Piperidine

Endpoint summary

Description of key information

Acute oral toxicity:
LD50 (male and female rat): 740 mg/kg bw, GLP, Guideline study, Toxicon 1992.
LD50 (male and female rat): > 200 to < 2000 mg/kg bw, non-GLP, comparable to OECD 401 (BASF 77/283, 1980).
LD50 (male and female rat): 445 mg/kg bw; non-GLP, non-Guideline Study, van den Heuvel et al., 1990.
LD50 (male and female rat): 337 mg/kg bw; non-GLP, non-Guideline Study, Yam et al., 1991.
LD50 (male and female rat): 520 mg/kg bw; non-GLP, non-Guideline Study, Smyth et al., 1962.
The test substance is harmful after a single oral administration.
The LD50 values reported for acute oral toxicity ranged from 337 to 740 mg/kg body weight. Clinical signs included ptosis, lethargy, ataxia, tremors, salivation, and lacrimation. Due to irritant and corrosive properties of the test item stomach and intestinal haemorrhage with ulcers was noted at autopsy.

Acute inhalative toxicity:
LC50 (male and female rat): 4.80 mg/L (4800 mg/m³), non-GLP, comparable to OECD 403 (BASF 77/283, 1980).
LD50 (rat): > 6.96 to < 13.92 mg/L; non-GLP, non-Guideline Study, Smyth et al., 1962.
The test substance is toxic after a single inhalative application.
Clinical signs included prostration, tremors, dyspnoea, clonic convulsions, and spasmodic respiration. Death occurred only at concentrations that caused dyspnea, central nervous system toxicity, and prostration. Due to the corrosive properties nasal irritation and signs of eye irritation, such as smoky-milky clouded cornea, watery-reddish or reddish secretion of eyes and nose were observed. Gross necropsy findings in rats included acute dilation and congestion hyperaemia of the heart, acute emphysema and pulmonary oedema, as well as bleedings in stomach and intestine.

Acute dermal toxicity:
LD50 (male rabbits): 276 mg/kg bw; non-GLP, non-Guideline Study, Smyth et al., 1962.
The test substance is toxic after a single dermal application.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Version / remarks:

July 1989

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Piperidine
- Physical state: Liquid, Colorless
- Analytical purity: no data
- Lot/batch No.: 20221AA
- Storage condition of test material: Room Temperature

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, MA
- Age at study initiation: 49 to 74 days
- Weight at study initiation: 200 and 300 g
- Fasting period before study: overnight
- Housing: polycarbonate cages
- Diet: rodent ration (AgWay Prolab, Waverly, NY), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days (Range finding), four days (LD50)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 10 to 13
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

USP

Details on oral exposure:

DOSAGE PREPARATION: Each dose preparation was placed on a magnetic stir plate and stirred for 10 minutes prior to dosing to ensure a homogenous solution

Doses:

Range Finding Trial: 2000, 1200, 800, 300, and 100 mg/kg
LD50 Trial: 300, 550 and 800 mg/kg

No. of animals per sex per dose:

in the range finding study one male, one female;
in the main study 5 animals per sex.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Frequency of weighing: day 0 (day of dosing), 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Statistics:

The LD50 was determined by the method of Linear Regression using the program "Linear Regression I" by R.J. Tallarida and R.B. Murray, (Manual of Pharmacologic Calculations with Computer Programs, Springer Verlag, New York, 1986, pp 10-13).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

740 mg/kg bw

Based on:

test mat.

Mortality:

800 mg/kg: 1/5 males and 2/5 females died within 4 hours; 2/5 males died within one day and 2/5 females died within 6 days; in total 7/10 animals died.
550 mg/kg = 0/10
300 mg/kg = 0/10

Clinical signs:

other: 800 mg/kg: rats showed the following clinical signs during the observation period: catalepsy, tremors and lethargy. One surviving male appeared emaciated from day 7 to day 10. 550 mg/kg: clinical signs observed in rats included somnolence, catalepsy, let

Gross pathology:

800 mg/kg: Gross necropsy findings in rats of this dose group included haemorrhaging in the stomach and small intestines; adhesion of the stomach, small intestine and spleen to the abdominal cavity wall; brownish fluid in the abdominal cavity and discoloration of the kidneys.
550 mg/kg: Gross necropsy findings in rats of this dose group included adhesion of the stomach and spleen and thickening of the forestomach mucosa.
300 mg/kg: no signs of toxicity were observed at gross necropsy.

