Piperidine

Carcinogenicity

Description of key information

Oral
Carcinogenicity, oral, rat, drinking study, non-GLP, non-Guideline: negative (Lijinsky and Taylor, 1977)
Carcinogenicity, oral, rat, drinking study, non-GLP, non-Guideline: negative (Garcia and Lijinsky, 1973)
Carcinogenicity, rat, implantation, non-GLP, non-Guideline: positive (Suzuki et al., 1984), no valid test system and thereofore disregarded for the evaluation.
There was no evidence of carcinogenicity when piperidine was administered to rats in drinking water with or without sodium nitrite.

Inhalative
No studies were available on the carcinogenicity of piperidine administered by inhalation exposure.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were treated by chronic administration for 75 weeks of piperidine with and without sodium nitrite in the drinking water. The animals were kept until death and subjected to complete pathological examination.

GLP compliance:

no

Specific details on test material used for the study:

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

Species:

rat

Strain:

other: MRC

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8 - 10 weeks
- Housing: 5 rats per cage

ENVIRONMENTAL CONDITIONS
- no data

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

- Animals were given 100 ml of solution containing piperidine and nitrite as drinking water.
- Treatment groups in detail:
• Piperidine (0.1 %)
• Piperidine (0.025 %) + sodium nitrite (0.05 %)
• Piperidine (0.1 %) + sodium nitrite (0.2 %)
• Sodium nitrite (0.2 %)
• Untreated Control

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

75 weeks

Frequency of treatment:

5 days per week in the drinking water

Post exposure period:

life-time

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

total dose: 9375 mg/animal; calculation based on 375 days of treatment and an average water consumption of 25 mL/day/animal; 0.1% in the drinking water

No. of animals per sex per dose:

15

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

- Survival of the experimental rats and the distribution of tumors in the animals were determined.

Sacrifice and pathology:

- The animals were kept until death and subjected to complete pathological examination.

Description (incidence):

- There was no significant difference in animal survival in any of the groups (mean survival of 80 % of the rats).

Description (incidence and severity):

- No significant difference between untreated or nitrite treated animals and treated groups (piperidine, piperidine plus nitrite) was observed in number of tumour bearing animals and in types of tumours.
- Common (spontaneous) tumours observed in treated and control rats were mainly pituitary adenomas and tumours of breast, uterus or testis.

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: max. dose level tested

Table 1 Tumours in Rats Treated with nitrosamino acids, amines and nitrite

Treatment	Total dose (g)	surviving animals at week						No. TBA* (%)	No. TF*	Pitui-tary	Breast	Testis	Uterus/Vagina	Adrenal	Pancreas	Skin	Other
		0	20	40	60	80	100
Piperidine (0.1%)	3.7	15♂   15♀	15   15	15   15	14   15	14   14	11   13	4 (27) 7 (57)	11   8	1   4	0   1	2   0	0   1	0   0	1   0	1   0	1 brain 2 ovary, 1 thymus
Piperidine (0.025%) + sodium nitrite (0.05%)	1.8   3.7	15♂   15♀	15   15	15   15	12   14	11   13	11   10	2 (13)  9 (60)	13   6	2   8	0   0	0   0	0   3	0   0	0   0	0   0	1 liver
Piperidine (0.1%) + sodium nitrite (0.2%)	3.7   7.5	15♂   15♀	15   15	15   15	15   15	15   14	12   11	7 (57)  7(57)	8   8	2   4	0   1	3   0	0   0	0   0	1   0	2   0	1 brain, 1 salivary gland, 1 ovary
Sodium nitrite (0.2%)	15.0	15♂   15♀	15   15	15   15	15   14	15   13	13   12	9 (60)  10 (67)	6   5	1   6	0   2	2   0	0   1	1   0	1   0	3   1	3 soft tissue, 1 stomach, 1 thymus
Untreated control		15♂   15♀	15   15	14   15	14   15	14   14	11   13	5 (33)  4 (27)	10   11	0   3	0   1	3   0	0   1	0   0	1   0	0   0	1 soft tissue

*TBA - Tumor bearing animals, TF = Tumor free

Reference 2

Endpoint:

carcinogenicity: oral

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

The possible formation of N-nitroso compounds in vivo from ingested secondary or tertiary amines and nitrite was determined by the incidence of tumour development. Thereby piperidine was administered to rats in the drinking water with or without sodium nitrite.

