4-tert-butyltoluene

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data are given.

Data source

Reference

Reference Type:

publication

Title:

Toxicological studies on p-tertiary-butyltoluene.

Author:

Hine CH et al.

Year:

1954

Bibliographic source:

AMA Arch Ind Hyg Occup Med 9: 227-244.

Materials and methods

Principles of method if other than guideline:

The test was carried out according to Hine CH et al. (1953). Toxicology and Safe Handling of CBP-55 (Technical 1-Chloro-3-Bromopropene-1).
AMA Arch Ind Hyg 7: 118-136.

GLP compliance:

no

Remarks:

pre-GLP study

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-tert-butyltoluene

EC Number:

202-675-9

EC Name:

4-tert-butyltoluene

Cas Number:

98-51-1

Molecular formula:

C11H16

IUPAC Name:

1-tert-butyl-4-methylbenzene

Details on test material:

- Name of test material (as cited in study report): p-tertiary-butyltoluene
- Physical state: liquid with distinct odour
- Analytical purity: no data
No further data

Test animals

Species:

rat

Strain:

Long-Evans

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
female Long-Evans rats
- Weight at study initiation: 150 - 200 g
no further data

ENVIRONMENTAL CONDITIONS: no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other:

Details on inhalation exposure:

All exposures at concentrations of 1000 ppm or less were carried out at 30 +/- 1°C (calculated saturated vapour concentration, 1170 ppm). Exposures to concentrations greater than 1000 ppm were carried out at 35 +/-1°C (calculated saturated vapour concentration, 1660 ppm). Nominal concentrations were calculated by the standard gas concentration formula described by Jacobs MB (1949). The Analytical Chemistry of Industrial Poisons, Hazards, and Solvents, Ed 2, (Chemical Analysis, A Series of Monographs oil Analytical Chemistry and Its Applications, Vol. 1). Edited by BL Clarke and IM Koltoff, New York, Interscience Publishers, Inc.
Analytical determination of the chamber vapour concentration indicated values ranging from 70 to 95% of the theoretical amount.
No further data.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

no data on method

Duration of exposure:

1 - 8 h

Remarks on duration:

for details, see table 1

Concentrations:

1-hour exposure: 2.72 - 9.09. mg/l (450 - 1500 ppm)
2-hour exposure: 2.72 - 9.09 mg/l (450 - 1500 ppm)
4-hour exposure: 0.817 - 2.72 mg/l (135 - 450 ppm)
8-hour exposure: 0.363 - 1.21 mg/l (60 - 200 ppm)
For details see table 1.

No. of animals per sex per dose:

6 females per group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 10 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, gross pathology and histopathology of decedents.
At the end of a 10-day observation period, the weight changes of tile survivors were calculated. Examinations were made for gross pathologic changes in all animals that died, and routinely samples of brain, thyroid, lungs, heart, liver, spleen, kidneys, stomach, small intestine, urinary bladder, adrenals, pancreas, spinal cord, and sciatic nerve were taken for histologic studies. The blocks of tissue were fixed in Carnoy's fluid and 10% formaldehyde, imbedded in paraffin, sectioned, and stained with hematoxylin and eosin. Frozen sections of liver and kidneys were stained with oil red (Sudan III) for histologic determination of possible fat infiltration of the tissues.

Statistics:

LD50 was calculated by the method of Miller LC and Tainter ML (1944). Estimation of the ED50 and Its Error by Means of Logarithmic-Probit Graph Paper. Proc Soc Exp Biol Med 57: 261-264.
Mortality ratios obtained were compared statistically by the "moving averages" method of Thompson WR (1947). Use of Moving Averages and Interpolation to Estimate Median-Effective dose. Bact Rev 11: 115-145.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LC50

Effect level:

ca. 1.5 mg/L air

Exp. duration:

4 h

Remarks on result:

other: Original value: LC50 = 248 +/- 36 ppm

Mortality:

Mortality rates after 10 days; 4-hour exposure:
135 ppm: 0/6
200 ppm: 2/6
300 ppm: 3/6
450 ppm: 5/6
For further details, see table 2.

Clinical signs:

other: Clinical signs are presented in a generalized manner and, therefore, are included as a quotation in this dataset. Due to the maximum size limit of this field, the detailed description of clinical signs is presented in the freetext, see below.

Body weight:

see table 2.

Gross pathology:

The results of gross pathology are described in a generalized manner.
Gross changes included liver damage and irritation of the pulmonary tract. Gross lesions were present in the majority of animals which showed intoxication and survived for 10 or more hours and were invariably present in moribund animals which survived for 24 hours. These lesions consisted of cerebral edema, engorgement of the abdominal viscera, and enlargement and yellowish discoloration of the liver.

