Piperidine

Endpoint summary

Description of key information

Skin:
(1) Rabbit, shaved, undiluted test item, occlusive, 3 min, washing: corrosive (non-GLP, OECD 404, BASF 77/283-3, 1982).
(2) Rabbit, occlusive, 3, 60 min, 4 hours, washing: corrosive (non-GLP, DOT Guideline, Toxikon, 1991).
(3) Rabbit, clipped, undiluted test item, occlusive, 4 hours, washing: corrosive (non-GLP, DOT Guideline, Biosearch, 1983).
(4) Rabbit, clipped, occlusive, treatment duration unknown: corrosive (non-GLP, non-Guideline, Smyth et al., 1962).

Eye:
(1) Rabbit, undiluted: irritating, risk of serious damage to eyes (non-GLP, non-Guideline, Sugai et al., 1962).
(2) Rabbit, undiluted: irritating, risk of serious damage to eyes (non-GLP, non-Guideline, Smyth et al., 1962).
The undiluted test item was corrosive to the skin of rabbits, caused serious damage to the eye of rabbits and was reported to induce respiratory irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

occlusive conditions

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Piperidine
- Substance-No.: 77/283
- Physical state: liquid
- Analytical purity: 99 %
- Expiration date of the lot/batch: september 1982

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Gaukler, Offenbach am Main, Germany
- Weight at study initiation: 2.39 kg (male); 2.96 kg (female)
- Housing: single
- Diet: Ovator Solikanin 4 mm, Muskator-Werke, Duesseldorf, Germany; ca. 130 g per animal, daily.
- Water: Deionized water (monday to friday); Tap water (weekend); ca 250 ml per animal
- Acclimation period: ca. 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 50 - 80
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml

Duration of treatment / exposure:

3 min, 1 h, 4 h

Observation period:

8 days

Number of animals:

2 (one female and one male)

Details on study design:

TEST SITE
- Area of exposure: area of 2.5*2.5 cm on the upper third of the back
- Type of wrap if used: moistened cotton lint, no further data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Lutrol, Lutrol:water (1:1)
- Time after start of exposure: 3 min, 1 h and 4 h

SCORING SYSTEM: According to JH Draize: Dermal Toxicity, in: Appraisal of the saftety of chemicals in foods, drugs and cosmetics. p 46 - 59, 1959. Washington, DC: The Association of Food and Drug Officials of the United States of America, Texas, State department of Health.

READINGS
- 15 to 30 minutes after remove of the test substance, as well as after 24, 48 hours and 8 days after application. 8 day reading only with treatment duration of 4 hours.

OTHER
- In case of clinical indication of necrosis, this will be confirmed by macroscopic-pathologic evaluation.

Irritation parameter:

other: Necrosis

Remarks on result:

other: Exposure duration of 3 min led to hard leathery necrosis observed after 24 hours.

Irritation parameter:

erythema score

Remarks:

(exposure duration: 3 min)

Basis:

mean

Remarks:

(animal 1 and 2)

Time point:

24/48 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Necrosis (leathery, hard), macroscopic-pathologic confirmation

Irritation parameter:

edema score

Remarks:

(exposure duration: 3 min)

Basis:

mean

Remarks:

(animal 1 and 2)

Time point:

24/48 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

erythema score

Remarks:

(exposure duration: 1 h)

Basis:

mean

Remarks:

(animal 1 and 2)

Time point:

24/48 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Necrosis (leathery, hard), macroscopic-pathologic confirmation

Irritation parameter:

edema score

Remarks:

(exposure duration: 1 h)

Basis:

mean

Remarks:

(animal 1 and 2)

Time point:

24/48 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

erythema score

Remarks:

(exposure duration: 4 h)

Basis:

mean

Remarks:

(animal 1 and 2)

Time point:

24/48 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks:

within 8 days

Remarks on result:

other: Necrosis (leathery, hard and extending beyond the area of application), macroscopic-pathologic confirmation

Irritation parameter:

edema score

Remarks:

(exposure duration: 4 h)

Basis:

mean

Remarks:

(animal 1 and 2)

Time point:

24/48 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Remarks:

within 8 days

Irritant / corrosive response data:

The undiluted test substance was applied for 3 min, 1 and 4 h under occlusive conditions to the backs of two rabbits each.Thick and leathery necroses were observed after exposure duration of 3 min; the findings were confirmed histologically.

