Pyrrolidine

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (non-GLP).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Pyrrolidine

EC Number:

204-648-7

EC Name:

Pyrrolidine

Cas Number:

123-75-1

Molecular formula:

C4H9N

IUPAC Name:

pyrrolidine

Details on test material:

- Name of test material (as cited in study report): Pyrrolidine
- Physical state: liquid, limpid
- Analytical purity: 99 %

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: 8 weeks
- Mean weight at study initiation: males: 246 ± 21 g, females: 173 ± 16 g,
- Housing: 5 animals per cage
- Diet: Kliba diet rat/mouse A 343, 10 mm pellets, Klingentalmuehle AG, Kaiseraugst, Germany, ad libitum
- Water: tap water after exposure, ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure system: Head-nose inhalation system INA 20 (glas-steel-inhalation chamber (BASF AG), V = 55 L.
- Animals are placed in tubes and projected into the inhalation chamber with their snoots.
- Generator system: Using a continuous infusion pump INFU 362 (Indigel, Switzerland) with 2 glass evaporators with thermostat (BASF AG) a vapour-air mixture was generated.
- Test performance: By means of the continuous infusion pump, constant amounts of the test substance were supplied to both evaporators heated to 25°C. The generated vapour was mixed with a flow of fresh air and passed into the inhalation chamber. As volumetric flow rate 1500 L/h of compressed air was adjusted. Supply air was air conditioned to an exposure temperature of 19 to 25 °C. Compared to the supply air the exhaust air system was reduced by 200 L (overpressure). The inhalation mixture was offered to the animals for inhalation for 4 hours.

TEST ATMOSPHERE
- Brief description of analytical method used:
1. Equipment: Gas chromatograph HP 5840 A (Hewlett Packard)
2. Sampling:
- Apparatus: two successive absorption vessels and downstream fritted flask
- Sampling station: (BASF AG, Germany)
- Sorption solvent: dimethylformamide
- Sampling rate: 1.25 m/s
- Withdrawn amount: 5 L
- Sampling site: in the immediate vicinity of the noses of the animals
- Sampling probe diameter: 4 mm
- Sampling frequency: one per hour (treatment group 2 - 4); half an hour (treatment group 1)
3. Analytical test method: gas chromatography;
- samples of pyrrolidine was determined in dimethylformamide.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gas chromatographical determination

Duration of exposure:

4 h

Concentrations:

Analytical concentration [mg/L]: Group 1: 15.5; group 2: 12.6; group 3: 9.8; group 4: 8.9
Nominal concentration [mg/L]: Group 1: 27.1; group 2: 22.6; group 3: 17.9; group 4: 19.05

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Weighing was done before treatment and after 7 and 14 days, respectively.
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: workdays 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).

Results and discussion

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

LC50

Effect level:

11.7 mg/L air (analytical)

Based on:

test mat.

95% CL:

10.6 - 12.9

Exp. duration:

4 h

Effect levels 2

Sex:

male

Dose descriptor:

LC50

Effect level:

13 mg/L air (analytical)

Based on:

test mat.

95% CL:

11.6 - 15.3

Exp. duration:

4 h

Effect levels 3

Sex:

female

Dose descriptor:

LC50

Effect level:

10.3 mg/L air (analytical)

Based on:

test mat.

95% CL:

8.1 - 12

Exp. duration:

4 h

Mortality:

Group 1 (15.6 mg/L):
males: in total 8/10 animals died (6/10 animals died within exposure duration, 2/10 animals died within 14 days post exposure);
females: in total 9/10 animals died within exposure duration.
Group 2 (12.6 mg/L):
males: in total 4 animals died (0/10 animals died within exposure duration, 4/10 animals died within 7 days post exposure);
females: in total 7/10 animals died (6/10 animals died within exposure duration, 1/10 animals died within 7 days post exposure);
Group 3 (9.8 mg/L):
males: in total 2/10 animals died (1/10 animals died within exposure duration, 2/10 animals died within 1 day post exposure);
females: in total 6/10 animals died (4/10 animals died within exposure duration, 2/10 animals died within 1 day post exposure);
Group 4 (8.9 mg/L):
males: 0/10 animals died;
females: in total 2/10 animals died (1/10 animals died within exposure duration, 1/10 animals died within 2 days post exposure);

