2-methoxy-5-nitroanilinium chloride

Endpoint summary

Description of key information

Skin Sensitization

The skin sensitization potential of 2-methoxy-5-nitroanilinium chloride was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. 2-methoxy-5-nitroanilinium chloride was predicted to be sensitizing to the skin of male Dunkin Hartley guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

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 v3.4 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Type of study:

other: Estimated data

Specific details on test material used for the study:

- Name of test material: 2-methoxy-5-nitroanilinium chloride
- IUPAC name: 2-methoxy-5-nitroanilinium chloride
- Molecular formula: C7H9ClN2O3
- Molecular weight: 204.6121g/mole
- Smiles: Cl.COc1ccc(cc1N)[N+](=O)[O-]
- Inchl: 1S/C7H8N2O3.ClH/c1-12-7-3-2-5(9(10)11)4-6(7)8;/h2-4H,8H2,1H3;1H
- Substance type: Organic
- Physical state: Solid powder

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male

Details on test animals and environmental conditions:

no data available

Route:

intradermal

Vehicle:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, open

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

10

Other effects / acceptance of results:

no data available

Reading:

1st reading

Group:

test chemical

Clinical observations:

signs of dermal sensitization observed

Remarks on result:

positive indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "S M W N"
Estimation method: Takes highest mode value from the 6 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 ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN1 AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids by DNA binding by OASIS v.1.4

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic nitro by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines by Protein binding by OASIS v1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aromatic amines by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Aromatic amines by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Ketones by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aromatic amines by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group CN Melting Point > 180 C AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group CN Molecular Weight > 290 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group CN Melting Point > 180 C AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Group CN Aqueous Solubility < 0.1 g/L by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group CN Melting Point > 180 C AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as (!Undefined)Group CNHal Lipid Solubility < 4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Similarity boundary:Target: COc1ccc(N(=O)=O)cc1N{+}.Cl{-}
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Alkylarylether AND Anion AND Aromatic compound AND Cation AND Ether AND Nitro compound AND Primary amine AND Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Alkylarylether AND Anion AND Aromatic compound AND Cation AND Ether AND Nitro compound AND Primary amine AND Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Tertiary amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.08

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.553

Interpretation of results:

other: Strong sensitizer

Conclusions:

2-methoxy-5-nitroanilinium chloride was predicted to be sensitizing to the skin of male Dunkin Hartley guinea pigs.

Executive summary:

The skin sensitization potential of 2-methoxy-5-nitroanilinium chloride was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. 2-methoxy-5-nitroanilinium chloride was predicted to be sensitizing to the skin of male Dunkin Hartley guinea pigs.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

Skin Sensitization:

 

Various studies have been investigated for assessing the dermal sensitization potential of 2-methoxy-5-nitroanilinium chloride to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs along with predicted data for target chemical and its structurally similar read across substances, 4-Amino-3-nitrophenol[CAS: 610-81-1] and 4-nitro-o-phenylenediamine[CAS: 99-56-9].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The skin sensitization potential of 2-methoxy-5-nitroanilinium chloride was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. 2-methoxy-5-nitroanilinium chloride was predicted to be sensitizing to the skin of male Dunkin Hartley guinea pigs.

Mouse local lymphnode assay(LLNA) was performed (Dermatitis, Vol 21, No 1 (January/February), 2010: pp 8–32) to assess the dermal sensitization potential of the structurally similar read across substance, 4-Amino-3-nitrophenol[CAS: 610-81-1]. The study was performed as per OECD 429 Guidelines. Groups of female CBA mice (7-12 weeks of age) were exposed topically on the dorsum of both ears to 25µl of the test material or to an equal volume of relevant vehicle only. Treatment was performed daily for 3 consecutive days.Five days after the initiation of exposure, all mice were injected via the tail vein with 250 µL of phosphate buffered saline (PBS) containing 20 µCi of tritiated thymidine. Mice were sacrificed 5 hours later, and the draining auricular lymph nodes were excised and pooled for each experimental group or each individual animal. The incorporation of tritiated thymidine measured by beta scintillation counting was reported in disintegrations per minute (dpm). A stimulation index (SI) was calculated for each chemical-treated group as the ratio of the dpm of the treated group (or mean dpm when individual animals were assessed) to the dpm or mean dpm of the concurrent vehicle control group.The approach to estimation of the relative skin sensitization potential was based on the mathematical estimation of the concentration of chemical necessary to obtain a threshold positive response (SI = 3); this is termed as the EC3 value.A substance was classified as a skin sensitizer if it induced a threefold or greater increase in local lymph node proliferative activity at one or more test concentrations when compared with concurrent vehicle-treated controls (SI≥3).

  The relative potency index of 4-Amino-3-nitrophenol was calculated to be 0.2.

Based on the relative potency index, 4-Amino-3-nitrophenol was considered to be a strong sensitizer.

 

The similar study was performed (Dermatitis, Vol 21, No 1 (January/February), 2010: pp 8–32) to assess the dermal sensitization potential of the structurally similar read across substance, 4-nitro-o-phenylenediamine[CAS: 99-56-9]. The study was performed as per OECD 429 Guidelines. Groups of female CBA mice (7-12 weeks of age) were exposed topically on the dorsum of both ears to 25µl of the test material or to an equal volume of relevant vehicle only. Treatment was performed daily for 3 consecutive days.Five days after the initiation of exposure, all mice were injected via the tail vein with 250 µL of phosphate buffered saline (PBS) containing 20 µCi of tritiated thymidine. Mice were sacrificed 5 hours later, and the draining auricular lymph nodes were excised and pooled for each experimental group or each individual animal. The incorporation of tritiated thymidine measured by beta scintillation counting was reported in disintegrations per minute (dpm). A stimulation index (SI) was calculated for each chemical-treated group as the ratio of the dpm of the treated group (or mean dpm when individual animals were assessed) to the dpm or mean dpm of the concurrent vehicle control group.The approach to estimation of the relative skin sensitization potential was based on the mathematical estimation of the concentration of chemical necessary to obtain a threshold positive response (SI = 3); this is termed as the EC3 value.A substance was classified as a skin sensitizer if it induced a threefold or greater increase in local lymph node proliferative activity at one or more test concentrations when compared with concurrent vehicle-treated controls (SI≥3).

The relative potency index of 4-nitro-o-phenylenediamine was calculated to be 0.05.

Based on the relative potency index, 4-nitro-o-phenylenediamine was considered to be an extreme sensitizer.

 

Based on the available data for the target as well as its structurally similar read across substances and applying the weight of evidence approach,2-methoxy-5-nitroanilinium chloride can be considered to be sensitizing to skin.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Available data for2-methoxy-5-nitroanilinium chloride indicates that it is likely to cause dermal sensitization to skin.

2-methoxy-5-nitroanilinium chloride can be considered to be sensitizer to skin.