Interpretation of results:

Category 1B (corrosive) based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

different scoring method

Principles of method if other than guideline:

Draize Test

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: Piperidine, Test substance No. 114
- no further data

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Takeo breeder (Shizuoka, Japan)
- Weight at study initiation: 2.0 - 2.2 kg
- Housing: metal cages
- Diet: RC4 diet (Oriental Yeas Co., Tokyo, Japan), ad libitum
- Water: ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 ± 1
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12 / 12

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

single treatment

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM: according.to the Draize score (Draize JH, Woodard G and Galvery H0 (1944); Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J. Pharmcol. Exp. Ther., 82, 377-390).

READINGS: The eyes were examined and the grade of ocular reaction was recorded 1, 4, 24, 48, 72, 96hr, 7, 14 and 21 days after the treatment.

Irritation parameter:

other: irreversible eye damage

Remarks on result:

other: Eye damage score about 86.1 of 110 that persists for more than 21 days after treatment.

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

In the key study, a non-GLP dermal irritation study similar to OECD 404 (BASF 77/283-3, 1982) one male and one female Vienna White rabbit (breeder) of 2.39 and 2.96 kg, respectively, were dermal exposed to 0.5 mL of the undiluted test item (purity: 99%) to an area of 6.25 cm² on the upper third of the back. Test sites were covered with an occlusive dressing for 3 min, 1 or 4 hours. Readings were performed 15 to 30 minutes after remove of the test substance and washing of the skin, as well as after 24, 48 hours. Animals were observed for 8 days. Irritation was scored by the method of Draize (Draize JH: Dermal Toxicity. 1959).

In animals treated for 3 min, 1 and 4 hours erythema score of 4, as well as hard leathery, macroscopic-pathological confirmed necrosis were detectable after 24 hours.

The skin irritation study is acceptable (reliability 2), and does not fully satisfy the guideline requirements for a skin irritation study (OECD 404) in rabbits (occlusive conditions).

In the key study, the test item is corrosive to the skin based on hard, leathery, macroscopic-pathologically confirmed necrosis observed after 3 min exposure at the reading time point of 24 hours in both animals.

 

In a non-GLP skin irritation study conducted by Toxikon (1991) according to the DOT guidelines (1987), 0.5 mL of the test item of unknown concentration was applied to an area of ca. 3 cm³ of intact skin of 6 albino rabbits (strain unknown). Test sites were covered with an occlusive dressing for the exposure period of 3 or 60 min or 4 hours. After removal of the test substance and washing of the skin, readings were performed at 30 minutes, as well as at 48 hours. Animals were observed for 48 hours. Tissue destruction, necrosis, occurred for all 3 exposure periods (3 and 60 min and 4 hours), at all test sites, with all 6 rabbits tested. Reading time point of the result was not given.

The skin irritation study is acceptable (reliability 2), but does not satisfy the guideline requirements for a skin irritation study (OECD 404) in rabbits (occlusive conditions, no readings after 24 and 72 hours, no purity of the test compound given).

The test substance is thus considered corrosive to the skin of rabbits based on necrosis following at least 3 min exposure as observed in all six animals.

In a further non-GLP dermal irritation study (Biosearch, 1983) according to the DOT guideline for Corrosivity, six New Zealand White rabbits were dermally exposed to 0.5 mL of the undiluted test item to an area of 2.54 cm² of the clipped skin. Test sites were covered with an occlusive dressing for 4 hours. After removal of the test substance and washing of the skin, readings were performed after 24 and 48 hours. Animals were observed for 48 hours. Severe erythema and corrosivity was observed 24 and 48 hours after treatment.