Clinical signs:

other: During exposure: Dose group 1, 2, 3 and 4: escape attempts; eyelid closure; watery to bloody nasal discharge; accelerated to intermittent respiration. After exposure: Dose group 1: flatulence of the abdomen; bilateral central, punctual, corneal opacity;

Body weight:

Mean body weight and body weight change (in parentheses):
Group 1: day 0: males: 246 g; females: 177 g; day 7: males: 179 (- 67) g; females: 126 (- 51) g; day 14: males: 237 (+ 58) g; females: 133 (+ 7) g;
Group 2: day 0: males: 254 g; females: 173 g; day 7: males: 235 (-19) g; females: 168 (- 5) g; day 14: males: 275 (+ 40) g; females: 195 (+ 27) g;
Group 3: day 0: males: 244 g; females: 172 g; day 7: males: 244 (± 0) g; females: 165 (- 7) g; day 14: males: 288 (+ 44) g; females: 193 (+ 28) g;
Group 4: day 0: males: 241 g; females: 170 g; day 7: males: 240 (- 1) g; females: 168 (- 2) g; day 14: males: 275 (+ 35) g; females: 196 (+ 28) g;
Control (historical): day 0: males: 240 g; females: 176 g; day 7: males: 280 (+ 40) g; females: 195 (+ 19) g; day 14: males: 313 (+ 33) g; females: 211 (+ 16) g.
Compared to the control group, body weight gain in the treatment groups 1, 2, 3 and 4 was reduced during 7 days post exposure.
In males of the treatment group 1 body weight gain was reduced to 36 % and in the treatment group 2 to 16 % compared to the controls. In animals of the treatment group 3 and 4 stagnation was observed in the first week after exposure. In the second week animals regained body weight without achieving control values.
Compared to the control group females of the treatment group 1 showed reduced body weight gain (- 26 %) in the first week after exposure. Stagnation was observed with the animals of the treatment groups 2, 3 and 4, when compared to the control group. In the second week animals of the treatment group 2, 3 and 4regain on body weight without achieving control values. Animals of the treatment group 1 did not recover.

Gross pathology:

Deceased animals:
congestion hyperaemia; gaseous intestine; pulmonary oedema; slight to pronounced pulmonary emphysema.
Sacrificed animals:
no abnormalities detected.

Any other information on results incl. tables

Table1. Acute inhalative toxicity.

 

Target concentration [mg/L air]	Mortality			Clinical signs
	N*	%	Time of death	N	Duration
Males
15.5	8/10	80	6 /10 during exposure (4 h); 1/10 on day 11; 1/10 on day 13	10/10	Until death/ 14 days
12.6	4/10	40	1/10 on day 3; 3/10 on day 4	10/10	Until death/ 9 days
9.8	2/10	20	1/10 during exposure (4 h); 1/10 on day 1	10/10	Until death/ 11 days
8.9	0/10	0	-	10/10 2/10	11 days Irreversible corneal opacity
Females
15.5	9/10	90	9 /10 during exposure (4 h);	10/10	Until death/ 13 days
12.6	7/10	70	6 /10 during exposure (4 h); 1/10 on day 4	10/10	Until death/ 9 days
9.8	6/10	60	4/10 during exposure (4 h); 2/10 on day 1	10/10	Until death/ 11 days
8.9	2/10	20	1/10 during exposure (4 h); 1/10 on day 2	10/10	Until death/ 11 days

*N= Number of animals/ number of animals used.

 

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information category 4 Criteria used for interpretation of results: EU

Conclusions:

LC50, rat, inhalation (vapour), 4 hours: 11.7 mg/L

Executive summary:

In this acute inhalation study (BASF 83/123, 1985) four vapour concentrations of the test substance in the range of 8.9 -15.6 mg/L were tested in 10 Wistar rats per sex and concentration group using 4-hour exposures. The concentrations were determined analytically by gas chromatography and the effectiveness of vapor generation analytical concentration/nominal concentrations was about 50%. The study resulted in a LC50 of 11.7 mg/L for both sexes combined (confidence interval 10.6 - 12.9). The observed clinical signs and necropsy findings can be attributed to the corrosive property of the test item.