GLP compliance:

no

Specific details on test material used for the study:

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

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8 - 10 weeks
- Housing: three animals per plastic cage
- Diet: Rockland rat diet ad libitum
- Water (e.g. ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- no data

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- The test substance was dissolved in distilled water (pH 6.8-7.0).

VEHICLE
- Concentration in vehicle: 0.09 %

TREATMENT
- For administration the suspension was simply shaken before being put in the drinking-water bottles.
- On the five working days of the week each cage of rats was given 60 ml of the solution to drink and on the remaining 2 days tap-water was given.
- One group of animals was administered 0.09% piperidine in the drinking water without addition of sodium nitrite;
- Another group was administered 0.09% piperidine in the drinking water with 0.2% sodium nitrite.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

50 weeks

Frequency of treatment:

continuously in the drinking water (5 days per week)

Post exposure period:

From the end of the treatment, which lasted 50 weeks, the animaIs were kept until they died spontaneously or until they became moribund and were killed.

Dose / conc.:

45 mg/kg bw/day (nominal)

Remarks:

corresponding to the original value 0.09 % in the drinking water, dased on a consumption of 25 mL/animal/day; total dose: 5625 mg/animal

No. of animals per sex per dose:

15

Control animals:

other: The results from a historical control group receiving 0.2% sodium nitrite in the drinking water for 2 years (26 males and 30 females) served as control.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, each animal was subjected to a complete autopsy.
HISTOPATHOLOGY: Yes, the tissues were fixed for full histopathological examination.

Description (incidence):

All animals in the two test groups survived for 20 weeks following cessation of exposure to the appropriate drinking water solution (i.e. through study week 70). Following is a list of survivors beginning on study week 90:
Test group 0.09% Piperidine: Males: Week 90: 10/15; Week 110: 4/15; Week 130: 0/15;
Test group 0.09% Piperidine: Females: Week 90: 11/15; Week 110: 7/15; Week 130: 1/15;
Test group 0.09% Piperidine with 0.2 % sodium nitrite: Males: Week 90: 11/15; Week 110: 2/15; Week 130: 0/15;
Test group 0.09% Piperidine with 0.2 % sodium nitrite: Females: Week 90: 10/15; Week 110: 3/15; Week 130: 1/15;
There was no significant difference in animal survival in any of the groups compared to the control.

Description (incidence and severity):

- No data

Description (incidence and severity):

- No data

Description (incidence and severity):

- No data

Description (incidence and severity):

- Table 1: Incidence of tumours is given in the attachment.
- The tumour incidences were not significantly different in any of the groups compared to the control.

Description (incidence and severity):

- No specific tumors from N-nitrosopiperidine were observed.

Dose descriptor:

NOAEL

Effect level:

ca. 45 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: max. dose level tested

Table 1: Incidence of tumours after administration of Piperidine to rats in the drinking water with and without sodium nitrite.

 

Tumour location		Control (0.2% sodium nitrite)		0.09% Piperidine		Piperidine with 0.2% Sodium Nitrite
		F (30)	M (26)	F (15)	M (15)	F (15)	M (15)
Breast		18	3	9	1	8	1
Pituitary		20	6	8	0	9	6
Adrenal		7	10	4	3	3	5
Uterus		9	-	5	-	3	-
Pancreas		1	4	1	1	0	0
Liver		0	1	0	0	1	1
Thyroid		4	4	0	1	0	3
Type of tumor
Duodenum		0	3	1	0	0	0
Zimball gland		1	1	1	1	0	0
Stomach		0	1	0	0	0	0
Brain		0	1	0	0	0	1
Ileum		1	0	0	0	0	0
Thymus		1	0	0	0	0	0
Myeloma		1	0	0	0	0	0
Kidney		0	0	1	0	0	0
Lymphosarcoma		0	0	1	0	0	1
Skin	Papilloma	0	0	0	2	0	0
	Sarcoma	0	0	0	0	0	1
Jejunum		0	0	0	1	0	0
Seminal vesicle		-	0	-	1	-	0
Osteosarcoma		0	0	1	0	0	0
Heart myxoma		0	0	0	1	0	0
Testis mesothelioma		-	0	-	0	-	1
Sarcoma		0	0	0	0	0	1
Lung adenoma		0	0	0	0	1	0

