Registration Dossier

Administrative data

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:
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.