Piperidine

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Seminal Cytology and Reproductive Toxicology of N-Chloropiperidine

Author:

Bempong MA, Scully FE

Year:

1983

Bibliographic source:

J. Am. Coll. Toxicol. 2, 209 - 219

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Mice were daily exposed to piperidine dissolved in ethanol for a period of 100 days and examined for induction of sperm abnormality and reproductive toxicity.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Piperidine

EC Number:

203-813-0

EC Name:

Piperidine

Cas Number:

110-89-4

Molecular formula:

C5H11N

IUPAC Name:

piperidine

Specific details on test material used for the study:

- Name of test material (as cited in study report): piperidine
- no further data

Test animals

Species:

mouse

Strain:

other: C57BL/J6 x DBA2

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratory Animal Division, Mogul Corporation, Madison, Wisconsin
- Age at study initiation: (P) 8 to 10 wks
- Weight at study initiation: (P) Males and Females: 20 to 26 g
- Diet: Purina Lab Chow, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- no data

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

ethanol

Remarks:

0.001 % ethanol

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- piperidine was dissolved in ethanol

VEHICLE
- Concentration in vehicle: 400 mg/kg bw/day in 0.001 % ethanol

Details on mating procedure:

- M/F ratio per cage: 1/2
- Length of cohabitation: 7 days
- Proof of pregnancy: vaginal plug
- After successful mating each pregnant female was caged (how): single

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Exposure period: 100 days
Premating exposure period (males): 1 week
Premating exposure period (females): 1 week
Duration of test: 100 days

Frequency of treatment:

daily exposure (ad libitum)

Details on study schedule:

The treatment groups consisted of (1) control female x control male (C x C); (2) piperidine-treated female x piperidine treated male (PD x PD).
Ethyl methanesulfonate (EMS) served as positive control.
In the study piperidine was used as negative control.

Doses / concentrations

Dose / conc.:

400 mg/kg bw/day (nominal)

No. of animals per sex per dose:

15 to 25 females

Control animals:

other: aqueous solution containing 0.001 % ethanol ad libitum

Details on study design:

- Dose selection rationale: Concentrations between 600 and 800 mg/kg bw/day killed between 70 and 90% of exposed animals within 10 days.

Positive control:

Positive control animals were exposed to 250 mg/kg bw/day of ethylmethane sulfonate (EMS) prepared in deionized water.

Examinations

Sperm parameters (parental animals):

Sperm Morphology Study
- Preliminary investigation showed that significant levels of sperm damage are observed after about 40 continuous days of treatment; accordingly, on day 40 and every subsequent 5 days, treated and control animals (3 animals per group) were sacrificed and both left and right vas deferens removed by dissection. Sperm were squeezed into saline solution (0.9%) and slides prepared and stained in eosin-Y.

Litter observations:

Fertility Studies
- Fifteen to 20 pregnant females were sacrificed by cervical dislocation on day 18 of pregnancy; the uteri were removed and examined for the site of implantation and foetal death. Five females in each treatment group were allowed to reach term and the number of offspring per female recorded.

Statistics:

Chi square and t-test were used for comparison of fertility index, abnormal sperm morphology, moles per pregnancy, and foetal death per implant between the test compound and the control groups.

Reproductive indices:

Fertility index expressed as the ratio of the number of pregnant females to the number of females mated in a specified mating period.

Results and discussion

Results: P0 (first parental generation)

Reproductive function / performance (P0)

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

The percentage of abnormal sperm was in the range of the vehicle control (determined at 40, 50, 60, 70, 80 and 90 days of treatment).

Details on results (P0)

The fertility index, determined weekly after 2 to 12 weeks of piperidine exposure, was in the range of 80 to 100 % (vehicle control 85 - 100 %).
The number of dead fetuses/pregnancy was also not influenced by 2 to 12 weeks of piperidine treatment.
Females which were allowed to deliver litter had with the exception of week 4 with 7 pubs/female, 8.5 - 10 pups/female after 1 to 3 and 4 to 10 weeks of piperidine treatment (weekly determination; vehicle control: 8.5 - 10 pups/female).

In the EMS-treated matings, reduced fertility indices were observed.
The number of dead fetuses/pregnancy was also influenced by 2 to 12 weeks of EMS treatment of about 0.8 to 1.4.
Females which were allowed to deliver litter had 6 pups/female after 1 to 10 weeks of EMS treatment (weekly determination; vehicle control:
8.5 - 10 pups/female).

Effect levels (P0)

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

400 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: corresponding to the highest dose tested

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

Details on results (F1)

No negative results to the offspring were reported.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:

no

Overall reproductive toxicity

Reproductive effects observed:

not specified