Other findings:

- Histopathology:
The results of microscopic examination are presented for a battery of studies conducted with several species (rat, mouse and rabbit) and several routes of administration (oral, by inhalation, and dermal) and are presented here as a quotation.
“Microscopic examination of the tissues confirmed the extent of visceral involvement and disclosed a number of lesions in the central nervous system. The changes in the liver were principally due to fatty infiltration, which was either centrilobular or diffuse. In the tubular epithelium of the kidneys there were fine granular changes and moderate fatty deposits at the base. Pulmonary emphysema was conspicuous, and in some animals there was diffuse pulmonary edema and severe hemorrhage. All organs were hyperemic.
The lesions of the central nervous system […] may be summarized as follows: In cerebrum, cerebellum, and cord, there was diffuse edema of the white matter and occasionally acute necrosis, particularly in the corpus callosum and the cord. In many areas large vacuoles had formed which contained palely staining material of colloid-like appearance. Acute neuronal changes were present-swelling, vacuolation, and chromatolysis in the cortex, hippocampus, and cerebellum. In the spinal cord, beginning in the medulla oblongata, the nerve cells in the anterior gray columns frequently showed vacuolar changes of nuclei and occasionally complete chromatolysis. No lesions were seen in the sciatic nerves.
In occasional rats there was evidence of decreased numbers of erythrocytes and leucocytes in the peripheral blood. This occurred usually in animals that were severely intoxicated but survived for from 10 to 14 days. There was also occasional increase in the fat content of the bone marrow. However, no uniform abnormalities were seen with respect to the blood of rats.”

Any other information on results incl. tables

Table 2: mortality rates, mean body weight change, LC50

Group	No. of rats	Exposure time [h]	Dose level		Mortality rate	Mean body weight change	LC50
			[ppm]	[mg/l]
1 a	6 females	1	450	2.72	1/6	+2.2	934 +/- 130 ppm (ca. 5.7 mg/l)
1 b	6 females	1	670	4.12	1/6	- 2.2
1 c	6 females	1	1000	6.05	3/6	-10.0
1 d	6 females	1	1500	9.09	6/6	---
2 a	6 females	2	450	2.72	1/6	+3.0	734 +/- 92 ppm (ca. 4.5 mg/l)
2 b	6 females	2	670	4.12	1/6	-4.5
2 c	6 females	2	1000	6.05	5/6	+11.3
2 d	6 females	2	1500	9.09	6/6	---
3 a	6 females	4	135	0.817	0/6	+0.6	248 +/- 36 ppm (ca. 1.5 mg/l)
3 b	6 females	4	200	1.21	2/6	-4.5
3 c	6 females	4	300	1.81	3/6	+5.1
3 d	6 females	4	450	2.72	5/6	-1.2
4 a	6 females	8	60	0.363	0/6	+2.3	165 +/- 19 ppm (ca. 1.0 mg/l)
4 b	6 females	8	90	0.544	1/6	0
4 c	6 females	8	125	0.817	4/6	+3.3
4 d	6 females	8	200	1.21	6/6	-2.7

Mean body weight change as % change of survivors during 10 days.

Clinical signs:

Clinical signs are presented in a generalized manner and, therefore, are included as a quotation in this dataset.

"The principal toxicologic responses were impairment of the central nervous and the respiratory systems. Changes in behavior and activity were not apparent below 135 ppm and occurred only after exposure of four or more hours. Signs of depression usually appeared after removal from the chamber rather than during the exposure. Loss of the righting reflex and moderate anesthesia preceded death in about half the cases. Disturbances in muscle- tone and activity were most striking. Paralysis of both spastic and flaccid types occurred at all concentrations where deaths ensured. Paralysis of the hind legs was more frequent than paralysis of the forelegs. A few animals survived with paralysis of all muscles other than those controlling the head, neck, and thorax. Other disturbances in motor function were peculiar retrograde movements, waddling, irregular gait; and increase in muscle tone. Evidence of extreme stimulation of the central nervous system appeared in some animals, gross tremors being followed by either tonic or clonic convulsions and epileptoid seizures. These were intermittent and recurred over a period of some hours. Carpopedal spasm and cross extension of the forelegs was noted in some animals. The majority of animals which showed neurologic lesions and survived the initial 24-hour period recovered only partially. In some there was evidence of atrophy of the hind legs, while in others paralysis was of the spastic type. The lowest concentration at which muscular weakness was seen was 90 ppm; it appeared after an exposure of about six hours.

The signs of respiratory disturbance varied from slight nasal discharge to profuse discharge, salivation, and pulmonary effusion, with extreme respiratory embarrassment.

The majority of animals showed some signs of irritation of the ocular and respiratory tracts on exposure, even at the lowest concentration (60 ppm). This usually lasted for only 10 minutes, however, as tolerance quickly developed. Dyspnea was noted at concentrations as low as 90 ppm but was not severe until concentrations of 135 ppm were reached and did not usually appear until from three to four hours after the commencement of exposure. However, exposure to 1500 ppm caused almost immediate respiratory distress, with extreme dyspnea. A bloody effusion from the nares was noted in moribund animals, exposed to concentrations of 300 ppm or higher, whose death was due principally to irritation of the respiratory tract."