Piperidine

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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:

Synthetic flavors: efficiency and safety factors for sweaty and fishy odorants

Author:

Amoore JE, Gumbmann MR, Booth AN, Gould DH

Year:

1978

Bibliographic source:

Chem. Senses Flavour 3, 307 - 317

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: Piperidine was administered to rats in a 90 day feeding study.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Piperidinium chloride

EC Number:

228-033-8

EC Name:

Piperidinium chloride

Cas Number:

6091-44-7

Molecular formula:

C5H11N.ClH

IUPAC Name:

piperidinium chloride

Details on test material:

TS-Freetext:
piperidine hydrochloride

Specific details on test material used for the study:

- Name of test material (as cited in study report): piperidine hydrochloride
- Physical state: chrystalline
- Impurities (identity and concentrations): contains odorous impurities.
- Source: obtained as crystalline hydrochloride (Aldrich Chemical Company, Milwaukee, Wisconsin).

Test animals

Species:

rat

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4 weeks
- Weight at study initiation: 90 g (tested in weight-matched groups of 5 or 6)
- Diet (e.g. ad libitum): diet composed of 30% dextrose, 20% cornmeal, 20% soybean meal, 10% casein, 9% corn starch, and 5% corn oil, with 4% salt mixture and 2% of a mixture of vitamins triturated in dextrose
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- no data

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- After allowing for ca. 40% hydration of the piperidine sample, it was added to the diet in its crystalline state (base content 35 -45%, w/w).

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily, continuously in the diet

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

80 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.08 % in the diet

Doses / concentrations 2

Dose / conc.:

160 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.16 % in the diet

Doses / concentrations 3

Dose / conc.:

310 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.31 % in the diet

No. of animals per sex per dose:

5 - 6 males

Control animals:

yes

Details on study design:

- Dose selection rationale: Initial 14-day trials were run to find the maximum concentration of additive that was compatible with normal food intake and weight gain. Having found the appropriate level, the feeding trial was continued to 90 days.
- Post-exposure recovery period in satellite groups: no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 80 days
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked:
∙ counts of erythrocytes,
∙ leukocytes,
∙ hematocrit and
∙ hemoglobin.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 80 days
- Animals fasted: No data
- How many animals: No data
- Parameters checked: tests run on plasma from the rats:
∙ albumin,
∙ total protein,
∙ total bilirubin,
∙ urea nitrogen,
∙ glutamic-oxaloacetic transaminase,
∙ glutamic-pyruvic trans-aminase,
∙ alkaline phosphatase, and
∙ ornithine-carbamoyl transferase.

URINALYSIS: Yes
- Time schedule for collection of urine: at 70 days
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked:
∙ Urine was examined microscopically, and tested for
∙ pH,
∙ specific gravity,
∙ occult blood,
∙ ketones,
∙ glucose,
∙ protein,
∙ bilirubin and
∙ urobilinogen.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, at the end of the 90-day feeding trial, the rats were killed by exsanguination under ether anesthesia and necropsied.
- Organs were weighed

HISTOPATHOLOGY: Yes
- tissues were fixed in neutral phosphate-buffered 10% formalin, embedded in paraffin, sectioned at six microns, and stained with hematoxylin and eosin. Thirty-five tissues were subjected to routine histological examination.

Results and discussion

Results of examinations

Clinical signs:

not specified

Description (incidence and severity):

no data

Description (incidence and severity):

- Growth, in grams per rat per day:

▫ after 14 days:
∙ 0.62 % dose group: -1.0 g/animal/day compared to the control: 6 g/animal/day; discontinued after 7 days;
∙ 0.31 % dose group: 1.9 g/animal/day compared to the control: 6 g/animal/day; significantly less growth than control rats without additive, p<0.05;
∙ 0.16 % dose group: 3.3 g/animal/day compared to the control: 6 g/animal/day; significantly less growth than control rats without additive, p<0.05;
∙ 0.08 % dose group: 5.2 g/animal/day compared to the control: 6 g/animal/day;
∙ 0.04 % dose group: 6.0 g/animal/day compared to the control: 6 g/animal/day;

▫ after additional 84 days:
∙ At the low dose group of 0.08 %: the growth was not influenced after the 90 days treatment. There were no significant differences in body weights between the 0.08 % dose group (5.2 g/animal/day) and the control (4.9 g/animal/day).
∙ In the mid- and high-dose group ( 0.16 %: 3.6 g/animal/day; 0.31 %: 2.5 g/animal/day) growth was significantly reduced in comparison to the control (4.9 g/animal/day).

Description (incidence and severity):

- At 0.08 % test substance in the diet, the food consumption was not influenced. During the first 14 days of the feeding trial, the maximum concentration of the test item in the diet, that was not significantly incompatible with normal food consumption and growth, was 0.08%.

Food efficiency:

not specified

Description (incidence and severity):

no data

Description (incidence and severity):

- There were no significant differences in haematology between the 0.08 % dose group and the control.

Description (incidence and severity):

- There were no significant differences in plasma constituents between the 0.08 % dose group and the control.

Description (incidence and severity):

- There were no significant differences in urinalysis between the 0.08 % dose group and the control.

Behaviour (functional findings):

not specified

Description (incidence and severity):

no data

Description (incidence and severity):

- There were no significant differences in organ weights between the 0.08 % dose group and the control.

Description (incidence and severity):

▫ 0.08 % dose group:
- There were no significant differences in histological appearance compared to the control group.
▫ 0.31 % dose group:
- Significant alterations involving the seminal vesicles and prostate occurred in the rats receiving 0.31 % piperidine.
- The seminal vesicles were markedly reduced in size and weight, and had a reduced number of secretory granules.
- The prostate changes were less pronounced and consisted of tubular collapse and reduction in the amount of secretory materials.
- Other lesions present in these animals were uniformly distributed throughout all groups, and were of types commonly observed in animals of this age, sex, strain and origin.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

80 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

LOAEL

Effect level:

160 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: At 160 mg/kg bw body weight gain is reduced.

Target system / organ toxicity

Critical effects observed:

not specified