Other findings:

Range Finding:
Body Weights: All of the surviving animals gained body weight
Clinical Observations: The surviving animals did not show any clinical signs during the observation period.
Mortality: All animals of the dose groups 2000, 1200 and 800 mg/kg (one male and one female each) died within 4 hours after treatment. The animals in the two lowest dose group levels (300 and 100 mg/kg body weight) survived the entire observation period.
Necropsy: Animals that died during the study revealed signs of toxicity that included haemorrhaging in the stomach and the small and large intestine. No unusual lesions were noted in any of the surviving animals.
Based on the results of the Range Finding Study, the doses for the the LD50 determination study were selected to be 800, 550, and 300 mg/kg.

Table1 Acute oral toxicity.

 

Dose [mg/kg bw]	Mortality			Clinical signs
	N*	%	Time of death	N*	Duration
Males
800	3/5	60	4h / day 1	4/5	-
550	0/5	0	-	5/5	-
300	0/5	0	-	0/5	-
Females
800	4/5	80	4 h / day 6	3/5	-
550	0/5	0	-	5/5	-
300	0/5	0	-	0/5	-

*N= Number of animals/ number of animals used

Interpretation of results:

Category 4 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

750 mg/kg bw

Quality of whole database:

The study is comparable to OECD Guideline 401 (Acute Oral Toxicity), GLP compliant and has Klimsch score 2.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

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 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material: Piperidine
- Substanz-No.: 77/283
- Physical state: liquid, limpid
- Analytical purity: 99 %

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: WIGA, Sulzfeld, Germany
- Mean weight at study initiation: 185 ± 15 g,
- Housing: 5 animals per cage
- Diet: Herilan, mouse/rat/hamster maintenance diet; H. Eggersmann KG, Rinteln, Germany, ad libitum
- Water: Fully demineralized water each workday ad libitum; on holidays tap water ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure system: Whole-body inhalation system (Groups of 5 animals are placed in wire cages which are located in a glass-steel inhalation chamber, V= 200 I.)
- Generator system: Continuous infusion pump UNITA I (B. Braun); Glass evaporator with thermostat (BASF).
By means of a continuous infusion pump, constant amounts of the test substance were supplied to an evaporator heated to 69°C .
The vapours that were formed were mixed with a flow of fresh air and passed into the inhalation chamber.
By means of an exhaust air system, the pressure ratios in the inhalation system were adjusted in such a way that there was a pressure slightly below
the atmospheric pressure (negative pressure). The inhalation mixture was offered to the animals for inhalation for 4 hours.

TEST ATMOSPHERE
- Brief description of analytical method used:
1. Equipment, chemicals and solutions: Gas chromatograph HP 5840 A
2. Sampling:
- Apparatus: two successive absorption vessels and downstream fritted flask
- Sorption solvent: xylene
- Sampling rate: 1 L
- Withdrawn amount: up to 10 L
- Sampling site: in the immediate vicinity of the noses of the animals
- Sampling probe diameter: 4 mm
3. Analytical test method: gas chromatography; piperidine was determined in xylene.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Nominal concentration [mg/L]: Group 1: 17.1; group 2: 7.7; group 3: 10.2; group 4: 5.1; group 5: 1.7
Analytical concentration [mg/L]: Group 1: 7.54; group 2: 5.30; group 3: 4.10; group 4: 2.80; group 5: 1.00

No. of animals per sex per dose:

10

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Weighing was done before treatment, after 7 days, after 14 days.
Observations were several times on the day of exposure and at least once daily afterwards.
- Necropsy of survivors performed: yes, animals were killed by C02 and similarly all animals deceased before scheduled sacrifice were necropsied.
- Other examinations performed: clinical signs and mortality: daily

Statistics:

The statistical evaluation of the study was carried out based on a probit analysis of DJ Finney (Finney, DJ; Probit Analysis 1971, pp 1-150.
Published by the Syndics of the Cambridge University Press, Bentley House, 200 Euston Road, London N.W. 1).

