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Description of key information

Repeated dose toxicity: oral
The No Observed Adverse Effect Level (NOAEL) for the test compound 1-Methyl-4-hydroxypiperidine for rats was estimated to be 1029 mg/kg bw/day (nominal).

Repeated dose toxicity: inhalation

A short term toxicity does not needs to be conducted because exposures of humans via inhalation in production and/or use is not likely as based on provided thorough and rigorous exposure assessment (exposure considerations).

Repeated dose toxicity: dermal
The acute toxicity value for 1-methylpiperidin-4-ol (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 1-methylpiperidin-4-ol shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 1-methylpiperidin-4-ol shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
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 predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
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:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
No data
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
No data
Frequency of treatment:
No data
Remarks:
Doses / Concentrations:
No data
Basis:

No. of animals per sex per dose:
No data
Control animals:
not specified
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
No data
Sacrifice and pathology:
No data
Other examinations:
No data
Statistics:
No data
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
No data
Key result
Dose descriptor:
NOAEL
Effect level:
1 029 mg/kg bw/day (nominal)
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: Estimated
Critical effects observed:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average 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 ("k" and ( not "l") )  )  and ("m" and "n" )  )

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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones 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) >> Quinones and Trihydroxybenzenes OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Amino Anthraquinones OR SN2 OR SN2 >> Alkylation OR SN2 >> Alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates 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 Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR No alert found by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Metalloids OR Transition Metals by Groups of elements

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.16

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.9

Conclusions:
The No Observed Adverse Effect Level (NOAEL) for the test compound 1-Methyl-4-hydroxypiperidine for rats was estimated to be 1029 mg/kg bw/day (nominal).
Executive summary:

Repeated dose toxicity study was performed for the test chemical 1-Methyl-4-hydroxypiperidine using SSS QSAR prediction database, 2016. The study assumed the use of rats in a subacute study. The No Observed Adverse Effect Level (NOAEL) for the test compound 1-Methyl-4-hydroxypiperidine is found to be 1029 mg/kg bw/day (nominal).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 029 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is from K2 prediction database

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: Oral

Prediction model based estimation and data from read across have been summarized to determine the toxic nature of the test compound 1-Methyl-4-hydroxypiperidin upon repeated application by oral route of exposure:

Repeated dose toxicity study was performed for the test chemical 1-Methyl-4-hydroxypiperidine (CAS NO 106 -52 -5) using SSS QSAR prediction database, 2016. The study assumed the use of rats in a subacute study. The No Observed Adverse Effect Level (NOAEL) for the test compound 1-Methyl-4-hydroxypiperidine is found to be 1029 mg/kg bw/day (nominal).

In a study for Read across chemical, Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the test compound1-Methylpiperazine (RA CAS no 109 -01 -3) upon repeated dosing by oral route (J check, 2016). The test was performed onmale and femaleCrl:CD (SD) rats at dose levels of 0, 80, 200, 500 mg/kg/day. The animals were observed for clinical signs, body weight, food consumption, urinalysis, hematological and blood biochemistry parameters, gross and histopathological changes. On the basis of observations made, The No Observed Adverse effect level (NOAEL) for the test compound 1-Methylpiperazine is found to be 80 mg/Kg bw/day in male and female Crl:CD (SD) rats.

The weight of evidence data summarized suggests the chemical 1-Methyl-4-hydroxypiperidine to be not likely classified for repeated dose toxicity by oral route of administration.

Repeated dose toxicity: inhalation
A short term toxicity does not needs to be conducted because exposures of humans via inhalation in production and/or use is not likely as based on provided thorough and rigorous exposure assessment (exposure considerations).

Repeated dose toxicity: dermal
The acute toxicity value for 1-methylpiperidin-4-ol (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 1-methylpiperidin-4-ol shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 1-methylpiperidin-4-ol shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

The weight of evidence data summarized suggests the chemical 1-Methyl-4-hydroxypiperidine to be not likely classified for repeated dose toxicity by oral route of administration.