Registration Dossier

Skin Irritation:

The dermal irritation potential of 4-chloro-1-methylpiperidinium chloride was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4-chloro-1-methylpiperidinium chloride was estimated to be severely irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 4-chloro-1-methylpiperidinium chloride can be considered to be severely irritating to skin and can be classified under the category “Category 1” as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 4-chloro-1-methylpiperidinium chloride was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4-chloro-1-methylpiperidinium chloride was estimated to be severely irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 4-chloro-1-methylpiperidinium chloride can be considered to be severely irritating to eyes and can be classified under the category “Category 1” as per CLP regulation.

Reference

Endpoint:

skin irritation: 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:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

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:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.5ml

Duration of treatment / exposure:

4 hours

Observation period:

124,48,72 hours

Number of animals:

6

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritant / corrosive response data:

Severe irritation observed

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 ("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" ) )

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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Similarity boundary:Target: CN{+}1(.Cl{-})CCC(Cl)CC1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

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: "j"

Referential boundary: The target chemical should be classified as Group 14 - Metalloids Si,Ge OR 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: "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 Primary and secondary aliphatic amines by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by Keratinocyte gene expression

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Very high gene expression OR Very high gene expression >> alpha-Halobenzyls by Keratinocyte gene expression

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Derivatives of alpha amino benzene by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.57

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.0985

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Conclusions:

4-chloro-1-methylpiperidinium chloride was estimated to be severely irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 4-chloro-1-methylpiperidinium chloride was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4-chloro-1-methylpiperidinium chloride was estimated to be severely irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 4-chloro-1-methylpiperidinium chloride can be considered to be severely irritating to skin and can be classified under the category “Category 1” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (corrosive)

Reference

Endpoint:

eye irritation: 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

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

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:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

14 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

6

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

14 d

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritant / corrosive response data:

Severe irritation observed

Estimation method: Takes mode value from the 8 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 ("n" and ( not "o") ) ) and ("p" and ( not "q") ) ) and ("r" and ( not "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 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 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 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 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 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 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides 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 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 Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Aliphatic alpha-halogen-esters OR Alkylalkanol-amines OR Halogenated alkanes OR Ketones OR Phenols OR Primary and secondary aliphatic amines OR Sulfonic acids or their salts OR Tertiary aliphatic amine by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "j"

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 >> Carbamates 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 >> alpha,beta-Carbonyl compounds with polarized double bonds OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aldehyde Type Compounds OR Alpha-Haloalkylamine Reactive Functional Groups OR Aromatic Amine Type Compounds OR C-Nitroso and Oxime Type Compounds OR Halogenated Aromatic Hydrocarbon Type Compounds OR Halogenated Cycloalkane Type Compounds OR Nitrogen Mustards Reactive Functional Groups OR Organophosphorus Type Compounds OR Siloxane Type Compounds by Oncologic Primary Classification

Domain logical expression index: "m"

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: "n"

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

Domain logical expression index: "o"

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: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alkoxysilanes OR Esters (Chronic toxicity) OR Hindered Amines OR Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Not categorized by OECD HPV Chemical Categories

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Primary amines OR Secondary amines by OECD HPV Chemical Categories

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.15

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.348

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

4-chloro-1-methylpiperidinium chloride was estimated to be severely irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of 4-chloro-1-methylpiperidinium chloride was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4-chloro-1-methylpiperidinium chloride was estimated to be severely irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 4-chloro-1-methylpiperidinium chloride can be considered to be severely irritating to eyes and can be classified under the category “Category 1” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irreversible damage)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies, 4-chloro-1-methylpiperidinium chloride has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its functionally similar read across substances, 1-methylpiperazine [CAS:109-01-3] and 1-(2-Aminoethyl) piperazine[CAS: 140-31-8]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for 4-chloro-1-methylpiperidinium chloride. 4-chloro-1-methylpiperidinium chloride was severely irritating to the skin ofNew Zealand White rabbits.

This result is supported by the experimental study summarized in American Industrial Hygiene Association Journal, 1962, 23:2, 95-107, for the functionally similar read across substance, 1-methylpiperazine [CAS:109-01-3]. Primary skin irritation on rabbits was recorded in a 10-grade ordinal series and was based upon the severest reaction that develops on the clipped abdominal skin of each of five albino rabbits within 24 hours of the uncovered application of 0.01 ml of undiluted sample or of solutions in water, propylene glycol, or acetone. Grade 1 indicates no irritation and Grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicates necrosis when undiluted and Grade 10 indicates necrosis from a 0.01% solution

Primary Irritation score after 24 hours for 1 -methyl piperazine was Grade 6.