The skin irritation study is acceptable (reliability 2), but does not satisfy the guideline requirements for a skin irritation study (OECD 404) in rabbits (occlusive conditions, no reading after 72 hours, no purity of the test compound given).

The test substance is considered corrosive to the skin of rabbits after 4 hours exposure at the reading time point of 24 hours in all six animals.

 

Smyth et al. (1962) reported a dermal skin irritation study at which the clipped skin of five albino rabbits was exposed uncovered to 0.01 mL of the test item. The animals were observed for 24 hours. Within 24 hours after application of the test item, a primary skin irritation grade of 6 of 10 grades indicates necrosis.

The skin irritation study is acceptable (reliability 2), but does not satisfy the guideline requirements for a skin irritation study (OECD 404) in rabbits (no readings after 48 and 72 hours, no purity of the test compound given).

Due to the primary skin irritation grade 6 of 10 within 24 hours, after application of 0.01 ml undiluted test substance, the test substance is considered to cause severe damage to the eye.

Eye irritation

In the key study, Sugai et al. (1990) performed a Draize test. 0.1 ml of undiluted test item was instilled to the eye of three rabbits. The animals were observed for 21 days. Scoring was performed according to Draize et al., 1944 (J. Pharmcol. Exp. Ther., 82, 377-390). Readings were conducted 1, 4, 24, 48, 72, 96 hours, 7, 14 and 21 days after the treatment. An eye damage score of about 86.1 of 110 was observed that persisted for more than 21 days after treatment.

The eye irritation study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an eye irritation study (OECD 405) in rabbits (limited documentation, different scoring system).

Due to the irreversible eye damage the test substance is considered to cause severe damage to the eye.

Smyth et al. (1962) reported an eye irritation study in which 0.005 ml of a 5 and 1 % solution of the test item was instilled to the eye of rabbits. The animals were observed for 24 hours. Within 24 hours after application of the test item, an irritation score of 9 of 10 grades indicates a > 87 % necrosis after instillation of 0.005 ml of 5 % solution and 63 - 87 % necrosis after instillation of 1 % solution.

The eye irritation study is acceptable (reliability 2), but does not satisfy the guideline requirements for an eye irritation study (OECD 405) in rabbits (limited documentation, different scoring system).

Due to the eye irritation grade 9 of 10 within 24 hours, after application of the test substance, the test substance is considered corrosive.

Respiratory system

There are no data available concerning the irritating potential to the respiratory system. Nevertheless, the test item is corrosive and causes burns. Irritating to the respiratory system is implicit. This is confirmed by human data. The irritation threshold for humans was reported as 90 mg/m³ (26 ppm), which is considered as LOAEL. Inhalation exposure to piperidine causes sore throat, signs of respiratory tract irritation (coughing, labored breathing), and dizziness (DASE (Dutch Association of Safety Experts), 1980). Piperidine. In: Handling Chemicals Safely - 1980. 2nd ed. Published by: Dutch Assoc. of Safety Factors, Dutch Chemistry Industrial Association, and Dutch Safety Institute. p. 757.). No exposure concentrations were provided.

Conclusion: The undiluted test item was corrosive to the skin of rabbits, caused serious damage to the eye in rabbits and was reported to induce respiratory irritation.

Justification for selection of skin irritation / corrosion endpoint:
Study comparable to guideline with acceptable restrictions (Klimisch code 2). Analytical purity of the test substance is given in the report (99 %) of the key study. No purity is given in the report of the supporting study of Toxikon 1991.

Justification for selection of eye irritation endpoint:
Study of highest quality.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Justification for classification or non-classification

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

The substance is already listed in Annex VI to Regulation (EC) No 1272/2008 and classified with Cat. 1B (H314, Causes severe skin burns and eye damage).

 

Additionally, the available experimental test data for irritation/corrosion are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. As a result the substance is considered to be classified for irritation/corrosion (Cat 1B, H314, Causes severe skin burns and eye damage ) under Regulation (EC) No.1272/2008 and therefore confirming the classification in Annex VI to Regulation (EC) No 1272/2008.