1-methylpiperidin-4-ol

Endpoint summary

Description of key information

Skin Irritation:

The substance 4-Piperidinol, 1-methyl- is estimated to be not irritating to skin of rabbit

Eye Irritation:

1-methylpiperidin-4-ol was estimated to be not irritating to rabbit eyes. Even though the QSAR prediction for the target suggests that it is not irritating to eyes, but information from various read across substances having high similarity with the target indicate the possibility of irritating nature of the test chemical. Therefore, by applying the weight of evidence approach, the target chemical, 1-methylpiperidin-4-ol can be considered as an eye irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

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 QSAR Toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Prediction is done using QSAR Toolbox version 3.4

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 4-Piperidinol, 1-methyl-
- Molecular formula: C6H13NO
- Molecular weight: 115.175 g/mol
- Smiles: C1N(CCC(C1)O)C
- InChl): 1S/C6H13NO/c1-7-4-2-6(8)3-5-7/h6,8H,2-5H2,1H3
- Substance type: organic
- Physical state: liquid

Test system:

other: not specified

Source species:

rabbit

Cell type:

other: not specified

Cell source:

other: not specified

Source strain:

not specified

Details on animal used as source of test system:

no data

Vehicle:

not specified

Control samples:

not specified

Amount/concentration applied:

no data

Duration of treatment / exposure:

no data

Duration of post-treatment incubation (if applicable):

no data

Number of replicates:

no data

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

no data

Duration of treatment / exposure:

no data

Observation period:

no data

Number of animals:

no data

Details on study design:

no data

Irritation parameter:

overall irritation score

Basis:

mean

Score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

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 "m") )

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 Alcohol AND Piperidine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as Alcohol AND Overlapping groups AND Piperidine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Amino, aliphatic attach [-N<] AND Hydroxy, aliphatic attach [-OH] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as Alcohol AND Amine AND Heterocyclic compound AND Hydroxy compound AND Secondary alcohol AND Tertiary aliphatic amine AND Tertiary amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

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 >> Quinones and Trihydroxybenzenes OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes OR Radical 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) >> Amino Anthraquinones 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 and Trihydroxybenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Thiols OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Haloalcohols 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 >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> N-Hydroxylamines OR SN2 >> Acylation >> Specific Acetate Esters 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 OR SN2 >> Alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Haloalcohols 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 and Sulfur Mustards OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones 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.1.4

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-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 >> Alkyl phenols 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 amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR No alert found 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 Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine  OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> Episulfonium Ion Formation OR SN2 >> Episulfonium Ion Formation >> Mustards OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary:The target chemical should be classified as Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.552

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.15

Interpretation of results:

GHS criteria not met

Conclusions:

The substance 4-Piperidinol, 1-methyl- is estimated to be not irritating to skin of rabbit

Executive summary:

The skin irritation potential for 4-Piperidinol, 1-methyl- is estimated using OECD QSAR toolbox version 3.4. The test substance 4-Piperidinol, 1-methyl- is estimated to be not irritating to skin of rabbit.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

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 from OECD QSAR toolbox v 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v 3.4

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): 1-methylpiperidin-4-ol
- Molecular formula: C6H13NO
- Molecular weight: 115.175 g/mol
- Substance type: Organic
- Physical state: Liquid

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

no data

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No data

Observation period (in vivo):

No data

Duration of post- treatment incubation (in vitro):

No data

Number of animals or in vitro replicates:

No data

Details on study design:

No data

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: No data

Score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

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 "m") )

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 Alcohol AND Piperidine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as Alcohol AND Overlapping groups AND Piperidine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Amino, aliphatic attach [-N<] AND Hydroxy, aliphatic attach [-OH] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as Alcohol AND Amine AND Heterocyclic compound AND Hydroxy compound AND Secondary alcohol AND Tertiary aliphatic amine AND Tertiary amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

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 >> Quinones and Trihydroxybenzenes 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones 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 and Trihydroxybenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Thiols OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Haloalcohols 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 >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> N-Hydroxylamines OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> N-Hydroxylamines OR SN2 >> Acylation >> Specific Acetate Esters 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 OR SN2 >> Alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Haloalcohols OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Nucleophilic substitution at sp3 Carbon atom 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.1.4

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-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 >> Alkyl phenols 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 amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR No alert found 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 Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary:The target chemical should be classified as Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.552

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.15

Interpretation of results:

GHS criteria not met

Conclusions:

1-methylpiperidin-4-ol was estimated to be not irritating to rabbit eyes.

Executive summary:

The ocular irritation potential of 1-methylpiperidin-4-ol was estimated using OECD QSAR toolbox v 3.4. 1-methylpiperidin-4-ol was estimated to be not irritating to rabbit eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

The skin irritation potential for 4-Piperidinol, 1-methyl- is estimated using OECD QSAR toolbox version 3.4. The test substance 4-Piperidinol, 1-methyl- is estimated to be not irritating to skin of rabbit.

Various studies for similar substances RA CAS 105-59-9 and CAS 551-16-6 (IUCLID Dataset, 2000) were conducted to evaluate their irritation potential.

A skin irritation test was carried out in rabbits to determine the skin irritation potency of the similar substance 105-59-9 by Draize Test. No known skin reactions were observed. Therefore the test chemical N-Methyldiethanolamine can be considered as not irritating to rabbits skin.