Sex:

male/female

Dose descriptor:

LC50

Effect level:

4.8 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

Group 1:
males: 10 animals died (9 animals died within the day of exposure, 1 animal died within 5 days post exposure);
females: all animals (10) died within the day of exposure.
Group 2:
males: 6 animals died (3 animals died within the day of exposure, 1 on day 1, 4 and 5 after exposure, respectively);
females: 1 animal died (1 animal died on day 12 after exposure);
Group 3:
males: 3 animals died (1 animal died within the day of exposure, 1 on day 1 after exposure, and 1 on day 7 after exposure);
females: 7 animals died (1 animal died after day 1 of exposure, 1 on day 5, 6, 7, 11, respectively and 2 on day 8 after exposure);
Group 4:
males: no animal died;
females: 1 animal died (1 animal died on day 12 after exposure);
Group 5: no animal died.

Clinical signs:

other: Dose group 1, 2 and 3: severe watery nasal discharge; severe red discharge of the eyes; eyelid closure; nose wiping; cornea opacity; dyspnoea; tremor; clonic and jumping convulsions; abdominal and lateral position (experimental group 1 and 2); squatting

Body weight:

Mean body weight and body weight change (in parentheses):
Group 1: day 0: males: 186 g; females: 177 g;
Group 2: day 0: males: 181 g; females: 179 g; day 7: males: 161 (-20) g; females: 155 (- 24) g; day 14: males: 187 (+ 6) g; females: 174 (- 5) g;
Group 3: day 0: males: 184 g; females: 187 g; day 7: males: 176 (- 8) g; females: 145 (- 42) g; day 14: males: 207 (+ 23) g; females: 169 (- 18) g;
Group 4: day 0: males: 181 g; females: 179 g; day 7: males: 191 (+ 10) g; females: 163 (- 16) g; day 14: males: 229 (+ 48) g; females: 178 (- 1) g;
Group 5: day 0: males: 175 g; females: 182 g; day 7: males: 223 (+ 48) g; females: 197 (+ 15) g; day 14: males: 257 (+ 82) g; females: 205 (+ 23) g;
Control: day 0: males: 188 g; females: 178 g; day 7: males: 223 (+ 35) g; females: 198 (+ 20) g; day 14: males: 264 (+ 76) g; females: 208 (+ 30) g.
Compared to the control group, body weight gain in the treatment groups 2, 3 and 4 was considerably reduced, whereas the body weight gain of the treatment group 5 for the males was slighly enhanced and for the females slightly reduced.

Gross pathology:

Group 1: Heart: acute dilation of the atria, acute congestion hyperemia; lung: slight acute emphysema, weak pulmonary edema;
Group 2: Heart: acute dilation of the atria, acute congestion hyperemia; stomach/intestine bleedings; intestine, flatulence; pulmonary edema;
Group 3: Heart: acute dilation of the atria, acute congestion hyperemia; lung: slight acute emphysema, acute lobular pneumonia;
Group 4: no abnormalities detected; one animal haggard;
Group 5: no abnormalities detected.
In animals sacrificed at the end of the study no abnormalities were detected.

Interpretation of results:

Category 3 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

4 800 mg/m³ air

Quality of whole database:

The study is comparable to OECD Guideline 403 (Acute Inhalative Toxicity), not GLP compliant and has Klimsch score 2.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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:

no guideline followed

Principles of method if other than guideline:

Treatment of the rabbit skin was performed using a method closely to the one-day cuff method according to Draize, JH et al., 1944 (Methods for Study of Irritation and Toxicity of Substances Applied Topically to the Skin and Mucous Membranes. J. Pharmacol. Exp. Therap. 82, 377)

GLP compliance:

no

Test type:

standard acute method

Specific details on test material used for the study:

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

Species:

rabbit

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.5 to 3.5 kg

ENVIRONMENTAL CONDITIONS
- no data

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: entire clipped trunk
- Type of wrap if used: impervious plastic film.

TREATMENT
- The animals are immobilized during the 24 hour exposure period. Afterwards the film is removed and the rabbits are caged.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 20 mL/kg

Duration of exposure:

24 hours

Doses:

no data

No. of animals per sex per dose:

4 males

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male

Dose descriptor:

LD50

Effect level:

275 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The original value: 0.32 (0.23 - 0.43) mL/kg was converted to mg/kg body weight using the density of 0.86 g/cm³.

Interpretation of results:

Category 3 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

276 mg/kg bw

Quality of whole database:

The study is an acceptable non-Guideline Study, not GLP compliant and has Klimsch score 2.

