000 mg/kg bw for P and 250 mg/kg bw for F1 generation when male and female Wistar rats were treated with Terephtalic acid orally in feed for 90 days.

Futher supported by experimental study given by OECD SIDS (OECD SIDS, October 2002) on structurally similar read across substance Trimellitic acid (CAS no 528-44-9), albino male and female rats treated with Trimellitic acid in the concentration of 0 and 500 mg/kg/day orally in feed for 90 days. No effect on histopathology of reproductive tissues (ovary, testes, seminal vesicle) was observed in rats. Therefore, NOAEL was considered to be 500 mg/kg bw for P generation when albino male and female rats were treated with Trimellitic acid orally in feed for 90 days.

Thus, based on the above study and predictions on Pyridine-2,4-dicarboxylic acid and its read across substances, it can be concluded that NOAEL value is 871.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, Pyridine-2,4-dicarboxylic acid can be not classified for reproductive toxicity.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus, based on the above study and predictions on Pyridine-2,4-dicarboxylic acid and its read across substances, it can be concluded that NOAEL value is 871.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, Pyridine-2,4-dicarboxylic acid can be not classified for reproductive toxicity.