Based on this grade, 1-methylpiperazine can be considered moderately irritating to rabbit skin.

These results are also supported by the experimental study summarized in American Industrial Hygiene Association Journal, 1962, 23:2, 95-107; for the functionally similar read across substance, 1-(2-Aminoethyl) piperazine[CAS: 140-31-8]. Primary skin irritation on rabbits was recorded in a 10-grade ordinal series and was based upon the severest reaction that develops on the clipped abdominal skin of each of five albino rabbits within 24 hours of the uncovered application of 0.01 ml of undiluted sample or of solutions in water, propylene glycol, or acetone. Grade 1 indicates no irritation and Grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicates necrosis when undiluted and Grade 10 indicates necrosis from a 0.01% solution. Primary Irritation score after 24 hours for 1-(2-Aminoethyl) piperazine was Grade 6.

Based on this grade, 1-(2-Aminoethyl) piperazine can be considered moderately irritating to rabbit skin.

Even though the results from the QSAR prediction imply that 4-chloro-1-methylpiperidinium chloride can be classified under the “Category 1” for skin irritation, but experimental results from the functionally related read across substances, put forward for consideration for classification under “Category 2”. Hence, using the weight of evidence approach, “Category 2” classification is proposed for 4-chloro-1-methylpiperidinium chloride.

Eye Irritation:

In different studies, 4-chloro-1-methylpiperidinium chloride has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its functionally similar read across substances, 1-methylpiperazine [CAS:109-01-3] and 2-(4-Morpholinyl)ethanol[CAS: 622-40-2]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated for 4-chloro-1-methylpiperidinium chloride. 4-chloro-1-methylpiperidinium chloridewas severely irritating to the eyes ofNew Zealand White rabbits.

This result is supported by the experimental study summarized in American Journal of Ophthalmology 29, 1363–1372, 1946; for the functionally similar read across substance, 2-(4 -Morpholinyl)ethanol[CAS: 622-40-2]. Normal albino rabbit eyes were selected on the basis of absence of grossly visible staining by a 5-percent aqueous solution of fluorescein sodium, flushed with distilled water 20 seconds after application. A 2 hour interval was given so that the eye could return back to normal condition. Then, 0.005 ml of the undiluted test material was applied to the center of the cornea while the lids were retracted. About one minute later, the lids were released. This procedure is necessary to prevent the removal of a portion of the dose by the very efficient wiping system of the lids before intimate contact has been made with the eye. 18 to 24 hours later, the eyes were examined in strong diffuse daylight, then stained with fluorescein, and the injury was scored.

2-(4-Morpholinyl)ethanol was grouped under Grade 5 injury (0.005 ml undiluted gives injury of up to 5 (0.02 ml gives over 5)) when rabbit eyes were observed for injuries. Based on the grades, it can be inferred that 2-(4-Morpholinyl)ethanol was severely irritating to rabbit eyes.

These results are also supported by the experimental study summarized in American Industrial Hygiene Association Journal, 1962, 23:2, 95-107; for the functionally similar read across substance, 1-methylpiperazine [CAS:109-01-3]. Eye injury in rabbits was recorded in a 10- grade ordinal series and was based upon the degree of corneal necrosis that resulted from instillation of various volumes and concentrations of chemical. Grade 1 indicates at most a very small area of necrosis resulting from 0.5 ml of undiluted chemical in the eye. Grade 5 indicates a so-called severe burn from 0.005 ml, and Grade 10 indicates a severe burn from 0.5 ml of a 1% solution in water or propylene glycol. Primary Eye Irritation score for 1-methyl piperazine was Grade 8. Based on the grade, 1-methyl piperazine was considered to be severely irritating to eyes.

Even though the results from the QSAR prediction imply that 4-chloro-1-methylpiperidinium chloride can be classified under the “Category 1” for eye irritation, but experimental results from the functionally related read across substances, put forward for consideration for classification under “Category 2”. Hence, using the weight of evidence approach, “Category 2” classification is proposed for 4-chloro-1-methylpiperidinium chloride.

Even though the results from the QSAR prediction imply that 4-chloro-1-methylpiperidinium chloride can be classified under the “Category 1” for skin and eye irritation, but experimental results from the functionally related read across substances, put forward for consideration for classification under “Category 2”. Hence, using the weight of evidence approach, “Category 2” classification is proposed for 4-chloro-1-methylpiperidinium chloride.