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Toxicological information

Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994
Reference Type:
publication
Title:
Final Report of acute neurotoxicity study of isobutanol in sprague-dawley rats
Author:
EPA
Year:
1995
Bibliographic source:
TSCATS/OTS0556315
Reference Type:
publication
Title:
OECD SIDS Isobutanol
Author:
OECD
Year:
2004
Bibliographic source:
OECD SIDS, UNEP Publications

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: 40 CFR 799 Multi-Substance Rule for the Testing of Neurotoxicity; 40 CFR Part 798.1150 Inhalation Test Guidelines; Test Guidelines 798.6050 & 798.6200 updated by Neurotoxicity Guideline 81-8, Subdivision F
Principles of method if other than guideline:
Male and female rats (10/sex) were exposed by inhalation for 6 hours to a vapor of isobutanol at 0, 1500, 3000 and 6000 ppm. The animals were observed for 14 days.
GLP compliance:
yes
Test type:
standard acute method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
- Name of test material (as cited in study report): Isobutanol
- Physical state: liquid
- Analytical purity: > 99.9 %

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Raleigh, NC, USA
- Age at study initiation: 8 weeks
- Weight at study initiation: males: 288-388 g; females: 187-290 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24 °C
- Humidity (%): 40-60 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
- Exposure Chambers: Four 2000-liter stainless steel and glass Hazelton H-2000 chambers
- Animal Housing during Exposure: Individual stainless steel wire mesh cages, positioned in one tier in the chamber
Exposure Duration: 6 hours
- Test Atmosphere Generation System: Test material was fed into a Laskin-type nebulizer mounted in a filtered supply air inlet at top of the inhalation chamber. Exposure concentrations were controlled by using an adjustable-flow valveless pump to regulate the
rate at which isobutanol was delivered to the nebulizer.
- Test Atmosphere Sampling Method: Six test atmosphere samples were drawn through a Miran 1A infrared detector calibrated for isobutanol.
Sampling Location: In the animal breathing area from a port halfway down on the chamber door
- Chamber Atmosphere Distributions: Chamber atmospheres were sampled in 2 different locations for all 3 exposure concentrations.
- Gas Chromatography Analysis: Samples of the chamber atmospheres were collected in two impingers, in series, containing methanol. The solutions were analyzed for isobutanol content using gas chromatography with a flame ionization detector.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 h
Concentrations:
0, 1500, 3000, 6000 ppm (0, 4.54, 9.09, 18.18 mg/l)
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: Checks for mortality and moribundity and noteworthy signs of toxicity were made daily from the day of
randomization until the day of sacrifice; weighing: day 0, day 7 and day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
A two-way ANCOVA and Duncan’s multiple comparison test was used to determine statistical significance. The FOB evaluation was similar to methods published by Mosher (1991).

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 18.18 mg/L air
Exp. duration:
6 h
Remarks on result:
other: original data: 6000 ppm
Mortality:
1/10 male animals died at 6000 ppm. This death was attributed to an ophthalmic examination where atropine drops were applied to its eyes.
All other animals survived.
Clinical signs:
during exposure: There was clear evidence of generalized depression of the central nervous system (animals were non-responsive to tapping on side
of inhalation chambers) and labored respiration in rats during the 6 hours of exposure to 6000 and 3000 ppm of isobutanol. One male amimal at the 6000 ppm concentration was prostrate at the end of his exposure, and another male animal at the same concentration level was lacrimating at the end of the exposure. The 6000 ppm concentration animals were affected to a greater extent than the 3000 ppm concentration rats. Minimal effects
(hypoactivity) were seen in rats at die 1500 ppm level.
Body weight:
Body weights of male rats in the 3000 and 6000 ppm groups were significantly lower than the male controls throughout the study. These statistically
significant results are due to pretest differences and not because of exposure to the chemical.
Gross pathology:
There were no treatment-related lesions or other gross changes in the tissues and organs examined during necropsy. Enlarged, dilated, distended
uteri were observed at necropsy in the low, mid, and high groups at incidences of 3/10, 1/10, and 1/10, respectively. This finding was not observed in the control group. The severity was minimal in all instances. This is a common observation and usually reflects physiologic changes related to the
estrus cycle. This is further substantiated by the inverse dose response. Therefore, although histologic examination was not conducted, it appears that these observations are unassociated with treatment and reflect the normal variation expected with different stages of the estrus cycle.

Applicant's summary and conclusion