Additional information

There are valid in vivo data available for the assessment of the acute oral, inhalative and dermal toxicity of the test item.

 

Oral

 

In the key study, an acute oral toxicity study conducted according to GLP and EPA OTS 798.1175 (Acute Oral Toxicity), fasted, 49 to 74 days old Sprague-Dawley rats (5/sex/dose) were administered a single oral dose (gavage) of the test item (analytical purity unknown) at dose levels of 800, 550, and 300 g/kg body weight (Toxikon, 1992). The dose levels were based on the results of a range finding study with dose levels of 2000, 1200, 800, 300, and 100 g/kg body weight. The test item was diluted in distilled water. The maximum dose volume applied is not given.

The animals were observed for a post-dosing period of 14 days. Subsequently, all surviving animals were killed and together with animals that died during the study subjected to gross pathology.

Mortality occurred within 4 hours, one and six days in the high dose group, solely. The symptoms reported were described as catalepsy, tremors and lethargy in the high dose group. Additionally, one surviving male appeared emaciated from day 7 to day 10. In the mid dose group clinical signs observed in rats included somnolence, catalepsy, lethargy and tremors during the initial four-hour observation period. In the low dose group no signs of toxicity were observed. Except of one female of the mid dose group, the surviving animals showed an expected gain in bodyweight during the study.

Gross necropsy findings in rats of the high dose group included haemorrhaging in the stomach and small intestines; adhesion of the stomach, small intestine and spleen to the abdominal cavity wall; brownish fluid in the abdominal cavity and discolouration of the kidneys. In the low dose group adhesion of the stomach and spleen and thickening of the forestomach mucosa was observed, whereas in the low dose group no abnormalities were noted at gross necropsy.

The acute oral toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an oral toxicity test(OECD 401) in rats (incomplete characterisation of the test substance - purity unknown).

The acute oral LD 50 of the test item for male and female rats was estimated to be 740 mg/kg body weight.

 

In a supporting study, performed comparable to OECD Guideline 401 (Acute Oral Toxicity) using a standardized test method, fasted, Sprague Dawley rats (5/sex/dose) were given a single oral dose (gavage) of the test item (analytical purity: 99 %) at the doses of 200 and 2000 mg/kg bw (BASF 77/283, 1981). The test item was diluted in distilled water at a concentration of 2 and 20 % and administered at a volume dosage of 10 mL/kg. The animals were observed subsequently for a period of 14 days. All surviving animals were killed and together with animals that died during the study subjected to gross pathology. All animals in the high dose group died. Thereby mortality occurred within 1 hour and 24 hours. One female of the low dose group died within 48 hours. Signs of systemic toxicity in the high dose group were pronounced gasping, pronounced irregular respiration, mild to pronounced apathy, stagger, atony, spastic gait, tremble, tremor, exsiccosis, salivation, lacrimation, very poor general condition, blood in the urine. In the low dose group good condition, strong yellow coloured urine were noted. All animals showed an expected gain in bodyweight during the study. Gross necropsy findings in rats of the high dose group included acute cardiac dilatation, congestional hyperaemia, strong oedema in the glandular stomach, haemorrhagic gastritis, haemorrhagic enteritis, diarrhoea content. No abnormalities were noted at necropsy in the low dose group.

The acute oral toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an oral toxicity test (OECD 401) in rats (the application volume was not calculated by the individual weight, but by the mean weight per sex, only 2 doses tested).

The acute oral LD 50 of the test item for male and female rats was estimatedto be > 200 to < 2000 mg/kg body weight.

 

Van den Heuvel et al.(1990) conducted a study in which the acute oral toxicity of the test item to rats was evaluated using a fixed-dose procedure and compared with results obtained using the classical LD50 test. Thereby, using the fixed-dose procedure, groups of ten, fasted rats (five males and five females) were treated with one of the predetermined dose levels (5, 50, 500 and 2000 mg/kg body weight), which were selected on the basis of a sighting study so that only evident toxicity and no deaths were observed. Depending on the outcome of the first dose, a second dose group was used.

The animals were observed subsequently for a period of 14 days. All surviving animals were killed and together with animals that died during the study subjected to gross pathology. As clinical signs ptosis, posture, respiratory effects, diarrhoea and diuresis, lethargy, ataxia, abnormal gait, tremors, convulsions, prostrate coma, salivation and lacrimation were observed within one day post dose and lasted between one and 11 days. Gross necropsy findings in rats included acute haemorrhage of the stomach, intestine, thymus and urinary bladder; stomach necrosis; ulceration and adhesions with the spleen and liver; and congestion of the kidney. No data about the body weight gain were reported.

