N-(2-chloroethyl)pyrrolidine hydrochloride

Endpoint summary

Description of key information

The skin sensitization potential of 1-(2-chloroethyl)pyrrolidine hydrochloride(7250-67-1) was estimate by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across1-(2-chloroethyl)pyrrolidine hydrochloride(7250-67-1)was predicted to be not sensitizing to the skin of Dunkin-Hartley guinea pig.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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:

OECD Guideline 406 (Skin Sensitisation)

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

No data avaliable

Specific details on test material used for the study:

Name of test material (as cited in study report): 1-(2-chloroethyl)pyrrolidine hydrochloride
Molecular Formula: C6-H12-Cl-N.Cl-H
Molecular Weight: 170.082g/mole
Smiles notation: N1(CCCl) CCCC1.Cl
Substance type: Organic
Physical state: not specified

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals and environmental conditions:

No data avaliable

Route:

intradermal and epicutaneous

Vehicle:

water

Concentration / amount:

Induction: 5% aquous solution (for injection and epicutaneous application)

Day(s)/duration:

48hr

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

3%

Day(s)/duration:

24hr

No.:

#2

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

3%

Day(s)/duration:

24hr

No. of animals per dose:

Total:18
Test group:12
Control group:6

Details on study design:

No data avaliable

Challenge controls:

yes

Positive control substance(s):

no

Statistics:

No data avaliable

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

3%

No. with + reactions:

0

Total no. in group:

12

Clinical observations:

No skin sensitization observed

Remarks on result:

no indication of skin sensitisation

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

3%

No. with + reactions:

0

Total no. in group:

12

Clinical observations:

No skin sensitization observed

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

24

Group:

test chemical

Dose level:

3%

No. with + reactions:

0

Total no. in group:

12

Clinical observations:

No skin sensitization observed

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

3%

No. with + reactions:

0

Total no. in group:

12

Clinical observations:

No skin sensitization 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 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and "p" )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and "u" )  and "v" )  and "w" )  and ("x" and ( not "y") )  )  and ("z" and "aa" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aliphatic Amines AND Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkyl halide OR No functional group found OR Pyrrolidine OR Saturated heterocyclic amine OR Saturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkyl halide OR No functional group found OR Overlapping groups OR Pyrrolidine OR Saturated heterocyclic amine OR Saturated heterocyclic fragment by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Amino, aliphatic attach [-N<] OR Chlorine, aliphatic attach [-Cl] OR No functional group found by Organic functional groups (US EPA) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alkyl chloride OR Alkyl halide OR Amine OR Halogen derivative OR Heterocyclic compound OR No functional group found OR Tertiary aliphatic amine OR Tertiary amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found AND SN2 AND SN2 >> Alkylation, direct acting epoxides and related after cyclization AND SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >>  Michael-type addition, quinoid structures >> Quinones OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation >> Dicarbonyl compounds 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 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 Non-covalent interaction >> DNA intercalation >> Quinones 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 by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds 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) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines 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 >> Monohaloalkanes OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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 >> DNA alkylation 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 after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found AND SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines AND SN2 AND SN2 >> Episulfonium Ion Formation AND SN2 >> Episulfonium Ion Formation >> Mustards by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethanolamines (including morpholine) OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethylenediamines (including piperazine) OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD

Domain logical expression index: "j"

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: "k"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> alpha,beta-carbonyl compounds with polarized multiple bonds by DPRA Cysteine peptide depletion

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found AND 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: "o"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> beta-Lactams  OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes by Protein binding by OASIS v1.3

Domain logical expression index: "p"

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

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 OR Alkaline Earth OR Metalloids OR Metals OR Rare Earth OR Transition Metals by Groups of elements

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Oxygen O OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens F OR Group 17 - Halogens I by Chemical elements

Domain logical expression index: "u"

Similarity boundary:Target: Cl_ClCCN1CCCC1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "v"

Similarity boundary:Target: Cl_ClCCN1CCCC1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

Similarity boundary:Target: Cl_ClCCN1CCCC1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Pro-Schiff base formation OR Pro-Schiff base formation >> Pro-cross linking Schiff base OR Pro-Schiff base formation >> Pro-cross linking Schiff base >> Hexamine by Respiratory sensitisation

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.228

Domain logical expression index: "aa"

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

Interpretation of results:

other: Not sensitizing

Conclusions:

The skin sensitization potential of 1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) 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-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) was predicted to be not sensitizing to the skin of Dunkin-Hartley guinea pig.

Executive summary:

The skin sensitization potential estimated1-(2-chloroethyl)pyrrolidine hydrochloride(7250-67-1) by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across1-(2-chloroethyl)pyrrolidine hydrochloride(7250-67-1)was predicted to be not sensitizing to the skin of Dunkin-Hartley guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization 

In different studies, 1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) 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 and human for target chemical 1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) and its structurally similar read across substancesN, N-diethylethanamine (121-44-8).The predicted data using the OECD QSAR toolbox and Danish QSAR has also been compared with the experimental data of read across.

The skin sensitization potential of 1-(2-chloroethyl)pyrrolidine hydrochloride(7250-67-1) was estimate by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across1-(2-chloroethyl)pyrrolidine hydrochloride(7250-67-1)was predicted to be not sensitizing to the skin of Dunkin-Hartley guinea pig.

Another prediction done using the Danish (Q) SAR Database, the skin sensitization was estimated to be negative on guinea pig and human for1-(2-chloroethyl)pyrrolidine hydrochloride Using Battery algorithm model of Danish QSAR, Allergic Contact Dermatitis for 1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) estimated to be not sensitizing when applied to human and guinea pig skin.

Supported by experimental study conducted by union carbide corporation (CODING FORM FOR SRC INDEXING, OTS0515586, 1986.) to evaluate the skin sensitizing potential of read across substanceN, N-diethylethanamine (121-44-8) in guinea pig.The skin sensitization study of N, N-diethylethanamine (121-44-8) was performed in 20 male albino guinea pigs.In induction phase,0.1% solution in 0.75% saline in deionised water was given by intradermal route as After 3 weeks rest period, challenge application of same concentration was given. The Observations were made after challenge application. 8 animals were died during study .No skin sensitization reaction was observed in any animal .Hence it was considered thatN, N-diethylethanamine (121-44-8) was not skin sensitizing in guinea pig.

Thus based on the above predictions on 1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) as well as its read across and applying weight of evidence, it can be concluded that1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) benzoate is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, 1-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) can be considered as not classified for skin sensitization.

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-(2-chloroethyl)pyrrolidine hydrochloride (7250-67-1) can be considered as not classified for skin sensitization.