M: Male; F: Female

Number in patenthesis (number of animals)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data for carcinogenicity are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. As a result, the substance is not warranted to be classified for carcinogenicity, under Regulation (EC) No.1272/2008.

Additional information

Oral

Lijinsky and Taylor (1977) performed a non-GLP, non-Guideline study in which groups of Sprague-Dawley rats (15/dose/sex), 8 – 10 weeks old, were administered 0.09 % piperidine (ca. 45 mg/kg bw/day) continuously in the drinking water with and without 0.2% sodium nitrite 5 days per week for 50 week. Each animal was subjected to gross pathology and histopathology. There was no significant difference in animal survival in the treatment groups compared to the control. No treatment related neoplasm developed during the lifetime of either test group. Thus the incidence of tumors for rats chronically exposed to 0.09% piperidine or 0.09% piperidine with 0.2% sodium nitrite was not significantly increased as compared to control rats receiving 0.2% sodium nitrite in drinking water. There was no untreated control.

In a non-GLP, non-Guideline drinking water study (Garcia and Lijinsky, 1973) simultaneous administration of nitrite and piperidine was proved to increase the incidence of tumor development. Thereby, groups of 15 female and 15 male MRC rats, 8 to 10 weeks old, received 5 days / week over 75 weeks each 100 ml of a solution as drinking water containing either 0.1% piperidine alone, 0.1 % (ca. 50 mg/kg bw/day) or 0.025% piperidine combined with 0.2 % or 0.05 % sodium nitrite, respectively. After treatment the animals were held until death and examined for tumor development. None of the treated groups showed significant differences in survival rate and the number and range of the incidence of tumors, compared with an untreated control.

Suzuki et al., 1984 detected a significant increase in the incidence of urinary bladder cancer by implanting cholesterol pellets containing piperidine into the bladder of mice and concurrent administration of sodium nitrite to the animals. In the non-GLP and non-Guideline study, groups of female mice of the ddy strain, about 18 g in weight, were administered 20 mg pellets consisting of cholesterol and 20% piperidine hydrochloride surgically into the bladder (total piperidine content 2.8 mg) with and without concurrent administration of 0.1 % sodium nitrite in the drinking water for 40 weeks. As controls, mice were implanted with cholesterol pellets without piperidine hydrochloride. The bladder of each animal was subjected to histopathological examination and incidence of urinary bladder cancer was determined. A significant increase in the incidence of bladder tumours of the animals by simultaneous administration of piperidine and nitrite was detected. No significant increase was observed following exposure to piperidine alone. The authors concluded that in the bladder of the animals N-Nitrosopiperidine was generated from piperidine and N-nitrite, leading to an enhanced incidence of bladder cancer.

Due to the special application form of the test substances as urinary bladder implantation, the biological relevance of this study is questionable.

Additionally, it has been demonstrated that in the stomach and the small intestine of the rat as well as in vitro in isolated gastric juice (Alam et al., 1971) sodium nitrite and piperidine react to form N-nitrosopiperidine. Thus, an indirect carcinogenic effect of piperidine following formation of N-nitrosopiperidine cannot be excluded.

Nevertheless, there was no evidence of carcinogenicity when piperidine was administered to rats in drinking water with or without sodium nitrite.

Inhalative

No studies are available on the carcinogenicity of piperidine administered by inhalation exposure.

Dermal

No data available