2-chloro-6,7-dimethoxyquinazolin-4-amine

Endpoint summary

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 five closest read across substances, repeated dose oral toxicity was predicted for the test compound 2-Chloro-6,7-dimethoxy-4-quinazolinamine. The study assumed the use of male and female Wistar rats in a study 5 days. No significant alterations were noted at the dose level of 566.666687012 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for 2-Chloro-6,7-dimethoxy-4-quinazolinamine is considered to be 566.666687012 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

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 from OECD QSAR Toolbox version 3.4 and the spporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.4, 2017

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 2-Chloro-6,7-dimethoxy-4-quinazolinamine
- IUPAC name: 2-chloro-6,7-dimethoxyquinazolin-4-amine
- Molecular formula: C10H10ClN3O2
- Molecular weight: 239.661 g/mol
- Smiles notation: n1c(c2cc(OC)c(cc2nc1Cl)OC)N
- Substance type: Organic

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

5 days

Frequency of treatment:

No data

Remarks:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

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

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

566.667 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant alteratins were noted at the mentiioned dose level

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

(((("a" or "b" or "c" or "d" )  and "e" )  and "f" )  and ("g" and "h" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines by DNA binding by OASIS v.1.4

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles (hypothesized) AND AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles (hypothesized) >> Heterocyclic Aromatic Amines AND Radical reactions AND Radical reactions >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base AND Radical reactions >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines AND SE reaction (CYP450-activated heterocyclic amines) AND SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base  AND SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base  >> Heterocyclic Aromatic Amines AND SNAr AND SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds AND SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds AND SR reaction (peroxidase-activated heterocyclic amines) AND SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base AND SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines by Protein binding by OASIS v1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SNAr AND SNAr >> Nucleophilic aromatic substitution AND SNAr >> Nucleophilic aromatic substitution >> Halo-pyrimidines by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Anilines (Unhindered) by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Similarity boundary:Target: COc1cc2c(cc1OC)c(N)nc(Cl)n2
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.09

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.13

Conclusions:

The predicted No Observed Adverse Effect Level (NOAEL) for 2-Chloro-6,7-dimethoxy-4-quinazolinamine is considered to be 566.666687012 mg/Kg bw/day.

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 five closest read across substances, repeated dose oral toxicity was predicted for the test compound 2-Chloro-6,7-dimethoxy-4-quinazolinamine. The study assumed the use of male and female Wistar rats in a study 5 days. No significant alterations were noted at the dose level of 566.666687012 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for 2-Chloro-6,7-dimethoxy-4-quinazolinamine is considered to be 566.666687012 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

566.667 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral

Prediction model based estimation and data from read across have been summarized to determine the toxic nature of the test compound 2-Chloro-6,7-dimethoxy-4-quinazolinamine. The studies are as summarized below:

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound 2-Chloro-6,7-dimethoxy-4-quinazolinamine. The study assumed the use of male and female Wistar rats in a study 5 days. No significant alterations were noted at the dose level of 566.666687012 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for 2-Chloro-6,7-dimethoxy-4-quinazolinamine is considered to be 566.666687012 mg/Kg bw/day.

Combined repeated dose repro-devp. Screen was performed (J check, 2016) for the test chemical 2-Amino-1-naphthalenesulfonic acid (RA CAS no 81 -16 -3) to evaluate its toxic nature upon repeated application by the oral route of exposure. The test compound was administered to Crj: CD (SD), (SPF) male and female rats at dose levels of 0, 8, 40, 200 or 1000 mg/Kg bw. The animals were observed for clinical signs, mortality, hematological and blood chemistry parameters, changes in body weight and alteration in gross and histopathology if any. Changes in organ weight in males and histopathological findings in females were noted at 1000 mg/Kg bw, no significant changes were noted at 200 mg/Kg bw in male and female animals. Therefore, the No Observed Adverse Effect Level (NOAEL) for the test chemical in Crj: CD (SD), (SPF) rats is considered to be 200 mg/Kg bw.

In a study for other read across chemical (RA CAS no 130 -13 -2) (J check, 2016), Repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compound4-amino-1-sodium naphthalene sulfonic acidupon repeated application by oral route of administration. The test chemical was dosed at levels of 0, 100, 300 or 1000 mg/Kg once daily for 28 days. Recovery test was set up in the study designed. During the administration period and during the recovery test period, no deaths were observed in any of the treatment groups, and the results of general condition, body weight, food intake and urinalysis, hematology examination, pathological examination were also used for administration of the test substance There was no change thought to be caused. On the other hand, in the blood biochemical test at the end of the administration period, high GPT activity was observed in the group administered 1000 mg / kg of male and female, and it was judged that it is highly likely that it is a finding attributable to administration of the test substance. Hence, The No observed adverse effect level (NOAEL) for the test compound in male and female SPF strain Sprague Dawley rats is considered to be 300 mg/Kg bw/day.

Based on the weight of evidence data summarized, the test chemical 2-Chloro-6,7-dimethoxy-4-quinazolinamine is not likely to be a toxic compound upon repeated application by the oral route of administration.

Justification for classification or non-classification

Based on the weight of evidence data summarized, the test chemical 2-Chloro-6,7-dimethoxy-4-quinazolinamine (CAS no 23680 -84 -4) is not likely to be a toxic compound upon repeated application by the oral route of administration.