1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine

Endpoint summary

Description of key information

The skin sensitization potential of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)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. 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)was predicted to be non sensitizing to the skin of 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 version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

Prediction is from OECD QSAR Toolbox version 3.3.

GLP compliance:

not specified

Type of study:

Buehler test

Justification for non-LLNA method:

Not specified.

Specific details on test material used for the study:

- Name of the test material: 1-(3-Chlorophenyl)-4-(3-chloropropyl)-piperazine
- IUPAc name: 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine
- Molceular weight: 273.205 g/mol
- Molecular Formula: C13H18Cl2N2
- Substance type: Organic
- Smiles: N1(c2cc(Cl)ccc2)CCN(CC1)CCCCl

Species:

guinea pig

Strain:

Pirbright-Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River GmbH - Wiga, Kisslegg, FRG
- Age at study initiation: young adult
- Weight at study initiation: 320 - 410 g
- Housing: Makrolon, type IV cage, 5 animals per cage
- Diet (e.g. ad libitum): Kliba Labordiat 341 ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 6 days before the beginning of the study in the laboratory for dermal toxicity

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12/12

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.25 ml of undiluted test substance

Day(s)/duration:

6 hour

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.25 ml of undiluted test substance

Day(s)/duration:

6 hour

Details on study design:

RANGE FINDING TESTS: Based on the results of a pre-test, 0.25 ml of undiluted test substance was chosen as the highest volume that can be applied without toxicity to the test animals. To ensure sufficient saturation of the gauze, the normal 6 layers were reduced to 3.

MAIN STUDYA
. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hours
- Test groups: one test group
- Control group: yes, no treatment on controls
- Site: anterior left flank
- Frequency of applications: one application per week; days 0, 7 and 14 on the same application area
- Duration: 6 hours
- Concentrations: undiluted test substance

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 14 days after the third induction
- Exposure period: 6 hours
- Test groups: one test group
- Control group: yes, untreated
- Site: right flank-
Concentrations: undiluted test substance
- Evaluation (hr after challenge): 24 and 48 hours after the removal of the patch

Challenge controls:

10 animals were used.

Positive control substance(s):

yes

Remarks:

historical data on alpha-hexylcinnamaldehyde

Statistics:

No data available.

Reading:

other: Challenge

Hours after challenge:

48

Group:

test chemical

Dose level:

undiluted test substance

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization 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 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 ("h" and ( not "i") )  )  and "j" )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and "o" )  and "p" )  and ("q" and ( not "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 SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine 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 SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine 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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

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 OR Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

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: "k"

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: "l"

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

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 Alkali Earth OR Metalloids by Groups of elements

Domain logical expression index: "o"

Similarity boundary:Target: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Similarity boundary:Target: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Basesurface narcotics by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.245

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.31

Interpretation of results:

other: not sensitising

Conclusions:

The skin sensitization potential of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)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. 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)was predicted to be non sensitizing to the skin of guinea pig.

Executive summary:

The skin sensitization potential of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)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. 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)was predicted to be non sensitizing to the skin of guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization

In different studies, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)has been investigated for potential for dermal sensitization to a greater or lesser extent. The prediction and studies are based on in vivo experiments in guinea pig for target chemical disodium 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0 and its structurally similar read across substances Vinyl Pyrrolidone (88-12-0). The predicted data using the OECD QSAR toolbox have also been compared with the experimental data of read across .

The skin sensitization potential of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)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. 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0)was predicted to be non sensitizing to the skin of guinea pig.

Supported by experimental data conducted byEUROPEAN COMMISSION JOINT RESEARCH CENTRE(European Union Risk Assessment Report 1-VINYL-2-PYRROLIDONE, RISK ASSESSMENT, 2003) on structurally similar read across substanceVinyl Pyrrolidone (88-12-0) on guinea pigs.The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on skin sensitization from the analogue substance.In the study Vinyl Pyrrolidone was assessed for its possible contact allergenic potential. For this purpose Buehler test was performed on 20 guinea pigs. In induction phase 0.25 ml of test material was applied under an occlusive dressing to the flanks of, and held in place for 6 hours. The treatment occurred once per week on three successive weeks. Since test material was applied without use of a vehicle, the control group of 10 guinea pigs remained untreated. No signs of irritation and no systemic toxicity were observed during the induction phase. After 14 days of rest period. Challenge exposure was performed using 0.25 ml of test material .It was applied under an occlusive dressing to the opposite flanks of all treated and control animals for 6 hours . The application sites scored 24 and 48 hours after removal of the patches. No skin sensitization effects were observed. Therefore Vinyl Pyrrolidone (88-12-0) was considered to be non sensitizing in guinea pigs by Buehler test.

Thus based on the above predictions on 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0) as well as its read across substances and applying weight of evidence, it can be concluded that 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0) is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0) can be considered as not classified for skin sensitization effects.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus comparing the above annotations with the criteria of CLP regulation, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (39577-43-0) can be considered as not classified for skin sensitization effects.