Using the fixed-dose method the acute oral LD 50 of the test item for male and female rats was estimated to be 445 mg/kg body weight.

 

Yam et al. (1991) reported an acute oral toxicity study conducted according to the up-and-down method described by Bruce (Fundamental and Applied Toxicology, 5, 151 - 157, 1985 and Fundamental and Applied Toxicology, 8, 97 - 100, 1987) and compared the results with those obtained using the fixed dose method. Only females were used as these are assumed to be generally equal or more sensitive than males. Thereby, fasted Sprague-Dawley rats were administered a single oral dose (gavage) of the test item (analytical purity unknown) at dose levels of 5, 50, 500 or 2000 mg/kg body weight. The animals were observed subsequently for a period of 14 days. All animals were killed and subjected to gross pathology. As clinical signs using the up-and-down method ataxia and salivation were observed, whereas motor activity decrease, respiratory effects, tremor, blanching, piloerection, ataxia and salivation were noted using fixed-dose procedure; both within one day post exposure and duration for one day. Stomach and intestinal haemorrhage with ulcers was noted at autopsy using the up-and-down method. Using the fixed dose method no autopsy findings were observed.

Using the up-and-down method the acute oral LD 50 of the test item for female rats was estimated to be 337 mg/kg body weight.

 

Smyth et al. (1962) reported an oral toxicity study in which animals were treated once with the test substance by means of gavage. Based upon mortalities during a 14-day observation period, the LD50 value is estimated.

The acute oral LD 50 of the test item for female and male rats was estimated to be 520 mg/kg body weight.

 

Conclusion: The LD50 values reported for acute oral toxicity ranged from 337 to 740 mg/kg body weight. Clinical signs included ptosis, lethargy, ataxia, tremors, salivation, and lacrimation. Due to irritant and corrosive properties of the test item stomach and intestinal haemorrhage with ulcers was noted at autopsy. Due to irritant and corrosive properties of the test substance, the LD50 values are based on local effects, which are covered by the evaluation as corrosive substance.

 

 

Inhalative

 

In the key study, an acute inhalation non-GLP study comparable to OECD 403 (BASF 77/283, 1980), Sprague-Dawley rats (10/dose/sex) were whole-body exposed to piperidine (99%) as a vapour at analytical concentrations of 7.54, 5.30, 4.10, 2.80, or 1.00 mg/L (corresponding to 2167, 1523, 1178, 805, 287 ppm, respectively) for 4 hours and observed for 14 days. The vapour was generated with an evaporation unit at 69°C and mixed with fresh air to obtain the different concentrations. Clinical signs, mortality, food consumption, body weights, and gross and microscopic findings were evaluated.

Mortality data for male rats, but not for females, showed a clear dose-response relationship.

All rats exposed to the high dose group of 7.54 mg/L died by day 7. Death was also observed at the concentrations of 5.30 mg/L (6 of 10 males and 1 of 10 females), 4.1 mg/L (3 of 10 males and 7 of 10 females) and 2.8 mg/L (one of 10 females). Most deaths occured before day 7 except for one female rat exposed to 5.3 mg/L and three female rats exposed to 4.1 mg/L that died after day 7.

Multiple clinical signs were observed at all concentrations, prostration, crouched position, tremors, dyspnoea, clonic convulsions and corrosion around the nose, rubbing of the snout, smoky-milky clouded cornea, watery-reddish or reddish secretion from the eyes and nose, lid closure, ragged fur, and spasmodic respiration was observed. After exposure to 1.0 mg/L no clinical signs were found more than 2 days.

Body weight loss during the first week of observation was found in male and female rats exposed to 4.1 and 5.3 mg/L and females exposed to 2.8 mg/L; during the second week body weight gain was observed. Compared to controls, reduced body weight of about 13-29% with males and 14-19% with females was found at the end of the observation period.

Gross necropsy findings in rats included acute dilation of the atria and acute congestion hyperaemia of the hearth, slight acute emphysema and weak pulmonary oedema, as well as bleedings in stomach and intestine.

The acute inhalative toxicity study is acceptable (reliability 2), and does satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats.

