4-chloro-N-methylpiperidine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Since no compound related effects on reproductive performance were observed, the no observed adverse effect level (NOAEL) relating to reproductive effects for the given test material 4-chloro-1-methylpiperidine in rats was estimated to be 210 mg/kg/bw by using QSAR toolbox.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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 by OECD QSAR Toolbox version 3.3. The supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Data is predicted by OECD QSAR Toolbox version 3.3.

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Remarks:

no data

Control animals:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

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

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

210 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

clinical signs

body weight and weight gain

reproductive performance

Remarks on result:

other: not specified

Critical effects observed:

not specified

Reproductive 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" )  and ("e" and ( not "f") )  )  and "g" )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and "p" )  )

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 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 Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> N-substituted aromatic amides by DPRA Cysteine peptide depletion

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 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 No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR SN2 OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom by DNA binding by OASIS v.1.3

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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: "n"

Referential boundary: The target chemical should be classified as Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.59

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.7

Conclusions:

Since no compound related effects on reproductive performance were observed, the no observed adverse effect level (NOAEL) relating to reproductive effects for the given test material 4-chloro-1-methylpiperidine in rats was estimated to be 210 mg/kg/bw.

Executive summary:

The reproductive toxicity of 4-chloro-1-methylpiperidine to rats was estimated using QSAR Toolboox version 3.3. Since no compound related effects on reproductive performance were observed, the no observed adverse effect level (NOAEL) relating to reproductive effects for the given test material 4-chloro-1-methylpiperidine in rats was estimated to be 210 mg/kg/bw.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

210 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is of K2 reliabilty and predicted by QSAR toolbox.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction:
The predicted data for target substance 4-chloro-1-methylpiperidine(CAS 5570-77-4) and the experimental study for its structurally related substances has been investigated for potential of toxicity to reproduction and is presented below as a weight of evidence approach for classification of the target substance:

The reproductive toxicity of 4-chloro-1-methylpiperidine to rats was estimated using QSAR Toolboox version 3.3. Since no compound related effects on reproductive performance were observed, the no observed adverse effect level (NOAEL) relating to reproductive effects for the given test material 4-chloro-1-methylpiperidine in rats was estimated to be 210 mg/kg/bw.

 

In a study from J-check authoritative database, 2010, Combined Repeated Dose Toxicity with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) was performed to evaluate the toxic nature of the structurally similar substance 1-Methylpiperazine (CAS 109-01-3) upon repeated dosing by oral route. The test was performed on male and female Crl: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 and reproductive performance. On the basis of observations made, The No Observed Adverse effect level (NOAEL) in relation to reproductive toxicity for the test compound 1-Methylpiperazine is determined to be 500 mg/Kg bw/day in male and female Crl:CD (SD) rats for both P0 and F1 generation.

In another study cited in report from National Technical Reports Library (NTRL); 2010, Reproduction/Developmental screening test in Wistar rats with another read across substance 2,2'-(methylimino)diethanol (CAS 105-59-9) was conducted according to OECD 421. The test substance was administered to groups of 10 male and 10 female young wistar rats (F0 parental generation) dissolved in olive oil, via daily gavage. The doses were 0, 100, 300 and 1000 mg/ kg bw. About 2 weeks after the beginning of treatment,F0 animals were mated to produce litter. Mating pairs were from same group. Pregnant females were allowed to give birth and offspring were brought up till postnatal day (PND) 4. The study was terminated with the sacrifice of the F1 animals on PND 4 and of lactating dams shortly thereafter.The parental animal of both the sexes in the high dose group (1000 mg/kg bw/day) showed salivation after treatment on several occasion during the study. Body weight/body weight gain decreased in male for entire treatment and in females during premating, gestation and on post natal day 1-4. Fertility remained unaffected. Relative Liver weight were increased dose dependently in all treatment groups. Pregnancy was unaffected at low and mid dose. For high dose post implantation loss(31 vs 6% in control) and decreased average litter size (4.6 vs 12.1 in control) was noted. Additionally, the average duration of pregnancy was slightly increased in high dose (22.8 vs 22.1 days in control) and 2 dams were unable to complete parturition at high dose group. No test substance related adverse clinical findings were noted at 300 and 100 mg/kg bw/day.  Therefore, No Observed Adverse Effect Level (NOAEL) for the test compound 2,2'-(methylimino)diethanol for wistar rats (male/female) was determined to be 300 mg/kg bw/day.

Based on the above mentioned prediction for target substance and its read across substance studies and by comparing these with the CLP criteria, it can be concluded that no adverse effects on reproductive performance was observed. Therefore by applying weight of evidence approach the substance4-chloro-1-methylpiperidineis not classified as Reproductive toxic chemical.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available