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

Endpoint summary

Description of key information

The skin sensitization potential of 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The substance 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated to be not sensitising to the skin of Pirbright White guinea pigs. Based on the estimated result 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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 QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

- IUPAC Name: 2-Chloro-6,7-dimethoxyquinazolin-4-amine
- Mol. formula: C10H10ClN3O2
- Molecular Weight: 239.661 g/mole
- Smiles: n1c(c2cc(OC)c(cc2nc1Cl)OC)N
- InChI: 1S/C10H10ClN3O2/c1-15-7-3-5-6(4-8(7)16-2)13-10(11)14-9(5)12/h3-4H,1-2H3,(H2,12,13,14)
- Physical state: Solid

Species:

guinea pig

Strain:

other: Pirbright White

Sex:

not specified

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

No data available

Challenge controls:

No data available

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization was observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode 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 ("h" and "i" )  )

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 Non binder, impaired OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Very strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.919

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.68

Interpretation of results:

other: Not sensitizing

Conclusions:

The substance 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated to be not sensitising to the skin of Pirbright White guinea pigs. Based on the estimated result 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.

Executive summary:

The skin sensitization potential of 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The substance 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated to be not sensitising to the skin of Pirbright White guinea pigs. Based on the estimated result 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs for target chemical2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) and its structurally similar read across substances4-amino-3-nitrophenol (CAS no: 610-81-1) and 3-nitro-phydroxyethylaminophenol (CAS No. 65235-31-6).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

The skin sensitization potential of 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The substance 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) was estimated to be not sensitising to the skin of Pirbright White guinea pigs. Based on the estimated result 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.

 

The above result was further supported by the two guinea pig maximization studies conducted byBurnett CL et al.,{International Journal of Toxicology 2009;Nov-Dec;28(6 Suppl 2):217S-51S} for two read across substances 4-amino-3-nitrophenol (CAS no: 610-81-1) and 3-nitro-phydroxyethylaminophenol (CAS No. 65235-31-6) as follows;

 

The sensitizing potential of 4-amino-3-nitrophenol (CAS no: 610-81-1) was studied in female Hartley albino guinea pigs (5 in a control group, 10 in the test group). During induction, the test group received 3 symmetrical intradermal injections of 0.1 mL that consisted of Freund’s complete adjuvant (FCA) and distilled water (1:1 vol/vol), 4-amino-3- nitrophenol diluted to 10% in distilled water, and 4-amino-3-nitrophenol diluted to 10% in mixture 1:1 (vol/vol) with FCA and distilled water. Adequate controls were used. The guinea pigs were not treated for a period of 6 days and then were reclipped at the injection sites. Because the material did not produce local irritation, the test areas of both the control and treated animals were coated with 0.5 mL of sodium lauryl sulfate at 10% in liquid petrolatum to produce irritation. After 24 hours, the treated group was patched with 0.5 mL of 4-amino-3-nitrophenol diluted to 50% for 48 hours. The control group was patched with 0.5 mL of distilled water. After an 11-day rest period, both groups of guinea pigs were clipped on the dorsolumbar region. Occlusive patches with 0.2 mL of 4-amino-3-nitrophenol at the maximal nonirritant concentration and a lower concentration were applied to all animals for a period of 24 hours. At 24 and 48 hours after challenge patch removal, the skin was observed for cutaneous reactions. Because of the dyeing properties of the test substance, assessment of erythema was impossible. No edematous reactions were observed. The researchers concluded that 4-amino-3-nitrophenol was not sensitizing by contact with guinea pig skin.

 

The next skin sensitization study was conducted on Hartley albino guinea pigs (10/sex) for read across chemical 3-nitro-phydroxyethylaminophenol (CAS No. 65235-31-6). In the induction phase, the guinea pigs were first intradermal injections of 0.1 mL of FCA diluted to 50% on day 1 and 10. After this, the treated guinea pigs were treated with 10 topical applications of 0.5 mL of pure 3-nitro-p-hydroxyethylaminophenol over the course of 24 days behind the right shoulder blade on clipped skin under occlusive patch. The challenge phase began on day 35 of the study with application of 0.5 mL of pure test material to the left flank with an occlusive patch. The patch was removed after 48 hours. The skin was observed for effects at 1, 6, 24, and 48 hours after patch removal. Because of the dyeing properties of the substance, erythema could not be scored. The researchers determined that 3-nitro-p-hydroxyethylaminophenol did not produce any sensitization in the guinea pigs.

 

Since no contact sensitization was observed in treated groups in both the studies, the chemicals 4-amino-3-nitrophenol (CAS no: 610-81-1) and 3-nitro-phydroxyethylaminophenol (CAS No. 65235-31-6) wereconsidered to be not sensitizing onHartley albino guinea pigs’ skin.

 

Thus on the basis of available data for thetarget chemical2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) and its structurally similar read across substances4-amino-3-nitrophenol (CAS no: 610-81-1) and 3-nitro-phydroxyethylaminophenol (CAS No. 65235-31-6),it can be concluded thatchemical 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) is unable to cause skin sensitization and considered as non- skin sensitizer. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) and its structurally similar read across substances 4-amino-3-nitrophenol (CAS no: 610-81-1) and 3-nitro-phydroxyethylaminophenol (CAS No. 65235-31-6) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS No: 23680-84-4) is not likely to cause skin sensitization and hence can be classified as non- skin sensitizer.