A skin irritation test was carried out in rabbits to determine the skin irritation potency of the similar substance 551–16–6. No known skin reactions were observed. Therefore the test chemical 6–aminopenicillanic acid can be considered as not-irritating to rabbit’s skin.

Based on the available information for the target as well various read across substances, and applying the weight of evidence approach,1-methylpiperidin-4-ol can be considered as non – irritant to skin.

 

Eye Irritation:

The ocular irritation potential of 1-methylpiperidin-4-ol was estimated using OECD QSAR toolbox v 3.4. 1-methylpiperidin-4-ol was estimated to be not irritating to rabbit eyes.

An ocular irritation study was performed (Invest Ophthalmol Vis Sci. 2005; 46:1640–1646) to assess the level of ocular injury caused due to exposure to the similar RA substance CAS 51-75-2. A total of 52 New Zealand Albino rabbits weighing 2.5 to 3.5 kg were used. All animal experiments were conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. One eye in each of 52 rabbits was exposed to 2% nitrogen mustard (NM).Eight eyes (four animals) that were not exposed to NM served as the control. Animals were anesthetized with ketamine HCl (Ketalar, 50mg/kg) injected intramuscularly in combination with the relaxing agent xylazine (0.5 mg/kg). Local anesthetic drops (benoxinate HCl 0.4) were administered. Briefly, NM (mechlorethamine), at a concentration of 2% in saline, was applied to the cornea of one eye of each animal (the experimental eye) for 5 minutes within a trephine. Immediately after application, NM was quickly absorbed from within the trephine with small Weck-cell sponges, followed by washing of the eye with copious amounts of normal saline. In control eyes (four additional animals, eight eyes), saline solution (instead of NM) was applied to the cornea for 5 minutes, also within the trephine. In control experiments, the vehicle (saline) was used as eye drops after exposure to NM. During the experiment and follow-up, intramuscular dipyrone injections (10 mg/kg) were given to animals showing pain or distress. Slit-lamp examinations were performed at 24 hours after exposure, and subsequently at days 4, 7, 10, 14, 17, 21, 25, and 29. In each examination, the following parameters were recorded: Area of corneal epithelial loss (corneal erosion), Degree of corneal opacity, Degree of iris pigmentation, Degree of corneal neo-vascularization (CNV). Exposure to NM causes severe and long-lasting injury to ocular anterior segment structures. Injury to the conjunctiva and cornea in a saline-administered eye 1 day after exposure to 2% NM was noted. Conjunctival and corneal injury, scarring, and neo-vascularization evolved over the entire duration of the experiment (4 weeks) in such eyes. Corneal Neo- vascularization developed to various degrees in all groups after exposure to NM. An increase in Intra Ocular Pressure occurred after exposure to NM, peaking at day 4 in all study groups. Exposure to NM caused iris atrophy and pigmentation together with pupil dilation in all study groups. On the basis of these observations, we can consider Nitrogen mustard to be irritating to eyes.

Acute toxicity studies (American Industrial Hygiene Association Journal, 1962, 23:2, 95-107) were carried out to estimate the toxicity of the similar RA substance 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 after 24 hours for 1-methyl piperazine was Grade 8. Based on the grade, 1-methyl piperazinewas considered to be severely irritating to eyes.

Another eye irritation study was conducted (RTECS Number - TM1225000;last updated: 201204) to evaluate irritation potential of the other RA similar substance CAS 109-01-3. 750micrograms of the test chemical was instilled in to rabbit eyes and effects were observed for 24 hours. Severe irritation effects were observed after 24 hours of instillation of the test chemical. Therefore,1-methyl piperazine was considered to be severely irritating to eyes.

An eye irritation study was conducted (The MAK Collection for Occupational Health and Safety, Volume 9, pg 292–294, 2012) to evaluate irritation potential of the similar substance CAS 105-59-9. 50 microliters of the test chemical was instilled into eyes of rabbits and effects were observed for 8 days. Symptoms like redness, swelling and clouding of the cornea as well as conjunctival bleeding were observed in rabbits which were reversible after 8 days. Based on these observations, 2, 2’-(methylimino)bisethanol was severely irritating to rabbit eyes.

Another eye irritation study was conducted (IUCLID Dataset, 2000) to evaluate irritation potential of the similar substance CAS 105-59-9. Eye injury in rabbits was recorded in a 10- grade ordinal series and was based upon the degree of corneal necrosis that results 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 2,2'-(methylimino)bisethanol was Grade 4. Based on the grade, 2,2'-(methylimino)bisethanolwas considered to be moderately irritating to eyes.

Even though the QSAR prediction for the target suggests that it is not irritating to eyes, but information from various read across substances having high similarity with the target indicate the possibility of irritating nature of the test chemical. Therefore, by applying the weight of evidence approach, the target chemical, 1-methylpiperidin-4-ol can be considered as an eye irritant under category 2.

Justification for classification or non-classification

Based on weight of evidence approach for target 4-piperidinol, 1-methyl- (CAS no 106-52-5) and its structurally related read across substances (CAS no 105 -59 -9 and 551 -16 -6) can be considered as non – irritant to skin. Also, by applying the weight of evidence approach, the target chemical, 1-methylpiperidin-4-ol can be considered as an eye irritant under category 2.