4-chloro-1-methylpiperidinium chloride

Endpoint summary

Description of key information

The skin sensitization potential of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was predicted to be not sensitizing to the skin of male and female Hartley guinea pig.

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 v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Type of study:

Buehler test

Justification for non-LLNA method:

No data available

Specific details on test material used for the study:

- Name of test material: 4-chloro-1-methylpiperidinium chloride
- IUPAC name: 4-chloro-1-methylpiperidin-1-ium chloride
- Molecular formula: C6H13Cl2N
- Molecular weight: 170.0817 g/mole
- Smiles : CN1CCC(CC1)Cl.Cl
- Inchl: 1S/C6H12ClN.ClH/c1-8-4-2-6(7)3-5-8;/h6H,2-5H2,1H3;1H
- Substance type: Organic
- Physical state: Solid crystal powder (White - Slightly pale yellow)

Species:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

No data available

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

Statistics:

No data available

Positive control results:

No data available

Reading:

1st reading

Group:

test chemical

Clinical observations:

No skin sensitization reaction was 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 7 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 ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and "w" )  and "x" )  and ("y" and "z" )  )

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 SN2 AND SN2 >> SN2 at an sp3 Carbon atom AND SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

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 OR AN2 >> Schiff base formation >> Polarized Haloalkene Derivatives 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 AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Polarized Haloalkene Derivatives 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 >> 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 >> 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 OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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, 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 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene 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 No superfragment by Superfragments ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aliphatic halogens OR alpha,beta-unsaturated aliphatic alkoxy group OR alpha,beta-unsaturated carbonyls OR Aromatic N-acyl amine OR Hydrazine OR Primary aromatic amine,hydroxyl amine and its derived esters by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Aliphatic nitriles (Hepatotoxicity) Rank B OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Ethionine (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as AN2 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 by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Not classified by Oncologic Primary Classification

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aldehyde Type Compounds OR Aromatic Amine Type Compounds OR Halogenated Aromatic Hydrocarbon Type Compounds OR Halogenated Cycloalkane Type Compounds by Oncologic Primary Classification

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Di-substituted hydrocarbons (24a) OR Inorganic chemical OR Known precedent reproductive and developmental toxic potential OR Not covered by current version of the decision tree OR Organophosphorus compounds (1b) OR Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "x"

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: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.25

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.158

Interpretation of results:

other: Negative

Conclusions:

The skin sensitization potential of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was predicted to be not sensitizing to the skin of male and female Hartley guinea pig

Executive summary:

The skin sensitization potential of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was predicted to be not sensitizing to the skin of male and female Hartley guinea pig

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

Skin sensitization

In different studies, 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) has been investigated for potential of skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pig for target chemical, 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) and its structurally similar read across substances11-aminoundecanoic acid (2432-99-7) andL-valine (72-18-4) ,the predicted data using the OECD QSAR toolbox has also been compared with the experimental data of read across.

The skin sensitization potential of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances of 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) was predicted to be not sensitizing to the skin of male and female Hartley guinea pig

The experimental study conducted by OECD SIDS (SIDS Initial Assessment Report for SIAM 15, Boston, Massachusetts, 22 - 25 October 2002.)to evaluate the skin sensitizing potential of read across substance11-aminoundecanoic acid (2432-99-7), The skin sensitization study of 11-aminoundecanoic acid (2432-99-7) was performed by guinea pig maximization method of Magnusson and Kligman using OECD guideline 406 on male and female guinea pig. Group of 30 animals were classified into two groups, test group 10 male and 10 female, whereas in control group 5male and 5 female. The sensitivity of the guinea-pigs in laboratory experimental conditions was checked with a positive sensitizer, 2,4-Dinitro Chlorobenzene (DNCB). During the induction period, the reference substance DNCB was applied at the concentrations of 0.1 % (w/w) (day 1) and I % (w/w) (day 8) in corn oil. For the challenge application, the reference substance DNCB was applied at the concentration of 1% (w/w) in corn oil.

In induction phase, On day 1, intradermal injections of Freund's complete adjuvant mixed with the test substance (treated group) or the vehicle (control group) were performed in the interscapular region in concentration test substance 0.1% w/w in corn oil. On day 7, the same region received a topical application of sodium lauryl sulphate in Vaseline (10% w/w) in order to induce local irritation and on next day the test substance in 40% w/w in corn oil was applied to the same test site which was then covered by an occlusive dressing for 48 hours.

In challenge phase, On day 22, after a rest period of 12 days, all animals of the treated and control groups were challenged by a cutaneous application of the test Substance in concentration 40% w/w in corn oil to the right flank. The left flank served as control and received the vehicle only. Test substance and vehicle were maintained under an occlusive dressing for 24 hours. Skin reactions were evaluated approximately 24 and 48 hours after removal of the dressing. The all animals were observed for any clinical signs. The species and strain which were used showed a satisfactory Sensitization response in 90% animals treated with DNCB. At the end of the study, animals were killed without examination of internal organs. No skin samples were taken from the challenge application sites. No skin sensitization was observed after the challenge application and no deaths were noted during the study. Hence11-aminoundecanoic acid was considered as not skin sensitizing in guinea pig.

Also it is further Supported by experimental study conducted byEuropean Food Safety Authority (EFSA),( EFSA Journal 2013;11(10):3429) to evaluate the skin sensitizing potential of read across substanceL-valine (72-18-4).The skin sensitization study ofL-valine (72-18-4)was performed by Buehler test .Using OECD guideline 406 on guinea pig.The 40 animals were classified into three groups; test group 20 animals were as in control group 10 and positive control group 10 animals.During the induction period, total 3 inductions once per week for three weeks were given in concentration 100mg/ml.After rest period of 2 weeks the challenge application given in dose concentration same as induction.The Clinical signs, body weight and skin response (at 30 and 54 hours after challenge) were surveyed.No skin sensitization was observed after the challenge application Hence theL-valine (72-18-4) was considered to be not sensitizing in guinea pig by Buehler test.

 Thus based on the above predictions on4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0)as well as its read across and applying weight of evidence, it can be concluded that 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) is not a skin sensitizer. Thus comparing the above studies with the criteria of CLP regulation, 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) can be considered as "not classified" for skin sensitization.

 

Justification for classification or non-classification

Thus comparing the above studies with the criteria of CLP regulation, 4-chloro-1-methylpiperidin-1-ium chloride (5382-23-0) can be considered as not classified for skin sensitization.