The 4 hour LC50 values for the test item in rats were as following:

LC50 (vapour inhalation; males and females combined) 4.8 mg/L (4800 mg/m³).

 

In a supporting acute inhalation hazard non-GLP test comparable to OECD 403 (adopted on 1981, 12th May; inhalation hazard test) (BASF 77/283, 1981), Wistar rats (3/dose/sex) were exposed to an atmosphere of saturated piperidine vapour at 20 °C for 3 (100 mg/L) or 10 (125.2 mg/L) minutes and observed for 7 days (BASF 1981). Mortality was observed with 2/12 within 24 hours and 3 days and 3/6 animals within 6 and 9 min, respectively. Clinical signs were intense escape attempts, eyelid closure, intermittent respiration; after 2 min gasping; nasal, discharge clear and red; cyanotic; at the end of the experiment hearable respiratory sounds; cornea opacity, detectable in 3 animals. On day 2 dyspnoea, hearable respiratory sounds; nasal discharge, red; sticky eyes, ruffled fur were found. On days 5 and 6 one animal was blind, respectively. No abnormal body weight gain was observed. Gross necropsy findings in rats included acute pneumonia and grey, broadened peripheral lobules in the liver. In the heart acute dilation and acute congestion hyperaemia was observed.

The acute inhalative toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats (no details on animal husbandry, no analytical verification of the test atmosphere concentration).

 

In supporting publications Smyth et al. (1962a) reported no deaths among six Wistar rats exposed to 2000 ppm (6.96 mg/L) of the test item for 4 hours. However, 6/6 rats died after inhalation of 4000 ppm (13.92 mg/L) of the test item for the same treatment duration. Inhalation of concentrated piperidine vapour at room temperature for 15 minutes killed 6/6 Wistar rats (Smyth et al. (1962b). There were no further data about the actual exposure concentration.

The acute inhalative toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats (no details on animal husbandry, no analytical verification of the concentration of the test substance in the vapour-air-mixtures).

 

No data were available for determining human variability to inhalation exposure to the test item.

 

Conclusion: According to the data the LC50 value for acute inhalative toxicity after vapour inhalation combined for female and male rats is 4.8 mg/L. Therefore, the test item is concluded to be harmful. Clinical signs included prostration, tremors, dyspnoea, clonic convulsions, and spasmodic respiration. Death occurred only at concentrations that caused dyspnoea, central nervous system toxicity, and prostration.

Due to the irritant and corrosive properties of the test item nasal irritation and signs of eye irritation, such as smoky-milky clouded cornea, watery-reddish or reddish secretion from the eyes and nose were observed. Gross necropsy findings in rats included acute dilation and congestion hyperaemia of the heart, acute emphysema and pulmonary oedema, as well as bleedings in stomach and intestine.

 

 

Dermal

 

In an acute dermal toxicity study performed as a non-GLP study according to Draize et al., 1944 (J. Pharmacol. Exp. Therap. 82, 377) , four male New Zealand White rabbits were dermally exposed (entire clipped trunk) to the test item (analytical purity unknown) diluted in water for 24 hours at 20 mL/kg body weight at unknown doses (Smyth et al., 1962). Animals were then observed for 14 days. There were no treatment related clinical signs, necropsy findings or changes in body weight.

The acute dermal toxicity study is acceptable (reliability 2), but does not satisfy the guideline requirements for a dermal toxicity test (OECD 402) in rabbits.

The acute dermal LD50 of the test item for males was estimated to be 276 mg/kg body weight. 

Conclusion: Due to the LD50 value reported for acute dermal toxicity for males of 276 mg/kg body weight, the test item is concluded to be harmful.

Justification for selection of acute toxicity – oral endpoint
Highest quality study.

Justification for selection of acute toxicity – inhalation endpoint
Highest quality study.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

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. 3 (H331, Toxic if inhaled), and Cat 3 (H311, Toxic in contact with skin), respectively.

 

Additionally, the available experimental test data for oral, inhalative and dermal toxicity 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 acute oral toxicity (Cat 4, H302, Harmful if swallowed), acute inhalative toxicity (Cat 3, H331, Toxic if inhaled) and (Cat 3, H311, Toxic in contact with skin), under Regulation (EC) No.1272/2008 and therefore confirming the classification in Annex VI to Regulation (EC) No 1272/2008 in part.