4-chloro-N-methylpiperidine

Endpoint summary

Description of key information

The skin sensitization potential of 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) failed to induce skin sanitization effects on guinea pig skin and hence considered to be not sensitizing to the skin.

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 version 3.3 and QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Sensitizers induce primary proliferation of lymphocytes in the lymph node draining the application site. The Local Lymph Node Assay (LLNA) assesses this proliferation. The lymphocyte subpopulations of the draining lymph nodes are studied by flow cytometry

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 4-chloro-1-methylpiperidine
- Molecular formula: C6H12ClN
- Molecular weight: 133.621 g/mol
- Smiles notation: N1(CCC(CC1)Cl)C
- InChl: 1S/C6H12ClN/c1-8-4-2-6(7)3-5-8/h6H,2-5H2,1H3
- Substance type: Organic
- Physical state: Liquid

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

No data available

Route:

epicutaneous, occlusive

Route:

epicutaneous, occlusive

No. of animals per dose:

No data available

Details on study design:

No data available

Challenge controls:

No data available

Positive control substance(s):

not specified

Key result

Reading:

1st reading

Group:

test chemical

No. with + reactions:

0

Clinical observations:

no skin sensitizing effects were observed.

Remarks on result:

no indication of skin sensitisation

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 ( not "i") )  )  and ("j" and ( not "k") )  )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and "q" )  and "r" )  and "s" )  and ("t" and "u" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aliphatic Amines by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides by Protein binding by OECD ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> N,N-Dialkyldithiocarbamate Derivatives OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Haloalcohols OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Haloalcohols OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Monohaloalkanes OR SN2 >> Alkylation, direct acting epoxides and related after cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards 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 Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Monohaloalkanes OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution after carbenium ion formation OR SN2 >> Nucleophilic substitution after carbenium ion formation >> Monohaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines AND SN2 AND SN2 >> SN2 at an sp3 Carbon atom AND SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Benzyl halides OR Low reactive OR Low reactive >> N-substituted aromatic amides OR Low reactive >> Primary haloalkanes OR Moderate reactive OR Moderate reactive >> Five-membered heterocyclic urea by DPRA Cysteine peptide depletion

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "m"

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: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Similarity boundary:Target: CN1CCC(Cl)CC1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

Similarity boundary:Target: CN1CCC(Cl)CC1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.382

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.89

Interpretation of results:

other: not sensitising

Conclusions:

The skin sensitization potential of 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) failed to induce skin sanitization effects on guinea pig skin and hence considered to be not sensitizing to the skin.

Executive summary:

The skin sensitization potential of 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) failed to induce skin sanitization effects on guinea pig skin and hence considered to be not sensitizing to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization:

Various studies has been investigated for the test chemical 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) 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 chemical4-chloro-1-methylpiperidine (CAS No: 5570-77-4) and its structurally similar read across substancesN-Methyldiethanolamine (CAS No: 105-59-9) and1-ethenylpyrrolidin-2-one (CAS No: 88-12-0).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 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. The substance 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) failed to induce skin sanitization effects on guinea pig skin and hence considered to be not sensitizing to the skin.

 

 

EUROPEAN COMMISSION – European Chemicals Bureau (2000) reported the guinea pig maximization test on structurally related read across substance N-Methyldiethanolamine (CAS No: 105-59-9) carried out in 20 guinea pigs which supports the above results. During induction animals were first induced intradermal with 5% test material in propylene glycol and dermally with 100%.following induction challenge was performed .since results at Challenge were equivocal a Re–Challenge was performed in the same manner as the Challenge, but at concentrations of 50% and 10% N–methyldiethanolamine. In order to differentiate dermal reactions produced by irritation from those produced by sensitization, 20 animals (5/sex/Challenge; treated concurrently during Induction with only vehicle or FCA/water emulsion) were subjected to the same Challenge or Re Challenge procedures as the animals which received test material during the Induction exposures. Fourteen days after the last induction exposure, the Challenge treatment was administered topically at 100%.Eighteen of the 20 animals challenged with 100%.N–methyldiethanolamine exhibited clear dermal responses. Index of Sensitization at Challenge to N–methyldiethanolamine was 90%.The Severity Indices at Challenge for the test material group at 24 and 48 hours are 0.8 and 1.8, respectively, compared to 0.8 and 1.6, respectively, for the irritation control group (out of a maximum Index of 3.0).Due to the responses seen in the irritation controls, a Re–Challenge was performed at lower, less irritating concentrations. Animals were re–challenged with both 50% and 10% N–methyldiethanolamine at separate sites. Dermal evaluations were made approximately 24 and 48 hours after the removal of Challenge/Re–Challenge patches. It was observed that the test animals treated with re-challenged dose 50% and 10% N–methyldiethanolamine were free of dermal responses. The Severity indices at Re–Challenge at 24 and 48 hours were both 0.0 for both the test group and the irritation control group. Hencethe chemicalN-Methyldiethanolamine (CAS No: 105-59-9) can be considered as non-sensitizing to guinea pigs at 50% and 10% concentration.

The above result was supported bythe Buehler testconducted by Henry F. Smyth Jr., Charles P. Carpenter, Carrol S. Well, Urbano C. Pozzani & Jean A. Striegel (1962) forstructurally similar read across substance1-methylpiperazine (CAS No: 109-01-3) in guinea pigs according to contemporary regulatory protocols under an occlusive condition. During induction, 20 guinea pigs received undiluted 0.25 ml of 1-ethenylpyrrolidin-2-one on the flanks under an occlusive dressing and held in place for 6 hours. The treatment occurred once per week on three successive weeks. Since 1-ethenylpyrrolidin-2-one was applied without use of a vehicle, the control group of 10 guinea pigs remained untreated. After 14 days of the final induction application, animals were challenged on opposite flanks to the for 6 hours under occlusive condition and application sites scored 24 and 48 hours after removal of the patches.No signs of irritation and no systemic toxicity were observed during the induction and challenge phase. Therefore the chemical 1-ethenylpyrrolidin-2-one (CAS No: 88-12-0) was considered to be not sensitizing to the skin of guinea pigs.

Based on the available data for thetarget chemical4-chloro-1-methylpiperidine (CAS No: 5570-77-4) and its structurally similar read across substancesN-Methyldiethanolamine (CAS No: 105-59-9)and1-ethenylpyrrolidin-2-one (CAS No: 88-12-0),it can be concluded thatchemical 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) is unable to cause skin sensitization and considered as non skin sensitizer.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) and its structurally similar read across substancesN-Methyldiethanolamine (CAS No: 105-59-9)and1-ethenylpyrrolidin-2-one (CAS No: 88-12-0) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 4-chloro-1-methylpiperidine (CAS No: 5570-77-4) is unable to cause skin sensitization and hence can be classified as non skin sensitizer.