Acetone

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles with the following deviation: exposure time 3 hrs, only male rats investigated; sufficient documentation; publication acceptable for weight of evidence approach

Data source

Reference

Reference Type:

publication

Title:

Evaluation of toluene and acetone inhalant abuse. I. Pharmacology and pharmacodynamics

Author:

Bruckner JV, Peterson RG

Year:

1981

Bibliographic source:

Toxicol Appl Pharmacol 61: 27-38

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Determination of 3-hr LC50 value, concentration range 30-120 mg/L, post-observation 21 hrs for concentration- and time-dependent induction of CNS depression or narcosis and reversibility of effects

GLP compliance:

no

Test type:

other: investigation of CNS depression and determination of LC50

Test material

Test material information

Constituent 1

Reference substance name:

Acetone

EC Number:

200-662-2

EC Name:

Acetone

Cas Number:

67-64-1

Molecular formula:

C3H6O

IUPAC Name:

propan-2-one

Details on test material:

anhydrous acetone, A.C.S. grade

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Madison, Wisconsin, USA
- Age at study initiation: 4 w
- Housing: maximal of 6 rats per cage during exposure
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 d

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 16-liter polypropylene cages in which the animals were housed also served as exposure chambers, the stainless steel lids were replaced with tightly fitting polyvinyl chloride lids.
- Exposure chamber volume: 16 L
- Source and rate of air: room air purified by passage through potassium permanganate and activated charcoal filters
- Temperature, humidity, pressure in air chamber: air flow 10 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: monitoring by gas chromatography
- Samples taken from breathing zone: no

Analytical verification of test atmosphere concentrations:

yes

Remarks:

(gas chromatography)

Duration of exposure:

3 h

Concentrations:

12,600; 19,000; 25,300; 50,600 ppm corresponding to ca. 30; 45; 60; 120 mg/L (two highest concentrations within flammability limits of acetone)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: up to 21 hrs
- Frequency of observations: during exposure: all groups after 30 min, 1, 2 and 3 hrs; after exposure: only in 19,000- and 25,300-ppm groups signs of CNS depression investigated at 1, 2, 3, 4, 5, 9 and 21 hrs after termination of exposure
- Necropsy of survivors performed: no
- Other examinations performed:
CNS depression was assessed by five simple tests of unconditioned performance and reflexes (tests from a battery of Irwin, 1968):
(1) wire maneuver: ability to keep from falling from a horizontally positioned wire
(2) visual placing: distance at which forelimb and/or hindlimb extension occurs upon being lowered by the tail to a flat grid
(3) grip strength: ability to maintain a hold on a grid being forcibly withdrawn
(4) tail pinch: vigor of response upon application of a uniform pressure to the tail
(5) righting reflex: ability of the animal to land on its feet when flipped into the air
Animal performance for each test was scored on a scale ranging from 0 to 8. Animals were tested by a person unaware of the actual exposure level. The five test scores were averaged to yield mean performance scores for individual animals and for group of animals.

Acetone concentrations were determined in blood, liver and brain of 35 rats at termination of exposure to 19,000 ppm acetone by a special technique that measured acetone concentrations in the head space vapor above blood or tissue samples via gas chromatography.

Statistics:

3-hr LC50 calculated according to method of Litchfield and Wilcoxon

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LC50

Effect level:

55 700 ppm

95% CL:

>= 54 000 - <= 57 400

Exp. duration:

3 h

Remarks on result:

other: CNS depression and narcosis

Effect levels 2

Sex:

male

Dose descriptor:

LC50

Effect level:

ca. 132 mg/L air

95% CL:

>= 128 - < 136

Exp. duration:

3 h

Remarks on result:

other: CNS depression and narcosis

Mortality:

120 mg/L: lethal within 2 hrs

Clinical signs:

other: 30 mg/L, after 2-3 hr exposure: definite ataxia with difficulty in locomotion 45 mg/L, after 2 hr exposure: definite ataxia with difficulty in locomotion; from 3 hr exposure to 1 hr post-exposure: animals immobile in the absence of stimulation; 9 hr post-

Other findings:

- Other observations:
CNS depression (animal performance/reflexes): for details see Table 1
reversibility of compromised animal performance: within 9 hrs at 19,000 ppm, nearly full reversibility within the 21-hr post-observation period at 23,500 ppm
Acetone tissue concentrations after 3 hrs exposure to 19,000 ppm: brain 2.7 mg/g, liver 2.5 mg/g, blood 3.3 mg/ml

Any other information on results incl. tables

Table 1: Time and concentration dependance of mean CNS performance score *

Experimental period	Timepoint (h)	30 mg/L(12,500 ppm)	45 mg/L (19,000 ppm)	60 mg/L (25,300 ppm)	120 mg/L (50,600 ppm)
Exposure	0	5.2	5.3	5.2	5.2
	1	4.7	4.9	4.1	1.1
	2	3.9	3.5	2.6	all animals dead
	3	3.3	2.6	1.1	-
Post-exposure	1	no data	2.8	2.1
	2		3.1	2.8
	3		3.2	3.1
	4		3.8	3.1
	5		4.2	3.9
	9		5.2	4.5
	21		5.3	5.0

* Manifestations of CNS depression in correlation to mean performance scores:

4: initial evidence of ataxia

3 -4: definite ataxia with difficulty in locomotion

2 -3: animals immobile in the absence of stimulation

1 -2: hypnosis with arousal difficult

<=1: unconsciousness

Applicant's summary and conclusion

Conclusions:

With a 3-hr LC50 of 132 mg/L air (55,700 ppm) acetone showed relative low toxicity.

Executive summary:

Groups of 5 male rats were exposed to acetone concentrations of 12,600, 19,000, 25,300, 50,600 ppm corresponding to ca. 30, 45, 60 and 120 mg/L for 3 hrs. Tests for CNS depression by impairment of unconditioned performance and reflexes were performed at 0, 1, 2, 3 hrs of exposure and at 1, 2, 3, 4, 5, 9, and 21 hrs of the post-observation period. At termination of exposure to 45 mg/L, acetone concentrations were determined in blood, liver and brain of 35 rats.

Impairment of animal performance started within 1 hr of exposure at all tested concentration showing a dose- and time-dependance. The performance scores at termination of exposure corresponded to clinical signs of definite ataxia with difficulty in locomotion at 30 mg/L. Animals were immobile in the absence of stimulation at 45 mg/L, and showed hypnosis with arousal difficult at 60 mg/L. All depressive effects were reversible within 9 hrs at 45 mg/L, and nearly fully reversible within the 21-hr post-observation period at 60 mg/L. At 120 mg/L, within 1 hr exposure rats mainfested hypnosis with arousal difficult and all rats were dead within 2 hrs of exposure. After 3 hrs exposure to 45 mg/L, acetone tissue concentrations were 2.7 mg/g brain, 2.5 mg/g liver, and 3.3 mg/mL blood. The 3-hr LC50 was calculated with a value of 132 mg/L air (55,700 ppm) acetone. The critical effect leading to death is CNS depression and narcosis.